Design
We conducted a two-arm, parallel-group, individually randomised, multicentre pilot trial of carer-administered as-needed SC medication for common breakthrough symptoms in patients dying at home compared with usual care, with a 1 : 1 allocation ratio and using convergent mixed methods.44
Qualitative and quantitative data were seen as complementary and were given equal importance. Data analysis of the two data sources was undertaken independently and then combined during the interpretation stage, during which the data were examined for convergence, divergence, contradictions and relationships between the two data sets.
The study was funded by the Health Technology Assessment programme of the National Institute for Health Research (NIHR). It received a favourable ethics opinion from the Wales 1 National Research Ethics Committee (REC) (reference: 17/WA/0208; IRAS project ID: 227970) and the Bangor University REC (project ID: 2016–15826). The UK Medicines and Healthcare products Regulatory Agency has advised that the CARiAD trial was not a Clinical Trial of an Investigational Medicinal Product (CTIMP). The study was registered on the International Standard Randomised Controlled Trials Number (ISRCTN) registry (ISRCTN11211024). Approval was granted from the NHS research and development departments of all three sites. Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 201345 recommendations and Consolidating Standards of Reporting Trials (CONSORT) 2010 statements46 (including those specific to randomised pilot and feasibility trials) guided protocol development. The current version of the trial protocol can be accessed from the NIHR project web page.47
Trial flow chart
details planned participant flow in the trial.
Anticipated trial flow chart.
Participants
Trial setting/context
The trial was carried out in community settings in North Wales {Betsi Cadwaladr University Health Board [BCUHB], the Vale of Glamorgan [i.e. Cardiff and surrounding areas, Cardiff & Vale University Health Board (CVUHB)] and Gloucestershire [Gloucester Care Services (GCS)]}, where patients were likely to die at home in accordance with their wishes and without the provision of round-the-clock paid care. The three pilot study sites were chosen as they are representative of the range of sites for a future definitive study.
Eligibility criteria
Inclusion criteria
Inclusion criteria for dyads were:
an adult (i.e. aged ≥ 18 years) patient in the last weeks of their life who was likely to lose the oral route for administration of medication and who had expressed a preference to die at home
their adult (unpaid) lay/family carer, who was willing to have this extended role and receive SC injection training.
Patient inclusion was not reliant on cognitive status.
Prognostication was reliant on the professional judgement of and agreement among the attending HCP team (i.e. clinical estimate of survival). There is an assumption that the carer will spend a significant amount of time with the patient.
In cases where more than one carer was available, we asked the patient to identify which carer they wanted to be included in the study.
Exclusion criteria
A dyad was excluded if any one of the following criteria were present:
The inclusion and exclusion criteria were incorporated in the RA tool (see Report Supplementary Material 2). The aim was to complete the tool:
prior to approaching a dyad (if the criteria were not met, dyads were not approached for consent to participate)
at intervals (at the discretion of the HCP or local research teams) for dyads included in the trial (if the criteria were not continued to be met, dyads were withdrawn from the trial).
Recruitment
Patient identification
Potential patient/carer dyads were identified consecutively from clinical caseloads in a number of ways: through the hospice, SPC service or DN teams. When a patient was deemed by the HCP team to be in the last weeks of their life and they had expressed a wish to be cared for and die at home, they were screened for approach.
Screening
To be eligible, dyads must have satisfied the RA criteria. A RA screening tool was refined for the CARiAD trial, which was based on existing self-medication tools (see Report Supplementary Material 2).42 RA took into account several factors as detailed above, and was conducted by the health-care team involved in the patient’s care. If a dyad did not satisfy the RA criteria, they were not approached.
Approach
The patient was approached with written material (PIS; see project web page at www.journalslibrary.nihr.ac.uk/programmes/hta/151037/#/documentation; accessed 5 January 2020) by a member of their health-care team. The initial patient approach was carried out separately from that of the carer, unless otherwise requested by the patient and if the attending HCP deemed this appropriate, that is when there was no perceived risk of patient–carer coercion. As the study involved sites in Wales, the PISs (see project web page at www.journalslibrary.nihr.ac.uk/programmes/hta/151037/#/documentation ; accessed 5 January 2020) and consent forms (see project web page at www.journalslibrary.nihr.ac.uk/programmes/hta/151037/#/documentation; accessed 5 January 2020) were translated into Welsh for the Welsh centres and offered bilingually to comply with the Welsh Language Act 1993.48 Dyads were given as much time as they needed to consider the information sheets and to discuss with family, friends or the health-care team whether or not to take part. They were told that they could decline to participate without giving reasons.
Informed consent
A RN sought consent at a time that was judged to be suitable by the attending HCP. This gave the patient and carer as much time as they needed to understand the nature of the research, ask questions and make their feelings clear on trial participation.49,50 If the patient was unable to consent or they had lost the capacity to do so after they had previously given consent, the assent of a personal consultee was sought (as required by the Mental Capacity Act 200551) to the patient’s participation in the trial.49,50 As the RA excluded dyads for whom there were concerns about relational issues between the patient and the carer, the carer could act as personal consultee.
