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. 2023 Mar 27;2023(3):CD009885. doi: 10.1002/14651858.CD009885.pub3

Pliszka 2017.

Study characteristics
Methods A 3 ‐week parallel trial with 2 arms:

  • DR‐MPH and ER‐MPH

  • Placebo


Phases: 2
Participants Number of participants screened: 163
Number of participants included: 163 (161 were included in the ITT analysis; 113 (70.2%) boys, 48 (29.8% girls)
Number of participants followed up: 138
Number of withdrawals: 25
Diagnosis of ADHD: DSM‐5. 145 (90.1%) combined, 0 (0%) predominantly hyperactive‐impulsive, 16 (9.9%) predominantly inattentive
Age: mean 9.3 years (SD 1.79, range 6‐12 years) (of the ITT sample)
IQ: not stated
MPH‐naive: 0%
Ethnicity: Hispanic/Latino (n = 34, 21.1%), non‐Hispanic/Latino (n = 126, 78.3%), missing (n = 1, 0.6%) (of the ITT sample). Race was reported from the ITT sample: white (n =105, 65.2%), black/African American (n = 45, 28.0%), Asian (n = 1, 0.6%), American Indian/Alaska native (n = 1, 0.6%), other (n = 9, 5.6%)
Country: USA
Setting: day clinic/research clinic or hospital
Comorbidity: many disorders and somatic comorbidities were exclusion criteria
Comedication: psychotropics not allowed. No use of prescription medication except those specified in exclusion criterion 9 and 10
Sociodemographics: none
Inclusion criteria

  • Participants must have a diagnosis of ADHD

  • 6‐12 years old (at the time of consent)

  • ADHD‐RS IV score of ≥ 90th percentile for age and gender and ≥ 26

  • CGI‐S score ≥ 4

  • CGI ‐ Parent score ≥ 10

  • At least a partial clinical response to MPH (judged by investigators)

  • Early Morning Functioning impairment and/or difficulties performing a morning routine of > 30 min in duration occurring between 6:00 and 9:00 am (parental or legal guardian confirmation)

  • Body weight ≥ 20 kg

  • Must be considered clinically appropriate for treatment with MPH and HLD200, including ability to swallow treatment capsules

  • General good health based upon the medical history, physical, and laboratory examinations (including urine drug screen)

  • Participant 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 (participant) prior to trial participation and to complete trial‐related materials. Participant and parent or legal guardian must plan to be available for the entire trial period

  • Female participants 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 trial)

  • A medically highly effective form of birth control must be used during the trial and for 90 days thereafter for participants 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

  • History of, or current, medical condition or laboratory result which, in the opinion of the investigator, unfavourably alters the risk‐benefit of trial participation, may jeopardise participant safety, or may interfere with the satisfactory completion of the trial and trial‐related procedures

  • Serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other cardiac problems that may place the participant at increased vulnerability to the sympathomimetic effects of a stimulant drug

  • History of seizure disorder (except febrile seizures prior to age 5 and with last occurrence at least 1 year prior to trial participation), Tourette's disorder, or intellectual disability of minor severity or greater (DSM‐5 criteria)

  • 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 jeopardise participant safety or may interfere with the satisfactory completion of the trial and trial‐related procedures

  • Active suicidal ideation as evidenced by an ideation score of ≥ 2 on the C‐SSRS

  • History of severe allergic reaction or intolerance to MPH

  • ALT, AST, total bilirubin, or creatinine > 1.5 x the upper limit of normal (elevated bilirubin due only to Gilbert's syndrome is not exclusionary)

  • History of alcohol abuse or illicit drug use

  • Use of prescription medications (except per protocol allowed medications) within 7 days of Baseline (Visit 2), except for ADHD stimulant medication (72 h) and 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 participant

  • Use of psychotropic medications including antidepressants, mood stabilisers, and antipsychotics

  • Participation in a clinical trial with an investigational drug within the 30 days preceding trial enrolment

  • Previous treatment experience with HLD200

  • Positive screening for illicit drug use or nicotine and/or current health conditions or use of medications that might confound the results of the trial or increase risk to the participant

  • In the opinion of the investigator, the participant may have problems complying with the protocol or the procedures of the protocol, or for which the trial could pose unnecessary safety risks. This includes current health conditions or use of medications that might confound the results of the trial or increase risk to the participant

