Regenerative medicine: Stroke survivor and carer views and motivations towards a proposed stem cell clinical trial using placebo neurosurgery

Abstract Background Few studies explore stroke survivor views and motivations towards stem cell therapy (SCT). This qualitative study explores the views and motivations of both stroke survivors and their partners/carers towards a proposed 2‐arm Phase III Randomised Controlled Trial (RCT) comparing intracerebral insertion of stem cells with placebo neurosurgery in stroke survivors with disability. Objective To explore views and motivations towards a proposed 2‐arm stem cell trial and identify factors that may impede and enhance participation. Design This study adopts a naturalistic design to explore the complexity of this field, employing a participatory action‐research approach comprising a specialized Conversation (World) Café form of focus group. Data were collected via 5 Conversation Cafés with stroke survivors (age 40‐75) and partners/carers between June and October 2016. Of 66 participants, 53 (31 male, 22 female) were stroke survivors and 13 (6 female, 7 male) were partners/carers. Qualitative data were analysed using a thematic approach. Discussion and Conclusion Stroke survivor views and motivations reflect anticipation of the personal and future benefits of regenerative medicine. Partners/carers sought to balance the value of stroke survivor hope with carrying the weight of hope as carer, a conflict burden adding to known caregiver burden. All participants expressed the need for during and post‐trial psychological support. This study provides a rare opportunity to explore the prospective views and motivations of stroke survivors and their partners/carers towards a proposed Phase III 2‐arm RCT. This adds weight to qualitative evidence exploring capacity, consent, decision making, perceptions of treatment risk and supports required for clinical trial participation.


| INTRODUCTION
Stroke is the third leading cause of complex disability: over half of 1.2 million stroke survivors live with disability caused by damage to brain tissue/cells as a result of blockage or haemorrhage of the blood supply. 1 Stroke can impair a range of cognitive and physical functions and significantly impact on individuals' and carers' quality of life.
Recent scientific research focuses on investigating the therapeutic value of stem cells to replace lost or damaged cells from stroke. Early stage phases I and II clinical trials have demonstrated the safety of injecting intracerebral stem cells. 2,3 The proposed Phase III Randomised Controlled Trial (RCT) aims to assess the safety, tolerability and efficacy of intracerebral stem cells in patients with disability following an ischaemic stroke. Participants will be randomized (2:1) to active or placebo neurosurgery. Stereotaxic methods will be used to inject the cells via a cannula into the damaged hemisphere using local or general anaesthetic and analgesia. For patients allocated to receive placebo, only the outer table will be removed and the dura will not be breached during the procedure. Similar placebo-controlled surgical trials have been conducted in other fields (in Parkinson's disease, eg 4,5 ), but the proposed stem cell therapy RCT is novel in the field of stroke and has the potential to raise questions from participants and the medical community.
Many trials struggle to recruit and retain target patient numbers, and only about 50% reach their recruitment target. 6,7 This jeopardizes the trial's internal and external validity, potentially delaying the development of more effective treatments. 8,9 Recruitment is reported to be particularly difficult for trials involving randomization and placebo arms [10][11][12] and is predicted to be challenging for trials involving stem cells due to anticipated ethical and moral uncertainties about riskbenefits. 13 Among the factors influencing trial recruitment rates, patients' beliefs and preferences have been identified as key barriers to participation. 14 This study provides further evidence highlighting the views and motivations of the target patient group and identifies factors that may impede and motivate patient participation. 15 Ethical principles governing clinical trials require that patients provide informed consent following a voluntary and informed decision about taking part or not. 16 An informed decision requires that individuals consider information about all available options and their consequences, evaluate this information in accordance with their own values, preferences and circumstances and make a deliberate choice based on trade-offs between these evaluations. 17 In the context of stem cell trials for stroke, this process is also likely to be shared among patients, carers and their health professionals, each bringing their own values and preferences. 18 Factors such as contrasting views and motivations, expectations of curative benefits, and the context in which trial recruitment takes place may render the decision-making process susceptible to biases. 19,20 Recruitment procedures therefore must ensure that patients and families are enabled to make an informed decision. Study sponsors must balance the ethical aspects of the Phase III trial protocol and potential therapeutic misconceptions against strategies to optimize trial recruitment. Standard processes put in place to enable informed consent have been recently criticized as suboptimal for not meeting the needs of patients in terms of making an informed decision, calling for alternative approaches to be developed. [20][21][22][23] Given the dual challenge of maximizing trial recruitment while respecting and supporting individuals' informed decision making, this research was sponsored to further understand the views and motivations of people affected by stroke and their partners/carers towards the proposed Phase III two-arm trial. While current evidence 13,24 highlights some positive motivations towards stem cell therapy, this study extends understanding by highlighting stroke survivor and partner/ carer views as a two-way involvement process, revealing key impediments that require targeted support to enhance participation in the proposed Phase III trial.

