A Flexible-Dose Titration Study of Aptensio XR in Children Ages 4 to Under 6 Years Diagnosed With ADHD

This randomized, double-blind, flexible-dose, placebo-controlled, parallel group study is
designed to evaluate Aptensio XR® compared to placebo in preschool age children with ADHD.
Male and female children ages 4 years, 0 months to 5 years, 8 months with a diagnosis of
ADHD (combined, inattentive or hyperactive/impulsive presentation) based on the Diagnostic
and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria will be enrolled.
Diagnosis will be determined using the Kiddie-Sads-Present and Lifetime Version (K-SADS-PL),
which has been used in this age group.11 ADHD-RS IV ratings obtained at screening will
include the 6-months immediately prior to screening.

There will be 6 phases in this study: a screening phase of up to 4 weeks, which will include
washout if applicable, an enrollment & parent training phase lasting 4 weeks, an eligibility
phase of up to 2 weeks to determine eligibility for the open-label phase, a 6-week
open-label dose titration phase, a 2 week double-blind phase for Aptensio XR® responders,
and a two-week follow-up call after study completion or early discontinuation to assess for
ongoing adverse events and concomitant medications.

Up to 150 subjects will be enrolled in this trial to allow for subjects who improve
significantly during the behavior training phase and drop-outs. Once 74 subjects have
completed the double-blind phase, no additional subjects will be enrolled in the trial.
Subjects who are already enrolled at that time will be allowed to complete the trial.

Phase 1: Screening Screening /washout period can last up to 4 weeks (28 days). Written
informed consent will be obtained from the parent/legal guardian prior to performing any
study related procedures. Assent will be obtained from subjects as appropriate. Current
medications and those taken during the 30 days prior to the date of informed consent will be
recorded.

Due to the length of assessments, screening may be conducted during more than one visit. The
K-SADS-PL, a semi-structured interview, will be administered by qualified and trained
clinicians to confirm ADHD diagnosis and determine whether psychiatric comorbidities are
present. See Section 6.1.1 for a detailed list of procedures to be performed during
screening.

If a subject meets all inclusion and exclusion criteria requirements after ECG results are
obtained, a phone call will be made to the parent/legal guardian to determine whether
inclusion and exclusion criteria are still met. If the subject continues to be eligible to
participate in the trial, instructions to discontinue ADHD medications will be given if
applicable. A minimum of a 3- day stimulant washout is required prior to Visit 2.

Phase 2: Enrolment & Behavior Management Training At Visit 2 families will begin a
standardized course of behavior management training. The purpose of this phase will be to
ensure that non-pharmacological intervention is attempted prior to initiation of study
medication. Four visits, each of 90 minutes duration (Study Visits 2-5), will be conducted
over a period of 2-4 weeks. Families will be expected to complete all 4 sessions of
behavioural training within a 4 week period. Primary caregivers will be the primary
attendees for these sessions and content will include education regarding ADHD, and behavior
management techniques, including the proper use of contingency management, time-out, and
response cost. Session content will be adapted from several well-established and empirically
validated interventions.

Participants will be allowed to skip the Parent Training Phase if either of the following
criteria are met: 1) the patient and her/his primary caregiver have participated in the last
12 months in a documented course of non-pharmacological treatment and resulted in minimal
benefit; and/or 2) the patient exhibits ADHD symptoms and impairment that are severe enough
to warrant moving immediately to the medication phase of the study. Each of these criteria
will be assessed by the site investigator in consultation with the study medical monitor and
a coordinating investigator. See Section 6.1.1 for a detailed list of procedures. The
initiation of any additional psychotherapy during the study will not be permitted. However,
patients that are already participating in psychotherapy that was initiated prior to the
study will be permitted to continue in these programs.

Phase 3: Eligibility for Open-Label Phase Following completion of the Parent Training Phase,
participants and their caregivers will attend two Baseline Visits (Study Visits 6 & 7) to
assess continued eligibility and to start open-label treatment. At Visit 6, clinical status
(including AEs) will be assessed and the ADHD-RS-IV and CGI-S and CGI-I will be
administered. Criteria for continuation to the Open-Label Phase will be less than a 30%
improvement from Screening on the total score of the Investigator administered ADHD-RS-IV
(Preschool Version)11 and a Clinical Global Impression-Improvement (CGI-I) of 3 (minimally
improved or less). For patients who are still eligible for continuation to the Open-Label
Phase, a medical evaluation will be conducted, including vital signs, and collection of
blood for routine blood chemistry/hematology assessment. Urine for urinalysis and urine drug
screen will also be obtained.

Once laboratory results are received, eligible subjects will be scheduled for Study Visit 7.
At Visit 7, subjects must continue to meet ADHD-RS-IV eligibility criteria. Subjects who can
continue in the trial will begin open-label treatment, study drug will be dispensed, and
participants will be scheduled for their next visit. See Section 6.1.1 for a detailed list
of procedures.

