Methods

Design: double‐blind, randomised, placebo‐controlled, cross‐over design

Duration of study: 3 weeks

Participants

Location: USA

Setting: recruitment from special education, psychiatric inpatient or psychiatric day treatment programmes

Study start date: not specified (prior to 2000)

Study end date: not specified

Number recruited: not specified

Number randomised: 13 children (10 boys, 3 girls)

Number completed: 12

Number of dropouts/withdrawals: 1

Mean age: 7.4 years (SD 6.5; range 5.6 to 11.2)

Ethnicity: African American (n = 7), white (n = 4), Latino (n = 2)

ASD Diagnosis: autistic disorder (n = 9), PDD‐NOS (n = 4)

ADHD diagnosis: a score of 15 points or more on the Hyperactivity Index of the Teacher Conners Rating Scale

Other diagnosis: oppositional defiant disorder, tuberous sclerosis, mosaic Down's syndrome

Cognitive function: ranged from severe/profound disability to average intelligence

Stimulant use history: uncertain, likely to have included a "mix of kids with prior experience with stimulants" Handen 2016 (personal communication) and some with no prior experience

Concurrent medication: none

Inclusion criteria

• Scores of 30 or more as determined by the Childhood Autism Rating Scale

• Diagnosis of autism or PDD‐NOS

• Score of 15 points or more on the hyperactivity index of the Conners' Teacher Rating Scale while off psychotropic medication

Exclusion criteria: not specified

Interventions

Intervention: 0.3 mg/kg and 0.6 mg/kg doses of MPH

Comparison: placebo

Administration: each MPH dose and the placebo dose was given 2 to 3 times a day for 7 consecutive days. Doses were given with breakfast and 4 hours later with lunch. 11 participants took a third MPH dose around 4:00 pm. The lower MPH dose always preceded the higher dose. This resulted in three possible drug orders:

• placebo → 0.3 mg/kg → 0.6 mg/kg

• 0.3 mg/kg → placebo → 0.6 mg/kg

• 0.3 mg/kg → 0.6 mg/kg → placebo

Outcomes

Primary outcome measures (teacher rated)

• Conners' Teacher Rating Scale (CTRS; 28‐item questionnaire with 4 subscales. The 10‐item hyperactivity index was used. Each item was rated on a 4‐point scale ranging from 'not at all a problem' to 'very much a problem')

• IOWA Conners' Teacher Rating Scale (IOWA CTRS; 10‐item questionnaire comprising a 5‐item aggression subscale and a 5‐item hyperactivity subscale. Items were rated on the same 4‐point scale as the Conners' Teacher Rating Scale. Only the aggression subscale was used)

• Aberrant Behavior Checklist (ABC; 58‐item questionnaire, normalised on a developmentally delayed population of children and adults. Items rated on a 4‐point scale from 'no problem' to 'major problem')

• Childhood Autism Rating Scale (CARS; used to assess any changes in behaviours associated with the core feature of autism/PDD. The scale comprised 15 questions covering primary symptoms of autism/PDD, such as relatedness, communication, and adaptation to change. Each question has 7 levels of description (from 'age and situation appropriate' to 'severely abnormal'). A single score, ranging from 15 to 60 points, was obtained, with higher scores indicative of the presence of greater autistic symptoms.

• Side Effects Checklist: checklist includes common side effects listed in the Physician Desk Reference (1988) for MPH, including appetite suppression, irritability and drowsiness. Respondents were asked to indicate if a particular side effect was present or absent, and if so, to indicate the level of severity (mild, moderate, or severe).

Primary outcome measures (parent rated): parents rated similar questionnaires but data were incomplete and not reported

Administration of outcome assessment: outcome measures were completed by the classroom teacher or programme staff at the end of the week for each MPH condition. Information is not available about the administration of questionnaires to parents.

