OROS-methylphenidate to reduce ADHD symptoms in male prisoners aged 16-25 years: a RCT

Article history

The research reported in this issue of the journal was funded by the EME programme as project number 14/23/17. The contractual start date was in August 2016. The final report began editorial review in August 2020 and was accepted for publication in December 2020. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The EME editors and production house have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the final report document. However, they do not accept liability for damages or losses arising from material published in this report.

Copyright statement

Copyright © 2022 Asherson et al. This work was produced by Asherson et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.

2022 Asherson et al.

Scientific background and rationale

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that develops during childhood or early adolescence and frequently persists into adulthood. The disorder is defined by a persistent pattern of inattention and/or hyperactivity/impulsivity that interferes with or reduces the quality of functioning in daily life. 1 The impairments associated with ADHD are often severe and are well documented. They include educational and occupational failure, transport accidents, difficulty forming social and personal relationships, and the development of behavioural problems, including antisocial behaviour and criminality. 2–6 Many adults with ADHD struggle with mental health symptoms, such as a mental and physical restlessness, distractibility, emotional dysregulation, low self-esteem and sleep problems. 3 A further source of impairment is the high rate of coexisting disorders associated with ADHD. 7 These include general and specific learning difficulties, anxiety, depression, bipolar disorder, personality disorder and drug abuse disorders.

Attention deficit hyperactivity disorder affects around 5–7% of children. 8,9 Prevalence estimates for ADHD in adults range from 2.5% to 3.4%,10,11 with the most recent review reporting an average prevalence of 2.8% for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), ADHD. 7 Currently, there are no prevalence estimates for ADHD using Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. These estimates are expected to be slightly larger than those for DSM-IV because of changes in symptom thresholds for adults and the age at onset criteria. The population prevalence contrasts considerably with the disproportionately high rate of people meeting ADHD diagnostic criteria in prison populations, which averages around 26%. 12 In this review and meta-analysis,12 studies using screening criteria for diagnosis had a significantly larger estimated ADHD prevalence (43%) than the subset of studies using a diagnostic clinical interview (26%), suggesting good sensitivity but a high rate of false positives when using screening tools. However, using clinical interview data,12 the rate of ADHD was estimated to be around 30% in male adolescents, 31% in male adults, 31% in female adolescents and 22% in female adults.

The National Institute for Health and Care Excellence (NICE) and the Scottish Intercollegiate Guidelines Network recommend stimulant medications, methylphenidate (MPH) or lisdexamfetamine, as first-line treatment for ADHD with significant impairment in children, adolescents and young adults. 13–15 These medications target the core symptoms of inattention and hyperactivity/impulsivity, and may also lead to reduced levels of emotional dysregulation. 16,17 Although psychoeducation and psychological interventions are also thought to be essential in the overall support provided for people with ADHD, they may not reduce core symptoms. Evidence for this conclusion comes from studies suggesting that psychological treatments may reduce coexisting problems (or enhance behaviours) relevant to the prison population, such as social skills, conduct problems and global mental health, but may not reduce core symptoms of the disorder. 18–20

Despite the recommendations from national guidelines, there is continued uncertainty about the value of diagnosing and treating ADHD in offender populations21 and in adults more generally. Raman et al. 22 reported that prevalence for medication use for ADHD averaged 0.03% in Western Europe (0.05% in the UK) among adults aged ≥ 19 years and 0.7% (0.64% in the UK) for children and adolescents. This is far below population prevalence for the disorder. The proportion of ADHD cases treated for ADHD in prisons is expected to be even smaller,21 yet clinical guidelines recommend the identification and treatment of ADHD at all ages, paying particular attention to the prison population, as well as those presenting with comorbid mental health disorders. 14 One potential reason for the low rate of treatment of ADHD in prisons is the lack of data on treatment effects in adolescents and adults presenting with complex coexisting mental health and behavioural disorders, and the limited research of the prison population. Concerns are expressed that the common occurrence of mental health, neurodevelopmental and psychosocial problems might provide a better explanation for impulsive, overactive and inattentive states in young offenders, or might interfere with the treatment response in cases of ADHD. For these reasons, NICE13 recommended that drug treatment efficacy trials are needed in offender populations (section 5.18.1.413) and repeated this recommendation in 2013. 23 The guideline13 stated that:

[T]here should be an assessment of efficacy in these groups (i.e. forensic and drug abuse populations) of the ADHD treatments already recommended for treatment in the community. Randomised controlled trial design is recommended.

Reproduced with permission from NICE. 13

© NICE 2008 Attention Deficit Hyperactivity Disorder: Diagnosis and Management. All rights reserved. Subject to Notice of rights. NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this product/publication

There are two potential reasons why the response of ADHD symptoms to stimulant medications may be different for young adult offenders than for the samples of children, adolescents and adults involved in previous studies of ADHD in community settings. First, offenders present with an array of complex mental health problems that may better explain the states of inattentive, overactive, restless and impulsive behaviours used to define ADHD. This includes disorders commonly seen in offenders such as personality, anxiety, post-traumatic stress and substance abuse disorders. Second, nearly all previous trials of ADHD medications have been conducted in carefully selected samples with generally low levels of co-occurring psychosocial, behavioural and mental health problems. However, the co-occurrence of mental health disorders might modify the efficacy of drug treatments for ADHD.

One example is comorbid drug abuse. A meta-analysis24 of treatment trials found no effect of MPH on ADHD symptoms in ADHD cases with comorbid drug abuse [standardised mean difference (SMD) 0.08; p = 0.59], whereas there was a medium effect in samples without comorbid drug abuse (SMD 0.51; p < 0.00001). A review and meta-analysis25 of ADHD medications among patients with ADHD and drug dependency found only small reductions in the levels of ADHD symptoms following treatment (eight studies of MPH, three of atomoxetine, one of pemoline and one of bupropion), with an average SMD of around 0.30. When stratified by type of medication, significant reductions in ADHD symptoms were identified for MPH, with a mean dose of 62.2 mg per day across the eight MPH studies included in this review. Furthermore, an international consensus statement on treatment of ADHD with comorbid substance use disorder (SUD) concluded that several studies report lower effectiveness of standard-dose pharmacotherapy for the treatment of ADHD in patients with ADHD with comorbid SUD, and uptitration may be considered in patients who are unresponsive to standard doses. 26 Finally, two recent studies of MPH found that a low MPH dose (i.e. < 36 mg) was associated with treatment discontinuation,27 and that ADHD patients with a SUD were, on average, prescribed 40% larger doses than those without a SUD after 2 years of treatment. 28 These findings may be relevant to prison populations, for whom a history of drug abuse and ongoing access to drugs in prison is common.

Furthermore, concerns have been expressed about the potential for stimulant medications such as MPH to worsen coexisting conditions. The most recent research recommendations from NICE14 state that:

[N]o evidence was identified to justify different medication choices in people with ADHD and a history of psychosis, mania, or personality disorder. However, these groups are often excluded from trials. There are reasons (for example, mechanism of action of medication options, previous reports of adverse effects) to suspect that these groups may respond differently to different drugs, but a lack of trials to confirm this.

Reproduced with permission from NICE. 14

© NICE 2018 Diagnosis and Management of ADHD in Children, Young People and Adults. 14 All rights reserved. Subject to Notice of rights. NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this product/publication

To address the questions raised, we have conducted a randomised controlled efficacy trial of osmotic releases oral system (OROS)-MPH, a sustained-release formulation of MPH, compared with placebo, in young male adult prisoners with ADHD who are aged 16–25 years.

Previous studies of methylphenidate in offenders with attention deficit hyperactivity disorder

This study followed on from an open-label study conducted by the chief investigator for this project that investigated the effects of OROS-MPH in 121 young male offenders in Her Majesty’s Prison and Young Offender Institution (HMP YOI) Isis in Southeast London, who met the criteria for DSM-5 ADHD. 29 The current study follows similar procedures to the open-label trial. This included screening all prisoners aged between 18 and 25 years admitted to the prison using a DSM-IV symptom checklist,30 with diagnosis confirmed using the Diagnostic Interview for ADHD in Adults 2.0 (DIVA 2.0),31 followed by medical review from consultant psychiatrists trained in the diagnosis of ADHD. Prevalence of ADHD in the prison was estimated to be 19%, of which 78% met criteria for the combined type presentation of ADHD. Large pre–post treatment reductions with SMDs of > 2, unadjusted for multiple outcome measures, were seen for investigator-rated ADHD symptoms using the Conners’ Adult ADHD Rating Scale-Observer (CAARS-O).

Previous community studies demonstrate the efficacy and cost-effectiveness of MPH in reducing ADHD symptoms in children, adolescents and adults with ADHD. 14 These conclusions are supported by a comprehensive review and meta-analysis of randomised controlled trials (RCTs) for MPH and other ADHD medications32 that, for MPH, found a large effect for children and adolescents [SMD –0.78, 95% confidence interval (CI) –0.93 to –0.62] and a moderate effect for adults (SMD –0.49, 95% CI –0.64 to –0.35). However, there are only limited trial data for the treatment of ADHD in young offenders presenting with a more complex mix of psychosocial, mental health and behavioural problems. One small RCT of MPH in a sample of 30 Swedish male prisoners with ADHD showed a very large effect (SMD 2.1) on ADHD symptom reduction. 33 Although this study supports the treatment of ADHD in offenders, it may not generalise to the young adult offenders in the UK with mainly short-term sentences investigated in this study because of the small sample size, older age group, selection of severe ADHD cases with long-term sentences and treatment on a special prison unit.

Pharmacoepidemiological studies provide another important source of information, particularly for longer-term benefits of treating ADHD and the impact on a broader range of important outcomes relevant to offenders with ADHD. 34 Unlike RCTs, these studies are representative of patients in real-world practice, include longer periods of follow-up and have large sample sizes. However, they are limited by confounding by indication, whereby patients may select treatments based on the nature or severity of their clinical condition. To account for this problem, these studies use within-individual designs, which compare periods of treatment with medication with periods of non-treatment. 34 A good example of this approach is suicidal behaviour, which was found to be more prevalent among adults treated for ADHD with stimulants than among those who had not been treated. However, there was a lower rate of suicidality when periods of treatment were compared with periods of non-treatment in the same individual. 35 These findings suggest that, although individuals with ADHD and suicidality may be more likely to be treated with MPH, during periods of treatment suicidality is likely to decrease. Using this approach, there is evidence for reductions in a range of outcomes relevant to offenders with ADHD, including serious transport accidents,36 depression,37 suicidality35 and SUDs. 38,39 In patients with ADHD and comorbid bipolar disorder, there was reduced relapse of mania when patients were also treated with mood stabilisers, but there was an increased risk of manic relapse when not taking mood stabilisers. 40 In patients with comorbid psychosis, there was no change in the risk of a psychotic relapse during periods of treatment and periods of non-treatment with MPH. 41

Of specific relevance to this application was a pharmacoepidemiological study using Swedish national registry data of 25,656 male patients with ADHD, which found a sixfold-higher rate of criminal convictions over a 4-year period among ADHD patients than among controls. 42 Regarding medication effects, they found a 32% reduction in the risk of criminal convictions using both ‘within’ and ‘between’ methods of analysis. Furthermore, these apparent protective effects on criminal convictions were seen for ADHD medications only (stimulants or atomoxetine), and not for commonly prescribed antidepressants, indicating the specificity of these findings to ADHD medications. Other important outcomes showing significant reductions during periods of treatment compared with periods of non-treatment included violent reoffending on release from prison43 and substance use. 38,39

Another area of interest is the potential for improving educational and behavioural outcomes for offenders with ADHD. 21 An initial descriptive study of ADHD in prisoners, conducted by co-applicant Susan Young, found a sixfold increase in critical incidents among prison inmates with high levels of ADHD symptoms, compared with inmates with low levels of ADHD symptoms. 44 The association of ADHD with behavioural problems in the prison remained significant, even after controlling for antisocial personality disorder (ASPD), suggesting that this is an important outcome for clinical trials in prison populations. Another important outcome is symptoms of emotional dysregulation, such as irritability, anger and aggression, which are commonly seen in offender populations. Although emotional dysregulation is commonly seen in young adults with ADHD, it is a transdiagnostic set of symptoms seen across a wide range of other common mental health disorders. 45–48 Meta-analyses of RCTs of ADHD medications found reductions in the symptoms of emotional dysregulation, including problems with temper control, mood lability and emotional over-reactivity. 16,17 Hence, treatment of offenders with ADHD might also lead to significant reductions in emotional dysregulation and, potentially, aggressive or violent behaviour. The symptoms of ADHD are also known to interfere with education and employment because of a combination of restlessness, reduced attention span, forgetfulness and problems with planning and organisation. 3 Treatment might therefore lead to greater positive engagement with prison education and rehabilitation programmes. In our open-label pilot study at HMP YOI Isis, we also found effects on all the secondary outcomes proposed for this study (all p < 0.001), including measures of emotional dysregulation, attitudes towards violence, the number of critical incidents and positive engagement with the education and rehabilitation programme. 29

Potential benefits and risks of the trial intervention

For many years, ADHD was thought to be a childhood-onset disorder that had limited impact on adult mental health. However, the symptoms and impairments that define ADHD often persist into adulthood, with similar responses to drug treatments, such as OROS-MPH, to those seen in children and adolescents. 3,32 Behavioural interventions can bring about further improvements in global clinical health, but only medication has been clearly shown to reduce the core symptoms of inattention and hyperactivity/impulsivity. For these reasons, clinical practice, expert consensus statements and national and international guidelines all indicate the need to diagnose and treat ADHD in adults using stimulants (MPH or lisdexamfetamine) as first-line treatments. 14

Currently, several pharmacological treatments for ADHD are recommended for use in adults in the UK. Among the most used in clinical practice is an extended-release formulation of OROS-MPH, which is thought to have clinical effects lasting up to 12 hours from a single dose. OROS-MPH is currently licensed for use in children and adolescents, and the subset of adults with ADHD who were diagnosed as children; however, it is not licensed in Europe for use de novo in adults who were not diagnosed with ADHD as children. This has been a source of concern for clinicians, who feel that there is no rationale for excluding treatments just because a diagnostic assessment was not performed in childhood, generating a considerable unmet need,4,5 particularly in the prison population for those aged > 18 years, among whom the prevalence of undiagnosed ADHD is high. 21,49 Furthermore, there is a risk that if ADHD is not included in adult mental health diagnostic assessments and treatment protocols, errors will be made, with patients put on antidepressants, antipsychotics or mood stabilisers for other conditions, while ADHD goes undiagnosed and untreated.

