DEcision-making Capacity: Intervention Development & Evaluation in Schizophrenia-spectrum Disorder

1. BACKGROUND \& RATIONALE FOR STUDY 'Treatment decision-making capacity' ('capacity'), is defined as the ability to understand, appreciate, and retain information relating to a proposed treatment, weigh that information and communicate a choice. Capacity is now a pivotal concept in healthcare and law, and clinicians are legally obliged to respect patient autonomy where capacity exists. Capacity has been referred to as the 'gatekeeper of autonomy'. When it is lost there is a legal and ethical imperative for clinicians to work to support its return and retention. However in their scrutiny of capacity-law implementation, the United Kingdom (UK) House of Lords concluded: "Our evidence suggests that (supported decision-making) is rare in practice" and The United Nations Committee on the Convention on the Rights of Persons with Disabilities (UNCRPD) advised that greater provision of supported decision-making is essential if the UK is to be compliant with Article 12 of the Convention on Human Rights. Despite the importance and legal obligation to support capacity there is a lack of evidence on how to do this effectively. A recent systematic review and meta-analysis synthesised evidence from 23 studies on capacity in psychosis and found there were no randomised controlled trials (RCTs) of supported decision-making interventions. Psychiatrists view the evidence in this area as weak, and the National Institute for Health and Clinical Excellence (NICE) have called for RCTs to enhance evidence in this area. Anticipating this, over the last 5 years the research team, comprising clinicians, legal experts and researchers, have produced 5 systematic reviews and meta-analyses addressing various aspects of decision-making capacity in psychosis, and 5 clinical studies. These indicate that a lack of capacity is likely to stem from interactions between cognitive, emotional and social factors, the effects of which are moderated by a person's awareness of them. This model specifically predicts that 'self-stigma', low self-esteem, and the 'jumping to conclusions' (JTC) bias are likely to have large, additive adverse effects on their capacity. Psychological interventions that selectively reduce each of these hypothesised 'causal mechanisms' have already been developed. The next stage of this research is therefore to conduct 'interventionist-causal RCTs' (IC-RCTs) to examine whether these interventions can also cause improvements in capacity. Recommended to accelerate the development of treatments for psychotic symptoms such as delusions, these sophisticated trials are capable of producing invaluable information on what causes and improves impaired capacity. If the trials are run consecutively, people with psychosis could wait 10-15 years for definitive findings and would involve setting up several costly trial infrastructures to support each trial. One simple solution is to conduct these IC-RCTs concurrently, within one trial infrastructure. This approach, also known as an 'Umbrella trial', could produce results in half the time, for half the cost, meaning an effective capacity-supporting intervention could be produced in 5-6 years, rather than 10-15. The aim of this study is therefore to conduct the first Umbrella trial in mental healthcare, using this to accelerate the development of an intervention to support capacity in psychosis. However, prior to conducting a definitive trial, a variety of feasibility issues need to be examined in a randomised pilot study. The planned study addresses these. 2. AIMS \& OBJECTIVES 2.1. Aims \& Linked Research Questions (RQs) Aim 1: Test data quality for a definitive trial (primary aim) (RQs 1,2,5); Aim 2: Test recruitment and retention rates for a definitive trial (RQs 2,3); Aim 3: Test trial procedures for a definitive trial (RQs 3,4); Aim 4: Assess acceptability of interventions for this group (RQs 3,4); Aim 5: Refine treatment protocols to ensure feasibility in clinical settings (RQs 3,4); Aim 6: Consolidate research infrastructure to support main trial (RQs 3,4). 2.2. Research questions (RQs) RQ 1: What data quality and completion rates can be obtained for the main outcome measures? RQ 2: What proportion of eligible patients consent, engage, \& complete the trial? RQ 3: What do participants, clinicians \& collaborators think will improve study processes, including interventions? RQ 4: Are trial procedures acceptable to them, and feasible to implement? RQ 5: What sample size is required in a full study? 3. DESIGN \& PROCEDURE 3.1. Overview This study has been designed to find out whether participants can be recruited and retained in a larger trial characterised by the same design parameters (e.g., allocation ratio, blind assessment, types of treatment and control offered, multiple sites). The planned randomised pilot study is therefore a 20-month feasibility/pilot of a multi-site single (rater) blind Umbrella trial of psychological interventions to support treatment decision-making capacity in people diagnosed with non-affective psychosis (schizophrenia-spectrum disorders). It has been designed primarily to examine post-treatment (8 week) data retention rates for the planned primary outcome \[MacArthur Competence Assessment Tool for Treatment (MacCAT-T) capacity ratings\] in a future definitive trial. In this and the future study, participants will be randomly allocated to receive treatment as usual (TAU) plus a psychological intervention to improve either (i) self-stigma, (ii) self-esteem, or (iii) the jumping to conclusions