Aim of study

To determine the efficacy and safety issues of MPH use among children with autism and symptoms of ADHD

Notes

Comment on design: the cross‐over trial design was appropriate for the clinical context, given that ASD is a relatively stable, chronic condition. No period or carry‐over effects would be anticipated for methylphenidate, even in the absence of a washout period, as the elimination half‐life for both the immediate‐ and extended‐release forms is 2 to 3 hours, and the average duration of action of (immediate‐release) methylphenidate is approximately 4 hours (Novartis 2014). Data collection was also focused at the end of each week of intervention, further reducing the risk of any carry‐over effect.

Other comments: none

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Drug order was randomly assigned. However the lower MPH dose always preceded the higher dose."

Comment: method of sequence generation not described

Allocation concealment (selection bias)

Unclear risk

Comment: method of allocation not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: all participants and parents were reported to be blinded to doses and/or placebo treatments. It is not reported whether participants had ever taken MPH previously and hence could have recognised the medication. The corresponding author indicated that some participants may have taken MPH previously.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Both parents and teachers were unaware of the fact that the lower MPH dose would precede the higher dose".

Comment: all respondents (parents and teachers) were blinded to doses, placebo treatments or both.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: 2 participants had 0.6 mg/kg dose discontinued after only 1 day. A 3rd participant was missing CARS data for placebo condition. For both of these conditions missing data were imputed using a maximum likelihood techniques as outlined in 'Inference and missing data'. A 4th participant was unable to complete the protocol for either MPH dose due to the presence of significant adverse side effects. Data (except for side effects data) for this participant were not included for analysis.

Selective reporting (reporting bias)

High risk

Quote: "Only questionnaires from teachers were used"
Comment: parent questionnaires were not reported because collection was incomplete (due to many participants residing in inpatient clinics or residential halls). In some cases only subsets of completed scales appear to be reported.

Other bias

Unclear risk

Comment: no information available on conflict of interest. The study was supported by a Research Foundation grant.

Methods

Design: double‐blind, placebo‐controlled, cross‐over trial

Duration of study: 4 weeks

Participants

Location: USA

Setting: recruitment from special education classrooms, all children were living at home

Study start date: not specified (prior to 2013)

Study end date: not specified

Number recruited: not specified

Number randomised: 24 children (19 boys and 5 girls)

Number completed: 24

Number of dropouts/withdrawals: 0

Mean age: 8.8 years (SD 1.7; range 7.1 to 12.7) years

Ethnicity: white (n = 13), Hispanic (n = 5), African‐American (n = 4), Asian (n = 1), and multiple races (n = 1)

ASD diagnosis: autistic disorder (n = 19), Asperger's disorder (n = 3), PDD‐NOS (n = 2)

ADHD diagnosis: combined type (n = 19), predominantly inattentive type (n = 5). Mean Conners' Parent Rating Scale ‐ Revised ADHD Index T score = 76.1 (SD 6.7) and mean Conners' Teacher Rating Scale ‐ Revised ADHD Index T score = 67.2 (SD 8.7)

Other diagnosis: oppositional defiant disorder (n = 5), obsessive compulsive disorder (n = 2), separation anxiety (n = 1)

Cognitive function: mean full scale IQ 85.0 (SD 16.8)

Stimulant‐use history: 13 children had previously taken stimulant medication. This was discontinued 1 week or more (mean = 63 days, range: 7–547 days) prior to entering the trial.

Concurrent medication: 7 children continued long‐term medications (at a constant dose) during the trial: risperidone (n = 3), aripiprazole (n = 1), sertraline (n = 1), bupropion (n = 1), and trazodone (n = 1)

Inclusion criteria:

• ASD

• ADHD

Exclusion criteria

• Serious neurological disorders (e.g. stroke, seizures)

