PERSPECTIVES: Stroke survivors' views on the design of an early‐phase cell therapy trial for patients with chronic ischaemic stroke

Abstract Background Stem cell research holds the potential for a paradigm shift in the management of diseases such as stroke. Patient and public involvement in research (PPIR) can bring a focus to issues of clinical relevance and accelerate translation to real‐world clinical practice. Objective A qualitative thematic analysis of the perspectives of stroke survivors regarding the conduct and design aspects of a proposed phase I clinical cell therapy study in stroke. Design Twelve stroke survivors were purposively recruited in July 2016–August 2017 and participated in semi‐structured, face‐to‐face interviews for input into the design of a proposed phase I clinical study of autologous dental pulp stem cells. Concurrent thematic analysis was conducted until data saturation was achieved. Discussion and conclusions Participants conveyed that the most relevant outcomes to them were regaining participation, decreased dependence on caregivers and improvement in cognition, memory, mood, pain and fatigue. The perception of risk vs. benefit was likely influenced by the time elapsed since stroke, with participants being more willing to accept a higher level of risk early in the post‐stroke disease course. They believed that all stroke survivors should be given an opportunity to participate in research, irrespective of their cognitive capacity. A relatively small sample population of 12 stroke survivors was studied as thematic saturation was achieved. PERSPECTIVES study applied principles of PPIR to early‐phase cell research. Incorporation of outcomes relevant to patients' need within the study design is critical to generate data that will enable personalized application of regenerative medicine in stroke.


| INTRODUC TI ON
The Global Burden of Disease Study (2015) reported that stroke was the second highest cause of years of life lost globally. 1 While the age-standardized mortality from ischaemic stroke in the past decade has declined, approximately 33 million ischaemic stroke survivors worldwide continue to experience lifelong disability and nearly 80% of patients with ischaemic stroke return home with residual impairment. 1 Regenerative medicine represents a paradigm shift in approach to disease management with the possibility of potential cure or long-lasting remission for many disease conditions with high-unmet need. Early clinical studies with stem cell therapies support a novel approach for neuroregeneration and repair following stroke with a potentially longer window of opportunity. 2 Cell therapy comprises a composite of different cell types being investigated in different phases of stroke, with use of different dose and delivery regimens.
Clinical translation in stroke has been riddled with a disappointing failure of numerous promising preclinical therapeutic candidates, over the last few decades. Currently available therapies are limited in application to the acute phase of stroke. 3 Stroke represents a diverse set of disease trajectories defined by distinct temporal patterns of neurovascular injury unique to a given patient. 4 The heterogeneity in patient and disease characteristics has contributed to challenges in choosing the appropriate trial design as well as population and efficacy parameters. This, in turn, makes it difficult to assess the effect size of an intervention and its clinical relevance and validity.
Recognition of patients as key partners/stakeholders in research has been increasing over the past decade. It represents a promising approach to generate evidence that is relevant and trustworthy for patients and their families as well as clinicians. 5 This is likely to contribute to a greater sense of empowered participation in patients who are the eventual users of the outcomes of such research. 6 Research evidence reporting facilitators and barriers to clinical trial participation and patient experiences with clinical research is increasing, particularly in areas such as cancer and stroke. 7 Studies have investigated the relative importance of issues regarding research, in people with stroke. 8,9 These reported that there was a discrepancy between priorities and relevance attributed to different outcomes by different stakeholders in research, such as patients, caregivers and researchers. 8,9 Early patient engagement is likely to be associated with increased recruitment and retention of study participants; development of research methods that are contextualized to patients' experiences with the disease; and utilization of relevant research questions and outcome measures. There is growing evidence for the value of 'patient and public involvement in research' (PPIR) in facilitating more patient-focused research by offering insights into prioritization, design and implementation and making trials more effective and credible. 10 PPIR is increasingly being mandated for publicly funded trials in many developed countries. 11 Active participation of potential participants is likely to provide a sense of empowerment to people with chronic stroke. Their engagement as 'lay experts' to provide their perspective on clinical relevance of different aspects of study design is likely to improve the eventual study design. The increase in transparency and credibility of research associated with such partnership is specifically critical in innovative areas of research such as stem cell therapies. This was a key issue raised by stroke survivors who participated in the Stroke