| Design
Qualitative methods are well suited for investigating concepts such as views and motivations within the patient community to help explain the processes at work in the uptake of new interventions and decision making around trial participation. 25 This study adopts a naturalistic design 26 to explore complexity in this field, adapting from a participatory action-research approach comprising a specialized World (Conversation) Café form of focus group.
The Café approach creates a relaxed, informal and conversational environment, facilitating constructive engagement around complex issues and critical questions. This is an effective format for hosting interactive and large group dialogue. Each Conversation Café event begins with an introduction by the lead host (first author) to set the context and put participants at ease. Each event comprises up to five tables (4-5 participants) and one host (researcher) and consists of a series of conversation topic rounds lasting up to 20 minutes (Table 1).
The role of each table host is to provide structure and orienteering as the café process unfolds, encouraging conversation without taking over. A final plenary session, delivered by the lead host, draws together key agreed themes, inviting individuals to share further insights from their larger group conversations. 27

| Population, sampling and participant recruitment
Potential participants were identified from UK stroke community support groups. These groups can be advantageous to stroke survivors and their partners/carers as they often combine social function with physical rehabilitation therapy. While each individual stroke T A B L E 1 Conversation Café rounds Round 1 Proposed trial: all views Round 2 Information needs Round 3 Trial protocol: skewed randomization and placebo group Round 4 0-12 months post-stroke experience may be unique, there are common themes within stroke narratives and many use the support group to share their strategies for overcoming challenges. 28 Sampling decisions were conceptually driven. 29 At the centre of this framework were the experiences of stroke survivors and their partners/carers. Purposive predetermined sampling procedures were used to identify community groups based on relevance to the research topic and to ensure a broad range of views and motivations. 30 Sample size was guided by early analyses taking place alongside continuing data collection, until no new themes emerged from the data and data saturation could be confirmed. 31  Conversation Café topic guides with probes ( Table 2) were informed by evidence and literature on experience and attitude towards placebo-controlled trial [31][32][33][34] ; the effect of randomization as a predictor of volunteering 35,36 ; therapeutic misconception, 37 attitudes to stem cell use and donation. 38,39 Each table, with refreshments provided by the research group, held a focused group conversation using the study topic guide. 40 All Conversation Café events were audio-recorded and transcribed verbatim. Participants were also provided with Post-Its, pens/pencils and writable tablecloths to record any notes or comments. This was also employed as an aid for those with speech difficulties or reluctant to voice opinion within a group setting.

| Analysis
Data were analysed using thematic analysis 41 to identify, interpret and report patterns and themes within the data. An initial coding framework ( the research team undertook this procedure simultaneously. Similarities and consistencies ensured reliability and trustworthiness of the analytical process. Table 4 provides example of the movement from the initial coding framework to the next stage mid-ordering of codes. The codes illustrated provide example of diversity and pattern within the data. Those too diverse or lacking in depth were discarded. The next analytic stage focused on searching for themes and combining different (and sometimes similar) codes to represent aspects within the data. Visual thematic mapping enabled the consideration of links and relationships to support the interpretive process. Figure 1 illustrates the movement between the mid-stage ordering of codes to first organizing themes.
This reflects a process of clustering, collapsing and combining codes that shared unifying features so that they reflected and described meaningful patterns. For example, we noticed code clustering and overlap around risk, motivation and caring. Examined in detail, we identified the codes reflected positive and negative talking and often conflicting views and motivations between patients and partners/carers.

| RESULTS
The themes identified below represent themes identified, albeit some elements may overlap. This does, however, represent relationships between views and motivations as opposed to suggesting all concepts Box 1 Example coded data

Data extract Coded for
So you would support him in this type of trial? (Café Table Host should be understood in isolation. The coding key used reflects Café (A-E), P or C (patient or partner/carer) and numerical participant identifier.

| Anticipation and regenerative medicine: Superman was right, wasn't he?
Anticipation

Box 2 Definitions and labels
Anticipation: Superman was right, wasn't he?
Outlines how stem cell therapy is a fast-developing area of research and treatment, driven by better understanding of potential therapeutic opportunities and promising early phase clinical trials. Participant narratives are influenced by strong media coverage exalting the recovery of people disabled by stroke often enhancing known therapeutic misconception. Participants-particularly stroke survivors-praised the potential assumed benefits via stem cell therapy-and in contrast to the measured information given to them. Generally, positive media reporting also appeared to influence the general acceptability of participation in stem cell trials. While some participants requested further detail, most expressed a lack of concern. In general, participants-stroke survivors in particular-held strongly positive optimism towards stem cells which may require specific and targeted support.