• Down syndrome

• Fragile X syndrome

• Tourette syndrome

• Psychosis

• Mood disorders

Interventions

Intervention: 1 week low‐dose MPH (0.21 mg/kg ER‐MPH morning and 0.14 mg/kg IR‐MPH afternoon), 1 week medium‐dose MPH (0.35 mg/kg ER‐MPH morning and 0.24 mg/kg IR‐MPH afternoon), and 1 week high‐dose MPH (0.48mg/kg ER‐MPH morning and 0.27 mg/kg IR‐MPH afternoon). No child received a dose greater than the equivalent of an IR‐MPH dose of 0.6 mg/kg, and no child's total daily dose exceeded the equivalent of an IR‐MPH twice‐daily dose of 50 mg

Comparison: placebo

Administration: 1 week of 2 days each of low, medium, and high MPH doses in ascending order to assess tolerability. All 24 children tolerated all 3 doses. 1 week each of the 4 MPH dosing regimens

Outcomes

Primary outcome measure: Conners' Teacher Rating Scale ‐ Revised ‐ Short Form (CTRS‐R‐SF; 28 items)

Secondary outcome measures

• Teacher behavioural instruments

  • Swanson, Nolan, and Pelham Questionnaire, Revised for DSM‐IV (SNAP‐IV‐Teacher, 18 items)

  • ADD‐H Comprehensive Teacher Rating Scale (ACTeRS, 24 items)

  • Conners' Global Index ‐ Teacher (10 items)

  • Aberrant Behavior Checklist ‐ Teacher (ABC‐T; a 58‐item behavior questionnaire developed to rate symptoms of hyperactivity, irritability, social withdrawal, stereotypic behaviour, and inappropriate speech in individuals with developmental disabilities)

• Clinician instruments

  • Clinician Global Impression ratings (Clinician Global Impression‐Improvement and Clinician Global Impression‐Severity. Both these ratings are scaled from 0 to 7, and were used to document overall severity (e.g. ADHD, autistic) and improvements relative to the baseline week of the trial. All sources of information were taken into account including data from behavioural questionnaires, interviews with the parents and children, and observations by the study staff.

• Parent instruments

  • Conners' Parent Rating Scale ‐ Revised (CPRS‐R) (CPRS‐R ‐ Short Form (CPRS‐R‐SF) 27 items)

  • Parent form of the Conners' Global Index (10 items)

  • Parent SNAP‐IV (18 items)

  • Parent (24 items)

  • Parent ABC (a 58 item behavior questionnaire developed to rate symptoms of hyperactivity, irritability, social withdrawal, stereotypic behavior, and inappropriate speech in individuals with developmental disabilities)

  • Parent Visual Analog Scale (VAS; for the most troublesome symptom their child displayed)

  • Parents and teachers also completed a medication side effects questionnaire each week referring to common side effects associated with MPH treatment (Physician's Desk Reference; Thompson Health Care 2009)

Administration of outcome assessment: Weekly at the end of each week of intervention/placebo

Aim of study

Quote: "The purpose of this study was to examine the behavioral effects of four doses of psychostimulant medication, combining extended‐release methylphenidate (MPH) in the morning with immediate‐release MPH in the afternoon."

Quote: "Our goals were to determine if:

1) ER‐MPH was associated with improvements in parent and teacher behavioral ratings, and

2) the MPH dose‐response curve was linear (i.e. higher MPH doses were associated with consistent improvements in behavioral functioning), or curvilinear (an initial behavioral improvement with MPH, followed by behavioral declines at higher doses)."

Notes

Comment on design: the cross‐over trial design was appropriate for the clinical context, given that ASD is a relatively stable, chronic condition. No period or carry‐over effects would be anticipated for methylphenidate, even in the absence of a washout period, as the elimination half‐life for both the immediate‐ and extended‐release forms is 2‐3 hours (Novartis 2014). The average duration of action of (immediate‐release) methylphenidate is approximately 4 hours, and the extended release form used in Pearson has a duration of action of approximately 8 hours (Novartis 2014). Data collection was also focused at the end of each week of intervention, further reducing the risk of any carry‐over effect.

Other comments

• Parents were asked to focus on weekend behaviour (at the end of the week of each dose) and morning behaviour (i.e. the effect of the ER dose, to align with teacher ratings); it appears, therefore, that the effect of the afternoon IR dose (in those children who took it) was not measured in the study at all.