Survivors' Forum held at the South Australian Health and Medical
Research Institute (SAHMRI), in Adelaide in 2014.
In response to this advice, the PERSPECTIVES study sought to formatively collect insight into the beliefs and perspectives of people with chronic stroke through their involvement in the design of the TOOTH study (The Open study Of dental pulp stem cell (DPSC) Therapy in Humans). The TOOTH study aimed to investigate the effectiveness of autologous administration of adult dental pulp stem cells in people with chronic ischaemic stroke. 12 The study aimed to explore the views of people with chronic stroke on: • the relevance and importance of an early phase clinical study such as TOOTH, with adult human dental pulp stem cells in chronic ischaemic stroke • the relevance and acceptability of the planned outcome measures and study design of the TOOTH study and • issues with consent to participate in the TOOTH study.

| Study design
The study involved a naturalistic design, adapting from a participatory action-research approach to explore stroke survivors' perspective on early clinical research design with cell therapy (TOOTH). The study methodology fits within a constructionist epistemology paradigm, utilizing an inductive thematic analysis.

| Ethics approval
Ethics approval for conducting this study was granted by the

| Study population, sampling and participant recruitment
The study recruited people with chronic ischaemic stroke who were residents of Adelaide and likely to fulfil the proposed selection criteria for participation in the TOOTH trial as listed below:

| Inclusion criteria
• Inclusion of both genders.
• Age of the participant 18 years or over.
• History of chronic ischaemic stroke with a stable level of disability.
• Sufficient cognitive and language ability to participate in an interview.

| Exclusion criteria
• Impaired cognition or significant psychological issues.
• Inability to communicate in the absence of a caregiver.
• Inability to travel to the interview location. Following an expression of interest in participation, all potential study participants received a participant information pack containing the participant information sheet for the PERSPECTIVES study and the summary information sheet on the TOOTH trial which described the study design and current understanding of the benefit and risk, given that this is a first-in-human safety study. AN followed up with the participants by telephone to address any queries regarding the study information provided and obtain verbal consent to participate. Following written informed consent, the individuals participated in a semi-structured interview at SAHMRI. The interview was conducted in line with key areas of enquiry defined in the interview guide (Table 1), regarding the research design of the TOOTH trial. The subquestions were adapted to lines of response provided by the participant. All interviews were audio-recorded and professionally transcribed verbatim by OutScribe Pty Ltd, Adelaide, South Australia.

| Data analysis
Analysis of audio transcripts was carried out immediately after every interview, and data were coded by AN using NVivo software Version 11 (QSR International). AN read and reread the transcripts and constructed an index of multiple emerging codes. This index was discussed and cross-checked with SK, SH and AHB. Coding was an iterative process that proceeded concurrently with on-going interviews. As new codes were added, previous transcripts were recoded to further refine the coding framework analysis of the data. 13 The inductive thematic analysis continued until no new code emerged from subsequent interviews; that is, data saturation was achieved.
Subsequent analysis crystallized the key themes that represented the aspects emerging from refining of codes from the data.

| Participant disposition
SH contacted 31 patients with stroke following review of their functional status. Following their indication of interest in participation, they were provided with study information by AN. Nineteen patients declined to participate, mostly due to time or mobility constraints.
Twelve patients participated in face-to-face interviews, following provision of written consent. Patients were asked to complete a patient profile to understand the overall impact of stroke on their lives along with their age and stroke latency. The population was diverse concerning these parameters, but representative of the potential target population for stroke trials ( Table 2).
Data saturation was achieved after twelve interviews with no new themes emerging after eight interviews.

| Themes
The themes described below represent themes identified, even though some elements may overlap ( Figure 1).

