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) will be enrolled.

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 2-4 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.

The primary objective of this study is to establish that an optimal dose of Aptensio XR® will result in a significant reduction in ADHD symptoms compared with placebo in children ages 4 to under 6 years.


Eligibility Criteria:
Inclusion Criteria:

1. Male and female subjects ages 48 months to 68 months inclusive at time of consent
2. Met Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (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)
3. ADHD symptoms must have been present for at least 6 months
4. Age- and sex-adjusted ratings of ≥ 90th percentile Total Score on the ADHD-RS-IV Preschool Version
5. Score of \< 65 on the Child Global Assessment Scale (CGAS)
6. Must have had a CGI-S score of ≥ 4 at Visit 2 (subjects who were granted a waiver to bypass parental training, and did not have a Visit 2, were still qualified to continue in the study based on their CGI-S score at screening)
7. Estimated intelligence quotient (IQ) ≥ 80 on the Kaufman Brief Intelligence Test, 2nd edition (KBIT-2). If results from the KBIT-2 were deemed invalid because of significant ADHD symptomatology, the PI could submit additional documentation to support average cognitive functioning. This documentation could include progress reports from preschool or other previous testing. These exceptions were evaluated by the Medical Monitor and Study PIs on a case-by-case basis for inclusion.
8. The subject had a parent or legal guardian who would give written informed consent for the subject to participate in the study
9. Subject and parent or legal guardian must have been able to speak and understand English
10. Subject must live with primary caretaker/rater and have been living with primary caretaker for at least 6 months
11. Subject and parent/guardian must have been willing and able to comply with all requirements of the protocol
12. Systolic and diastolic blood pressure below the 95th percentile for age and gender

Exclusion Criteria:

1. The subject had a lack of response to a trial of adequate dose and duration of MPH or intolerance to previous methylphenidate (MPH) treatment
2. The subject was using any other current psychotropic medication except clonidine, guanfacine, atomoxetine and/or stimulants or had taken an investigational drug in the 30 days prior to screening
3. The subject had used monoamine oxidase inhibitors (MAOIs) within 14 days of the screening visit
4. The subject planned to use prohibited drugs or agents at any point between the screening visit and the end of the study
5. Use of anticonvulsants, antidepressants, or antipsychotics in the 30 days prior to screening
6. The subject should not plan to start any additional psychotherapy outside of the trial during the duration of the study
7. The subject had a history of chronic vocal or motor tics or Tourette's syndrome
8. The subject had any clinically significant ECG abnormalities at screening
9. The subject had any major medical conditions that would have interfered with involvement in the study or could have been affected negatively by methylphenidate
10. The subject had 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
11. 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 have put the subject at risk if he/she participated in the trial or which could have confounded study results
12. Family history (parent or sibling) of structural cardiovascular disease
13. Current or recent (past 12 months) history of drug abuse in someone living in the subject's home
14. 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 required treatment with additional medication or, in the opinion of the PI, would have contraindicated study participation
15. History or presence of suicidal ideation or significant self-injurious behavior
16. The subject showed evidence of current physical, sexual, or emotional abuse
17. Both biological parents of the subject had a history of bipolar disorder