• As regards the high incidence of previous MPH use in participants (13/24), "the overall pattern of MPH‐related improvement was found in exploratory analyses to be similar in the sub‐sample of children who were and were not stimulant naive."

• One child was excluded from randomisation based on being a "placebo responder" in the test dose week

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: the order of dosage administration was "counterbalanced across children" using diagram‐balanced Latin squares. This is not a randomising procedure and is more commonly used in larger studies.

Allocation concealment (selection bias)

Unclear risk

Comment: it is not clear how dosing sequences were allocated.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "All study personnel with patient contact were blind with respect to dosages given during the drug trial".

Comment: it is not stated whether parents were blinded. However, 13/24 participants had previously taken MPH so may have identified whether or not they were taking the active medication based on previous experience. The study physician and the study psychologist were also unblinded during the test‐dose week.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: 13/24 participants had previously taken MPH so parents and teachers are likely to have identified whether or not the children were taking the active medication based on previous experience. 2 blinded clinicians completed the Clinician Global Impression measures, after achieving reliability on training vignettes.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: all 24 participants completed the trial but 5/24 children discontinued the afternoon IR‐MPH dose because of behavior concerns in late afternoon/evening. All 5 of these children experienced irritability, 2 experienced decreased sleep, and 2 showed increased stereotypical behaviours. Parent ratings were available for all 24 children, whereas teacher ratings were only available for 18 children (6 were assessed in summer when school was in recess). Outcomes are reported for all participants, with the above exceptions.

Selective reporting (reporting bias)

Low risk

Comment: comprehensive reporting of outcomes

Other bias

Unclear risk

Comment: The authors report having received financial support from a number of pharmaceutical companies (including manufacturers of pharmaceuticals for behavioural syndromes in children). The study was funded by grant MH072263 from the National Institute of Mental Health (NIMH).

Methods

Design: double‐blind, cross‐over study

Duration of study: 6 weeks

Participants

Location: New York, USA

Setting: recruitment from psychiatric outpatient clinic

Study start date: not specified, prior to 1995

Study end date: not specified

Number recruited: not reported, and the attempt made to contact the corresponding author to clarify this was not successful

Number randomised: 10 children (6 boys; 4 girls)

Number completed: 10

Number of dropouts/withdrawals: 0

Mean age: 8.5 years (SD 1.3; range 7 to 11)

Ethnicity: not specified

ASD diagnosis: Baseline Childhood Autism Rating Scale scores between 30.0 and 59.5

ADHD diagnosis: not specified

Other diagnosis: not specified, "wide range of baseline behaviours" reported

Cognitive function: 7 children met criteria for mild intellectual impairment

Stimulant‐use history: nil

Concurrent medication: nil (all participants had previously been prescribed neuroleptic medication but this was ceased prior to study)

Inclusion criteria

• Met DSM‐III‐R and Childhood Autism Rating Scale criteria for autistic disorder

• Willing to cease neuroleptic medication for at least 1 month prior to the start of the study

Exclusion criteria

• Seizure disorder

• Major neurological or medical illness

• Any previous MPH medication

Interventions

Intervention: MPH treatment appeared to consist of one week of MPH 10 mg twice daily followed by a second week of MPH 20 mg twice daily, although it may have consisted of either 2 weeks of MPH 10 mg twice daily, or two weeks of MPH 20 mg twice daily.