Interview: Topic guide
What has been the impact of stroke on your daily life?
What are your views on using stem cell therapies for managing stroke?
What are your thoughts on the usefulness of a study like TOOTH?
What are the effects that are important to measure in a study like TOOTH?
Are there any specific risks that you feel should be measured in the TOOTH?
Would it be appropriate for participants with impaired thinking or understanding to participate in a study like TOOTH?

| Real-life relevance of study outcomes-Are all equally meaningful?
The participants conveyed that the most meaningful change for them would be a change in their ability to participate in life interactions and their ability to get back to doing activities of interest, that is, 'being more normal' with lessened dependence on significant others (caregivers) in their lives. The interviewees also expressed their interest in measuring change in pain and fatigue, which they associated with a significantly adverse quality of life experienced post-stroke.
Participant 005: I've met so many people who've had strokes … but I think the only real common theme is the fatigue and, possibly, the pain.
While improvement in speech was acknowledged as a relevant outcome to be measured, the issue of interest was the impact of this impairment on ease of communication and confidence in social interactions.

| Risk-benefit-perception
Interviewees were quite pragmatic in their expectation of recovery of function, accepting that full recovery to pre-stroke level of functioning may not be achievable.
Participants believed that perhaps it was not realistic to expect complete recovery of function and they would consider any positive change in functional ability to be meaningful. The interviewees accepted that potential safety issues could be expected, given the early stage of the research. The perception of risk was consistent across the participant group. Participants expressed concern regarding risk of further functional impairment.
Participant 010: I would worry that I could end up, worse off. That something unforeseen could happen and, maybe another part of my brain could die off.
Participants also expressed concerns with the transplantation procedure, related to the extent of hospital stay required and risk of complications (eg infections) associated with the procedure.
Interestingly, these concerns were related to risk associated with the surgical procedure per se and not with the issue of stem cell implantation under MRI guidance.
Death or cancer derived from cell transplantation was not cited as the most critical concerns, which is interesting, given that these adverse events are considered the most important events to investigate and report by the research community. However, participants expressed their desire to know about any available information with regard to cancer risk.

| Attitude towards trial participation
The interviewees expressed varied interest in participation ranging from no interest, to unsure, to a very keen interest to participateoften this related to their perceived level of current disability. Interviewees expressed an opinion that the proposed TOOTH study was relevant for people with disability following stroke. The predominant driver of this belief seemed to be an altruistic thought process regarding this research contributing to a potentially beneficial therapy to answer a current lack of meaningful therapy options and consistent rehabilitation.

| Attitude towards participant selection
Participants communicated that study participation should, in principle, be available to any patient with existing disability and that it was inappropriate to exclude patients with cognitive incapacity.
Proxy consent in such situations may be deemed acceptable but only in situations where consent was provided by a close member of the family, who would likely be aware of the patient's wishes and likely preferences. However, such consent should not be provided by a professional caregiver. They recognized that proxy consent represents a significant psychological burden on the carers.  itation studies. 22 While it assesses a range of outcomes, including severe disability and death, it is not adequately sensitive to assess cognition, mood or return to social and occupational functioning. 19 The use of these endpoints on their own to define success or failure of studies, particularly those involving personalized therapy options such as stem cell therapies, may not adequately measure the range of outcomes found to be critical from a patient perspective.