reasoning bias, or TAU plus an attention control condition. RQs 3 \& 4 will be addressed through qualitative interviews with participants and referrers/clinicians, using Framework analysis. Qualitative analysis of change in participant appreciation, as measured by the MacCAT-T, will be performed using qualitative case study methodology. MaCAT-T appreciation ratings will also be compared to ratings on the Expanded Schedule for the Assessment of Insight (SAI-E). Concordance between overall MacCAT-T judgements and pre and post clinical judgements of referring clinicians, assessed using a version of the Clinical Global Impression Scale (modified to assess global capacity ratings), will also be assessed. To minimise piloting costs 75% of the 60 patient participants will be recruited in the lead site (NHS Lothian). Each intervention group will be compared to its own control group (each receive the same standardised procedure) to ensure participants in each trial are equivalent with respect to their presenting mechanism. 3.2. Participants \& setting Adults (aged 18-65) diagnosed with schizophrenia-spectrum disorder with impaired treatment decision-making capacity, and presence of either low self-esteem, high self-stigma or the JTC bias will be recruited from inpatient and outpatient NHS mental health services across three UK sites; 75% from NHS Lothian; 12.5% from Pennine Care; 12.5% from Lancashire Care. Of these patient participants, 6 will be invited to attend a qualitative interview to understand their experiences of participating in the trial, as part of the Framework analysis. Up to a further 10 will be invited to attend a qualitative interview to understand and verify any change in their 'appreciation' of their illness and its treatment. Six clinical or social care staff who have either referred a participant to the study or have provided substantial care and treatment to a participant during the study, will also be invited to attend a qualitative interview to understand their experiences of the trial, again as part of the Framework analysis. 3.3. Allocation, randomisation and assessment Allocation \& randomisation: Participants will be assigned to one of the two-arm IC-RCTs based on whether they have predominantly low self-esteem (defined as scoring 14 or less on the Rosenberg Self-Esteem Inventory), high self-stigma (defined as scoring 60 or more on the Internalised Stigma of Mental Illness Scale), or the JTC bias (defined as selecting 2 or fewer beads on The Beads Task). Participants with multiple mechanisms will be randomly assigned. All participants will then be randomised (1:1) at the start of treatment session 1 to treatment or control, using randomised-permuted blocks of random size (block sizes of two or four), administered via a study-specific web-based portal according to a concealed randomisation sequence. Assessments: All participants will receive a full research assessment, by a Research Assistant (RA) masked to treatment group allocation, at week 0 (baseline) and week 8 (end of treatment). In addition to measures of change (see outcomes), the Clinical Interview for Psychotic Disorders and the Brief Neurocognitive Assessment will be administered to confirm diagnosis and assess cognitive functioning, respectively, at week 0. Participants randomised in the first 8 (Scotland) or 5 (England) months will be invited to complete a follow-up assessment at week 24. All qualitative interviews will be conducted with participants and their referrers/clinicians following the patient participants' 24-week assessment. 3.4. Study interventions Active interventions (each 6 sessions over 8 weeks): Each intervention is structurally equivalent and will be delivered by the same therapist. The self-esteem intervention is informed by a previous protocol tested with people with persecutory delusions. The JTC intervention, developed and trialled by the researchers and colleagues previously, has been lengthened to 6 sessions by addressing positive beliefs about JTC decision-making and providing greater practice of non-JTC decision-making. The self-stigma intervention developed by a team including the current PI, has been reduced from 12 to 6 sessions by removing self-esteem focused elements. Inactive attention control (6 sessions over 8 weeks): The therapeutically inactive assessment component of a protocol developed and piloted previously by the researchers will be used. To maximise clinical benefit of participation, the potentially active component of this protocol (psychological formulation) will be provided, but only after the participant exits the trial. 3.5. Data Analysis Quantitative: An independent statistician will conduct blind analysis of outcome data. Proportions, means, standard deviations, effect sizes and 95% confidence intervals for all time points will be reported descriptively, on both a strict intention-to-treat and per-protocol basis (≥50% attendance in treatment or control). Concordance between (a) MacCAT-T ratings and clinician ratings of capacity and (b) MacCAT-T appreciation ratings and SAI-E scores will be analysed. Qualitative: A trained RA will prepare topic guides, conduct, record and transcribe the interviews. Under supervision, the RA will also analyse the qualitative data following established guidelines for Framework analysis and qualitative case study methodology. For the Framework analysis, interviews with participants and referrers/clinicians will address feasibility and acceptability of the trial procedures, problems indicated in the quantitative data, and potential solutions. This ensures that the issue is not explored through one lens, but rather various lenses facilitating understanding about multiple facets of the phenomenon. For the qualitative case study analysis, interviews with participants will address their views on their diagnosis and treatment, any subjective change, and the participant's views on the reason for this change. 