The potential value of treatment with OROS-MPH in young offenders with ADHD is that this is an established treatment with short- and long-term trial and post-marketing data to support the efficacy and safety of this medication in the treatment of ADHD. Potential benefits of treating young adult offenders with ADHD with OROS-MPH include improvements in clinical and behavioural outcomes. These include ADHD symptoms, emotional dysregulation, attitudes towards violence, critical incidents and engagement with educational and rehabilitation programmes. 29 Demonstrating the efficacy and safety of OROS-MPH on ADHD symptoms and associated impairments may provide the data required to develop effective health-care pathways, including the use of OROS-MPH for a substantial group of young offenders. Establishing efficacy of OROS-MPH in this population would provide the foundation needed to establish long-term effectiveness studies with the potential for demonstrating significant reductions in criminal behaviour and improved health economic outcomes.

One potential risk that is often raised is the risk of abuse or diversion, particularly in a population of offenders with ADHD and high rates of substance abuse. Stimulants can be abused by crushing short-acting formulations, such as immediate release MPH, which can then be insufflated (snorted) or dissolved in water for injection, leading to a rapid entry of drug into the brain and the experience of euphoria. The importance of the route of administration was demonstrated in a study that showed that, although there is a dose–response relationship between intravenous MPH and a feeling of euphoria, this is not the case with oral MPH. 50 This may not completely exclude the risk of abusing OROS-MPH in this way, but the evidence that this occurs is extremely limited; in addition, OROS-MPH is difficult to crush and it is difficult to extract MPH from OROS-MPH for injection. Risk of abuse was therefore reduced in this study by using this formulation of MPH. Furthermore, in the pilot study at HMP YOI Isis, we did not observe excessive drug-seeking behaviour for stimulant medication. 29 Indeed, the young adult offenders being treated for ADHD were noted to be generally cautious about increasing the dose of medication and were titrated to modest daily doses, compared with community samples: 18% used 18 mg, 37% used 36 mg, 14% used 54 mg, 26% used 72 mg and only 4% used 90 mg.

Related to dosing, the other potential risks are the usual range of common adverse effects observed when treating ADHD with OROS-MPH. In the pilot open trial, the low doses the participants were titrated to was thought to be related to a greater focus by prisoners on minor adverse effects such as appetite loss, headaches and sleep problems, compared with patients in the community. This potentially could be reflected in lower dosing, reducing the potential effects on reducing the core symptoms of ADHD. Other potential risks on heart and blood pressure are routinely monitored. Diversion for non-medical use is another potential problem, but has been mainly identified as a risk in higher education settings to enhance education performance. 51

Trial objectives

The overall aim of the trial was to investigate the effects of OROS-MPH on reducing ADHD symptoms in young male prisoners aged 16–25 years who meet the DSM-5 diagnostic criteria for ADHD. The following study questions are addressed in three main objectives:

• Primary objective – what is the efficacy of OROS-MPH in reducing inattention and hyperactivity/impulsivity in young male prisoners who meet the diagnostic criteria for DSM-5 ADHD?

• Secondary objective: what is the efficacy of OROS-MPH in reducing secondary outcomes that are key indicators of behavioural and functional impairments used in the management of young male prisoners in the UK? These include emotional dysregulation, antisocial behaviour in the prison, violent attitudes (a measure linked to aggression) and reports of behaviour from prison staff.

• Tertiary objective: are improvements in secondary behavioural outcomes mediated by improvements in ADHD symptoms or emotional dysregulation?

Trial design

Concerta in Adult Offenders with ADHD (CIAO)-II is a Phase IV, 8-week, parallel-arm, double-blinded, randomised, placebo-controlled trial of an extended-release formulation of MPH (OROS-MPH). ADHD symptoms, emotional dysregulation, attitudes towards violence, and behavioural outcomes were compared between the two trial arms.

Participants in the trial were young male prisoners aged 16–25 years who met the DSM-5 criteria for ADHD. Participants were randomised to 8 weeks of treatment with either OROS-MPH or placebo, titrated over the first 5 weeks to balance ADHD symptom improvement with adverse effects. A total of 200 participants were randomised and allocated in a 1 : 1 ratio to either the drug or placebo. By the end of the trial, 101 participants had been randomised to receive OROS-MPH and 99 had been randomised to the placebo arm. Randomisation was conducted by the King’s Clinical Trial Unit (KCTU), with blinding of investigators, including pharmacy staff, and participants. On completion of the 8-week trial, OROS-MPH or another medication for ADHD was offered to both the OROS-MPH and placebo groups as part of their ongoing clinical care.

Changes to protocol after trial commencement

A full list of all minor and substantial amendments to the protocol can be found (see Appendix 1, Table 31). Following the start of the trial, two minor amendments were made to the protocol, related to a clarification regarding the assessment of intelligence quotient (IQ), and to clarify that the Reactive–Proactive Aggression Questionnaire (RPQ) measure would be collected at baseline only. In addition, a substantial amendment was implemented on 18 December 2018. This amendment was approved by the Medicines and Healthcare products Regulatory Agency (MHRA), the Health Research Authority (HRA), Her Majesty’s Prison and Probation Service (HMPPS) (formerly known as the National Offender Management Service) and the Scottish Prison Service (SPS). Changes included an amendment to the timing of the database lock and clarifications to the wording describing the inclusion and exclusion criteria. The revised inclusion and exclusion criteria definitions had been applied from the start of the trial, but were not sufficiently well documented in the protocol. In addition, one of the secondary outcomes, the number of Incentive and Earned Privileges (IEPs) was dropped because these data are not recorded in Scottish prisons. No other outcomes were changed. A report on the final approved protocol is published in Trials. 52 This report refers to the final approved protocol.

Eligibility criteria for participants

Eligibility for the study was checked and recorded once a consent form (consent II: consent for the clinical trial) had been signed and baseline assessments had been completed, prior to randomisation. Using an algorithm that applied the DSM-5 criteria to the DIVA 2.0 interview data, cases were checked to ensure that they met the diagnostic criteria for DSM-5 ADHD. A clinical review by a psychiatrist trained in the diagnostic assessment of ADHD was then completed to check all of the inclusion and exclusion criteria. Mental capacity required for consent was evaluated by the clinician, including ability to understand all information, rating scale and interview questions, and to provide detailed descriptions of symptoms and behaviour.

The initial exclusion criteria of an IQ score of < 60 was based on the Wechsler Abbreviated Scale of Intelligence^® Second Edition (WASI-II) estimates of IQ. This was later changed to include those with a WASI-II IQ estimate of < 60, for whom the score’s 95% CI spanned 60, and clinical assessment by the psychiatrist concluded that IQ was > 60 and that the participant had the mental capacity to provide informed consent. As there are no validated IQ tests for the visually impaired, including the WASI-II, this criterion was based on clinical judgement for participants with this impairment. This was also the procedure for anyone unable to complete the WASI-II assessment because of the severity of their ADHD symptoms or other mental health problems. This approach was applied to one participant with a low initial WASI-II test score.

Trial setting

Participants were recruited from two prisons. HMP YOI Isis in London, England, opened in 2010 for sentenced young adults aged 18–25 years, but was later extended to include older prisoners. This is a category C prison, defined as suitable for prisoners who cannot be trusted in open conditions but who are unlikely to try to escape. There are two house blocks with four wings each, with mixed single and double cells, plus a segregation unit located between the house blocks. Operational capacity was 621 in January 2016. The prison focuses on rehabilitation and resettlement, and all prisoners are engaged with full-time education, occupation and rehabilitation programmes. There is a broad-based educational and vocational curriculum for young sentenced prisoners and available activities are, among others, mathematics, English, business studies, painting and decorating, waste management, mechanics and barbering.

Her Majesty’s Young Offender Institution (HM YOI) Polmont in Falkirk, Scotland, is a holding facility for young offenders in Scotland aged 16–21 years, with sentences ranging from 6 months to life. All participants were sentenced prisoners when screened for entry to the trial. It has the capacity to hold 760 prisoners and, since 2016, female prisoners have been housed in a separate wing. Individuals may stay in Polmont until age 23, depending on circumstances. In March 2019, Polmont had 370 male young offenders and 90 female young offenders. There are three house blocks and a segregation unit. Various activities are offered at Polmont, such as education and vocational training, and rehabilitation programmes such as Pathways, Moving Forward and Making Changes.

Recruitment procedure

Following consent to be screened for ADHD (consent I), screening questionnaire data were collected by the research teams using the Barkley DSM-IV ADHD symptom rating scale. 30 Prisoners who screened positive were invited to complete the DIVA 2.0. 31 This was followed by a clinical assessment by a psychiatrist trained in the diagnostic assessment of ADHD, including collateral information obtained from an informant whenever feasible. Participant’s expected release date could change at any time and additional convictions and charges could be added. Hence, it was not always possible to predict if a participant would be transferred, released or deported. For this reason, it is possible that some participants initially excluded because of a high risk of release could have taken part in the trial.

Following clinical review, prisoners who met the diagnostic criteria for ADHD and who met the other eligibility criteria for the trial were invited to take part in the clinical trial. Eligibility for the trial was further checked and recorded once the consent form for the clinical trial (consent II) had been signed and baseline assessments had been completed, prior to randomisation. Using an algorithm that applies the DSM-5 criteria to the DIVA 2.0 data, cases were checked to ensure that they met diagnostic criteria for DSM-5 ADHD. A clinical assessment and review by a psychiatrist trained in the diagnostic assessment of ADHD checked all inclusion and exclusion criteria prior to randomisation.

Intervention

Unblinding

An emergency unblinding service was provided, but was not required at any stage of the trial. It was set up so that any health-care staff would be able to call an emergency number that was added to the labels for both the bottle and the box with the trial kit. In addition, code-breaking envelopes were printed and held at the company providing the unblinding service in case of an emergency, but were not used. Unblinding did not take place for any participants during the trial.

Adherence to trial medication

Based on experience from the pilot study, we envisaged that adherence to medication would present a challenge for around 20% of participants. This could be for several reasons. Some offenders may not feel motivated to take the trial medication if they experience adverse effects or do not feel that they are improving. They may also take medication intermittently because of strict prison regimes that allow only a brief time for leaving their cells to obtain medication or difficulty in getting to the location where medicines are dispensed. These cases were not expected to contribute to missing data, but could affect the overall outcome of the intention-to-treat (ITT) analyses.

In the pilot study at HMP YOI Isis, we accrued considerable experience in managing the expectations of offenders and providing the support needed to help participants adhere to the trial protocol. The following steps were therefore adopted to maximise adherence to medication:

• In the pilot study, minor adverse effects were the most common reason for non-adherence to medication, affecting 13% of participants. This was linked to the observation that this population may be more sensitive to minor adverse effects, particularly changes in appetite, and sleep problems. To minimise this effect, we took care to identify the early signs of minor adverse effects such as appetite loss and to adjust the medication dose accordingly by systematic evaluation of ADHD symptoms and minor adverse effects during the titration phase of the trial.

• Seven per cent of the pilot sample did not wish to take medication in the mornings and the protocol for the current trial was adjusted to allow for medication to be taken later in the day, until noon. This allowed for participants who got up later in the day, who worked mainly in the afternoons or who had a strong preference for mid-day dosing. This flexibility in dosing time reflects dosing decisions in non-trial patients and can provide a better match to participants’ daily routines.

• During the pilot study, prison staff did not always let patients out of their cells to receive medication or remind participants to get up on time. To resolve this problem, we initiated the use of research staff, whenever possible, to assist in the delivery of medication by checking that prisoners were always out of their cells in time to receive trial medication.

• In the pilot study, treatment was disrupted because of religious customs for several participants. We took care to check that participants were not randomised during periods when religious customs might interfere with adherence to the trial protocol.

• In the pilot study, daily adherence to the trial medication reduced when participants were not reviewed weekly. One of the findings in the pilot study was the importance that prisoners gave to the weekly follow-up meetings during the titration process, during which they could discuss their symptoms and response to the treatment process in addition to completing trial assessments. We also provided brief support on an ad hoc basis or in the form of advice, if approached by prisoners when visiting the prison wings.

Concomitant treatments

All concomitant medications were recorded. Concomitant treatments were allowed with medications that are not contraindicated with MPH. Use of the following medications in the 4 weeks prior to the start of treatment with OROS-MPH was not permitted based on potential adverse drug interactions: clonidine, coumarins, monoamine oxidase inhibitors, moclobemide and rasagiline. There were no exclusions for this reason.

Measures

A schedule of trial assessments is provided in Table 1.

Baseline-only measures were collected for all participants prior to randomisation, and included descriptors of the trial population and putative moderators of the treatment response. The primary outcome was the investigator-rated CAARS-O score at 8 weeks after the initial trial prescription. There were 13 secondary outcome measures (see Table 2) also assessed at 8 weeks. Baseline (pre-randomisation) values of the primary and secondary outcome measures were collected so that we could assess change. In addition, week-5 values were collected for variables that featured as putative mediators (see Table 2).

Once a participant had signed consent II for the RCT, baseline measures were obtained through face-to-face administration of the questionnaires. Help in reading or understanding questions was provided by research staff in most cases. Because of the large number of baseline measures, these were frequently collected across two sessions. All baseline measures were obtained prior to randomisation.

Data such as days incarcerated, release date, prison regime, adjudication, attendance at offender behaviour and educational programmes, demographic details and medical history were obtained by accessing prison and medical health records. The assessments were completed at baseline and at week 8 for the subset of outcome measures taken from prison records. Reports on the behaviour of participants were obtained from prison and education staff, reflecting behaviour at baseline and at week 8. Not all of the participants attended educational or rehabilitation programmes; hence, it was not possible to obtain measures from education staff for all participants. In addition, it was not always possible to obtain ratings from education staff because they did not always know the pupils or their names, and because of frequent staff changes and difficulties getting hold of teachers. The researchers tried to overcome these issues and found that the best option was to obtain the measure over the telephone.

Participant timelines

A flow diagram of participant timelines is illustrated in Figure 1.

