A Pivotal Efficacy Trial to Evaluate HLD200 in Children With ADHD in a Naturalistic Setting

This Phase 3 pivotal efficacy trial will examine the effects of HLD200 (methylphenidate) in patients aged 6-12 years with ADHD in a naturalistic setting. Following a screening/washout period (Visit 1), subjects will randomized to double-blind placebo or HLD200 for a period of 3 weeks (Visits 2-5) before assessing clinical study endpoints at last study visit.

To address the unmet need for early morning ADHD symptom control, Ironshore has developed a novel drug delivery system that incorporates the active ingredient methylphenidate HCl in a delayed/extended release formulation. This formulation provides a controlled, approximately 8-hour delay in initial drug release, followed by a subsequent controlled rate of drug release throughout the day. The goal of this system is to enable nighttime dosing of methylphenidate to provide control of ADHD symptoms at the beginning of the next morning (immediately upon awakening) and throughout the remainder of the day.

At Visit 2, Baseline Visit), subjects were randomized to receive either HLD200 or placebo and instructed to begin dosing at 40 mg each evening (8:00 pm ±30 minutes) for 1 week, with scheduled titration, as medically indicated and tolerated, over the subsequent 2 weeks to 60 mg (Visit 3) and 80 mg (Visit 4) and/or a dose not to exceed 3.7 mg/kg (based on the subject's most recently assessed weight). Following dose escalation above 40 mg (i.e., after Visit 3), subjects were permitted to reduce the dose by 1 step (i.e., from 60 to 40 mg or from 80 to 60 mg), if necessary, for safety or tolerability. Subjects who were unable to tolerate a dose of at least 40 mg during the final (third) week of treatment, from Visit 4 to 5, were discontinued. Subjects were also permitted to adjust the timing of the evening dosing at Visits 3 and 4 in increments of 30 to 60 minutes/week to achieve optimal morning control of observed ADHD symptoms; however, the dose was not to be taken any later than 9:30 pm or any earlier than 6:30 pm, regardless of the ±30-minute dosing window.

Eligibility Criteria:
Inclusion Criteria:

1. Subjects must be male or female children (6 to 12 years at the time of consent).
2. Subjects must have a diagnosis of ADHD as defined by DSM5 criteria and confirmation using the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID).
3. Subjects must have a baseline ADHD-RS-IV score at or above the 90th percentile normalized for sex and age in total score. In addition, this ADHD-RS-IV total score must be ≥26 at Baseline.
4. Subjects must have a Clinical Global Impression of Severity (CGI-S) score ≥4 and a CGI-P score \>10 at the Baseline Visit.
5. Subjects have demonstrated, in the judgment of the investigator, at least a partial clinical response to MPH.
6. Parental or legal guardian confirmation of the child's before-school functional impairment and/or difficulties performing a morning routine of at least 30 minutes minimum duration occurring between 6:00 and 9:00 am.
7. Subject body weight must be ≥20 kg.
8. Subject must be considered clinically appropriate for treatment with MPH and HLD200, including ability to swallow treatment capsules.
9. Subject must be in general good health based upon the medical history, physical, and laboratory examinations (including urine drug screen).
10. Subject and parent or legal guardian must be able to read, write, and/or understand at a level sufficient to provide informed consent (parent/legal guardian) and assent (subject) prior to study participation and to complete study-related materials. Subject and parent or legal guardian must plan to be available for the entire study period.
11. Female subjects of childbearing potential (i.e., post-menarche) are required to have a negative result on urine pregnancy testing at screening (and will be given specific instructions for avoiding pregnancy during the study).
12. A medically highly effective form of birth control must be used during the study and for 90 days thereafter for subjects of either sex of childbearing potential. Examples of medically highly effective forms of birth control are as follows:

    * No sexual activity
    * Use of acceptable methods of birth control including intra-uterine device, oral, implantable,or injectable contraceptives.

Exclusion Criteria:

1. History of, or current, medical condition or laboratory result which, in the opinion of the investigator, unfavorably alters the risk-benefit of study participation, may jeopardize subject safety, or may interfere with the satisfactory completion of the study and study-related procedures.
2. Serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other cardiac problems that may place the subject at increased vulnerability to the sympathomimetic effects of a stimulant drug.
3. History of seizure disorder (except febrile seizures prior to age 5 and with last occurrence at least 1 year prior to study participation), Tourette's disorder, or intellectual disability of minor severity or greater (DSM5 criteria).
4. History of psychosis, bipolar disorder, anorexia nervosa, bulimia, or suicide attempt. Current depression, anxiety, conduct/behavior disorder, substance use disorder, or other psychiatric condition which, in the investigator's opinion, may jeopardize subject safety or may interfere with the satisfactory completion of the study and study-related procedures.
5. Active suicidal ideation as evidenced by an ideation score of 2 or greater on the C-SSRS.
6. History of severe allergic reaction or intolerance to MPH.
7. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, or creatinine greater than 1.5x the upper limit of normal. Elevated bilirubin due only to Gilbert's syndrome is not exclusionary.
8. History of alcohol abuse or illicit drug use.
9. Use of prescription medications (except per protocol allowed medications) within 7 days of Baseline (Visit 2), except for ADHD stimulant medication (72 hours) and monoamine oxidase inhibitors (MAOIs) (14 days), and over-the-counter medications (except birth control and allowed medications) within the 3 days preceding Baseline (Visit 2). Medications not covered in allowed medications or prohibited medications must be cleared by the medical monitor prior to enrolling the subject.
10. Use of psychotropic medications including antidepressants, mood stabilizers, and antipsychotics.
11. Participation in a clinical trial with an investigational drug within the 30 days preceding study enrollment.
12. Previous treatment experience with HLD200.
13. Positive screening for illicit drug use or nicotine and/or current health conditions or use of medications that might confound the results of the study or increase risk to the subject.
14. In the opinion of the investigator, the subject may have problems complying with the protocol or the procedures of the protocol, or for which the study could pose unnecessary safety risks. This includes current health conditions or use of medications that might confound the results of the study or increase risk to the subject.
15. A sibling or step-sibling that is concurrently participating in this study who resides with and is cared for by the same parent/legal guardian as the subject.