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Impact of Combined Medication and Behavioral Treatment for ASD & ADHD

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ClinicalTrials.gov Identifier: NCT03242772
Recruitment Status : Recruiting
First Posted : August 8, 2017
Last Update Posted : December 18, 2018
Sponsor:
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  ICMJE August 4, 2017
First Posted Date  ICMJE August 8, 2017
Last Update Posted Date December 18, 2018
Actual Study Start Date  ICMJE May 30, 2018
Estimated Primary Completion Date July 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 14, 2018)
Change in Adaptive Behavior [ Time Frame: Weeks 0, 10, 24, and 52 ]
The primary outcome measure is change in the mean of the interview version of the VABS-3 socialization subscale and communication subscale standard scores. These standardized scores have real clinical significance, account for the variable rates of change observed developmentally, and reflect the core symptom domain targeted by P-ESDM: social communication.
Original Primary Outcome Measures  ICMJE
 (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.
Change History Complete list of historical versions of study NCT03242772 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 4, 2018)
  • Change in Sustained Attention [ Time Frame: Weeks 0, 10, 24 (week 0 = baseline) ]
    A naturalistic parent-child interaction task (PCIT) (DeVito et al. 2016) will be administered to assess sustained attention. Children and their parents are observed during a series of tasks that include play interactions with developmentally appropriate toys. Tasks are video recorded and children are reliably coded using a behavioral coding scheme by raters naïve to diagnostic status in terms of each of several engagement states: unengaged, onlooking, object-focused, person-focused, supported joint attention, and coordinated joint attention.
  • Change in ADHD symptoms [ Time Frame: Weeks 0, 2, 6,10,16, 24, 52 (week 0 = baseline) ]
    ADHD Rating Scale (ADHD-RS) will assess symptom frequency using data from clinician completed ADHD-RS and parent completed ADHD-RS (only parent-completed ADHD-RS is completed at week 52). 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. Normative scores are available. Clinically significant scores in boy are 14 for inattention items and 17 for hyperactivity/impulsivity items. Clinically significant thresholds in girls are 12 and 14 respectively. A supportive exploratory analysis will examine change to a nonclinically significant score by week 24 (using clinician rating) and week 52 (using only parent ratings) . If subscales are used, they would be summed to compute the total score.
Original Secondary Outcome Measures  ICMJE
 (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  ICMJE Impact of Combined Medication and Behavioral Treatment for ASD & ADHD
Official Title  ICMJE 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. 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 prior to initiating early behavioral intervention, and (2) identify changes in behavioral and neurophysiological activity that may underlie improved outcomes in children with comorbid ASD and ADHD. The primary aim of this study is to evaluate whether a stimulant treatment augments efficacy of a novel, parent-delivered, behavioral intervention based on the Early Start Denver model (P-ESDM). 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 1 year long (52- 60 weeks). Eligible participants will be randomly assigned to the active medication or placebo, which will be administered over the course of 24 weeks (weeks 0-24). The behavioral intervention with coaching will be provided for 12 weeks (weeks 10-22) to all participants. Between weeks 24 to 52 participants will continue behavior intervention without coaching and will be given the option to pursue ADHD medication outside of the research study.
Detailed Description

The overall study design and key outcomes and assessments are shown in the Schema in the synopsis. 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 < 96 months of age. Children who are 73 months to < 96 months must have a receptive language developmental age of = or < 72 months. The active medication treatment will be an orally dissolvable, extended release amphetamine preparation (Adzenys-XR-ODT) administered from weeks 0-24 and carefully titrated to the optimal dose using an algorithm (see MOP) 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 one curriculum assessment visit (~90 minutes) and twelve ~75-minute coaching sessions in parent-delivered Early Start Denver Model early intervention (P-ESDM) delivered between approximately study weeks 12 through 23. The implicit behavioral intervention is the parent-delivered behavioral intervention provided during interactions with the child at home and in the community. P-ESDM is a modification of the evidence-based behavioral treatment of ESDM, which is typically delivered as 20 hrs/week of 1:1 interaction between the child and a trained therapist over a 2 year period. The P-ESDM modification reduces rigid time demands on families and is more likely to be sustainable and available in the current healthcare environment.

Seventy-eight 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 24 weeks. Exploratory analyses will explore changes between weeks 0 and 52 and will compare changes between weeks 0 and 10 with those between weeks 10 and 24.

The primary outcome measure is change in the mean of the interview version of the VABS-3 socialization subscale and communication subscale standard scores. These standardized scores have real clinical significance, account for the variable rates of change observed developmentally, and reflect the core symptom domain targeted by P-ESDM: social communication.

Our key secondary outcomes will be changes in objective JERI ratings made by blinded coders of parent-child joint attention and engagement during the semi-structured parent child interaction task (PCIT) and clinician ratings of ADHD symptoms. The JERI ratings use a 7 point ordinal scale that considers both amount and quality of joint attention and engagement. The amount of time spent in coordinated joint attention has shown significant differences between two different parent interventions for ASD(Kasari et al 2014). The ratings have been shown to correlate well with time measures but to be more sensitive in distinguishing ASD from Down's syndrome and typical development and in distinguishing between children with increased ASD interventions over time (Adamson 2017; Suma 2016). We also will examine several other supportive behavioral outcomes including parent ratings of social functioning (SRS 2), several aberrant behaviors including social withdrawal, attention, irritability, repetitive behavior, and abnormal speech (ABC), executive function (BRIEF), parental ratings of ADHD symptoms (ADHD-RS-parent) and sluggish cognitive tempo, and cargiver strain (CSQ). We will also assess the safety and tolerability of Adzenys-XR-ODT compared to placebo. During the initial titration period of the trial (weeks 0-10) we will be able to directly compare both attentional and social/communication outcomes between the active medication and placebo.