Comparison: placebo

Administration: cross‐over MPH versus placebo study completed in 6 weeks, with 2 weeks medication‐free baseline, 2 weeks placebo or MPH followed by cross‐over

Outcomes

Primary and secondary outcomes were not specified

Clinician instruments

• Childhood Autism Rating Scale (CARS, 15‐item) rated independently by 2 psychiatrists

• Aberrant Behaviour Checklist (ABC, 58‐item) rated independently by 2 psychiatrists

• Hyperactivity factor of the Conners Teacher Questionnaire (CTQ, number of items not specified) rated independently by 2 psychiatrists )

• Abnormal Involuntary Movements Scale (AIMS) rated by a paediatrician

• Side Effects Checklist for Stimulant Medication, rated by a paediatrician

Parent Instruments: Conners Abbreviated Parent Questionnaire (CAPQ; 10‐item)

Administration of outcome assessment: participants were rated by clinicians in a 3‐hour simulated classroom situation and during free play at the day hospital, at the end of each week. Parent questionnaires were completed weekly based on at‐home behaviour for the week prior to the day hospital assessment

Aim of study

To evaluate "MPH efficacy and side effects in the treatment of children with autistic disorder"

Notes

Comment on design: the cross‐over trial design was appropriate for the clinical context, given that ASD is a relatively stable, chronic condition. No period or carry‐over effects would be anticipated for methylphenidate, even in the absence of a washout period, as the elimination half‐life for both the immediate‐ and extended‐release forms is 2‐3 hours and the average duration of action of (immediate‐release) methylphenidate is approximately 4 hours (Novartis 2014). Data collection was also focused at the end of each week of intervention, further reducing the risk of any carry‐over effect.

Other comments

• All ratings improved on placebo cf baseline, which may reflect time taken for participants to adjust to new, day‐hospital experimental environment

• Quote: "The data for placebo and MPH were collapsed" because ANOVA showed no medication order effects. "Mean placebo and MPH scores were used for statistical analysis" (two tailed paired t‐tests) because there were no significant differences between the two MPH doses.

• Clinicians rated using an instrument validated for teachers.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: not described

Allocation concealment (selection bias)

Unclear risk

Comment: not described but reported as "randomly assigned"

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: nursing staff administering morning dose on day of observation may not have been blinded to drug and drug dose, although the "investigators, the children and the parents were blind to drug and drug dose".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: Clinicians, children and parents were reported to be "blind to drug and drug dose". None of the children had been on MPH before entry into the study, which minimises the risk of recognition of the effects of MPH.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: unclear if all participants completed study, but table 2 reports n = 10 in the title of the table.

Selective reporting (reporting bias)

High risk

Comment: Outcomes for all mentioned instruments are reported in table 2 and in the text except the CARS. This is an autism scale that rates the severity of symptoms based on observation. It was listed as an outcome, and it is unclear why this was omitted in the reporting of the results.

Other bias

Unclear risk

Comment: no reporting of conflicts of interest or financial support

Methods

Design: randomised, double‐blind, placebo‐controlled, cross‐over trial, including a 1‐week test‐dose phase to check the tolerability of MPH at each dose; a 4‐week randomised‐order, placebo‐controlled, double‐blind cross‐over phase; and an 8‐week, open‐label continuation phase for responders, at best dose identified in cross‐over phase. Only the results from the 4‐week randomised cross‐over phase are included in our analysis.

Duration of study: 4 weeks

Participants

Location: USA

Setting: 5 centers forming the Research Units on Pediatric Psychopharmacology Autism Network

Study start date: 14 November 2001

Study end date: 5 September 2003

Number recruited: 72 (6 of these participants had intolerable adverse events with more than 1 methylphenidate dosage level during the test‐dose phase, and they exited the study prior to randomisation as per protocol)

Number randomised: 66 (59 boys, 7 girls)

Number completed: 58

Number of dropouts/withdrawals: 8. 1 participant who was randomised withdrew prior to cross‐over phase and 7 children withdrew during cross‐over phase due to intolerable adverse events.

Mean age: 7.5 years (SD 2.2; range 5.0 to 13.7 years)

Ethnicity: white (n = 48), African‐American (n = 9), Asian (n = 6), Latino (n = 3)

ASD diagnosis: autistic disorder, Asperger's disorder, or PDD‐NOS‐ based on DSM‐IV.