FIGURE 1.

Flow diagram of participant timelines. a, Prior to consent to be screened for ADHD, potential participants were provided with information about the trial. Initial consent (screening and diagnostic step) allowed for the use of screening questionnaires (Barkley ADHD self-rating scale for DSM-IV ADHD symptom); b, if ADHD was suspected, a diagnostic interview for ADHD was carried out, which included the DIVA interview for adult ADHD. Diagnosis of ADHD and suitability for the trial were then confirmed by a medical assessment prior to consent for the trial.

Sample size

The sample size of 200 young male offenders was determined as follows. The primary outcome was ADHD symptoms, measured using the CAARS-O, a total 18-item ADHD symptom score. The results of a single-arm open-label pilot study of young male prisoners with ADHD who were given MPH showed a mean decrease of 25.0 points with a standard deviation (SD) of 9.1. 29 This suggested a large standardised effect size of SMD 2.75. It could reasonably be assumed that at least 20% of this effect might be attributed to the effects of MPH. On this basis, this trial is powered to detect a standardised effect size of d = 0.55. Assuming a SD of 9.1, this would translate into a treatment difference of 5.0 points. This effect size is consistent with the results of a 2018 meta-regression analysis,32 which estimated the effect of treatment to be a SMD of 0.49 (95% CI 0.08 to 0.64). The sample size calculation used G*Power version 3 (Heinrich Heine University Düsseldorf, Germany)80 and was based on the use of a t-test to compare the means of the treatment groups. To have 90% power at the 5% significance level to detect a standardised effect of SMD 0.55, this trial would need to collect outcome data on 142 participants. Inflating for the expectation that loss to follow-up may be as high as 25%, a minimum of 190 participants are required, with the target for the trial set at 200. A 25% loss to follow-up was expected to be easily achieved, as, in the pilot study, 10% of participants left the prison as a result of unexpected transfers from the prison, whereas problems with adherence to trial medication were rarely followed by problems obtaining follow-up assessment data.

Randomisation and blinding

Withdrawal of subjects

Participants had the right to withdraw from the trial at any time for any reason. Health-care staff had the right to withdraw participants from the trial if they thought that the trial was having an adverse effect on the participants; this was not applied for any participant in the trial.

However, when participants discontinued trial medication, we invited them to remain in the trial to complete trial assessments, thereby minimising loss of data. When participants decided to withdraw from the trial, all efforts were made to report the reason for withdrawal as thoroughly as possible. Withdrawal from the trial was defined as withdrawal from taking the trial medication and from providing further follow-up assessment data. There was a significant group who continued to provide follow-up assessments, but who had withdrawn from taking trial medication.

Owing to potential concerns about the interaction of trial medication with unknown psychoactive substances, if a participant disclosed to any member of the research team that they had used ‘spice’ (synthetic cannabis or other unknown psychoactive substance) or there were suspicions of use reported by health-care or prison staff, while participating in the trial, a clinical evaluation was made. If this was current use (defined as within the previous 2 days), the trial medication was stopped. If this occurred earlier in the trial and was considered an isolated incident, the trial medication could continue. If the trial medication was stopped, the participant remained in the trial and was asked to complete trial assessments. A clinical assessment was made on a case-by-case basis to consider the safety of restarting trial medication 48 hours after stopping the trial medication.

Statistical analyses

A detailed SAP was developed by the trial statisticians in collaboration with the chief investigator, was reviewed by the DMC, and was reviewed and approved by the Trial Steering Committee (TSC) before the trial database was locked. Here we provide a summary of the statistical analysis approaches employed according to this plan. However, note that the decision of some analyses could be finalised only after having sight of the data, namely the necessity to employ multiple imputation (MI) to handle the missing data generating process and the distributional assumptions for some of the non-questionnaire secondary outcomes.

An ITT approach was used for all primary and secondary week-8 outcomes, that is participants were analysed in the groups to which they were randomised, irrespective of adherence to trial medication. The primary outcome measure, the CAARS-O, and the secondary outcome measures, MEWS, WRAADDS, ARI-S, CORE-OM, BSI, MVQ and CGI scale, were continuous variables. Their modelling relied on normal assumptions for error terms and the treatment effects were quantified by trial arm differences (and standardised differences). The MOAS-E, MOAS-P, BRC-P and BRC-E had also been expected to follow normal distributions and critical incidents had been expected to follow a Poisson distribution. However, on review, the residuals or all of the MOAS-P, MOAS-E, BRC-P, BRC-E and critical incidents were noticeably positive skewed, and possibly overdispersed or zero inflated, and so could not be modelled by a normal distribution (see Table 2).

The number of education sessions scheduled at 8 weeks was defined as being scheduled to attend any of offender training, vocational training or education sessions. We had intended to use logistic regression to analyse education as a binary variable of whether or not any education sessions were scheduled, but, at baseline, almost all (187/200) of the participants had some form of education session scheduled. At week 8, this increased to 191 out of 200 participants. Owing to this lack of variability in the binary education outcome, we instead analysed the underlying count variable ‘number of any form of education scheduled between baseline and week 8’ using a negative binomial distribution to allow for positive skewness and overdispersion of this variable. The proportion of education sessions attended out of those scheduled was also described by arm.

Education outcomes were considered for only the subpopulation of prisoners enrolled in education at baseline. A total of 187 trial participants were enrolled in some form of education at baseline. However, within this subpopulation, only 83 MOAS-E baseline forms were completed. Similarly, only 67 BRC-E forms were completed. We considered an actual sample size of less than half of the intended size at baseline to be too small to attempt meaningful formal inference. Thus, the education outcomes MOAS-E and BRC-E were summarised descriptively only.

The BRC-P was approximated by a negative binomial distribution, which is appropriate as, although not directly defined as a count of incidents, the questionnaire is a weighted proxy count of incidents of inappropriate behaviour. Thus, BRC-P was modelled in the same way as the number of education session scheduled.

The MOAS-P exhibited large zero inflation and too few remaining data points to allow modelling of the distribution (143/200 participants who were included in the trial were rated ‘0’ on the MOAS-P at 8 weeks). We therefore dichotomised this outcome to give a binary variable (1 = participant had any aggressive event, 0 = no aggression) and analysed it using logistic regression.

For critical incidents, which is a count of incidents, the data were positively skewed and zero inflated. However, the residuals were no longer zero inflated after baseline count of incidents was included in the analysis model. A negative binomial model, rather than a Poisson distribution, was employed to allow for overdispersion. In addition, the time in prison was included in the model as an offset to model the fact that the number of critical incidents reported at week 8 are proportional to the time spent in prison between randomisation and withdrawal from or the end of the 8-week trial.

Trial timelines

The project was planned to be delivered in 36 months, with the first 2 months for recruitment and training of research staff, and to ensure that all approvals were in place. A full-time trial manager was appointed before the formal start of the trial, funded from other resources, to ensure that all procedures and permissions were in place; this took an additional 10 months. The recruitment period was planned for 32 months, with 2 months for analysis and preparation of the final report. The recruitment target was met within this timeline despite HMP YOI Isis being told it could no longer randomise participants in February 2019 because the pharmacy had trial kits left for only one treatment arm. Therefore, the final participants were randomised at HM YOI Polmont to ensure that recruitment from the sites was more even and to avoid the need to transfer trial medication kits from one site to the other.

A 5-month no-cost extension was requested in February 2019 for two main reasons:

1. Extensive database checks were needed before the database lock and there was not sufficient time to complete these. The task was made more difficult because it was not possible to conduct all of the database checks outside of the prisons, and there were additional restrictions on access to medical and prison records dependent on whether a participant was still in prison, released, transferred to another prison or deported. These checks needed to be undertaken while research staff were still employed and on site.

2. The SAP for the project was very detailed and required 2–3 months of analysis. In addition, more time was needed to write the report and obtain feedback from co-applicants during the writing process.

Following database lock and review of the preliminary SAP, there was a planned meeting in November 2019 to discuss the trial findings with the DMC, TSC and Trial Management Group (TMG). This meeting led to a recommendation to conduct additional post hoc analyses that might provide an explanation for the main findings. As these further analyses were proposed after database lock and review of the main trial results, they should be regarded as exploratory in nature. The aim was to identify potential factors that might explain the trial findings and that could be considered in future research. These further analyses are reported in Chapter 5. These further analyses were acknowledged, but not formally reviewed, by the DMC and TSC chairpersons. To allow for this work, an additional no-cost extension was approved until 30 June 2020.

Trial set-up

The CIAO-II project started on 1 August 2016; within the first 3 months, it had received a favourable opinion from the East of England–Essex Research Ethics Committee (REC) (reference number 16/EE/0117, Integrated Research Application System project identifier: 179456), as well as HRA approval. The ethics application was submitted prior to the introduction of the HRA and approval was given for the trial to be processed through pre-HRA approval systems. Research and development (R&D) approvals were obtained from Oxleas NHS Foundation Trust and NHS Forth Valley (reference number FV908). In addition, permission was required from HMPPS (reference number 2016-129) and the SPS.

The KCTU provided the randomisation service, IMP management, and the clinical trial database system with full audit trail (InferMed MACRO, London, UK). These were set up in the 10 months before the trial started.

All research and pharmacy staff undertook good clinical practice (GCP) training. This was arranged by King’s Health Partners Clinical Trials Office (KHP CTO) or by NHS Forth Valley. Some pharmacy staff attended a GCP pharmacy training tailored for pharmacy staff and facilitated by KHP CTO. In addition, a GCP light training was provided by KHP CTO on site for health-care staff. Those health-care staff who were unable to attend the training owing to shift patterns were able to review GCP slides and complete a self-certificate. The GCP training was reviewed continuously throughout the trial to ensure that all new staff were trained and that they were added to the delegation log. All staff were retrained by KHP CTO or by NHS Forth Valley after 2 years. Curricula vitae for all health-care staff were collected and updated every 2 years, as per guidelines.

In September 2016, training was provided to all research staff on the standard operating procedure for the project and for the following measures: DIVA, MINI, ZAN-BPD, CAARS-O, CGI scale and WRAADDS. Subsequent new staff received in-house training or attended training events.

The trial was monitored by the KHP CTO on behalf of the sponsor. KHP CTO deemed the sites ready for recruitment with an e-mail confirming ‘green light’, which was obtained for HMP YOI Isis on 11 October 2016 and for HM YOI Polmont on 3 November 2016. An initial site initiation visit for Polmont took place on 13 October 2016, but there was a delay in obtaining ‘green light’ status because of major information technology (IT) issues in King’s College London, which caused a delay in accessing certain records required for the project. Seven participants had to be randomised ‘manually’ with the assistance of the KCTU as a result of the IT issues.

At HM YOI Polmont, there was no routine service for identifying young prisoners with ADHD. For this reason, a two-stage consent process was developed to avoid the situation of asking participants to sign consent for a trial for which they would not be eligible. The first consent (consent I) was for screening using the Barkley ADHD self-assessment form, followed by a DIVA 2.0 assessment for those who screened positive with the self-assessment form. Consent II was the main trial consent, required prior to collection of further baseline data and randomisation. At HMP YOI Isis, there was already an established ADHD service set up by the chief investigator, Philip Asherson. This site also ran the pilot study and screening for ADHD had been established as part of routine clinical care. This meant that, for this site, there was a pre cohort that had already been screened prior to trial commencement. The pre cohort participants who had already completed the Barkley ADHD self-assessment and had screened positive were invited to sign consent I (for the screening and diagnostic stage of the trial) if they attended a DIVA 2.0 assessment for ADHD.

In June 2015, the Scottish Government published a youth justice strategy82 with the aim of reducing the number of young people sent to prison by establishing an early and effective intervention that provided more community options. This meant that the prison population at HM YOI Polmont was less than half of its capacity at the start of the trial, thereby affecting the expected recruitment pool for the trial. This resulted in uneven recruitment between sites.

In March 2017, we were informed that the potential third site, Her Majesty’s Prison (HMP) Rochester, would close in November 2017 for refurbishment. It was therefore decided that this site would not be launched. Owing to the recruitment targets being met, it was decided not to set up an alternative third site. The planned refurbishment at HMP Rochester was later postponed.

Accountability for trial medication

All aspects of treatment and accountability for managing the medication storage and delivery were managed locally by the prison pharmacies and health-care teams, as per standard practice for this medication in the prisons. IMP accountability was recorded and verified. All aspects of treatment compliance and recording of treatment administration/refusal were managed by the prison mental health teams and locally by health-care staff, as per standard practice for these sites. Participants were observed when they were given medication and were checked to ensure that the capsules had been swallowed. This information was then recorded (signed off) by the nursing staff who had delivered the medication on prison pharmacy record sheets or digital records. Despite precautions taken by nurses with regards to seeing prisoners swallow medication, there are documented cases when prescribed medication was diverted. Although there were no such cases documented for the trial medication in this trial, it cannot be ruled out.

Safety checks

Participants were monitored daily by the prison mental health and health-care teams. Safety checks were conducted in line with NICE guidelines. 13

With regard to the research procedures of the trial, there was little risk to participant safety. Participants were aware that they could withdraw from the trial if they wished to do so. Participants who become upset or distressed were offered support by the research team and/or the prison mental health team.

The health-care team followed national guidelines on safety,13 which are predominantly related to the monitoring of cardiovascular function. More specifically, the clinical care followed the following procedures:

• checks on heart rate and blood pressure before commencing treatments, and review of health-care records

• potential cardiovascular abnormalities evaluated for risk

• heart rate and blood pressure checked once a week for the first 5 weeks and at the end of the 8-week trial.

Other safety checks included the monitoring of AEs during assessments. In addition, participants were monitored daily by prison staff and any potential AEs were reported to the prison health-care team.