If the carer did not wish to act as the personal consultee and there was no additional family member or close friend to take on this role, we appointed a nominated consultee (e.g. a HCP not associated with the research) who would act for all patients in this situation in the trial.
The PI retained overall responsibility for the informed consent of participants at their site and was mandated to ensure that any person who was delegated responsibility to participate in the informed consent process was duly authorised, trained and competent to participate according to the ethically approved protocol, principles of Good Clinical Practice and Declaration of Helsinki.52,53
Randomisation
Method of implementing the allocation sequence
Once the dyad had consented and baseline data collection had been completed, the dyad was randomised to one of the trial arms. Secure online randomisation hosted by the North Wales Organisation for Randomised Trials in Health (NWORTH) Clinical Trials Unit was carried out by the researcher who obtained consent or the trial manager. The system used a dynamic adaptive method of randomisation in which it stratified for recruitment centre and diagnosis (cancer/non-cancer).54 Confirmation of allocation was sent only to those members of study staff who needed to be aware of the result.
Blinding
The CARiAD trial was an open-label trial in which blinded-outcome assessment was not feasible; therefore, it was important that outcomes were as robust as possible in the light of the lack of blinding. See Appendix 2 and Table 27 for details of the primary outcome contenders, methods of assessment, strategies to reduce bias (by increasing subjectivity) and criteria for assessing feasibility as a primary outcome measure for a future definitive trial. Outcome assessors were experienced RNs.
Data entry was completed unblinded; the trial statistician who carried out the data analysis was the only individual who was blinded to randomisation allocation. The analysis was unblinded at a combined Trial Steering Committee (TSC) and Data Monitoring and Ethics Committee (DMEC) meeting, with independent members present.
Withdrawal criteria
Participants were free to withdraw from the trial at any time without giving reasons and without prejudicing their further treatment. This was made clear to all potential participants at the time that they consented and throughout their time in the trial. Non-completion of the follow-up questionnaires did not constitute formal withdrawal from the trial; unless the participant requested withdrawal of their data completely, all data collected were used for analysis. The RA was reviewed at intervals based on the HCP’s judgement, and if the criteria were not met the dyad was withdrawn from the trial.
Duration of the feasibility study
The study opened to recruitment in BCUHB on 10 January 2018, in CVUHB on 21 March 2018 and in GCS on 1 April 2018. Recruitment closed on 15 March 2019.
Interventions
Schedule of study procedures
details the planned study procedures.
Schedule of study procedures
Health technologies being assessed
The technology under scrutiny was the extended role of lay carers to administer as-needed SC medication for common symptoms to a person who was dying at home. Lay carers were trained in this practice, and their training was supported by a manualised training package that was based on the Australian package Caring Safely at Home (see Chapter 2 for details of the development of the intervention).
Of note, it is usual practice in the UK to ensure that there is provision of as-needed medicines for breakthrough symptoms in the patient’s home for administration by the attending HCP.55–57 The difference in this technology is that lay carers were trained and, therefore, had the option to administer these medicines (instead of and/or in addition to HCP administration).
Carer training
Carers in both groups received training on the trial materials. This was carried out by a DN or RNs at their visit to the dyad’s home to collect baseline information.
In addition, carers in the intervention group received one-to-one face-to-face training that was delivered by a HCP (usually a DN or SPC nurse) and was supported by written materials. The training covered common symptoms that may occur in the last days of life and how to assess if their loved one needed medication for a particular symptom; how to prepare (draw up) medication and dispose of sharps (glass ampoules and drawing-up needles); how to administer SC medication by needle-less technique (using a butterfly SC catheter); how to assess the effect of the medication; and the support that was available, including the primary care team as well as dedicated 24/7 SPC support. If a symptom occurred for which medication was deemed necessary (either as expressed by the patient, if able, or as assessed by the carer), the carer could use the training outlined above to administer the appropriate medication.
Training was to be tailored to the individual lay carer. As competence and confidence in practical tasks develop over time,24 HCPs were asked to be ready to deliver the training over the course of a few visits until the carer attained competency.
When carer competency in the task was attained, HCPs offered ongoing support in building confidence:
The first time that the patient needs an injection, the carer should call a HCP and observe administration.
The carer should then administer an injection at a subsequent opportunity, while a HCP is present.
Finally, the carer should administer an injection and call the HCP.