Capacity and decision making: Making a snap decision
Outlines how participants identified key issues in relation to capacity and vulnerability during the proposed trial decision making and treatment period. Participants highlighted the difficulties of known cognitive, orientation and functional impairments post-stroke and expressed concern around capacity for informed consent during the time-period proposed. Many also highlighted the unknown difficulties that may emerge during and beyond participation.

Care conflict: Balancing hope
Focuses on developing understanding of known caregiver burden 54,55 and in relation to participation in clinical trials. This third theme also represents elements of the above 1st and 2nd final themes. Negative and positive discussions around the proposed trial reflected conflicting motivations and competing pressures. Partners and carers narratives illustrate a two-way involvement in trial participation decision making, constantly weighing up perceived risks and benefits and assuming some responsibility for managing motivations. While all partners and carers provided support, the strong notes of caution and concern constitute important additional elements in our understanding of caregiver burden, trial decision making and the extended supportive interventions required during trial recruitment, participation and post-participation.

Mark my words [emphasis] and watch for the papers! [E: P5]
Highly anticipative discussion can be contextualized against the sudden impact of stroke and often long-term effects. Views and motivations were conditionally influenced by strong assumptions around therapeutic benefit and may extend beyond motivations towards the collective good. While these findings resonate with known work highlighting conditional altruistic motivation 43,44 towards trial participation, in this study, participation-benefit-risk reasoning was measured against at times unrealistic assumptions around treatment outcomes.

| Capacity and decision making: A snap decision?
Participants were invited to reflect back to the 3-to 11-month period post-stroke during conversation. All groups raised concerns over the value of physical therapy and rehabilitation services. For many, these services had been restricted to 6 weeks post-stroke. Many described a sense of abandonment by mainstream health services when this ended. The proposed trial offers assignation to a physical therapy programme pre-randomization, to be self-delivered after an initial training programme. Physical therapy would be continued for 12 weeks post-surgery. (C: C1) Participants described the trajectory towards depression as a slow one-a real fear for some and a reality for many. The difficulty negotiating this trajectory combined with trial participation while hoping for recovery was a strong concern. All participants identified the need for during and post-trial psychological support.

| Care conflict: Balancing hope
Caregiver burden is recognized as a significant health-care concern 46 and elevated for an indefinite period following stroke. 47 Carers play an important role in post-stroke rehabilitation, may enable a return to live at home or in the community and potentially positively impact on health outcomes. In this study, partner/carer views towards the The prevalence of neurological impairment, depression and anxiety is known effects continuing up to 5 years after an incidence of stroke. 48 Partner/carer views about the proposed trial also highlighted psychological concerns in relation to the possibility of post-treatment regret, anticipated to bring additional difficulties not only to stroke survivors but also to partners/carers. Partners/carers reported watching "from the outside" Across all groups, discussion revealed some key differences between stroke survivors and partners/carers. This provided further insight into the needs of stroke survivors and partners/carers and the support mechanisms that may be required to enhance participation.

| DISCUSSION
This study provides a rare opportunity to explore the prospective views and motivations of stroke survivors and their partners/carers towards a proposed 2-arm RCT using stem cells via placebo neurosurgery. Our findings add qualitative weight to recent evidence (see Ref. 24). The following section considers the factors that further impede participation and suggests strategies to enhance participation.

| Conflict burden
It is important to highlight that supportive views and motivations towards the trial were influenced by high expectations of personal benefits, a "conditional altruism" influenced by (i) strong media reporting of earlier trial results and (ii) therapeutic misconception concerning the restorative potential of stem cells. 43,49 However, partners/carers revealed contrasting viewpoints and motivations. Partners/carers of survivors with neurological disease are known to have a higher risk of physical, mental and emotional depletion and reduced quality of life. 47 Our findings indicate that partner/carer views and motivations were influenced by different perceptions and trade-off between riskbenefit. We introduce the concept "conflict burden": carers report conflict, guilt and increased concern in relation to assumed physical and psychological risks involved when faced with stroke survivor's motivations towards clinical trial participation. This "conflict burden" was underlined via described tension between stroke survivor hopefulness and carers felt-conflict supporting hopefulness.