Procedures for recording and reporting adverse events

Safety remained the responsibility of the prison mental health care team. AEs of any medical or non-medical intervention were identified or recorded by the research team at each site, and were verified by the clinician who was part of the research team, an assigned medical colleague at specialist registrar grade or above who was a member of the prison health-care team, or the clinical lead for the project. The decision to stop treatment following an AE remained the responsibility of the clinical team. Minor AEs that did not fall under official reporting procedures were reported to the clinical team, for example sleep disturbance, minor levels of anxiety or dysthymia, small increases in heart rate and blood pressure, reduced appetite and other minor physical symptoms that did not endanger patients or cause more than minor distress. All other AEs from medication were recorded and reported in line with The Medicines for Human Use (Clinical Trials) Regulations 200483 and Amended Regulations 2006. 84

The research team, acting on behalf of King’s College London as sponsors, delegated the delivery of the sponsor’s responsibility for pharmacovigilance [as defined in Regulation 5 of the Medicines for Human Use (Clinical Trials) Regulations 200483] to the KHP CTO. Reporting of serious adverse events (SAEs) continued until the last participant’s final dose had been completed. For each participant, AEs were recorded from randomisation and reporting of AEs was from the time of first dose of the trial medication to the end of their involvement in the trial (last dose at the end of 8 weeks). All SAEs, serious adverse reactions (SARs), suspected unexpected serious adverse reactions (SUSARs) and important medical events (IMEs) (except those specified in the protocol as not requiring reporting) were reported immediately by the chief investigator or designated site investigators to the KHP CTO, in accordance with the current pharmacovigilance policy. Janssen-Cilag Ltd were notified at the same time.

The KHP CTO reported SUSARs and other SARs to the MHRA, who are competent authorities of other European Economic Area states in which the trial is taking place. The chief investigator reported to the relevant ethics committees. In this trial, there were no SUSARs or SARs, and only one SAE, identified as an IME.

Reporting timelines were as follows:

• SUSARs that are fatal or life-threatening must be reported no later than 7 days after the sponsor is first aware of the reaction. Any additional relevant information must be reported within a further 8 days.

• SUSARs that are not fatal or life-threatening must be reported within 15 days of the sponsor first becoming aware of the reaction.

The chief investigator and KHP CTO (on behalf of the co-sponsors) submitted a Development Safety Update Report relating to this trial IMP to the MHRA and REC annually.

Trial Steering Committee

A TSC was convened to provide overall supervision of the trial and ensure that the trial was conducted to the rigorous standards set out in the Medical Research Council guidelines for GCP. 85 The TSC monitored progress, adherence and safety. The TSC chairperson was Professor Jenny Shaw (Consultant Forensic Psychiatrist, University of Manchester); the other TSC members were Dr Ylva Ginsberg (Consultant Psychiatrist specialising in ADHD in prisoners, Stockholm, Sweden), Dr Peter Mason (Forensic Psychiatrist and specialist in ADHD, Cheshire and Wirral), Mr Anthony Davis (R&D Manager, Oxleas NHS Foundation Trust, London), Dr Ulrich Müller-Sedgwick (Barnet, Enfield and Haringey Mental Health NHS Trust, London) and Mrs Beverley Nolker (Prison Officers’ Association Learning, London, and user representative). Other user representatives were included, but had to be replaced during the trial. Non-independent members were lead applicants in London and Edinburgh (Philip Asherson and Lindsay Thomson). Other members of the TMG attended TSC meetings as observers and to report to the TSC. During the trial, four TSC meetings were conducted, all face to face, and all members of the TMG were able to attend these meetings.

Data Monitoring Committee

A DMC was convened to monitor the safety of participants, the ethical conduct of the trial and the quality of the data. The committee consisted of three members experienced in clinical trials, including an independent statistician. The DMC chairperson was Professor Seena Fazel, University of Oxford (an experienced Forensic Psychiatrist). Other members were Professor Chris Hollis, University of Nottingham (an expert on the Clinical Management of ADHD); and Adrian Cook (a trial statistician). DMC meetings were timed to occur prior to TSC meetings so that they could report to the TSC. There were four DMC meetings during the trial. The first two were face-to-face meetings, which the majority of members attended, and the last two were by telephone conference.

Trial management

The project was led by Professor Philip Asherson in London, supported by a trial manager. The trial manager liaised with the trial monitors and ethics board when required and supported the completion and ongoing management of the project. The research psychiatrist at HMP YOI Isis co-ordinated all daily activities on site. Principal investigator Lindsay Thomson led the project in Edinburgh and was supported by the local research assistant, who conducted similar day-to-day co-ordinating tasks in HM YOI Polmont. Weekly telephone conference calls were held throughout the trial with Philip Asherson, Lindsay Thomson, the trial manager and the on-site clinical research teams (psychiatrists and research assistants) to allow for discussions regarding recruitment, diagnosis and other procedures being followed by the clinical teams.

A TMG was established to review AEs and reporting, to review the progress of the trial, to review and report on file notes and potential protocol violations, and to discuss changes to the protocol. This group, led by the chief investigator, Philip Asherson, consisted of Lindsay Thomson, the statisticians, the trial manager and the clinical teams. Other co-applicants were invited to these meetings and occasionally attended. During the initial stages of the trial, the TMG met at the same time as the TSC. After the first two TMG meetings, the frequency of these meetings was increased to monthly (from December 2017, when 94 participants had been randomised to the trial) to facilitate a greater level of ongoing monitoring of the trial. Prior to these regular monthly TMG meetings, informal meetings between the trial manager (LJ) and, separately, with the trial statistician (RH) and with the clinical research associate (CRA) monitoring the trial on behalf of the sponsor were held, file notes were reviewed, and protocol deviations were discussed and documented as required.

Ethics issues specific to this project

The trial was conducted in compliance with the principles of the Declaration of Helsinki (1996),86 the principles of GCP87 and in accordance with all applicable regulatory requirements, including but not limited to the Research Governance Framework and the Medicines for Human Use (Clinical Trials) Regulations 2004,83 as amended in 200684 and any subsequent amendments. The protocol and related documents were submitted for review to the East of England–Essex REC and to the MHRA for clinical trial authorisation. Annual progress and safety reports were completed, and a final report was submitted to the KHP CTO (on behalf of the sponsor), the REC and the MHRA within the timelines defined in the regulations.

Osmotic release oral system-MPH is licensed for first time use in young people with ADHD and severe impairment under aged 18 years only, although NICE also recommends OROS-MPH as a first-line treatment for ADHD in adults. The 8-week trial included a placebo group, so we were denying this group a recommended treatment for ADHD during this period. However, currently, prisoners with ADHD are rarely treated because of uncertainty regarding the validity of the ADHD diagnosis, efficacy of treatment, and concerns about potential drug abuse and diversion in prison populations. To address the issue of unequal access to treatment, we offered treatment to all participants once the trial was completed. Care was taken to ensure that no coercion was involved in recruiting prisoners to the trial. It was made clear that taking part in the trial would not have an effect in either a negative or positive way on their time in the prison or the prison regime.

Some participants might benefit from treatment that was offered as part of the clinical trial.

Participants were informed that their anonymised research data from this trial will be stored securely and may be shared with other scientists or research groups if this helps understanding of the trial findings. The data may also be used in combination with data from other similar studies. All personal information was stored in a secure place (a locked cabinet in a locked office in the prisons) and not allowed to leave the prison. Outside of the immediate health-care team involved in this research, no one will be able to match personal information (name and prison number) with the information gathered for research. Personal details were not linked to clinical or prison records in the research database. After completion of the trial, personal identifiable data relating to the trial will remain in the prison and be destroyed in accordance with GCP guidelines, and after authorisation from KHP CTO, on behalf of the sponsor. To achieve anonymity, each participant had an allocated identifiable number accessible to the local research team only.

Quality assurance

Monitoring of this trial to ensure compliance with GCP and scientific integrity was managed and oversight was retained by the KHP CTO Quality Team.

Data handling

The chief investigator, Philip Asherson, acts as custodian for the trial data. Data were stored on a database set up by KCTU. Patient data were pseudo-anonymised. All personal identification information and research identifier codes were stored on a password-protected computer by the clinical research teams. All data were stored, handled, processed and archived in line with the Data Protection Act 199888 and the Medicines for Human Use (Clinical Trials) Amended Regulations (2006). 84

Data management

Data were stored on a MACRO system trials database (Elsevier UK, London, UK), set up and managed by the KCTU. This allowed for full audit information and for checks on data entry that were used to ensure the integrity of the data collection and monitoring of the trial progress. At the end of the trial, all research records were transferred by secure courier service to the relevant NHS trust R&D department for archiving. The Trial Master File will be archived on behalf of the sponsor using Iron Mountain Inc. (Boston, MA, USA).

Researchers had unique log-in access to the trial database for their site. The system was designed to allow users to register participants and then collect and track data and manage their progress throughout the trial. The data entry system had restricted answer options, including values for ‘not applicable’, ‘not done’ and ‘unknown’. Any data field was tested for valid dates. The data entry system had pre-set minimum or maximum values on all questions requiring numerical values; anything outside of that range was flagged to the user to ensure that the value entered was correct. Data were collected on hard copies from various sources, such as participants’ records and prison and medical records. At the end of the trial, for each participant, the researcher conducted a SDV checklist to ensure that all the data entered had been entered correctly by double-checking the paper copies and any other source data, such as electronic medical and prison records. This was then signed and dated by the researcher and sent to the trial manager.

The trial manager and CRA had read-only access, but were able to raise SDV or discrepancies (data clarification request). The trial statistician conducted high-level checks after data extractions and any data checks needed were sent to the trial manager. The CRA monitored the trial on behalf of KHP CTO and 10% of participants had all of their research data checked against source data. In addition, the primary end point (CAARS-O score) was verified at 100% for all participants.

Patient and public involvement

Valuable feedback was given by participants in the pilot study and by prison staff. We also had positive feedback from Her Majesty’s Inspectorate of Prisons regarding the pilot trial. 89 Throughout the set-up and duration of the trial, we received advice from service users with ADHD or professionals working with prisoners. Special attention was paid to ensure that the information sheet and consent forms were written in appropriate language, as it was expected that there would be low levels of reading ability in this setting.

We lost contact with one service user member of the TSC during the trial, who was replaced by a service user with experience of both ADHD and prisons. Further insights were also given by Beverley Nolker, a service user who works for Prison Officers’ Association Learning. We had hoped to more directly include additional service users with both experience of ADHD and prisons; however, it was difficult to identify suitable individuals with the relevant experiences and to maintain their involvement and engagement.

We worked closely with Dr Kai Syng Tan, a King’s College London artist in residence with lived experience of ADHD. Kai visited HMP YOI Isis during the trial to understand the prison environment and what might motivate participants to engage in the trial. Following this, Kai generated images that emphasised choice, control, autonomy, self-care, self-respect, and, at the same time, was mindful of the stigma attached to ADHD. She designed an image that was used during the trial to remind participants of medication times for all their medications. The image was produced in the form of a flyer that prisoners could stick on the walls of their cells or use as a coaster.

At the end of the project dissemination took place at the Great Hall, Strand Campus, King’s College London. The event, attended by around 100 delegates, focused on the prevalence of ADHD in prisons, ADHD and comorbidities, what research has been done to further the management of ADHD in prisons and what ADHD services in prisons should look like. The event was free and open to the public, and generated a lot of interest from professionals in ADHD services and forensic settings and from members of the public.

Two consensus meetings, leading to publications, were organised and led by co-applicant Susan Young before and during the trial. 21,49 These included multidisciplinary groups of health-care and criminal justice system professionals and service users across sectors relevant to the management of children, adolescent and adult offenders. The initial meeting in November 2009 provided an overview of recommendations for ADHD services in the criminal justice system, and was the foundation for setting up the ADHD service at HMP YOI Isis, and the subsequent pilot study for this trial. The second meeting, in November 2016, provided an updated consensus opinion and recommendations for the identification and treatment of offenders with ADHD in the prison population.

Participant flow

The Consolidated Standards of Reporting Trials (CONSORT) diagram illustrates the recruitment process (Figure 2). A total of 200 participants were randomised to treatment with OROS-MPH or placebo.

FIGURE 2.

The CONSORT diagram. a, Two participants in the placebo arm were transferred to an accessible prison and the outcomes were collected from those persons. Outcomes not collected on other participants labeled as transferred, deported or released. Reproduced with permission from Asherson et al. 61 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

Reproduced with permission from Asherson et al. 61 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

During trial recruitment, all male prisoners aged 16–25 years in HMP YOI Isis (London, Oxleas NHS Foundation Trust) and HM YOI Polmont (Scotland, NHS Forth Valley) were invited to be screened for ADHD. It was estimated that 1368 prisoners aged 16–25 years were asked to consent to screening for ADHD. Of these, around 185 (13.5%) declined to take part in the screening step and did not provide consent that would have allowed us to record this information. It is unknown whether or not those declining consent for screening differ from those participants who consented to be screened.

The CONSORT diagram shows that, of the 1183 prisoners who consented to be screened, 585 screened negative on the Barkley ADHD self-rating scale and a further 52 were excluded who were identified at this stage as not meeting eligibility criteria for the trial. The exclusions included 38 prisoners who were at high risk of early transfer or release during the trial period, one who posed a serious risk of violence towards researchers, one who was not an English speaker, five who were currently prescribed ADHD medication, four who had current major depression and one who had contraindications to the use of stimulants. Another individual was excluded due to low BMI (a clinical decision) and one was mistakenly excluded who was thought to be outside of the age range for the trial, despite being aged 25 years at the time of consent. This left 546 participants who were considered for a diagnostic assessment. Of these, 28 participants were excluded because they were thought to be at high risk of transfer or early release and 518 were invited for an ADHD assessment using the DIVA 2.0. Of these, 86 did not attend the assessment and 432 completed the DIVA 2.0 assessment. Of the 432 prisoners who completed DIVA 2.0 assessments, 279 were found to meet diagnostic criteria for DSM-5 ADHD, of which six did not meet one of the other eligibility criteria and were excluded. This left 273 prisoners who were invited to sign consent for the trial, of which 54 declined their consent. This left 219 prisoners who signed consent for the trial and were formally checked for eligibility. Of the 219 prisoners, three were no longer willing to participate, two were assessed after the trial had completed recruitment and 14 failed to meet eligibility criteria, leaving 200 participants who were randomised.

Post-randomisation losses to trial

At the primary outcome time point of 8 weeks, follow-up rates were good, with 90 and 94 participants completing final outcome measures in the OROS-MPH and placebo arms, respectively. Of these, 26 (OROS-MPH arm, n = 19; placebo arm, n = 7) had stopped medication, but provided 8-week outcome data, because they refused to take further medication during the trial (n = 24) or because they moved to an accessible prison where it was not possible to provide trial medication (n = 2). The other 16 participants had withdrawn from the trial (OROS-MPH arm, n = 4; placebo arm, n = 2); withdrawn from all aspects of the trial, but allowed prison record data to be used (OROS-MPH arm, n = 1); or had been released, deported or transferred to an inaccessible prison (OROS-MPH arm, n = 6; placebo arm, n = 3).