ADHD diagnosis: based on SNAP‐IV and Clinician Global Impression‐Severity

Other diagnosis: not specified

Cognitive function: Slosson IQ, mean 62.6 (SD 32.9), range 16‐135

Stimulant‐use history: excluded if adequate trial of MPH within past 2 years

Concurrent medication: nil (ceased prior to baseline visit)

Inclusion criteria

• Boys and girls aged 5‐14 years, inclusive, with a diagnosis of autistic disorder, Asperger's disorder, or PDD‐NOS based on the criteria set forth in the DSM‐IV. The ADI‐R was administered to corroborate the DSM‐IV diagnosis of autistic disorder based on clinical interview and examination

• Symptoms of hyperactivity, impulsivity (or both) present for at least 6 months, beginning prior to the age of 7 years, and rated on Clinician Global Impression‐Severity subscale with a score of 4 or higher (rated 'moderately ill', taking into account all of the symptoms) and a total score of 27 or higher on both a parent‐rated and teacher‐rated Swanson, Nolan, and Pelham, 4th version (SNAP‐IV) ADHD scale (items 1‐18), with a score of at least 10 on the hyperactivity‐impulsivity subscale (items 10‐18). Participants were also eligible for entry if the hyperactivity‐impulsivity subscale score on the SNAP‐IV ADHD scale was at least 15 even in the absence of notable inattentiveness

• Cessation of psychotropic medications for at least 1 to 3 weeks (1 week for stimulants and clonidine hydrochloride; 2 weeks for antidepressants except fluoxetine and citalopram hydrobromide; 3 weeks for fluoxetine, citalopram hydrobromide, or antipsychotics) prior to baseline visit

Exclusion criteria

• Mental age less than 18 months as determined by Slosson Intelligence Test

• Other neuropsychiatric disorders that might require alternative medical management

• For participants with a tic disorder, tic severity of more than mild severity on a Clinician Global Impression‐Severity subscale rating pertaining to tics only

• Any significant medical condition, such as heart or liver disease, that could make treatment with methylphenidate unsafe

• For participants with a seizure disorder, any seizures in the past 6 months or unstable anticonvulsant dose in the past 1 month

• Hypertension

• Treatment with an adequate trial of methylphenidate hydrochloride (0.4 mg/kg per dose given at least twice daily for a minimum of 2 weeks) within the past 2 years

• History of severe adverse response to methylphenidate

Interventions

Test‐dose phase

• Day 1: placebo capsules

• Days 2‐3: low dose MP (calculated based on participant weight)

• Days 4‐5: medium dose MP

• Days 6‐7: high dose MP

Participants were excluded from the cross‐over study if they experienced a severe adverse event, or were rated 'much worse' or 'very much worse' on the CGI, at the low or medium dose. Participants were randomised to a modified cross‐over schedule (omitting high dose) if the adverse event or clinical worsening occurred only on the high dose (15 participants)

Study phase

Intervention: 3 different doses of MPH (low, medium, high)

Comparison: placebo

Administration: 4‐week cross‐over phase. Each participant received 1 week placebo and 1 week each of 3 different doses of MPH in random order (except high dose never followed placebo). 16 participants received the modified cross‐over schedule (medium dose administered twice*, no high dose).

Outcomes

Primary outcome: teacher‐rated hyperactivity subscale (16 items) of Aberrant Behavior Checklist (ABC) (RUPP 2005)

Secondary outcomes

• Teacher instruments

  • Teacher‐rated additional subscales (irritability, lethargy/social withdrawal, stereotypy and inappropriate speech) of 58‐item Aberrant Behavior Checklist (ABC) (RUPP 2005)

  • Teacher‐rated Swanson, Nolan, and Pelham Questionnaire, Revised for DSM‐IV** (26‐item with 3 subscales: inattention, hyperactivity/impulsivity and oppositional defiant disorder) (RUPP 2007)

• Clinician instruments

  • Clinician Global Impression ‐ Improvement subscale (combined with the Parent‐rated and Teacher‐rated ABC hyperactivity subscale to give an overall definition of response) (RUPP 2005)