In subsequent aims, we will examine the relationship between changes in behavioral outcomes (independent of treatment group) and more objective measures of attention (p-CPT, eye gaze tracking to social stimuli, JERI and video activity measures of overall activity and attention, and parent child interactions such as time spent near parent, latency to approach parent). Finally, we will examine whether improvements in ASD and ADHD symptoms are associated with changes in electroencephalographic (EEG) neural functioning measures related to enhanced neural connectivity (EEG coherence), neural stability (ITPC) and social processing (evoked response potentials (ERPs) and spectral power to faces vs. objects).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Autism Spectrum Disorder
  • Attention Deficit Hyperactivity Disorder
Intervention  ICMJE
  • 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 by 1 tablet = 3.1 mg or 0 mg every 2 weeks unless there are intolerable adverse effects or great improvement in ADHD symptoms to a target dose of 4 tablets = 12.4 mg or 0 mg of Adzenys- XR-ODT. The allowable dose range will range from 1.6/0 mg (1/2 tablet) to 18.6/0 mg (6 tablets). Doses may be reduced at any point during the trial (typically in 1 tablet increments) but only may be increased every two weeks in order to fully assess potential benefits and adverse events of the current dose.
    Other Name: Adzenys XR-ODT
  • Behavioral: P-ESDM
    Weekly sessions of the behavioral intervention will be delivered by a certified P-ESDM therapist. All participants in the trial and their primary caregivers will receive coaching following a manualized intervention (includes individualized learning objectives, intervention coaching for behavior management, handouts).
    Other Names:
    • Early Start Denver Model
    • Parent-Delivered Early Start Denver Model
  • Drug: Placebo Oral Tablet
    Matched placebo tablets will be administered in the morning and provided for 24 weeks (starting 10 weeks prior to initiation of P-ESDM Intervention). Placebo appears identical to the active drug (Adzenys-XR-ODT) and flexible titration schedule will also be used.
Study Arms  ICMJE
  • Active Comparator: P-ESDM + Amphetamine

    Amphetamine regimen (24 weeks total duration) will begin 10 weeks prior to initiation of Parent-Delivered Early Start Denver model (P-ESDM), continue throughout 12 weeks of P-ESDM, and 2 weeks after P-ESDM. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine.

    Both arms will receive 12 consecutive weekly P-ESDM sessions (1 hr each)

    Interventions:
    • Drug: Amphetamine
    • Behavioral: P-ESDM
  • Placebo Comparator: P-ESDM + Placebo Oral Tablet

    Placebo regimen (24 weeks total duration) will begin 10 weeks prior to initiation of Parent-Delivered Early Start Denver model (P-ESDM) and continue throughout 12 weeks of P-ESDM. The placebo contains no active drug and appears identical to the amphetamine (active drug).

    Both arms will receive 12 consecutive weekly P-ESDM sessions (1 hr each)

    Interventions:
    • Behavioral: P-ESDM
    • Drug: Placebo Oral Tablet
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 7, 2017)
78
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2021
Estimated Primary Completion Date July 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 96 months.
  4. Children who are 73 months to < 96 months must also have a receptive language developmental age of = or < than 72 months to ensure that child's abilities are in the appropriate range for P-ESDM.
  5. 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), the Standardized ADHD Diagnostic Interview for Preschoolers and the parent completed ADHD-RS.
  6. In good general health as evidenced by medical history, physical exam and review of safety labs and electrocardiogram.

Exclusion Criteria:

  1. Recent use of prohibited psychoactive medication in close proximity of baseline (Study Visit 2, Day 0). 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 P-ESDM or completion of key assessments (see MOP for details).
  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 P-ESDM coaching as deemed by the PI or clinician.
  8. Significant change in the type or intensity of behavioral interventions received by the child during the 8 weeks prior to Week 0.
  9. Presence of more than one psychiatric condition in addition to ASD and ADHD confirmed with a semi-structured psychiatric interview and expert consensus diagnosis. See MOP for procedures for senior clinician review of psychiatric conditions other than oppositional defiant disorder, dysthymic mood dysregulation disorder, or anxiety conditions.
  10. Study clinician judgment that it is not in the best interests of the participant and/or the study for the child to participate.
  11. 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)
  12. 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).
  13. History of neonatal brain damage. (eg., with diagnoses hypoxic or ischemic event)
  14. Any known environmental circumstances that is likely to account for the picture of autism in the proband (severe nutritional or psychological deprivation etc.)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 36 Months to 84 Months   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Geraldine Dawson, PhD (919) 684-3165 geraldine.dawson@dm.duke.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03242772
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Responsible Party Duke University
Study Sponsor  ICMJE Duke University
Collaborators  ICMJE Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators  ICMJE Not Provided
PRS Account Duke University
Verification Date June 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP