| Study characteristics |
| Methods |
A 4‐week parallel trial with 5 arms:
MPH‐ER (PRC‐063) 25 mg/d MPH‐ER (PRC‐063) 45 mg/d MPH‐ER (PRC‐063) 70 mg/d MPH‐ER (PRC‐063) 85 mg/d placebo
Phases: 4 (1 week washout, 2 weeks forced titration, 2 weeks stable dose, 6‐month open‐label, follow‐up trial) |
| Participants |
Number of participants screened: 450
Number of participants included: 367; after exclusion of 1 trial site, 354 remained randomised (239 boys, 115 girls)
Number of participants followed‐up: 323
Number of withdrawals: 31 (+ 13 from excluded trial site)
Diagnosis of ADHD: DSM‐5 (255 combined, 5 hyperactive/impulsive, 94 inattentive)
Age: placebo 14.1 mean years, MPH 14.2 mean years (range 12 to ≤ 17)
IQ: > 80
MPH‐naive: 66%
Ethnicity: not stated
Country: Canada and USA
Setting: outpatient
Comorbidity: no allowed comorbidity specified. Many somatic and psychiatric disorders were exclusion criteria
Comedication: a stable dose of melatonin was permitted (5.1% of participants); 1 participant in a MPH group received a hypnotic/sedative medicament
Additional sociodemographics: none
Inclusion criteria
Participant must be male or non‐pregnant female at least 12 years of age and < 18 years of age Must have an ADHD diagnosis, in attentive, hyperactive/impulsive or combined, as defined by the DSM‐5 based on clinician assessment using multiple informants and a structured interview Must be unsatisfied with his or her current pharmacological therapy for treatment of ADHD or not currently receiving pharmacological therapy for ADHD. Inclusion of participants naïve to pharmacological therapy for ADHD is permitted Female participants must be one of the following: a. surgically sterile prior to screening; b. if of childbearing potential, abstinent or willing to use a reliable method of contraception, such as oral contraceptive, 2 barrier methods, a barrier method plus a spermicidal agent Female participants of childbearing potential must be a negative serum β‐hCG pregnancy test at screening Must have a minimum level of intellectual functioning, as determined by an IQ score of ≥ 80 based on the WASI or the KBIT Mentally and physically competent to sign an informed assent document, in the case of the participant, and an informed consent document, in the case of the parent/guardian, indicating that they understand the purpose of and procedures required for the trial and are willing to participate in the trial Able and willing to comply with the trial procedures for the entire length of the trial, including a successful swallow test of an empty 85 mg capsule Total score of ≥ 24 on the clinician‐rated ADHA‐5‐RS, as assessed at Visit 2
Exclusion criteria
Having an allergy to MPH or amphetamines or a history of serious adverse reactions to MPH Known to be non‐responsive to MPH treatment. Non‐response is defined as MPH use at various doses for a phase of at least 4 weeks at each dose with little or no clinical benefit Being diagnosed with or having a history of strokes, epilepsy, migraine headaches (> 1 instance every 2 months), glaucoma, thyrotoxicosis, tachyarrhythmias or severe angina pectoris or have serious or unstable medical illness. Participants with controlled or stable asthma or diabetes permitted Elevated BP, defined as any values > 89 DBP or 139 SBP, as assessed at Visit 1 Clinically significant ECG abnormalities, as assessed at Visit 1 Clinically significant laboratory abnormalities, as assessed at Visit 1 Currently receiving guanethidine, pressor agents, MAOIs, coumarin anticoagulants, anticonvulsants (e.g. phenobarbital, phenytoin, primidone), phenylbutazone, tricyclic antidepressants (e.g. imipramine, desipramine), SSRIs or herbal remedies (unless on a stable dose for 4 weeks) Participant has known history of symptomatic cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary heart disease, transient ischemics attack or stroke or other serious cardiac problems that may place the participant at increased vulnerability to the sympathomimetic effects of a stimulant drug Participant has a known family history of sudden cardiac death or ventricular arrhythmia Participants who are currently considered a suicide risk by the investigator Having a primary diagnosis of schizophrenia, schizoaffective disorder, primary affective disorder, schizotypal personality, major depression, bipolar disorder, generalised anxiety, borderline personality disorder, antisocial personality or another unstable psychiatric condition requiring treatment, as assessed by the structured interview conducted at Visit 1 Having a history or suspected physiological dependence (excluding nicotine) on narcotic analgesics or other psychoactive drugs (including barbiturates, opiates, cocaine, cannabinoids, amphetamines and benzodiazepines) Excessive consumption of alcohol (consumes alcohol in quantities > 15 drinks/week; 1 drink is defined as 360 mL/12 oz. of beer, 120 mL/4 oz. of wine, or 30 mL/1 oz. of hard liquor), or history (within previous 6 months) of alcohol abuse Currently (or within 30 days before the planned start of treatment) receiving an investigational drug or using an experimental medical device Homeless
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| Interventions |
Participants were randomly assigned to either MPH PRC‐063 (25, 45, 70 or 85 mg) or placebo once/d.
Number randomised to each group: first 367 were randomised (293 to MPH PRC‐063 groups and 74 to placebo). Due to major protocol violations, 13 participants from 1 site were excluded from the analysis, leaving 71 randomised to placebo and 283 randomised to MPH PRC‐063 groups (25 mg/d: n = 71, 45 mg/d: n = 69, 70 mg/d: n = 73, 85 mg/d: n = 70)
Mean medication dosage: participants were evenly distributed to a forced dose of 25, 45, 70 or 85 mg/d.
Administration schedule: once daily
Duration (of (each) medication): 4 weeks
Washout before trial initiation: 1 week
Titration period: 2 weeks (blinded forced‐titration)
Treatment compliance: compliance was evaluated by counting and recording the number of dispensed capsules and the number of returned capsules. Noncompliance was defined as missing ‡2 doses from a single bottle of trial medication. 83.7% compliance |
| Outcomes |
ADHD symptom severity
Serious AEs
General behaviour
Non‐serious AEs
As no SD was reported in the trial articles, we have not been able to use the ADHD Symptom or General Behavior data for the analysis. |
| Notes |
Sample calculation: yes, 360 participants
Ethics approval: yes. “For each study site, the study protocols were approved by an independent ethics committee or institutional review board, as appropriate. The studies were conducted in accordance with the Declaration of Helsinki, International Council for Harmonisation Good Clinical Practice (GCP), and all applicable local, state, and federal regulations.” (Weiss 2021a, p 2)
Comments from trial authors
The double‐blind study was only powered to determine the overall effect of PRC‐063 relative to placebo, and individual dose groups were too small to evaluate dose effectiveness. The fixed‐dose design of the double‐blind study may have resulted in some participants (most of whom were treatment naïve) being titrated too rapidly to an 85 mg dose. Overall, 77% of participants were randomised to a dose that was either too low or too high, potentially leading to the treatment response being underestimated and AE rates being overestimated.
Key conclusion of trial authors
Significant improvements in ADHD symptomatology were observed based on the primary and secondary outcome measures and across 3 different sets of informants: clinicians, parents, and adolescents themselves. PRC‐063 was generally well tolerated, with an AE profile consistent with other long‐acting stimulants. Significant improvements in executive function and patient satisfaction were also observed with no negative impact on sleep quality or unexpected safety findings.
Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH: yes
Any withdrawals due to AEs: yes, 10 participants all from the MPH PRC‐063 groups
Funding source: Rhodes Pharmaceuticals, LP
Email correspondence with trial authors: no correspondence |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Low risk |
“Randomization schedules were generated by Y‐Prime, Inc., using an integrated web response system” |
| Allocation concealment (selection bias) |
Low risk |
Central allocation through Y‐Prime, Inc. and identically appearing drug containers and capsules |
| Blinding of participants and personnel (performance bias)
All outcomes |
Low risk |
“PRC‐063 and placebo were supplied in bottles, each containing 10 capsules. To maintain blinding, placebo and PRC‐063 at each dose were identical in appearance. No emergency unblinding occurred during the study.” |
| Blinding of outcome assessment (detection bias)
All outcomes |
Low risk |
“No emergency unblinding occurred during the study.” |
| Incomplete outcome data (attrition bias)
All outcomes |
Low risk |
Due to multiple protocol violations and Good Clinical Practices (GCP) issues, it was necessary to exclude efficacy data for the 13 participants enrolled at one trial site from the primary efficacy analysis. A sensitivity analysis including data from this trial site was performed. As a further sensitivity analysis to assess the impact of missing data, the primary efficacy analysis for the full analysis population was repeated using Markov Chain Monte Carlo (MCMC) multiple imputation. Missing data were imputed 20 times.
Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no |
| Selective reporting (reporting bias) |
Low risk |
All protocol outcomes reported |