Phase 4: Six-week Open-Label Phase Subjects will begin Aptensio XR® 10 mg at the morning
following Visit 7. Dosing should occur prior to 10 am each morning. At weekly visits (Visits
8-13), dosing may be maintained or increased until an optimal dose or the maximum dose is
reached. The ADHD-RS-IV rating scale will be used to determine optimal dose. An optimal dose
is a dose that produces a reduction from Visit 7 of ADHD symptoms of at least 30% and a
CGI-I compared to Visit 7 of "much improved" or "very much improved" with tolerable side
effects. Subjects who meet improvement criteria but may benefit from additional dose
increases, may have their dose further optimized. If a higher dose is not tolerated,
subjects may step down one dose level. See Section 6.1.1 for a detailed list of procedures.

Phase 5: Two-week Double-Blind phase Eligible subjects who have found an optimized dose
during Phase 4, see above, will be randomized to receive their best dose of Aptensio XR® or
matching placebo and will enter the two-week parallel Double-Blind Phase. Blinded study drug
will be dispensed at visit 13 and double-blind treatment will follow on the morning after
Visit 13.

Subjects who have a ≥50% worsening of symptoms on the ADHD-RS-IV at Visit 14 (compared to
Visit 13, one week into the Double-Blind Phase) and a CGI-I of "much worse" or "very much
worse" compared to Visit 13 will be eligible to discontinue the Double-Blind Phase and enter
the Open-Label Extension Study at the investigator's discretion, after completing end of
study (Visit 15) procedures.

At study Visit 15, in the ADHD-RS-IV, CGI-S, CGI-I, adverse event collection and a physical
exam will be repeated along with an ECG. Subjects not completing Visit 15 procedures will
not be eligible for the Open-Label - Extension Study

Phase 6: Follow-up Phone Call A follow-up phone call will occur approximately two weeks
after treatment discontinuation to assess for ongoing adverse events and concomitant
medications.

Inclusion Criteria:

- Male and female subjects ages 48 months to 68 months inclusive at time of consent

- Meets DSM-5 criteria for ADHD, combined, hyperactive/impulsive or inattentive
presentation made during a clinical interview by an experienced clinician and
confirmed with Kiddie-Sads-Present and Lifetime Version (K-SADS-PL)

- ADHD symptoms must have been present for at least six months

- Age- and sex-adjusted ratings of ≥ 90th percentile Total Score on the ADHD-RS-IV
Preschool Version (rated over past six months)

- Score of <65 on the Child Global Assessment Scale

- Must have a score of ≥4 on the Clinical Global Impressions Severity (CGI-S) at Visit
2

- Estimated IQ ≥80 on the Kaufman Brief Intelligence Test, Second Edition (KBIT-2)

- The subject has a parent or legal guardian who will give written informed consent for
the subject to participate in the study

- Subject and parent or legal guardian must be able to speak and understand English

- Subject must live with primary caretaker/rater and have been living with primary
caretaker for at least 6 months

- Subject and parent or legally authorized representative must be willing and able to
comply with all requirements of this protocol

- Systolic and diastolic blood pressure below the 95th percentile for age and gender

Exclusion Criteria:

- The subject has had a lack of response to a trial of adequate dose and duration of
MPH or intolerance to previous MPH treatment

- The subject is using any other current psychotropic medication except clonidine,
guanfacine, atomoxetine and /or stimulants or has taken an investigational drug in
the 30 days prior to screening

- The subject has used monoamine oxidase inhibitors within 14 days of the screening
visit

- The subject plans to use prohibited drugs or agents at any point between the
screening visit and the end of the study.

- Use of anticonvulsants, antidepressants or antipsychotics in the 30 days prior to
screening

- The subject should not start any additional psychotherapy outside of the trial during
the duration of the study

- The subject has a history of chronic vocal or motor tics or Tourette's syndrome

- The subject has any clinically significant ECG abnormalities at screening

- The subject has any major medical conditions that would interfere with involvement in
a study or could be affected negatively by methylphenidate

- The subject has chronic medical illnesses including a seizure disorder (excluding a
history of febrile seizures), severe hypertension, untreated thyroid disease, known
structural cardiac abnormalities, serious arrhythmias, cardiomyopathy, glaucoma, or a
family history of sudden death

- History (in the past 12 months) or presence of clinically significant cardiovascular,
cerebrovascular, renal, hepatic, gastrointestinal, pulmonary, immunological,
hematological, endocrine, or neurological disease that in the opinion of the
investigator could put the subject at risk if he/she participates in the trial or
could confound study results

- Family history (parent or sibling) of structural cardiovascular disease

- Current or recent (past 12 months) history of drug abuse in someone living in the
subject's home

- Current symptoms or history of major psychiatric illness (for example schizophrenia,
psychosis, bipolar disorder, post-traumatic stress disorder, depression, severe
anxiety disorder, obsessive compulsive disorder or autistic spectrum disorder) in
addition to ADHD that requires treatment with additional medication or, in the
opinion of the PI, would contraindicate study participation History or presence of
suicidal ideation or significant self-injurious behavior

- The subject shows evidence of current physical, sexual, or emotional abuse

- Both biological parents of the subject have a history of bipolar disorder