3.6. Progression criteria for a full trial Funding for a larger trial, using the same trial design, will be sought if the target recruitment is met and post-intervention (8 week) MacCAT-T data from ≥75% of those randomised is retained. If this target is not met, findings from the Framework Analysis will be used to modify the design before further piloting and/or progression. 3.7. Research Team \& Expert Advisory Group This project will receive strong support from: (i) An Expert Advisory group, comprising of experts by experience, experts in law and policy, and experts in psychosis research; (ii) Professor Richard Emsley (Co-Investigator) is Professor of Trial Methodology and former Director of the Manchester Clinical Trials Unit. He sits on the Expert Advisory Group for the world-leading STAMPEDE Umbrella trial of interventions for prostate cancer; and (iii) An experienced multi-disciplinary research team selected to ensure experience and expertise in relation to the interventions, population, outcomes, methodology and ability to manage the various sites, and to strengthen their trial infrastructure for the later trial, building on their existing robust collaborations. 4. STUDY POPULATION 4.1. Number of Participants and Sample Size Calculation The National Institute for Health Research (NIHR) guidance was used to calculate that 60 participants (average of 3-4 per month over 12-months) will allow for an estimated drop-out rate (i.e., data non-retention) of 15%, at week 8, to within a 95% confidence interval of +/- 9%. The proportion of people with schizophrenia-spectrum disorders and impaired capacity who have at least one of the proposed causal mechanisms is estimated to range from 80-100%. Pilot trials suggest ≥80% of those who have one of these mechanisms will consent and be randomised, ≥85% of whom will complete the trial. Six of the 60 participants and six of their referrers or clinicians will be invited to participate in a qualitative interview for the Framework analysis. Up to a further 10 of the 60 participants will be invited to participate in the qualitative interview for the qualitative case study of change in appreciation. 4.2. Identification and Recruitment of Participants One pathway in which participants will be identified is through self-referral. To facilitate this, a poster will be placed in NHS mental health services to advertise the study. A study website will be available, including participant information sheets. Contact details will be provided for those interested in self-referral. Individuals who self-refer, will only be included in the study if they agree that a mental health professional involved in their care, can be contacted to obtain information for risk assessment purposes and to ensure participation is not contraindicated in some way. Another pathway in which participants will be identified is through clinician-referral. As per previous trials, local site Principal Investigators will support RAs to visit clinical services to present the trial, determine initial interest, and distribute information sheets. The information sheet will detail what participants are asked to do, how their information will be used and the possible risks and benefits of taking part in the study. For potential participants entering the study through self-referral, the RA will obtain their explicit verbal consent to contact their key worker/ care-coordinator to determine whether they meet inclusion criteria for the study and to conduct an initial risk assessment. The RA will also ask the clinical care team if they have any concerns about the potential participant's capacity to consent to take part in research. Should participants meet inclusion criteria for the study and continue to express an interest in taking part, the RA will contact them to arrange an appointment. All potential participants will have as long as they wish to consider the information sheet prior to being contacted by the RA, with a minimum period of 48 hours. For potential participants entering the study through the clinician-referral pathway, their clinicians will discuss the study with them and seek their verbal consent to pass their details on to the research team. A trained and supervised RA will then obtain contact details of potential participants from their clinicians and contact the potential participants directly to discuss the study further. Consenting participants will be given a participant information sheet and any initial questions will be answered. As in the self-referral case, consenting participants will be recontacted after a minimum period of 48 hours, with a longer period if required. They will also be risk assessed, and the eligible ones will participate in the trial. For those lacking research capacity, the same initial process will be followed. However in England, the opinion of the potential participant's Consultee will be sought, and in Scotland, consent from the appropriate person (see consent section) will be sought. In both countries, the study will not proceed if there is any indication that the potential participant objects to taking part. 4.3. Consenting Participants During the first meeting with the potential participant, the RA will ensure they have received an information sheet. They will be given the option to review