  • Clinician‐rated Children's Yale‐Brown Obsessive Compulsive Scales for PDD (CYBOCC‐PDD; 5‐item scale) (RUPP 2007)

  • Social communication measures rated by trained observers (subset of participants only) (RUPP 2009)

• Parent instruments

  • Parent‐rated hyperactivity subscale (16 items) of 58‐item Aberrant Behavior Checklist (ABC) (RUPP 2005)

  • Parent‐rated additional subscales (irritability, lethargy/social withdrawal, stereotypy and inappropriate speech) of 58‐item Aberrant Behavior Checklist (ABC) (RUPP 2005)

  • Parent‐rated Swanson, Nolan, and Pelham Questionnaire, Revised for DSM‐IV** (26 items with 3 subscales: inattention, hyperactivity/impulsivity and oppositional defiant disorder) (RUPP 2007)

Administration of outcome assessment: ratings were performed at the end of each week of treatment

Aim of study

To determine the efficacy and safety of MPH in children with PDD and hyperactivity

Notes

Comment on design: the cross‐over trial design was appropriate for the clinical context, given that ASD is a relatively stable, chronic condition. No period or carry‐over effects would be anticipated for methylphenidate, even in the absence of a washout period, as the elimination half‐life for both the immediate‐ and extended‐release forms is 2‐3 hours, and the average duration of action of (immediate‐release) methylphenidate is approximately 4 hours (Novartis 2014). Data collection was also focused at the end of each week of intervention, further reducing the risk of any carry‐over effect.

Other comments: RUPP 2005 only reports means and SDs for teacher and parent rated hyperactivity subscale of ABC; very partial reporting of secondary outcomes (other ABC subscales), with a few effect sizes and P values only. The 2007 article reports means and SDs of a secondary analysis. The 2009 article reports mean and SD for social communication measures in their subset secondary analysis (only measured at some sites of the multicentre trial).

*Data from both medium dose weeks were combined.

**The Parent and Teacher SNAP‐IV and Clinician CYBOCC‐PDD outcomes were only mentioned and reported in the 2007 secondary analysis article

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Comment: randomisation was balanced by site to avoid repeating the treatment order within the site. Randomisation lists were generated centrally and were held by an investigational pharmacist at each site. Authors do not describe the exact method of generating the list.

Allocation concealment (selection bias)

Unclear risk

Comment: no information on the role of the pharmacist. Clinicians, the patient, and the caregiver were blind to treatment assignment during cross‐over phase, but not during test‐dose week preceding the study.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: clinicians, the patient, and the caregiver were blind to treatment assignment during cross‐over phase, but not during test‐dose week preceding the study. No information on the success of blinding is reported. Participants had not had an adequate trial of MPH in past 2 years (exclusion criteria), but they had been exposed to the test dose.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: clinicians, the patient, and the caregiver were blind to treatment assignment during cross‐over phase, but not during test‐dose week preceding the study. No information on the success of blinding is reported. Participants had not had an adequate trial of MPH in past 2 years (exclusion criteria), but they had been exposed to the test dose.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: Study dropouts and reasons for drop out are reported. Data for social communication outcomes are incomplete (only 33 out of total of 66 randomised children completed the trial for this outcome).

Selective reporting (reporting bias)

High risk

Comment: the main study publication (RUPP 2005) reports all mentioned outcome measures. The overall response outcome was only reported as a combined number, without results for the individual CGI‐I component of this composite outcome measure. The RUPP 2005 study also reports adverse events, but this is not mentioned as an outcome in the methods section of the paper. 2 additional publications (in 2007 and 2009) subsequently reported additional outcomes that were not mentioned in the original publication. Three secondary outcome measures were only mentioned and reported in the 2007 secondary analysis article. 1 outcome measure (social communication) was only mentioned and reported in the 2009 secondary analysis article on a subset of the original patient population.

Other bias

Unclear risk

Comment: study supported by funding from National Institutes of Mental Health (NIMH) and universities, USA. Several authors report affiliations with a number of pharmaceutical companies.