Eligibility violations

One participant was randomised despite scoring 51 on the WASI-II assessment for IQ. However, the clinical judgement was that the participant did in fact meet the trial criterion of IQ score of > 60, although the test result did not reflect this. Nevertheless, this was recorded as an eligibility violation on the basis of the test result. The participant was included in the target population because the low score was thought to reflect inattention on the day of the WASI-II assessment; WASI-II is not validated for people with ADHD and the eligibility criterion of 60 was within the 95% CI for the test result. This event led to a change in the protocol that clarified that the IQ assessment for the purpose of eligibility would be based on clinical judgement in addition to review of the WASI-II results owing to the limitations of the WASI-II test. A list of all protocol deviations is reported in Appendix 2, Table 32.

Baseline characteristics

Tables 3–6 summarise the baseline (pre-randomisation) characteristics of this sample. Site-specific baseline data are reported in Appendix 3, Tables 33–36, for HMP YOI Isis and in Appendix 4, Tables 37–40, for HM YOI Polmont. Table 3 summarises categorical demographic variables for each trial arm and overall. Table 4 summarises continuous baseline variables, including age, IQ, height and BMI; baseline values for clinical measures; and summaries of putative baseline moderators. Table 5 summarises coexisting mental health disorders defined by the MINI 7.0.1 assessment. Table 6 summarises prison behavioural reports from prison and educational staff, and the prison records. As expected from randomisation, these tables show that the two trial arms were well balanced with regard to clinical and demographic variables.

Participants had a mean age of 20.7 years at randomisation. A total of 62.5% were of white ethnicity and 37.5% were of black and minority ethnic backgrounds, which was representative of the prison population (see Chapter 6, Generalisability). General cognitive ability was below general populations norms, with an estimated mean IQ of 89.4 (SD 13.0). Regarding education, 39.5% had no qualifications and most participants left school before the age of 16 years or refused to give an age, with 39% leaving school aged ≥ 16 years. They were mostly unemployed: 66.5% unemployed, and 33.5% employed, self-employed or students. A large proportion of participants (76.5%) had not previously received ADHD medication.

Regarding mental health, participants in both trial arms were moderately ill according to the CGI severity scale, with a mean score of 3.9 (SD 1.0). Criteria for coexisting ASPD was met by 149 (74.5%) participants. Potential problem alcohol use was reported for 149 (74.5%) participants. Illicit drug use was reported by 194 (97%) of participants; however, in additional analyses, we found that around half of the sample met the criteria for high-risk problem use of alcohol, whereas few met the criteria for high risk of substance involvement, according to their self-reports (see Table 25).

Other mental health disorders recorded on the MINI were less frequent, including 38 cases with any type of anxiety disorder and 38% with any type of mood disorder. A total of 149 (74.5%) participants met diagnostic criteria for ASPD, but only 15 (7.5%) met criteria for BPD. High levels of childhood trauma were reported (see Table 24 for more details); however, only 13 (6.5%) participants met formal criteria for PTSD.

The mean baseline score for the primary outcome variable, the CAARS-O, was 36.8 (SD 9.2). Participants scored equally high in the inattentive and hyperactive symptom domains, with average symptom scores on the CAARS-O of 18.2 and 18.6, respectively.

Adherence to trial protocol and medication

Titration and prescribing of trial medication

All participants started on one capsule per day and were titrated weekly up to a maximum total of four capsules per day. A stable dose was prescribed for the final 3 weeks. The daily prescribed dose was recorded at the start of weeks 1, 2, 3, 4 and 5. From week 5 onwards, the dosage was stable for all participants, apart from 13 participants who had a dose increase at the start of week 6.

Participants were titrated by increasing the dose by one capsule per day up to a maximum of four capsules unless the ADHD symptoms reduced to negligible, there were limiting adverse effects or a participant objected. By the start of week 5, participants had been titrated to an average of 2.99 and 3.41 daily capsules in the OROS-MPH and placebo arms, respectively (Table 7). Concomitant medications were allowed during the trial and are listed in Appendix 6.

TABLE 7 - Summaries of daily capsules prescribed and taken by week, trial arm and overall

Week (number of participants prescribed treatment at the start of the week)	OROS-MPH arm (N = 101)			Placebo arm (N = 99)			Overall (N = 200)
	Mean (SD) number of capsules prescribed	Mean (SD) number of capsules taken	% of prescribed capsules taken	Mean (SD) number of capsules prescribed	Mean (SD) number of capsules taken	% of prescribed capsules taken	Mean (SD) number of capsules prescribed	Mean (SD) number of capsules taken	% of prescribed capsules taken
1 (200)	1.00 (0.00)	0.76 (0.32)	76.0	1.00 (0.00)	0.86 (0.23)	86.0	1.00 (0.00)	0.81 (0.28)	81.0
2 (197)	1.66 (0.50)	1.23 (0.69)	74.1	1.71 (0.46)	1.35 (0.60)	78.9	1.68 (0.48)	1.29 (0.65)	76.8
3 (191)	2.20 (0.80)	1.49 (0.98)	67.7	2.44 (0.67)	1.89 (0.88)	77.5	2.32 (0.75)	1.69 (0.95)	72.8
4 (183)	2.71 (1.08)	1.55 (1.22)	57.2	3.03 (1.00)	2.22 (1.20)	73.3	2.87 (1.05)	1.88 (1.25)	65.5
5 (177)	2.99 (1.21)	1.60 (1.38)	53.5	3.41 (0.84)	2.40 (1.27)	70.4	3.21 (1.05)	2.00 (1.38)	62.3
6 (171)	2.99 (1.21)	1.57 (1.38)	52.5	3.41 (0.84)	2.33 (1.32)	68.3	3.21 (1.05)	1.95 (1.40)	60.7
7 (171)	2.99 (1.21)	1.59 (1.38)	53.2	3.41 (0.84)	2.25 (1.43)	66.0	3.21 (1.05)	1.92 (1.44)	59.8
8 (158)	2.99 (1.21)	1.41 (1.34)	47.2	3.41 (0.84)	1.99 (1.41)	58.4	3.21 (1.05)	1.70 (1.40)	53.0

The dose of prescribed trial medication taken was recorded by the prison nurse on a daily basis (see Table 7). Participants received the medication directly from nursing staff each day, who then observed participants taking the medication. Although prescribed for daily use, participants did not always take the trial medication every day, which required them to attend the nursing station where the trial medication was dispensed. However, on the days when they did attend to take the trial medication, they took the full dose prescribed. By week 5, participants were taking an average of 1.60 and 2.40 capsules in the OROS-MPH and placebo arms, respectively. This dropped to 1.41 and 1.99 capsules per day for the OROS-MPH and placebo arms, respectively, by week 8. Participants in the OROS-MPH arm were less likely to take the medication each day (see Table 7) (Figure 3).

FIGURE 3.

Weekly mean number of capsules taken by trial arm.

We defined compliance with the treatment regimen as taking one or more prescribed capsules on any given day in the trial, irrespective of the dose prescribed. Full compliance would mean taking one or more capsules on all 56 days, as this was the intended treatment regimen. By the end of week 4, 177 participants (82 in the OROS-MPH arm and 95 in the placebo arm) continued on treatment; by the end of week 8, 158 participants (71 in the OROS-MPH arm and 87 in the placebo arm) continued on treatment. The status of participants (ongoing; withdrawn from treatment, but not from the trial; withdrawn from trial; and released, deported or transferred) was recorded at weeks 1–5 and 8.

Table 7 reports on the number of capsules prescribed and the number of capsules taken each day for those whose status was reported as ‘ongoing’ at each trial visit. For this report, it was assumed that all participants who were ‘ongoing’ at the end of week 5 continued to take the same dose for the remainder of the trial. Of the 56 days of the trial, the mean number of days on which participants took treatment was 31.5 (SD 16.5) and 39.5 (SD 13.3) in the OROS-MPH and placebo arms, respectively, which is 56.3% and 70.5%, respectively, of the 56 days of the trial.

The assumption that the dose prescribed at the end of week 5 was continued to the end of the trial was made because a variable with prescribing information was included in the trial database at the start of weeks 1–5, but not at the start of week 6. In Chapter 5, we report additional analyses that account for 13 participants who increased the number of capsules at the start of week 6, estimated from the reports of dose taken each day throughout the trial (see Chapter 5, Could the trial outcome be affected by adherence to trial medication?).

Analysis of primary and secondary outcomes

Outcome measures

Outcome measures are summarised by assessment time point and trial arm in Tables 8 and 9. Results of formal trial arm comparisons are provided in Tables 10–12. Figure 4 provides a graphical display of mean CAARS-O scores by trial arm. Table 8 and Figure 4 show that improvements over time were observed for the primary outcome, CAARS-O score, in both the OROS-MPH and placebo trial arms.

TABLE 8 - Summaries of continuous outcomes by trial arm and assessment time point

The CAARS-O score was reported for 100 cases in the OROS-MPH arm, because there were > 20% missing items (2/9) in the hyperactivity/impulsivity subscale for one individual.

Reproduced with permission from Asherson et al. 61 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The table includes minor additions and formatting changes to the original table.

Outcome measure	Time point	OROS-MPH arm		Placebo arm		Overall
		Participants (n)	Score, mean (SD)	Participants (n)	Score, mean (SD)	Participants (n)	Score, mean (SD)
CAARS-O	Baseline	100a	36.4 (9.8)	99	37.2 (8.7)	199	36.8 (9.2)
	Week 1	96	32.4 (9.9)	98	31.2 (11.5)	194	31.8 (10.7)
	Week 2	92	28.8 (11.2)	97	29.6 (11.3)	189	29.2 (11.3)
	Week 3	93	28.3 (11.3)	94	30.3 (12.0)	187	29.3 (11.7)
	Week 4	92	26.0 (12.5)	96	29.1 (11.9)	188	27.6 (12.3)
	Week 5	92	27.5 (12.7)	95	28.8 (11.5)	187	28.2 (12.1)
	Week 8	90	28.0 (11.9)	94	29.3 (11.6)	184	28.7 (11.7)
MEWS	Baseline	101	25.7 (6.7)	99	26.8 (6.2)	200	26.3 (6.5)
	Week 5	92	20.5 (9.3)	95	21.4 (9.4)	187	21.0 (9.3)
	Week 8	90	19.8 (10.0)	94	21.9 (9.2)	184	20.9 (9.6)
BSI	Baseline	101	52.5 (32.5)	99	52.9 (35.9)	200	52.7 (34.2)
	Week 5	92	38.4 (28.6)	95	36.3 (25.3)	187	37.4 (26.9)
	Week 8	88	35.0 (25.1)	93	39.0 (34.1)	181	37.1 (30.0)
WRAADDS	Baseline	101	17.5 (5.7)	99	18.1 (5.6)	200	17.8 (5.7)
	Week 5	92	13.6 (5.8)	95	14.3 (6.5)	187	14.0 (6.2)
	Week 8	90	13.4 (6.1)	94	14.5 (7.0)	184	13.9 (6.6)
ARI-S	Baseline	101	9.3 (3.5)	99	9.3 (3.7)	200	9.3 (3.6)
	Week 5	92	8.2 (3.7)	95	7.6 (4.2)	187	7.9 (3.9)
	Week 8	90	8.2 (4.1)	94	8.0 (4.5)	184	8.1 (4.3)
CORE-OM	Baseline	101	43.5 (13.9)	99	44.8 (15.3)	200	44.2 (14.6)
	Week 8	89	38.0 (12.3)	94	39.0 (13.4)	183	38.6 (12.8)
MVQ	Baseline	101	33.2 (9.4)	99	34.6 (9.9)	200	33.9 (9.6)
	Week 5	92	30.8 (11.2)	94	32.4 (10.9)	186	31.6 (11.0)
	Week 8	90	30.6 (12.5)	94	33.1 (11.7)	184	31.9 (12.1)
CGI therapeutic effect	Week 5	84	10.0 (4.1)	94	10.9 (3.0)	178	10.5 (3.6)
	Week 8	86	10.1 (4.2)	93	10.9 (3.4)	179	10.5 (3.8)

TABLE 9 - Summaries of outcomes by trial arm and assessment time point as reported by prison officers and education staff

Proportions of more than one are possible because participants could attend more education sessions in a time period than had been scheduled. We are aware of potential inaccuracies in the reporting systems within prisons.

Reproduced with permission from Asherson et al. 61 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The table includes minor additions and formatting changes to the original table.

Outcomes	Time point	OROS-MPH arm		Placebo arm		Overall
		Participants (N)	Minimum/median/maximum	Participants (N)	Minimum/median/maximum	Participants (N)	Minimum/median/maximum
Prison officer-reported outcomes
MOAS-P score (range 0–40)	Baseline	101	0/0/15	99	0/0/19	200	0/0/19
	Week 8	88	0/0/24	91	0/0/20	179	0/0/24
BRC-P score (range 6–30)	Baseline	101	6/8/24	99	6/8/21	200	6/8/24
	Week 8	88	6/9/25	91	6/8/25	179	6/9/25
Number of critical incidents	Baseline	101	0/0/6	99	0/0/10	200	0/0/10
	Week 8	97	0/0/8	97	0/0/8	194	0/0/8
Education staff-reported outcomes
			n (%)		n (%)		n (%)
Number of participants in any kind of education	Baseline	101	94 (93.1)	99	93 (94.0)	200	187 (93.5)
	Week 8	101	94 (93.1)	99	97 (98.0)	200	191 (95.5)
			Minimum/median/maximum		Minimum/median/maximum		Minimum/median/maximum
MOAS-E score (range 0–40)	Baseline	38	0/0/12	45	0/0/10	83	0/0/12
	Week 8	31	0/0/1	37	0/0/2	68	0/0/2
BRC-E score (range 6–30)	Baseline	31	13/19/41	36	13/17/40	67	13/19/41
	Week 8	28	13/17/29	36	13/18/48	64	13/18/48
Number of education sessions scheduled	Baseline	101	0/21/123	99	0/25/126	200	0/23/126
Number of education sessions attended	Baseline	101	0/15/112	99	0/19/126	200	0/17/126
Number of education sessions scheduled	Week 8	94	0/34/146	97	1/32/142	191	0/32/146
Number of education sessions attended	Week 8	94	0/23/143	97	0/22/142	191	0/23/143
			Mean (SD)		Mean (SD)		Mean (SD)
Proportion of education sessions attendeda	Baseline	101	0.78 (0.31)	99	0.82 (0.26)	200	0.81 (0.29)
	Week 8	94	0.80 (0.28)	97	0.82 (0.26)	191	0.81 (0.27)

TABLE 10 - Estimated trial arm differences for the continuous primary and secondary outcomes at week 8a

DF, degrees of freedom; N/A, not applicable.

