Impact of Combined Medication and Behavioral Treatment for ASD & ADHD

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).

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.)