PUMA Working Groups

PUMA Working Groups

Patient and Carer Engagement Working Group (PCEG)

Aim: To ensure effective and meaningful lived experience (patient and carer) contribution to all aspects of the design of PUMA, alongside increasing awareness to support and facilitate recruitment and retention.

Each of the other WGs including Trial Design, Outcomes Selection, Drug Selection, and Infrastructure will have 2 patients and 1 carer to represent lived experience expertise per WG. All these lived experience experts (LEEs) come together in the Patient and Carer Engagement Group (PCEG).

The aims of the PCEG are to provide an opportunity for LEEs to: (i) provide an update on their WG discussions and raise any questions that requires further discussion; (ii) raise any issues they feel should be addressed, for instance in terms of how the WGs are managed, the topics discussed, how included/supported they feel/or feel not.

Plan: In PCEG, the members discuss among themselves everything that is discussed in other WGs so that the LEEs will have contribution across the piece and not just to their one WG. Each of the other WG meetings ends with a debrief of the meeting Chair and the LEEs and the minute-taker. The LEEs will bring a summary of main issues that were discussed and key decisions that were made to PCEG meetings to discuss and get ideas and feedback and will report them back to their WG.

Combining our team’s extensive experience in working with LEEs with learnings from the ACT-PD and OCTOPUS, we will use various ways to maximise contribution of LEEs while making it a positive experience for everyone and ensuring an equitable relationship is maintained in all WGs. Examples of these include the following:

• Upskilling the LEEs: We will prepare a training package for the recruited LEEs to ensure they have the opportunity to develop the required knowledge and skills for feeling prepared and confident for contributing to this project. This will include, for instance, training on health research in general, more specifically about MAMS trials, e.g an overview of the terms used or analysis, but also skills on how to provide feedback, or influence decision-making. We will adapt the training offer based on the needs that will be raised by the group. If some of the LEEs have less experience in research, we would ensure to provide them extra support and training from experts within the study team.

• Upskilling the WG Chairs/Co-Chairs: WG Chairs/Co-Chairs will be responsible for ensuring that LEEs have an equal voice at all tables. We will brief the WG Chairs/Co- Chairs on effective and inclusive ways of working with LEEs and will provide refresher training for them if needed. The need will be identified based on the feedback from LEEs who are part of each WG.

• On the agenda of other WG meetings, PCEG report will always be the first item so the meetings start by the feedback of PCEG on questions that were raised in the last WG meeting.

• We will pay particular attention to availability and preferences of the LEEs when choosing meeting times and locations - the latter if in-person.

• We will be conscious of the potential burden of long and in-person WG meetings on LEEs so we will consider offering a flexible involvement model so people who fancy long meetings could do that, with in-person and remote options, and people who prefer to have shorter check-in meetings one-on-one with a project team member to give input - they could. For long in-person meetings, we will provide a chill-out room with water and snacks so LEEs could leave meetings to recharge anytime. We will have project team members who will be on hand to chat and check in if people need it or need any further support.

• We will use The Learning Together Evaluation framework for Patient and Public Engagement (PPE) in Research to plan and to evaluate engagement before, during and at the end of the project.

• We will pay the LEEs for their time and contribution based on the NIHR payment guidance and will reimburse expenses related to this project, e.g. travel cost for attending in-person meetings. 

We will appoint a Principal Safeguarding Officer (PSO) for the project (Lea Milligan, CEO of MQ) who will have oversight of safeguarding management of the project and we will have a Designated Safeguarding Lead (DSL) in all of the collaborating canters on this application. We will develop a Safeguarding Policy Statement based on the risk assessment that will be done in the beginning of the project and in consultation with Wellcome. Online training on the project safeguarding policy will be provided to all relevant members of the team likely to be in contact with vulnerable adults.

Trial design Working Group

Aim: To develop a Master Protocol that will describe the objective(s), design, methodology, statistical considerations, and organisation of a MAMS trial, and ensure the safety of the trial participants and integrity of the data collected. The Master Protocol will also include intervention specific appendix for each treatment included to the platform throughout the duration of the trial. The trial design will incorporate details of interim analyses that allow each intervention to stop early for futility, stop early for superiority, or continue to randomise participants. This group will have a funded postdoctoral statistician to undertake modelling of trial design scenarios. This member of staff will also be a member for treatment prioritisation and outcome measure selection working groups, to enable close communication between the groups.

Rationale: Design of a MAMS trial needs to take careful consideration of the control group, since the group of participants randomised to receive standard of care placebo must be sufficiently comparable with each of the active treatment arms. This becomes more challenging if there is any variability regarding the inclusion and exclusion criteria between the active treatment arms. Therefore, the randomisation tools in a MAMS trial must take account of all restrictive inclusion criteria to ensure that there is numerical balance between the placebo arm and active treatment arms. While this may mean that the overall control arm will ultimately contain more people than each of the individual active trial arms alone, it will still be far smaller than the previous requirement of having a separate placebo arm for every active comparator. Other advantages include the incorporation of both phase II and phase III evaluation within a single protocol, with seamless transitions and data from the early stages contributing to the final evaluation; and opportunities to stop recruitment early to interventions that are not showing promise, allowing redirection of resources. The design also allows addition of new therapeutic arms over time, as they become relevant, dramatically reducing set-up times relative to initiating a new study. The design allows the use of an intermediate outcome. A suitable intermediate outcome increases power to weed out potentially ineffective  treatments much faster and in a more efficient way. 