Positive differences indicate an improvement in the OROS-MPH arm, compared with the placebo arm.

All inferences were derived by MI, as described in Chapter 2. Each model used k = 100 imputations.

Differences were standardised by dividing by the baseline SD for the relevant variable. CGI therapeutic effects was not recorded at baseline.

Reproduced with permission from Asherson et al. 61 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The table includes minor additions and formatting changes to the original table.

Outcome measure	OROS-MPH arm vs. placebo arma
	Estimated differenceb	95% CI	Test (DF); p-value	Standardised differencec
CAARS-O	0.57	–2.41 to 3.56	t (183) = 0.38; 0.71	0.06
MEWS	1.06	–1.39 to 3.52	t (182) = 0.85; 0.39	0.16
WRAADDS	0.83	–0.83 to 2.48	t (175) = 0.98; 0.34	0.15
ARI-S	–0.31	–1.37 to 0.75	t (176) = –0.58; 0.57	–0.09
CORE-OM	–0.18	–3.46 to 3.10	t (175) = –0.11; 0.91	–0.01
BSI	2.46	–4.81 to 9.74	t (177) = 0.67; 0.51	0.07
MVQ	1.08	–1.16 to 3.33	t (179) = 0.95; 0.34	0.11
CGI therapy effect	0.65	–0.46 to 1.76	t (171) = 1.15; 0.25	N/A

TABLE 11 - Reduction in CAARS-O score as percentage of baseline scores and number of responders defined as a 20% reduction from baseline CAARS-O scores

Outcome measure	OROS-MPH arm (N = 89)	Placebo arm (N = 94)	Overall (N = 183)
Reduction in CAARS-O score as percentage of baseline scores
	Mean (SD)	Mean (SD)	Mean (SD)
Total scale	21.2 (33.8)	20.1 (29.7)	20.7 (31.7)
Inattention subscale	26.4 (36.9)	22.1 (35.6)	24.2 (36.1)
Hyperactivity/impulsivity subscale	11.7 (59.3)	16.3 (36.4)	14.1 (48.8)
Responder rate at 8 weeks defined as 20% reduction from baseline CAARS-O score
	n (%)	n (%)	n (%)
Total scale	43 (48.3)	45 (47.9)	88 (48.1)
Inattention subscale	50 (55.6)	51 (54.3)	101 (54.9)
Hyperactivity/impulsivity subscale	39 (44.3)	44 (46.8)	83 (45.6)

TABLE 12 - Estimated odds ratios or incidence rate ratios comparing secondary binary and count outcomes between trial arms at 8 weeks

IRR, incidence rate ratio; OR, odds ratio.

Ratios > 1 indicate an improvement in the OROS-MPH arm.

Reproduced with permission from Asherson et al. 61 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The table includes minor additions and formatting changes to the original table.

Measure	Description	OROS-MPH arm vs. placebo arma
		Estimated OR [ln(OR)]	95% CI for OR [95% CI for ln(OR)]	Test (z)	p-value
MOAS-P	Any act of aggression reported in the week prior to the week-8 time point (yes/no)	0.57 [–0.56]	0.28 to 1.15 [–1.26 to 0.14]	–1.56	0.12
		Estimated IRR [ln(IRR)]	95% CI for IRR [95% CI ln(IRR)]
BRC-P	Behavioural report score for the week prior to the week-8 time point	0.95 [–0.06]	0.85 to 1.06 [–0.16 to 0.06]	–0.98	0.33
Critical incidents	Number of critical incidents recorded across the 8 weeks of the trial	0.75 [–0.28]	0.45 to 1.25 [–0.79 to 0.23]	1.09	0.28
Education sessions scheduled	Number of any type of education session scheduled across the 8 weeks of the trial	0.98 [–0.02]	0.84 to 1.14 [–0.17 to 0.13]	–0.28	0.78

FIGURE 4.

The CAARS-O mean scores and 95% CIs by trial arm.

Sensitivity analyses

Four sets of sensitivity analyses were conducted to check whether or not the results on the primary outcome were sensitive to collection of outcomes within the specified window, starting treatment within the specified time, sufficiently high IQ confirmed by a standardised test, or sufficient level of compliance with the treatment. In each case, the primary analysis, estimating the difference between trial arms in CAARS-O scores at 8 weeks, was repeated. The primary analysis was robust to all assumptions tested in these sensitivity analyses.

Moderator analyses

The following baseline variables were tested as putative moderators of the treatment effect: ZAN-BPD, CTQ, RPQ-Reactive and RPQ-Proactive. A term representing the interaction between trial arm and each potential moderator was included in the primary analysis model in addition to the moderator. No moderator had any significant effect either on its own or through interaction with trial arm (Table 13).

Mediation analyses

We analysed the individual mediating effects of CAARS-O hyperactivity/impulsivity subscores, CAARS-O inattention subscores and WRAADDS emotional dysregulation, measured at 5 weeks, on BRC-P scores and the number of critical incidents measured at 8 weeks. The natural direct effect, natural indirect effect and total effect are shown in Table 14. The mediation observed was negligible (around zero) and no mediation test was statistically significant. All mediator effects were in the same direction as the total effect. The CIs shown are derived by bootstrapping (1000 replicates), with zero included in the respective interval, implying that an effect was not statistically significant.

Serious adverse events

One SAE took place during the trial. The SAE was classified as an IME after a participant tied a cord around his neck as a protest to a prison officer’s treatment. It was concluded that the participant did not intend to do any harm to himself, he did not require any treatment after the event, and it was not thought to be related to the trial medication. The blind was kept and the prisoner continued in the trial.

Adverse events

The numbers of AEs in a category are reported by person, rather than by number of events (Table 15). Of 336 AEs reported, 184 occurred in the OROS-MPH arm and 152 in the placebo arm. The numbers of participants reporting AEs were broadly similar across the two trial arms, with the exception of the High-Level Group Term categories for ‘appetite and general nutritional disorders’, ‘depressed mood disorders and disturbances’ and ‘dizziness’. This reflected appetite loss (13 participants in the OROS-MPH arm vs. 2 in the placebo arm), depressive symptoms (12 in the OROS-MPH arm vs. 4 in the placebo arm) and reports of dizziness (6 in the OROS-MPH arm vs. 0 in the placebo arm).

Expected adverse effects were also followed-up systematically at each visit using the medication AES (Tables 16 and 17). Question 23 in the AES, ‘Feeling worse or different when the medication wears off (rebound)’, was not applicable, so we report on only 22 items. Each item on this scale is rated as follows: 0 = not at all, 1 = sometimes, 2 = often and 3 = all the time. The scale was dichotomised 0 (not at all or sometimes) and 1 (often or all the time) to reflect the absence or presence of the AE, respectively. The mean and SD of the total AES scores show that there was only a minor difference in total burden of AEs at 8 weeks in the OROS-MPH arm [mean 7.4 (SD 7.5)], compared with the placebo arm [mean 5.5 (SD 5.4)]. At baseline, these values were slightly larger [mean 10.3 (SD 7.5) for the OROS-MPH arm; mean 9.8 (SD 7.3) for the placebo arm], indicating that some reported AEs may reflect phenomena of the clinical condition that improved during the 8-week period of the trial.

The numbers and percentages of participants reporting each individual symptom are reported at baseline (see Table 16) and across the entire post-randomisation period between randomisation and week 8 (see Table 17). This shows that the most common adverse effects in the post-randomisation period that were related to the use of OROS-MPH, compared with the use of placebo, were headache (17.8% vs. 10.1%, respectively), dry mouth (19.8% vs. 10.1%, respectively), sweating (19.8% vs. 8.1%, respectively) and appetite reduction (34.7% vs. 19.2%, respectively).

Finally, blood pressure and heart rate were recorded at baseline, at each titration point during weeks 1–5 and at week 8. BMI (weight/height) was recorded at baseline, week 5 and week 8. The values overall and by trial arm are shown in Table 18. There was no noticeable difference between trial arms at any point in the trial.

For a list of all concomitant medication, see Appendix 5, Tables 41 and 42.

Introduction

The findings from the primary trial analysis according to the prespecified SAP provide no evidence for a difference in effect between the placebo and treatment arms. Indeed, across all primary and secondary outcome variables, outcomes were remarkably similar in the trial arms at 8 weeks and do not indicate any advantage of OROS-MPH over placebo, even at trend level. Furthermore, findings from the per-protocol analyses, as laid out in the SAP, did not provide any evidence for efficacy of the OROS-MPH intervention either.

As outlined in the justification for this study, MPH has been investigated in adults with ADHD in community ADHD clinics in previous studies and was found to have an average SMD between-group effect of around 0.51. 24 A 2018 comprehensive network meta-analysis32 estimated an effect size from RCTs of MPH in reduction of ADHD symptoms in adults, with a SMD of 0.49 (95% CI 0.35 to 0.64). One of the key rationales for this study was to investigate whether or not OROS-MPH had a different effect in a young adult male prison population, compared with the previous studies. It was proposed that the symptoms of inattention and hyperactivity/impulsivity could potentially have a different meaning in this population, reflecting different comorbid mental health or neurodevelopmental disorders. It was further proposed that high levels of drug and alcohol use among offenders might modify the previously reported effects. Although a change in the effect size, compared with previous studies, was envisaged, the absence of even a small effect was unexpected (the estimated between-arm standardised effect is < 0.1).

Although there appeared to be no between-group effects, there was a change over the observation period indicating an apparent improvement in symptoms in both arms. The mean CAARS-O scores dropped from 36.4 points at baseline to 28.0 points at week 8 (a difference of 8.4 points) in the OROS-MPH arm of the trial and from 37.2 points to 29.3 points (a difference of 7.9 points) in the placebo arm (see Table 8). This is not unexpected as significant change has been observed in placebo arms of most RCTs for MPH in ADHD. However, we saw a much greater change in symptoms in the pilot study for this project at HMP YOI Isis, which included 121 participants in a single unblinded group receiving OROS-MPH. 29 The pilot study found the mean change over time for CAARS-O scores to be 22.6 points (decreasing from 37.6 to 15.0 points) using the primary outcome at week 12 and a last observation carried forward approach to deal with missing observations. For the week 8 secondary outcome data in the pilot using the last observation carried forward approach, the difference was even greater: 29.3 points (decreasing from 37.6 to 8.31 points). This is far larger than the change observed in either of the two treatment arms of the current trial.

For these reasons, we completed a set of further analyses to explore possible explanations for the unexpected findings in this trial. These further analyses were proposed after database lock and the review of the findings from the primary trial analyses according to the SAP. They are post hoc analyses and should be regarded as entirely exploratory in nature, with the aim of making suggestions for possible explanations of the trial findings.

Investigating differences between the open pilot study and the randomised controlled trial

We observed that the pre–post differences for both the treatment and placebo arms were smaller in this trial than in the previous open-label pilot study. To investigate the potential reasons for this we looked at differences in the conduct of the pilot study and the trial, and compared the estimated pre–post differences between the open-label pilot study (CIAO-I) and the RCT (CIAO-II) at the HMP YOI Isis site only (because the pilot was conducted at this site only).

Checking data integrity

To check for the possibility of a ‘hidden’ effect in the trial data for any reason, we investigated the possibility that there are two distinct clusters of outcomes. We would expect to see a bimodal distribution if there were any drug effects, reflecting the existence of two response groups. To achieve this, we checked the distribution in the change of CAARS-O scores from baseline to week 8 to see if there is any evidence for two clusters of the primary outcome data, by plotting the distribution of change scores from baseline to week 8. As shown in Figure 5, there is no evidence for two potential clusters.

FIGURE 5.

Distribution of change in CAARS-O scores from baseline to week 8.

Investigating efficacy in specific populations (subgroup analyses for CAARS-O)

We conducted a series of subgroup analyses of the trial data to identify subgroups potentially showing a greater or smaller effect of the trial medication. These further analyses were designed to address specific questions that might explain the current findings and could form the basis for future studies. Subgroup analyses on very small subpopulations are unlikely to be informative; for this reason, we did not conduct analyses on subgroups of ≤ 30 participants.

Could the trial outcome be affected by including participants with prior experience of stimulant medication, leading to biased reporting of the attention deficit hyperactivity disorder symptom response to medication?

Prior exposure to stimulant treatment for ADHD could change the reporting of symptoms because of prior experience of effects of medication on ADHD symptoms and adverse effects, leading to biased reporting. There is also the possibility that medication was stopped in these cases because of previous non-response or significant adverse effects. To investigate the possibility that these effects might reduce the overall effect of medication in the trial, we conducted subgroup analyses for a group with and a group without previous exposure to stimulant medication for ADHD.

A total of 153 participants had no previous treatment with stimulants for ADHD; one participant was not assessed. The subgroup that had not previously been treated with stimulants for ADHD had an estimated score difference between the OROS-MPH and placebo arms of 0.63 (95% CI –2.93 to 4.19; t = –0.35; p = 0.72) and the OROS-MPH arm performed better than the placebo arm. Forty-six participants had received stimulants for ADHD in the past, with the last dose taken at least 3 months previously. The estimated score difference between the OROS-MPH and placebo arms for this subgroup was 2.01 (95% CI –4.17 to 8.19; t = 0.66; p = 0.51): a small improvement in the OROS-MPH arm, which was not statistically significant.

Could the trial outcome be affected by underdosing of participants?