| Two-way involvement
Stroke survivors and their partners/carers discussion highlighted a two-way involvement in decision making. These findings remind us that when developing information and decision-aids, survivor views should be placed at the core but this should not be to the exclusion of the views of partners/carers. Our study adds to evidence for trial information to be framed in the context of patients' and partners/ carers-interpersonal relationships and complex decision-making processes. 22,50,51 It is worth noting that some consideration has been given to this issue in related fields. [52][53][54] Alzheimer's, as an irreversible neurological disease, also impairs cognition, orientation and functional capacity.
The carer is often actively supported to be involved in decision making. Current recommendations to support participation in clinical trials position the carer as "study partner" to aid with decision making and consent. 55 Stroke carers also experience the effects of stroke as sudden, unpredictable and disruptive, affording insufficient time for preparation in advance of complex care responsibilities. While carer involvement in decision making may relieve some of the difficulties of cognition, orientation and functional capacity, conversely, this responsibility may also cause conflict and add weight to known carer burden. 56,57 Our data suggest interventions should be mindful of the complex and at times, conflicting caring and interpersonal context 14,18,32 when exploring ways of involving and supporting carers through the clinical trial decision-making process.
The timing of the proposed trial during the 3-to 11-month period post-stroke was a concern for all participants, particularly in relation to the difficulties of survivor cognition, orientation and functional capacity. The acute effects of stroke may also include being prone to impulsive decision making and experiencing impairment balancing rewards with risk. 58 This may combine with uncertainty, disruptive and shifting changes, a trajectory of post-stroke depression, either in the early or in late stages after stroke. During this period, stroke survivors must evaluate the trial and make decisions about risk-benefit. This represents a delicate trade-off 59 and one that may be compromised during the acute recovery period.
Our findings highlight key concerns and add evidence to recent work exploring decision making and strategies to alleviate recruitment difficulties. 20,43,60 The conflicting effects of hope on stroke survivors and partners/carers are a notable concern. These effects may make trial participants more vulnerable and carers/partners more burdened. While many trials seek tools to inform and facilitate improved recruitment rates, there is less emphasis on requirements for post-trial support. In our study, retrospective consideration revealed concerns around psychological support during and post-trial participation; particularly, if the nature of impairment may escape detection during pretrial cognitive screening. For example, participants expressed concern their depression trajectory emerged during later months post-stroke, and the possible negative impacts from trial participation, particularly unblinding to placebo post-trial.

| Enhancing participation
This study suggests strategies to enhance participation should include: consideration of consent as a two-way involvement process between stroke survivors and carers, best obtained as (at least) a two-stage process: initial consent followed by reaffirmed consent at interval and including appropriate time for reflection. Known and unknown cognitive and functional impairment and concerns around capacity and vulnerability were primary concerns in this study. Following NICE guidelines, this may be supported via the implementation of a stroke-specific stepped-care model of support at key interval periods.
The support needs of partners/carers should be given independent consideration. Carer strain, burden and conflict should be reassessed regularly. This could coincide with trial follow-up dates and be accompanied by direction to regularly scheduled counselling services and/or partner support groups.

| CONCLUDING REMARKS
Achieving optimal recruitment rates can be difficult, particularly in relation to highly invasive trials. Our findings highlight critical stroke

| STRENGTHS AND LIMITATIONS
The use of Conversation Café created a relaxed, informal yet supportive environment to encourage discussion around this topic, creating rich data with the added bonus participants enjoyed the event.
Some stroke survivors experienced moderate-to-severe aphasia, making prolonged speech tiring and full-participation difficult. However, group organizers advised that the Café topic had generated such a high level of interest that some group members experiencing moderate-tosevere aphasia had spoken in public for the first time at this event.
Retrospectively, many participants revealed suggested cognitive and functional difficulties that could affect informed decision making.
Nevertheless, retrospective questions concerning motivational, attitudinal, cognitive or affective states may also be affected by recall bias.
Further, participants were not reflecting on actual trial participation.
Therefore, views and motivations within a real setting are unknown.
Participants are not fully representative of the stroke survivor community. For example, Group A advised that while group numbers had significantly increased for the Conversation Café event, some people had advised they had chosen not to attend because they disagreed with research involving stem cells.