Plan: This WG will therefore consider the various components of trial design including: (i) participant selection  criteria across placebo and treatment arms; (ii) stratification; (iii) outcomes (both clinical/primary outcomes and suitable intermediate outcomes, working closely with the outcomes working group; iv) duration of follow up and frequency of assessments; and (v) treatments and their mode of delivery. The group will work with clinical trials and drug licensing regulatory agencies to ensure trial protocol meets all regulatory requirements.

 Exclusion criteria should be as few as possible, and only if essential i.e. people should not be excluded on the grounds of  comorbidity, age, gender, illness severity, language. The ambition is that most people with psychosis who want to take part in research are able to do so. The lesson from other MAMS trials is that using remote monitoring and home-based trial visits as much as possible was much more acceptable to participants. The trial design working group will link closely with the outcome measures working group and treatment prioritisation working group, as the outputs of these groups are of fundamental importance to the trial design. There will be cross-representation of members between the trial design and treatment prioritisation and outcome measures working groups.

Treatment prioritisation Working Group

Aim: To develop a priority list of drugs for inclusion in the trial. Also, to prioritise and select 'high potential' drug candidates that will allow seamless addition of investigational arms in the future to the MAMS trial. 

Rationale: A key component of the MAMS design is the multiple treatment arms that can be flexibly incorporated into the overall trial and continued or discontinued according to interim analyses and corresponding safety profiles. This requires a robust process for selecting treatment arms, and ensuring they are ready for addition to the MAMS trial. Selection of appropriate candidates will require the in-depth knowledge and expertise of psychopharmacology. An important consideration will be patient acceptability of any proposed intervention.

Plan: The process involved for the treatment selection for an MS MAMS has been published. For every drug that was shortlisted the patient community were asked to assess the acceptability of the drug, based on mode of delivery, side effect profile and risks. The selection process is evidence-based, including the preparation of ‘drug CVs’ with all available clinical and pre-clinical data for consideration by the committee. It involves a systematic, comprehensive assessment of all available compounds, including existing clinical trials, input from the community and from industry contacts. 

The steering group and trial management group review the drug CVs and priority list, bringing in other relevant information, such as practicality, patient acceptability, cost, etc., to pick the best 2 to be included in the initial trial, reviewing and updating all this information for subsequent randomisations. Final decisions are taken by the steering group.

We will start with repurposed licensed drugs that would be available for immediate use in a clinical trial rather than products that do not have a license yet for any condition, therefore we will particularly focus on recent reviews and meta-analyses of promising compounds, such as Correll et al 2017.13 This review and meta-analysis identified 21 interventions, with a diverse range of mechanisms, that showed a possible therapeutic effect in psychosis, when added to antipsychotic medication. 

The committee will select mechanistically diverse drugs so that the MAMS trials are as rapidly informative as possible, and so that interventions shown to be effective can potentially be combined to investigate additive effects. This WG will also include development of processes for considering access to drug supplies, access to placebo versions and/or feasibility of over-encapsulation, and considerations relating to pharmacy, distribution and labelling requirements.

Following the initial selection process the prioritisation will then convene as required to review new proposals for proposing as additional arms for the platform. This will be done on a regular basis, depending on need. This group would be available for companies to approach with a view to using the platform to trial promising new drugs. In this situation there would be discussion regarding access to compounds and contracts negotiated with the sponsor. Wherever possible we would use model agreements regarding costs and IP to make the process as streamlined and attractive to companies as possible.

There are novel compounds currently going through development that would be early potential compounds for testing through PUMA in the next phase. Both Karuna therapeutics (muscarinic receptor agonist) and Sunovion (trace amine-associated receptor 1 (TAAR1) agonist) are submitting to FDA this year, with likely availability of their compounds in 2024. Other companies are trialling Vesicular monoamine transporter 2 (VMAT2) inhibitors, which already have existing licences for use in movement disorders.

Non-drug therapies: Whilst the initial focus of the treatment selection working group will be on drugs, our ambition is for this group to evolve over time and enable the future inclusion of other types of treatment, whether psychological, or social, either individually or in combination. This was achieved with the STAMPEDE trial, which has, for example, included radiotherapy and drug treatments. This will require the recruitment of additional working group members over time.

Outcome measure selection working group.

Aim: To select the most appropriate intermediate and final phase outcomes to be used, which are clinically relevant, meaningful to patients and align with regulatory requirements.