The optimal dose of MPH used in the treatment of adult ADHD is highly variable; hence, we adopted a titration procedure to individually titrate each participant to the optimal dose of trial medication. However, as noted in the CIAO-I open-label pilot study, this population was concerned by minor adverse effects and were titrated to relatively low average doses of the trial medication. This suggests that, in this population, the titration protocol might lead to underdosing of participants, potentially accounting for lesser effects of the drug, compared with placebo. To investigate this possibility, we compared the trial outcome for a subgroup titrated to a low dose with that of a subgroup titrated to a high dose, defined as subgroups titrated to one or two capsules for the low dose, and those titrated to three or four capsules for the high dose.

Table 26 shows the distribution of the prescribed dose at the start of week 5 and at the start of week 6 by trial arm (see Could the trial outcome be affected by adherence to trial medication? for an explanation of week-6 prescriptions) for those who were ongoing in the trial. As noted in the primary analyses, those allocated to OROS-MPH were titrated to lower doses than those in the placebo arm. For example, at the start of week 5, 74% were prescribed the higher dose (three or four capsules) in the OROS-MPH arm, compared with 86% in the placebo arm.

At the start of week 5, 143 participants were prescribed three or four capsules. The estimated score difference between the OROS-MPH and placebo arms in this subgroup was 0.47 (95% CI –3.03 to 3.97; t = –0.27; p = 0.79), which was an improvement in the OROS-MPH arm. Fifty-seven participants were prescribed one or two capsules at the start of week 5. The estimated difference between the OROS-MPH and placebo arms in this subgroup was 0.68 (95% CI –6.15 to 7.51; t = 0.20; p = 0.84), which is a small improvement in the OROS-MPH arm, but is not statistically significant.

Could the trial outcome be affected by adherence to trial medication?

Adherence to taking the trial medication on a daily basis was highly variable; this might have affected the assessment of efficacy by ITT. The high levels of poor adherence to medication was previously documented in the CIAO-I open-label pilot study, in which 40 out of 121 (33.9%) participants dropped out of treatment before the 8-week assessment; therefore, efforts were taken in the current trial to minimise this. 29 However, the per-protocol analysis, carried out according to the SAP-defined ‘compliance’ for the trial medication (i.e. having taken medication on 75% of the days during the trial period), did not show any different effect from the ITT analysis, suggesting that poor compliance is unlikely to explain the trial findings. Nevertheless, it is possible that our definition of compliance is not adequate to rule out all effects of adherence to the trial medication on the trial outcome. To address this problem, we investigated the impact of a set of alternative definitions of adherence with the trial medication on efficacy in this trial.

Summary of adherence to medication data

To provide an overview of the amount of drugs prescribed and taken, we produced descriptors of the dose prescribed and dose taken. This is already reported as part of the main results (see Chapter 4, Titration and prescribing of trial medication) for those ongoing on medication and uses the prescription data from the start of week 5 of the trial.

The protocol also allowed a final dose change at the start of week 6, prior to the final 3-week maintenance phase of the trial. Note that for weeks 1–5, the prescription was explicitly recorded in the database. For week 6, the prescription was not recorded, but is inferred from the maximum dosage taken by participants. In all cases, the nurses providing the prescriptions recorded a daily log of the dose taken. It is therefore reasonable to infer a prescription change for week 6 from the maximum dose taken on days 36–39, which is in line with the protocol for week-6 prescriptions. Using this approach, we describe the number of participants prescribed different doses of trial medication from the start of week 6 (see Table 26), which was maintained until the end of the trial. Table 27 shows the numbers recorded as prescriptions for weeks 1–5 and the inferred prescription for week 6.

TABLE 27 - Mean daily capsules prescribed by week of those who were continuing treatment

Week	Number (%) of participants prescribed trial medication	Mean (SD) numbers of capsules prescribed
		OROS-MPH arm (N = 101)	Placebo arm (N = 99)	Overall (N = 200)
1	200 (100.0)	1.00 (0.00)	1.00 (0.00)	1.00 (0.00)
2	197 (98.5)	1.67 (0.47)	1.71 (0.46)	1.69 (0.46)
3	191 (95.5)	2.24 (0.74)	2.44 (0.67)	2.35 (0.71)
4	183 (91.5)	2.80 (0.98)	3.06 (0.96)	2.95 (0.97)
5	177 (88.5)	3.14 (1.03)	3.41 (0.84)	3.28 (0.94)
6	171 (85.5)	3.20 (1.03)	3.49 (0.81)	3.36 (0.92)

To describe the overall adherence to prescribed trial medication, we describe the mean number of daily capsules taken by week and percentage of prescribed dosage taken (Table 28). Prescriptions for weeks 1–5 are based on the recorded prescription. The prescription for week 6 is inferred from the maximum number of capsules taken. The prescription for weeks 7 and 8 is identical to that of week 6. Note that, by the final week, the data are skewed; however, it is the percentage of medication taken of that prescribed (documented or inferred) that is of interest. Throughout the trial, the placebo group took a larger percentage of the capsules prescribed. By week 4, this difference had become more marked and remained more marked for the remaining weeks.

TABLE 28 - Mean number of daily capsules taken by week and percentage of prescribed dosage taken

Week	OROS-MPH arm (N = 101)		Placebo arm (N = 99)		Overall (N = 200)
	Mean (SD) number of capsules taken by week	Percentage of prescribed medication	Mean (SD) number of capsules taken by week	Percentage of prescribed medication	Mean (SD) number of capsules taken by week	Percentage of prescribed medication
1	0.76 (0.32)	76.0	0.86 (0.23)	86.0	0.81 (0.28)	81.0
2	1.23 (0.69)	73.7	1.35 (0.60)	78.9	1.29 (0.65)	76.3
3	1.49 (0.98)	66.5	1.89 (0.88)	77.5	1.69 (0.95)	71.9
4	1.55 (1.22)	55.4	2.22 (1.20)	72.5	1.88 (1.25)	69.6
5	1.61 (1.38)	51.3	2.40 (1.27)	70.4	2.00 (1.38)	61.0
6	1.57 (1.38)	49.1	2.33 (1.32)	66.8	1.95 (1.40)	58.0
7	1.59 (1.38)	49.7	2.25 (1.43)	64.5	1.92 (1.44)	57.1
8	1.41 (1.34)	44.1	1.99 (1.41)	57.0	1.70 (1.40)	50.6

Figure 6 illustrates the mean adherence of participants by trial arm. The weekly adherence is defined as the number of days on which at least one tablet was taken, divided by seven. At the start of the trial, the mean adherence was 71.6% and 81.5% in the OROS-MPH and placebo arms, respectively. This dropped to 50.6% and 70.4% in week 5, and to 43.7% and 56.6% by week 8 for the OROS-MPH and placebo arms, respectively. The proportion of participants in the placebo group adhering was consistently larger throughout the trial, but adherence dropped off consistently throughout the trial in both arms.

FIGURE 6.

Mean adherence to prescribed trial medication.

Could adverse effects be driving adherence to the trial medication?

To investigate the potential association of adverse effects on adherence to trial medication, we investigated the proportion of prescribed medication taken by the presence or absence of the most commonly reported adverse effects of OROS-MPH, compared with placebo. We used the AES data from across the trial. As can be seen in Table 17, the common items from the AES showing the greatest difference between the two trial arms were sweating, headache, appetite loss and dry mouth. These were reported by 16%, 18%, 16% and 30% of participants, respectively, and 50% of participants reported one or more of these items.

For this analysis, we investigated the adherence to medication for each of these four AES items, as follows: (1) we measured adherence as the proportion of days on which any dose was taken divided by number of days medication was prescribed; (2) we calculated the mean proportion for groups reporting the presence or absence of each of the four AES items, and ran t-tests to compare the present with the absent groups; and (3) we considered an overall AES item measure of having at least one of the four items.

In Table 30, the mean adherence is shown by the group for which the AES items were present and the group for which they were not present. A difference in mean proportion of adherence by symptoms was tested using a t-test. There was no evidence to suggest that the adherence varied between those who did and those who did not display the most common adverse effects.

Generalisability

The trial targeted a sample that could be generalised to other prison populations of young males aged 16–25 years, meeting diagnostic criteria for ADHD, in the UK. To increase generalisability, a screening approach was taken to ensure that as many prisoners as possible who met diagnostic criteria were identified and invited to take part in the trial. Exclusion criteria were kept to a minimum and focused on excluding the minority of participants who posed a high risk to researchers, or who had coexisting disorders for which medical treatment of ADHD was a strong caution or contraindicated. Other criteria ensured that participants were able to understand the trial procedures and provide their own fully informed consent to the take part in the trial. The first step of the protocol was therefore a screening step in which all offenders entering the prisons were screened for ADHD, prior to being invited to complete detailed diagnostic assessments and review by a psychiatrist trained in the diagnosis of ADHD and other common mental health disorders. It is unknown if those prisoners who refused consent to be screened or did not attend the diagnostic interview for ADHD differ in any way from the trial participants.

The site HMP YOI Isis in London is a category C prison for sentenced prisoners, including male offenders aged 18–25 years deemed to be relatively low risk with short- to medium-length sentences. HM YOI Polmont in Scotland differs because it is the only prison in Scotland for young persons aged 16–21 years; therefore, there was no selection on type of crime, sentence or level of risk. Nevertheless, the range of crimes and sentencing was largely similar to HMP YOI Isis. The trial did not include any remand (pre-trial) or convicted but unsentenced prisoners, who generally show higher rates of comorbidity than sentenced prisoners. 90 The sample was all male, so these findings cannot be generalised to the female prison population.

The focus in this study and in the pilot study, as well as the previous Swedish study,33 was male prisoners; therefore, little is known about the efficacy of pharmacological treatments in treating female prisoners with ADHD. It is unknown whether or not there would be similar safety concerns and similar levels of behavioural problems, mental health disorders and substance misuse. It is expected that the profile of comorbid disorders might differ between male and female offenders, and their effects on pharmacological treatment in female offender populations remains largely unknown. The best evidence that similar effects may arise comes from pharmacoepidemiogical data from Sweden, although the number of females with ADHD at risk of committing criminal offences is far smaller. 91

Regarding ethnic background, at HMP YOI Isis, a clinical audit conducted in June 2019 found that ethnic minorities were approximately 70%, whereas the ADHD service had a case load of 38% ethnic minorities and 63% non-ethnic minority (white) prisoners. This indicated a considerable bias in the prisoners being referred for diagnosis and treatment by the health-care and prison staff within the London prison. These figures contrast with the proportion of people from ethnic minority backgrounds in London, reported in the 2011 UK National survey,92 of 59.8% from white, 18.4% from Asian, 13.3% from black and 8.5% from mixed and other backgrounds. This clearly demonstrates the well-established finding that ethnic minority groups are greatly over-represented in the prison population, which is an issue of general national and international concern. 93 The sample from which we recruited in London is representative of the prison population, but is not representative of the general population of youth with ADHD in the London area.

Regarding recruitment to the trial, we found that, at HMP YOI Isis, 34.8% of the participants came from white, 25.2% from other (including Asian and mixed background) and 40% from black backgrounds. The figure of 34.8% participants from a white background is close to the estimated proportion of 30% in the prison, indicating no bias in the selection for this trial based on ethnicity, in keeping with the screening approach we adopted for this trial. For Scotland, the 2011 survey reported a low rate of ethnic minority populations, of around 4%. At the time of writing, we had no information on the proportion of different ethnic groups residing at HM YOI Polmont, but, among participants in this trial, we found that > 98% were from white British backgrounds, providing a good representation of the ethnic mix in Scotland.

Previous research has also shown high rates of comorbidity in children, adolescents and adults diagnosed with ADHD in both clinical and epidemiological samples. A 2017 review7 of population surveys for adults with ADHD found that 52% met criteria for one or more comorbidities: oppositional defiant disorder (as children) or ASPD, 8%; intermittent explosive disorder, 13%; an anxiety disorder, 34%; a mood disorder, 22%; and a drug or alcohol problem, 11%. This compares with the findings in the current trial of 82% who had one or more comorbid mental health disorders: 19% with a mood disorder, 19% with an anxiety disorder, 75% with ASPD, 45% with problematic alcohol use (AUDIT-C score of ≥ 16) and 64% with moderate- to high-risk drug use (see Table 5 and Chapter 5, Could the trial outcome be affected by including participants with high levels of drug and alcohol usage?). This suggests that the prison population of young adults meeting diagnostic criteria for ADHD that we investigated here have a similar profile for anxiety and mood disorders, but higher rates of ASPD and problem alcohol and drug use. For the overall male convicted prison population, it would be expected that 7% had a psychosis, 40% a neurotic disorder, 63% a history of alcohol abuse, 43% a history of drug dependence and 63% a personality disorder. 90 Internationally, a meta-analysis of > 33,000 prisoners found that 3.6% of men had a psychosis and 10.2% had major depression. 94

Interpretation of primary and secondary outcomes

This report describes the results of a RCT of the short-term effects of OROS-MPH on ADHD symptoms and behavioural outcomes in young male prisoners aged 16–25 years with ADHD. The trial was completed within the planned time scale, meeting all recruitment targets at HMP YOI Isis (London, UK) and HM YOI Polmont (Falkirk, UK), with randomisation of 101 participants to the drug treatment arm and 99 to the placebo arm of the trial. The aim of the trial was to establish whether or not the efficacy of a long-acting formulation of MPH in this population was similar to the effects observed in comparable trials in non-prison (community) populations. The rationale for this trial consisted of arguments supporting both smaller and larger effects than previous studies in non–offender populations, reflecting the potential complexity of the diagnosis and response to ADHD drug treatments in young adult prisoners.

The primary and secondary outcomes of this trial failed to show statistically significant differences between the OROS-MPH and placebo treatment groups in the outcome assessment at 8 weeks. Any differences between the mean or median scores for the two arms were negligible for all of the outcome measures and are unlikely to be clinically meaningful even if found to be significant in a larger trial sample. To check for the possibility of a hidden effect in the trial data for any reason, we conducted a further analysis to look for two distinct clusters of outcomes in the data. We would expect to see a bimodal distribution if there were any drug effects, reflecting the existence of two response groups. We checked the distribution in the change of CAARS-O scores from baseline to week 8 by plotting the distribution of change scores, but found only a single smooth function that gave no hint of two distinct responder groups within the data (see Figure 5).