this again and answer any further questions. All potential participants will be reminded that participation is entirely voluntary and that deciding not to take part in the study will have no impact upon the clinical care they receive. They will also be informed of their right to withdraw from the study at any time, without giving a reason, and reassured that exercising their right to withdraw will have no impact upon the ongoing care they receive. Potential participants who still wish to take part will be asked to provide written informed consent at this stage. Once this has been completed, the study will commence. This process will be followed for referrers or clinicians who take part in the qualitative study but adapted to consider the fact that they are not receiving care or treatment. They will be assured that non-participation or withdrawal will have no effect on their employment. Capacity is decision-specific. This means capacity to consent to medication or a hospital admission is distinct from capacity to consent to research or psychological therapy. Nonetheless, a number of potential participants will lack the capacity to consent to both. As with a prior case-series, those with research capacity will be included, but specialist ethical approval to include those who lack it has also been secured. In Scotland, the legislative requirements of the Adults with Incapacity (Scotland) Act 2000, which makes provisions for research with this group will be followed. This means that in Scotland, Guardians, Welfare Attorneys or nearest relatives will be asked to provide consent on participants' behalf to taking part. They will be provided with Research Ethics Committee (REC) approved information sheets and consent forms. In England, the legislative requirements of the Mental Capacity (England and Wales) Act 2005, which also makes provisions for research with this group will be followed. This means that in England, Consultees will be asked to provide advice (which is binding on the researcher) as to whether a participant would wish to take part. They will be provided with a REC-approved information sheet and consultee declaration form. If a participant lacks capacity initially but regains it, their consent to continued participation in the study will be sought. Participants will be provided with a REC-approved continued participation information sheet and consent form designed for those who regain capacity. If a participant has capacity initially but loses it during the study, procedures for participants who lack capacity at the outset will be adhered to. This means that in Scotland, Guardians, Welfare Attorneys or nearest relatives will be asked to provide consent on participants' behalf so that they can continue participating in the study. Participants will be provided with a REC-approved continued participation information sheet and consent form. In England, Consultees will be asked to provide advice (which is binding on the researcher) as to whether a participant would wish to continue to take part. They will be provided with a REC-approved continued participation information sheet and consultee declaration form. A trained RA will, in conjunction with the Principal Investigator, determine whether participants have the capacity to give consent. The latter will ensure RAs and the Trial Manager attend NHS Scotland and NHS England training on informed consent and working with people who lack research capacity. 4.4. Participant withdrawal Participants can withdraw from the study at any point, without giving any reason and without their legal rights or usual care being affected. Participants may also be withdrawn if their continuation is deemed to be harmful. The data monitoring and ethics committee (DMEC) will review all instances of adverse events, whether or not they are judged to be attributable to the trial or interventions, and, based on this information, determine whether the participant should be withdrawn. All events will be reported to the REC. Advance consent from all participants with capacity will be sought to retain existing data. This is in the event that they subsequently withdraw due to loss of contact, or loss of capacity to consent to research, where they have not otherwise informed the investigator that they wish their data to be removed. No data will be retained for individuals who lose capacity if the legal representative (Scotland) or Consultee (England) objects to this. 5. STUDY SUSPENSION OR DISCONTINUATION The research would be stopped in the event of a number of therapy-attributable adverse events. As earlier noted, any serious adverse events will be passed on to the independent DMEC for review and advice on whether to suspend or discontinue the study. This advice would be acted upon by the researchers, in consultation with the Sponsor and REC. 6. ADVERSE EVENTS The interventions being tested have each been used previously with people with psychosis, including in randomised controlled trials and no severe adverse events have been reported. However, to improve the recording and reporting of adverse effects of psychological interventions, a robust protocol for assessing and managing any such risk will be completed at end of treatment and at follow-up by RAs masked to treatment condition. This protocol, excluding the Adverse Events Questionnaire (which is designed to be completed after treatment), will also be completed by clinicians during the intervention (i.e., every session) to complete an assessment of severe adverse events. They will be instructed to report all adverse events to the trial manager, using a standardised form.