Rationale: Traditional trial design works particularly well for diseases where a relatively simple and straightforward outcome can be used to measure the desired effect of the drug. In clinical trials for cancer, for example, such outcome measures would be the effect of treatment on tumour size, or more often, the survival time of patients given the new treatment. Other diseases, for which survival is not a valid outcome measure, may have other

measures which give a direct, objective and definitive measure of drug effect on disease activity. For example, measuring blood sugar levels is used when evaluating effects of new diabetes treatment. We do not currently have a clear, direct, objective and commonly accepted measure to evaluate the effect of therapies in early psychosis.  Instead, trials have focussed on clinician rated symptom scales, which largely ignore important outcomes from the patient perspective.

Plan: As a first step we will scope existing research, both completed and ongoing, to examine common outcome measures in psychosis. We will include ongoing research, such as the Wellcome funded common measures programme, directly into the working group. The results of the review of the literature and key factors will be presented to the patient and carer group for face validity - and to ask if there is anything we might be missing that we need to consider. Likely candidate outcomes include symptoms (psychotic and affective), cognitive factors, functional status, quality of life, perceived (subjective) recovery, and other behavioural markers (e.g. sleep, activity levels). At the moment, we do not consider it likely that there will be separate intermediate outcomes that are reliable indicators of later, final phase outcomes.

The primary and secondary outcomes to be selected for the trial will be informed by patient priorities, acceptability and deliverability considerations as considered by the relevant elements of the Delphi study. Importantly, the outcome measure chosen must be acceptable to regulators that ultimately make the final decisions regarding whether a drug should be licensed or not for use in Early Psychosis. Another important component of this working group will be horizon scanning for future outcome measures and to work collaboratively with the infrastructure working group to ensure that future measurement needs are anticipated and enabled within the developing MAMS infrastructure. Our group will include expertise in collection of outcome measures in early psychosis, such as digital tools, which are likely to be more acceptable to participants. (eg https://www.digitalpsych.org/first-episode-apps.html).

Trial Infrastructure Working Group

Aim: To develop a model for the infrastructure to support successful MAMS trial delivery.

Rationale: The success of a MAMS trial will depend on: (i) the agility to rapidly recruit the large numbers of participants required from the outset and (ii) the ability to recruit multiple sites for the multi arms. Furthermore, depending on the trial design characteristics of the trial and the treatments selected, there may be a requirement to stratify the patients in the treatment (and control) arms.

This group will scope the infrastructure necessary for delivering the platform trial and develop a recruitment strategy. The ambition is for the MAMS to be the single trial platform in psychosis and available to as many people experiencing early psychosis as possible. It therefore needs to be pragmatic and aligned with routine clinical practice. It must be deliverable in all parts of the country. 

This will be done alongside the Clinical Research Network (CRN) and the Mental Health Mission, both of which are tasked with increasing clinical trial activity across England. The CRN enables high-quality health and care research in England by meeting the costs of additional staff, facilities, equipment and support services so that research is not subsidised with funding that has been provided for health and care treatments and service. The CRN also provides a vast range of national and local resources and activities that support health and care organisations, staff, and patients and service users to be research active, such as specialist training, information systems to manage and report research, patient and public involvement and engagement initiatives, and communications expertise. We will build on this network, exploring the potential for expanding and developing this network further, for instance through supporting a network of junior doctors to recruit into the trial.

We have established and maintained a large network of EIS, including clinicians and local CRN funded staff in more than 40 NHS mental health trusts in England and Scotland through our study on the prevalence of pathogenic antibodies in psychosis (PPiP2; IRAS 99740). Most study PIs in this study are consultant psychiatrists in EIS. The relationship with sites is maintained by close recruitment monitoring, quarterly webinars, training and monthly or fortnightly meetings aimed at supporting the development of effective recruitment strategies adapted to local settings.

We have invested in the development of the local research culture by offering virtual face-to face and website-based study recruitment training to all junior doctors at the start of each rotation in participating sites. More than 380 junior doctors have been trained in the last two years.

Plan: The WG will aim to establish a network of trial-ready study delivery sites with appropriately trained workforce. As an initial step, in order to be able to best build and learn from existing infrastructure, we will map the current research infrastructure in terms of current and historic recruitment to clinical trials. We are at an advantage because we already have high quality, epidemiologically informed prevalence heatmaps of first episode psychosis through www.psymaptic.org 

This WG will identify areas where patients are well served, but also could identify areas of potential, where improvements in research infrastructure could lead to significant increases in recruitment. Site engagement will be a crucial element in ensuring that recruitment of participants to the platform is maximised and is retained. We will employ a communications lead to work with us on this, jointly with RCPsych CCQI. They will be tasked with building a research team community across EIS teams, developing a culture of embedding research into routine clinical care. Site selection and readiness will be supported by National Institute for Health Research Clinical Research Network (NIHR CRN). Initiating patient identification and recruitment at multiple centres, (without randomisation) will establish the real-world acceptability of the decisions taken in the setup phase with respect to inclusion criteria, outcome measures and local resources.