The World Health Organization (WHO) proposed the International
Classification of Functioning (ICF) 23 and recommend outcomes evaluation within dimensions of body function impairments, activity limitations and participation restrictions. In the context of stroke, a very small percentage of pharmacological or rehabilitation studies have to date examined impact on participation restriction, as is also the case for cognition and mood outcomes. 19 Evidence for widespread prevalence of issues in these domains reported by patients has been steadily increasing in recent years. 20 Research involving patient-reported outcomes has described persistent and significant impact on patients' lives even for those that fully recover their pre-stroke func- Participants indicated an acceptance of their current level of functioning and that the return of functioning over time was due to consistent effort on their part to engage with the rehabilitation options available. This drove the heightened concern for the potential risk of loss of this functional improvement that they worked very hard to achieve. They indicated that they would have been more accepting of this potential risk if an opportunity to participate in a clinical study such as TOOTH had arisen 'earlier' in their disease course, defined as within a year of their stroke occurrence. This insight has important implications for study recruitment for stem cell studies in chronic stroke.
A recently reported study also highlighted these as important determinants of interest in participation. 25  In a broader societal and medical practice context, the increased awareness of current state of regenerative neurology in stroke and evidence-based estimation of risk and benefit to be expected can become a deterrent to unscrupulous use of unproven stem cell therapies for commercial use and stem cell tourism.

| Strengths and limitations
The study utilized face-to-face interviews with stroke survivors, as the method of qualitative enquiry. This enabled a relaxed and supportive environment in which they shared their individual preferences, contextualized to their unique lived experience with stroke.
The study findings highlighted key outcomes considered important from patient perspectives and that need to be measured within study design.
This approach also minimized the dilution of information likely with other modalities such as combined focused groups with other stakeholders such as caregivers. Our study is a part of a wider exercise that will also explore views from different stakeholders, particularly caregivers, in separate studies. The rationale behind this strategy is based on the growing body of evidence for disconnect in the perception/acceptance of risk and benefit, between patients and caregivers. 15,17,25,30,31 The requirement to travel and engage in an in-depth interview meant that the study did not include patients with very severe disability, cognitive deficits and severe aphasia. The participants were therefore not fully representative of the overall stroke survivor community. However, the perspectives shared by them in the context of preferences for study design components were largely agnostic to the degree of severity of post-stroke disability and may well be more relevant to the broader group. The severity of present disability has been shown previously to impact on motivation to participate in other studies, 8,29 and this was corroborated in our study.
However, it did not appear to influence the relative importance assigned to different outcome and design elements. The intention of our study was to provide rich thematic description of our qualitative enquiry. Previous studies with similar research methodology have reported this to be possible, though recruiting large number of patients was found to be challenging. [32][33][34] The eventual number of participants may appear rather small. However, the research team conducted constant comparison of emerging themes to ensure that data saturation was confirmed to ensure validity of study findings.

| CON CLUS IONS
The PERSPECTIVES study applied principles of patient and public involvement in research in early clinical stem cell research in stroke.
Engagement of stroke survivors as 'lay experts' to provide input into study designs can provide critical insights that can enable more targeted research. In an evolving field such as cell therapy in stroke, this partnership can potentially help researchers to efficiently address the challenges posed by the inherently 'personalized' field of regenerative medicine.

ACK N OWLED G EM ENTS
We thank Stroke SA (South Australia) Incorporated, a not-for-profit charitable foundation, for financial support for conduct of this research.

CO N FLI C T O F I NTE R E S T
The authors declare no conflicts of interest, however Professor SA Koblar is the Patron of Stroke SA Inc. and Affiliate Associate Professor MA Hamilton-Bruce is the Chairperson of the Stroke SA Inc. Management Committee.

AUTH O R S ' CO NTR I B UTI O N S
AN involved in ethics application, study design and conduct (participant consent/ recruitment/interviews), data collection, analysis and manuscript preparation. SH involved in supervision of study design and conduct, provided access to the patient database for study recruitment and critical review of data analysis and manuscript. AGM involved in ethics application and critical review of manuscript.
MAHB and SAK involved in supervision of study design and conduct and critical review of data analysis and manuscript.

E TH I C A L A PPROVA L
Ethics approval for conducting this study was granted by the Human Research Ethics Committees of the University of Adelaide

DATA S H A R I N G
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy restrictions.