  • A sibling or step‐sibling that is concurrently participating in this trial who resides with and is cared for by the same parent/legal guardian as the participant
Interventions Participants were randomly assigned to DR/ER‐MPH oral capsules containing beads, titrated to 40, 60 or 80 mg (week 1, 2 and 3 respectively), or placebo matched to DR/ER‐MPH oral capsules but containing microcrystalline cellulose beads in place of MPH for 3 weeks
Number randomised to each group: DR/ER‐MPH 82, placebo 81
Mean medication dosage: DR/ER‐MPH 68.1 mg (at endpoint)
Administration schedule: once daily in the evening at 8:00 pm ± 30 min; “Participants were also permitted to adjust the evening dose time between 6:30 and 9:30 pm in 30‐ or 60‐minute increments per week to achieve optimal morning control of observed ADHD symptoms”
Duration (of (each) medication): DR/ER‐MPH titrated to 40 mg 1st week, 60 mg 2nd week, 80 mg 3rd week (if increases were not tolerated 1‐down titration was allowed to a minimum of 40 mg), or placebo 3 weeks
Washout before trial initiation: up to 2 weeks (phase 1). Stimulants, clonidine, and guanfacine required a >72‐h washout, and any other medication used to treat ADHD required a >7‐day washout before randomisation
Treatment compliance: nothing stated besides percentage that completed the trial
Outcomes ADHD symptom severity

  • ADHD‐RS‐IV


Serious AEs

  • Spontaneous reporting

  • C‐SSRS


General behaviour

  • Parent Rating of Evening and Morning Behavior‐Revised, evening (PREMB‐R PM) subscale (Sutton 2003)

  • Parent Rating of Evening and Morning Behavior‐Revised, morning (PREMB‐R AM) subscale (Sutton 2003)

  • Before School Functioning Questionnaire (BSFQ; Wilens 2010)


Non‐serious AEs

  • Spontaneous reporting

  • Direct query at each visit for patients and parents on treatment emergent AEs of special interest (appetite suppression and insomnia, with sleep disturbances (onset, quality, and quantity))

  • Vital signs

  • ECGs

  • Clinical laboratory tests

  • Physical examination findings
Notes Sample calculation: yes; 180 with an estimated dropout rate of 20%‐25% = 70 participants per treatment arm after dropout
Ethics approval: yes; “All participants and parents/legal guardians provided informed assent and consent, respectively, under procedures approved by each site’s institutional review board”
Comments from trial authors

  • “The short duration of the study limits the ability to extrapolate the findings over the long term. The study included school‐age children (aged 6–12 years) only and, therefore, the applicability of these findings to other age groups (i.e., preschool children, adolescents, and adults) is unknown”.

  • Enrolled participants have previously shown at least a partial response to MPH, and, therefore, the response and safety profiles in MPH‐naïve patients may be different than those achieved in this study


Key conclusion of trial authors

  • “The results of this trial demonstrated that 3 weeks of treatment with evening‐dosed DR/ER‐MPH is more effective than placebo in improving ADHD symptoms and at‐home functional impairments from early morning to evening in children with ADHD.”

  • “Evening dosed DR/ER‐MPH was generally well tolerated and demonstrated a safety profile consistent with previously reported studies of MPH.”


Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH: yes
Any withdrawals due to AEs: yes, 5
Funding source: Ironshore Pharmaceuticals
Email correspondence with trial authors: September 2021. We received supplemental information regarding risk of bias assessment through personal email correspondence with the trial authors in September 2021 (Storm 2021f [pers comm])
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk "Medication randomisation will be performed using an interactive web response system (IWRS). The IWRS will assign subjects to a treatment group based on the pre‐defined randomisation list."
Allocation concealment (selection bias) Low risk "A kit identification number corresponding to the assigned treatment will be assigned by IWRS."
Blinding of participants and personnel (performance bias)
All outcomes Low risk "Treatment assignments will be masked to the investigator, the sponsor, trial statistician, and the trial subjects."
"If an investigator, site personnel performing assessments, or subject/parent/legal guardian is unblinded, the subject must be withdrawn from the trial, and procedures accompanying withdrawal are to be performed."
Blinding of outcome assessment (detection bias)
All outcomes Low risk "Treatment assignments will be masked to the investigator, the sponsor, trial statistician, and the trial subjects."
Incomplete outcome data (attrition bias)
All outcomes Low risk "The ADHD‐RS‐IV was analysed by using a mixed‐model repeated measures (MMRM) analysis that included the participant’s intercept as a random effect; treatment, trial center, and visit‐by‐treatment interaction as fixed effects; and baseline ADHD‐RS‐IV total score at Visit 2 as a covariate. The BSFQ and ADHD‐AM‐RS were also analysed using the MMRM, as described for the primary efficacy analysis."
Selection bias (e.g. titration after randomisation → exclusion): no
Selective reporting (reporting bias) Low risk All outcomes reported