The lack of any benefit of the active drug against placebo was unexpected. MPH has been used in numerous previous RCTs of ADHD in children and adults, and shows a consistent moderate to large effect across the various studies using outcome measures that are the same or closely similar to the CAARS-O investigator-rated scale used in this trial. In a 2018 comprehensive network meta-analysis32 comparing the effects of different pharmacological treatments for ADHD, the data for MPH were found to have a SMD of 0.78 (95% CI 0.62 to 0.93) in children and 0.59 (95% CI 0.35 to 0.64) in adults with ADHD. We therefore need to consider possible reasons for seeing such robustly negative findings in this study of young male adult prisoners with ADHD.

Limitations

There were a number of limitations that should be considered when interpreting the findings reported here.

Throughout the trial, the research teams had weekly telephone conference calls during which there was an opportunity to discuss the diagnosis of individual cases prior to randomisation. However, to reduce the potential for biasing outcome assessment data by the rater (who was part of the trial team in the prison), post-randomisation outcome assessments were not discussed. Initial training was provided for the primary outcome measure, but further training and evaluation throughout the trial to ensure that all staff continued to conduct the primary outcome assessments in a reliable way were not conducted. This might have led to a reduction in inter-rater reliability, although, in most cases, the same investigator conducted both the baseline and outcome assessments on the primary outcome measure, limiting the effects of using different raters on within-individual change in the primary outcome measure over the period of the trial.

Drug usage in prisons is a well-reported and documented problem. However, it was decided early on in the design phase of the protocol development that there would be no recording of drug usage during the trial because this would be unreliable if based on participants’ accounts of drug use in the prison. We considered the use of drug-testing as part of the trial, but one of the most common drugs found in the prison (spice) has no test, and we were concerned by the impact on recruitment and on patient selection that would be introduced, minimising the generalisability of the findings. During the trial, 18 participants were found to have been using drugs (cannabis or spice), or suspected to have been using drugs, by prison or health-care staff or disclosed drug use to the researchers during the trial, where it was recorded as an AE. However, there were probably other undetected cases. A high level of undetected drug use by participants might account, in part, for the lack of differences between the two trial arms, if, for example, drug use generates short-term effects that are similar to the ADHD symptoms captured in the primary and secondary outcome measures.

A potential confounder not measured in this trial was traumatic brain injury (TBI), which is seen in around 60% of prisoners. 101 In a study from co-applicant Susan Young,102 43% of prisoners were deemed to have suffered TBI using a strict definition, with a mean age at first head injury of 12.5 years. A further study103 reported that 60% of prisoners self-reported head injuries, with 16% reporting moderate to severe TBI. Adults with TBI were also younger when entering the criminal justice system. 103 Although there may be some clinical effects of MPH in ADHD secondary to TBI, this is not yet well established and the efficacy in this context remains uncertain. 104

Poor adherence to treatment in the current trial might be related to the aspects of the prison environment including a limited time window for receiving medication, safety concerns regarding gang relations exposing them to be targeted during dispensing, and inconsistent release of prisoners from cells to receive medication. These potential risks were not measured; however, in additional analyses we found no evidence for an effect in a subgroup with good adherence to treatment.

In addition to pharmacological treatments, some participants in this trial might also have received additional psychological therapies from prison health care or general practitioners (GPs), although this information was not recorded. Although such treatments could potentially reduce reported levels of ADHD symptoms, it is expected that these were evenly distributed across the two arms of the trial, and previous trials have found significant effects of MPH, but no effects of ADHD-tailored psychological interventions, compared with clinical management as usual. 105 Nevertheless, because this was not recorded, it is possible that psychological treatments were not evenly distributed between the two arms of the trial.

The number of behavioural problems recorded in the prison records were very small at baseline, and the prison officer ratings of aggression on the MOAS-P and BRC-R were both very low at baseline, meaning that these measures were largely uninformative. This could reflect a high level of tolerance by prison officers for minor to moderate levels of disruptive behaviour in this population.

The relationship between participants and research and prison staff might also play a key role in influencing participants’ reports of symptoms and behaviours, and could potentially have led to reported improvements in the placebo arm that swamped any potential effects of OROS-MPH. For this reason, we included information from prison records and behavioural reports from prison and education staff, although these were largely uninformative and lacked power to detect any potential differences. We also considered the use of more objective tests, such as QbTest, which measures both cognitive performance during a continuous performance task and motor activity, measured as head movement. However, in the pilot study, during which we did collect QbTest data, the data were found to be of too poor quality to report as a result of poor engagement with the test procedures by young prisoners with ADHD. Given the results of the present trial, it would be important to consider what other objective tests of clinical improvement could be used in future studies of young offenders with ADHD.

There are several potential sources of bias on ratings of the primary and secondary outcomes during the trial. For example, participants might have been very keen to please the researcher for a number of reasons. They may have looked forward to their assessments as a change from their usual prison routine, and a chance to discuss a broader range of problems related to their diagnosis and treatment in the prison. It should also be noted that the staff working on the trial at both sites were mostly female, potentially enhancing the motivation to appear to be doing well to please the research staff. This may have led to social desire bias,106 which might have had a similar impact on reporting of symptoms and behaviours in the two arms of the trial, thereby minimising potential differences in outcome.

Another potential bias could be the halo effect. These are young men on relatively short tariffs and quite a different sample to the older sample in Sweden who were on longer tariffs. They are likely to be aware that they might get a reduced tariff for good behaviour, and there may also be an expectation of greater privileges in the prison through participation in certain prison programmes. A further motivation might be the possibility that taking part in the trial and reporting good outcomes might increase the possibility of earlier release. This knowledge of the system might mean that they were highly motivated to communicate improved functioning or reduced impulsive or disruptive behaviours equally in the two arms of the trial. Although it was made clear that this was a research project that would have no influence on outcome, they may still have perceived that reporting good outcomes can only help their situation.

Another potential bias could be the Hawthorne effect,107 in which being aware that you are being observed can lead to changes in behaviour; this may have potentially affected both arms of the trial. This effect might be greatly exaggerated in prisons, where participants are aware that they are constantly watched by both health-care and prison staff, and intense relationships are formed.

Related to these potential effects of the participant–rater interactions, participation in the trial may also have increased the sense of self-worth of participants, as some commented that they had never been asked to consent to anything before. They liked the idea that they were given a free choice whether or not to participate. Because of our screening procedure, many of the participants diagnosed with ADHD for this trial may not otherwise have engaged with the mental health team at all and the constant contact with the researchers, who had more time to spend than the health-care staff, may also have had a positive effect on participants’ well-being. It is also feasible that improvements in a general sense of well-being as a result of the research procedures might have led to lower clinical and behavioural ratings in both arms equally. Although the research staff were trained to enquire about specific examples of current symptoms and behaviours to minimise these potential effects on the primary outcome, it would not be difficult for participants to report symptom improvements when they are asked the same questions at each research assessment because they would come to understand, to an extent, the questions they were being asked.

Regarding the recording of prison record data, it was discovered early on during the trial that, at HMP YOI Isis, the prison record data for participants who were transferred, released or deported would no longer be accessible to the research team. These were accessible with assistance from HMPPS. It was also found that the adjudication data may not be a true reflection of all of the critical incidents that took place, as only issues that had been witnessed were logged by prison officers. There has also been a reduction in prison officers and increased staff turnover during the preceding few years that might have led to an overall lack of sensitivity to reporting critical incidents. This reduction was considerable. The HMPPS budget was reduced from £3.47B in 2010/11 to £2.71B in 2016/17; as a consequence, there was a 30% reduction in front-line prison officers. 108–110

At HM YOI Polmont, it was discovered during the data-checking stage at the end of the trial that the educational, vocational training sessions scheduled and attended were different on the trial database (using data collected at the time) from the prison database (using data at the end of the trial, which had changed from the time the data had been collected). This issue was explored and it was discovered that there was no audit trail on this information within the prison system, and that the prison database could have been entered or modified at any stage. This was discussed between the chief investigator, statistician, sponsor representative and the trial manager, and it was agreed that the data obtained at the time of data-gathering at baseline and week 8 should be used, as these were records of the prison database at those times.

The system in place to give IEPs for negative and positive behaviour was abandoned at HM YOI Polmont just before the start of the project, meaning that these data were available at the HMP YOI Isis site only. For this reason, IEPs were dropped from the SAP.

No pre tests were completed to compare the placebo with the active medication in relation to shape, size, colour, taste or smell. Even though the outer shell between the placebo and active medication was identical, once opened, there is a slight visible difference in size, with the distinctive black ink mark on the active medication that was not possible to replicate on the placebo capsules. This means that a participant who hid the medication in his mouth while being observed to swallow it could potentially open the shell and then establish whether or not he had received OROS-MPH. However, it is not likely that this had a significant impact on the trial outcome because adherence to treatment and dosing was lower in the OROS-MPH arm, guessing of trial medication arm was similar for participants and researchers (for OROS-MPH guessing was close to 50%, indicating random awareness for the active medication) and dosing might have been driven by the presence of adverse effects.

Conclusions and recommendations for future research

In conclusion, the trial is robustly neutral and does not support the routine treatment of young adult offenders with MPH.

Although this conclusion is disappointing, there are several lessons to be considered for future research and clinical practice. We divide these into the following: two recommendations with the highest priority, questions that address limitations of the current trial, general considerations for mental health research in prisons, and the future of clinical care for ADHD among prisoners.

Research teams

A huge thank you to all the fantastic research staff who have worked with us over the years: Craig Marsh, Megan Bedding, Laura Giannulli, Megan Mansfield, Caroline Kelly, Lauren Wilson, Clare McCafferty, Grace Williamson, Khuram Khan, Donnie McPherson, Sharon Jakobowitz, Lydia Carter-Mackie and Prajakta Patil.

Contributions of authors

Philip Asherson (https://orcid.org/0000-0003-2667-2254) (Chief Investigator) had overall responsibility for the trial design and trial management.

Lena Johansson (https://orcid.org/0000-0002-4473-1134) (Clinical Trial Manager) co-ordinated the implementation of the trial and day-to-day management, and contributed to the interpretation of the trial findings.

Rachel Holland (https://orcid.org/0000-0002-8630-2821) (Trial Statistician) developed the SAP, prepared DMC reports, completed all analyses and contributed to the interpretation of the trial findings.

Megan Bedding (https://orcid.org/0000-0002-5256-0021) (Research Worker) contributed to data collection, was a TMG member and contributed to the the interpretation of the trial findings.

Andrew Forrester (https://orcid.org/0000-0003-2510-1249) (Co-applicant) contributed to the design and interpretation of the trial findings, and dissemination activities.

Laura Giannulli (https://orcid.org/0000-0002-4182-1820) (Research Worker) contributed to data collection, was a TMG member and contributed to the interpretation of the trial findings.

Ylva Ginsberg (https://orcid.org/0000-0003-1934-376X) (TSC member) contributed to the interpretation of the trial and writing of the final report.

Sheila Howitt (https://orcid.org/0000-0002-2489-2440) (Co-applicant, Research Psychiatrist) contributed to the design, data collection and interpretation of the trial findings.

Imogen Kretzschmar (https://orcid.org/0000-0002-4615-7754) (Research Psychiatrist) was a TMG member and contributed to data collection and the interpretation of the trial findings.

Stephen Lawrie (https://orcid.org/0000-0002-2444-5675) (Co-applicant) contributed to the design and interpretation of the trial findings.

Craig Marsh (https://orcid.org/0000-0003-2149-8189) (Research Psychiatrist), Caroline Kelly (https://orcid.org/0000-0003-4349-5915) (Research Worker), Megan Mansfield (https://orcid.org/0000-0003-2896-3119) (Research Worker), Clare McCafferty (https://orcid.org/0000-0002-3633-2686) (Research Nurse) and Khuram Khan (Research Psychiatrist) contributed to data collection, were TMG members and contributed to the interpretation of the trial findings.

Ulrich Müller-Sedgwick (https://orcid.org/0000-0002-5499-4077) (TSC member) contributed to the interpretation of the trial findings.

John Strang (https://orcid.org/0000-0002-5413-2725) (Co-applicant) contributed to the design and interpretation of the trial findings.

Grace Williamson (https://orcid.org/0000-0002-4618-5819) (Research Placement Student) and Lauren Wilson (https://orcid.org/0000-0001-8817-6788) (Research Placement Student) contributed to data collection, were TMG members and contributed to the interpretation of the trial findings.

Susan Young (https://orcid.org/0000-0002-8494-6949) (Co-applicant) contributed to the design and interpretation of the trial findings and dissemination activities.

Sabine Landau (https://orcid.org/0000-0002-3615-8075) (Statistician and Co-applicant) provided senior statistical support throughout the trial.

Lindsay Thomson (https://orcid.org/0000-0002-0748-6547) (Principle Investigator and Co-applicant) was instrumental in the development of the trial, led the group in Scotland and contributed to analysis and interpretation of the trial findings.

All authors contributed to the writing of the report and had the opportunity to revise it prior to submission.

Publications

Asherson P, Johansson L, Holland R, Fahy T, Forester A, Howitt S, et al. Randomised controlled trial of the short-term effects of OROS-methylphenidate on ADHD symptoms and behavioural outcomes in young male prisoners with attention-deficit/hyperactivity disorder (CIAO-II). Trials 2019;20:663.

Asherson P, Johansson L, Holland R, Bedding M, Forrester A, Giannulli L, et al. Randomised controlled trial of the short-term effects of osmotic-release oral system methylphenidate on symptoms and behavioural outcomes in young male prisoners with attention deficit hyperactivity disorder: CIAO-II study [published online ahead of print June 3 2022]. Br J Psychiatry 2022.

Data-sharing statement

All data-sharing requests should be submitted to the corresponding author for consideration. Access to available anonymised data may be granted, following review. The data set that will be shared will be a pseudo-anonymised data set and will not include date of birth, initials or prison name.

Patient data

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it’s important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.

Disclaimers

This report presents independent research. The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the MRC, the EME programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, the EME programme or the Department of Health and Social Care.

Concomitant medication at baseline

A total of 60 participants (33 in the OROS-MPH arm and 27 in placebo arm) had no concomitant medication at baseline. Note that paracetamol was not logged at HM YOI Polmont, as such medication was dispensed by prison officers.

Concomitant medication during the trial

A participant was given a standard dose of OROS-MPH from commercial stock in error.