| Study characteristics |
| Methods |
A 1‐week parallel trial with 2 arms:
DR/ER‐MPH (HLD200) placebo
Phases: 4 (screening and wash‐out (up to 4 weeks), open‐label dose‐optimisation (6 weeks), double‐blind trial (1 week), and follow‐up call (after 2 weeks) |
| Participants |
Number of participants screened: 161 included in open‐label phase
Number of participants included: 155 randomised (85 (68.0%) boys, 40 (32.0%) girls of 125)
Number of participants followed‐up: 117
Number of withdrawals: 38. Of these, 36 were due to exclusion (after randomisation) of a full trial site by the FDA due to concerns about data integrity.
Diagnosis of ADHD: DSM‐5 (108 (86.4%) combined, 0 hyperactive‐impulsive and 17 (13.6%) inattentive type)
Age: mean 9.4 years (SD 1.65, range 6‐12 years)
IQ: not stated
MPH‐naive: no
Ethnicity: Hispanic/Latino (n = 49, 39.2%), non‐Hispanic/Latino (n = 76, 60.8%). Race: white (n = 99, 79.2%), black/African American (n = 15, 12.0%), Asian (n = 0), native Hawaiian/Pacific Islander (n = 2, 1.6%), other (n = 9, 7.2%)
Country: USA
Setting: outpatient; assessment on last trial day in laboratory classroom
Comorbidity: not stated, but many were defined as exclusion criteria
Comedication: specified list of allowed comedication not available for review authors
Additional sociodemographics: none
Inclusion criteria
Participants must be male or female children (6‐12 years at the time of consent) Participants must have a diagnosis of ADHD as defined by DSM‐5 criteria and confirmation using the MINI‐KID -
Participants must have a baseline ADHD‐RS‐IV score at or above the 90th percentile normalised for sex and age in at least 1 of the following categories:
Participants must have a CGI‐S score ≥ 4 and a CGI‐P score >10 at the baseline visit. -
Participants who are not currently on MPH treatment must either
have prior experience with MPH treatment and have shown clinical response to therapy during that time; or be treated with the same dose of MPH and show a clinical response with acceptable tolerability to MPH for ≥ 2 weeks prior to screening.
Parental or legal guardian confirmation of before‐school function impairment and difficulties performing morning routine Regular weekday morning routine of no less than 30 min Participant must be considered clinically appropriate for treatment with DR‐MPH and ER‐MPH (HLD200), including ability to swallow treatment capsules Participant must be in general good health based upon medical history, physical examination, and laboratory results (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 a parent/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 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 to MPH History of no response or intolerance to the adverse effects of 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 within 7 days of baseline (visit 2), except for ADHD stimulant medication (5 days) 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. Participation in a clinical trial with an investigational drug within the 30 days preceding trial enrolment Previous treatment experience with ER‐MPH (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 could face unnecessary safety risks from the trial. This includes current health conditions or use of medications that might confound the results of the trial or increase risk to the participant. Participant's SBP or DBP measurement exceeds the 95th percentile for age, sex, and height at the baseline visit Participant is significantly underweight based on CDC BMI‐for‐age sex‐specific values at the screening visit. Significantly underweight is defined as a BMI < 5th percentile. Participant is significantly overweight based on CDC BMI‐for‐age sex specific values at the screening visit. Significantly overweight is defined as a BMI > 95th percentile.
|
| Interventions |
Participants went through a 6‐week open‐label dose‐optimisation phase before being randomised.
Participants were randomly assigned to: continuation of optimised dose of ER‐MPH (HLD200) (20, 40, 60, 80 or 100 mg/d) or placebo for 1 week
No. randomised to each group: 65 to ER‐MPH (HDL200), 54 to placebo
Mean medication dosage: 66.2 mg/d
Administration schedule: once/d in the evening (8:00 ± 1.5h)
Duration of each medication: mean of 40.4 days of MPH during open‐label phase, plus 1 week MPH or placebo
Washout before trial initiation: not stated
Medication‐free period between interventions: no
Titration period: 6 weeks, starting at 10 mg, increases/decreases of 10‐20 mg
Treatment compliance: not stated |
| Outcomes |
ADHD symptoms
SKAMP Score, assessed at 8:00 am, 9:00 am, 10:00 am, 12:00 pm, 2:00 pm, 4:00 pm, 6:00 pm, 7:00 pm, and 8:00 pm during the laboratory classroom day
Serious AEs
General behaviour
PREMB‐R PM PREMB‐R AM PERMP
"PREMB‐R results were investigator‐rated summary scores derived from clinician‐administered parent interviews, with the parent PREMB‐R ratings based on the last 2 weekdays before the laboratory classroom day." (Childress 2020b p 4). "PREMB‐R AM and PREMB‐R PM at Visit 9 were assessed by using an analysis of covariance model with treatment as the main effect and trial centre and baseline score at baseline (Visit 2) as the covariates" (Childress 2020b p 5)
Non‐serious AEs
Spontaneously reported TEAEs queried at each visit, from informed consent through the follow‐up call 14–3 days after final dose Vital signs, no information on timing of outcome assessment ECG, no information on timing of outcome assessment Clinical laboratory tests, no information on timing of outcome assessment Physical examination findings, no information on timing of outcome assessment
|
| Notes |
Sample calculation: no
Ethics approval: yes, approved by each site’s Institutional Review Board
Comments from trial authors
First, the exclusion of a trial site (n = 36) may have reduced power to detect significant differences at some secondary endpoints. Furthermore, differences in baseline characteristics, with more children diagnosed with predominantly inattentive only and with less clinical severity based on the CGI‐S in the placebo group, may have also affected treatment differences. Moreover, the trial included only school‐age children (6–12 years of age) with a history of at least partial response to MPH and most psychiatric comorbidities were excluded. Therefore, the applicability of these findings to other age groups (i.e. preschool children, adolescents, and adults), MPH‐naive, and other presentations of ADHD is unknown.
Key conclusion of trial authors
Evening‐dosed, treatment‐optimised DR/ER‐MPH significantly improved ADHD‐related functional impairment in the before‐school early morning period, during the laboratory classroom period, and in the late afternoon/early evening period compared with placebo in children with ADHD. Treatment‐optimised DR/ER‐MPH was well tolerated: during the double‐blind phase there were no discontinuations due to TEAEs, TEAEs did not differ between DR/ER‐MPH and placebo groups, and all TEAEs were mild/moderate.
Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH: yes
Any withdrawals due to AEs: no
Funding source: Ironshore Pharmaceuticals
Email correspondence with trial authors: September and October 2021. No supplemental information was gained through personal email correspondence with trial authors in September 2021 and no answer was received in October 2021. |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Unclear risk |
Not stated |
| Allocation concealment (selection bias) |
Unclear risk |
Not stated |
| Blinding of participants and personnel (performance bias)
All outcomes |
Unclear risk |
Double‐blind, method not stated |
| Blinding of outcome assessment (detection bias)
All outcomes |
Unclear risk |
Not stated |
| Incomplete outcome data (attrition bias)
All outcomes |
Unclear risk |
A full trial site was excluded: 36 participants. Beside that only 2 withdrawals from double‐blind phase (1.7%)
Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no |
| Selective reporting (reporting bias) |
High risk |
CSSR‐S is reported as a safety assessment, but no results are reported. |