Medication regimens
Guidelines for anticipatory prescribing for care in the last days of life are in place across the UK.55,56 They cover common symptoms in the dying phase, such as pain, nausea and/or vomiting, restlessness/agitation and noisy breathing/rattle. The CARiAD trial recruitment sites were advised to follow usual prescribing practice for dosing anticipatory medication. For example, in Wales, as-needed SC medication prescribing advice includes:58
for pain – morphine or diamorphine at one-sixth of the 24-hour dose, or if a patient is not on background strong opioids a starting dose of diamorphine of 2.5 mg or morphine of 2.5 mg
for nausea and/or vomiting – 50 mg of cyclizine (maximum dose in 24 hours = 150 mg), 6.25 mg of levomepromazine (maximum dose in 24 hours = 25 mg) or 1.25 mg of haloperidol
for restlessness/agitation –2.5 mg or 5 mg of midazolam
for noisy breathing/rattle – 400 µg of hyoscine hydrobromide (maximum dose in 24 hours = 2.4 mg) or 200 µg of glycopyrronium (maximum dose in 24 hours = 1.2 mg).
For patients in the intervention group only, prescribers were provided with specific additional advice, including instructions not to prescribe dose ranges/steps and that dose changes could be made only after a face-to-face assessment (not remotely, e.g. over the telephone) (see Report Supplementary Material 2).
Care pathways
In both groups, the following aspects of the current care pathway remained in place:
Patients were visited regularly (ideally daily) by a member of the health-care team, usually a DN. ‘Usual routes’ for support applied. These usual routes were different across the recruitment sites. For some areas, there was direct access to a 24/7 SPC advice line for carers in addition to support from the patient’s primary care team or OOH. In other areas, support for the carer was via their primary care team, and the GPs and DNs could ask for advice from the SPC clinicians.
As per local guidelines for anticipatory care of common symptoms in the last days of life, there was a supply of drugs in the patient’s home and the apparatus needed to administer them.
55,56Measures for managing background symptoms were unchanged (usually through medication delivered via continuous SC infusion). If a patient requires several doses of as-needed medication for a particular symptom in a 24-hour period, it is usual practice for a prescriber to review and either start a continuous SC infusion of a medication or increase the dose if the medication is already given, to reduce the likelihood of further as-needed doses.
In summary, the usual-care group followed an unchanged care pathway for dealing with breakthrough symptoms at home, with the usual palliative care in place and DNs administering as-needed SC medication.
In the intervention group, carers were trained to administer as-needed SC medication, although they were not obliged to actually administer medication. If the carer needed the support of a HCP, either because they would feel more confident having a HCP present when they administered the medication or because they wished the HCP to assess and give the medication, they could obtain it via the usual routes in their area. If the carer had reached the limit of the number of administrations of medication that could be given in 24 hours (maximum of three medication administrations for each indication per 24-hour period, unless the prescribing clinician advised a maximum of fewer than three), they were asked to contact a HCP as review was required. Usual routes for support included the DN team, the GP, the GP/DN OOH, the hospice at home team or a hospice advice line. The use of such support was captured in carer diaries.
For each recruitment site, the following were clearly set out as standard operating procedures:
clinical support for dyads and for their primary care HCPs regarding SPC advice (relevant contact details will be recorded in the carer diary)
research support, including when, how and in what circumstances the research team should be accessed.
If a patient in the intervention group was admitted to an inpatient unit (including a hospital, hospice or nursing home), carers were made aware that they should not administer SC medications to the patient during the admission.
Health-care professional training requirements
All DNs (or SPC nurses) who were providing carer training had undertaken detailed standardised training on:
trial background, including why it is needed, the legal framework (see
Appendix 1), ethics considerations and the research support team in their area
detailed trial processes, including inclusion/exclusion criteria, screening and approach, consent, randomisation, trial assessments and outcome measurements, safety, recruitment targets, post-trial care and the delegation log
training the trainers, including detailed guidance on how to disseminate the training within their team and maintain training records.
Training was designed to be delivered by the trial manager to the DN team leads, the DN educator or another nominated individual who would be able to disseminate the training to the rest of the DN team. A record of attendance was kept for each training session. Standardised training documents [Microsoft PowerPoint® (Microsoft Corporation, Redmond, WA, USA) slides and training materials] were made available to the DN team leads for disseminating training.
Randomised pilot trial outcomes
The main outcomes of interest were those appropriate to a pilot trial, including feasibility, acceptability, recruitment rates, attrition and selection of the most appropriate outcomes measures. Outcomes were measured for patients, their lay carers and HCPs. System barriers were also noted. These measurements were made at baseline, on a daily basis for symptom control and lay carer confidence, and at 6–8 weeks post bereavement.
Recruitment measurements
Recruitment measurements were the number of eligible patients who fulfilled the inclusion criteria and were willing to be randomised, which was expressed as a percentage of the number of patients screened, the number who withdrew after baseline assessment and randomisation, the number who completed the various outcome measurements at baseline and at later time points, and reasons for any non-completion.
Patient measurements
Patient measurements were baseline information (including demographic information, medical history, capacity assessment, preferred place of care in the last days of their life and current drug management) and a daily carer diary during the study that was related to the presence and treatment of breakthrough symptoms (for use in both trial groups). Data points in each medication administration diary entry included the initial time when the breakthrough symptom triggered a perceived need for an additional SC dose; whether this was noted by the patient or the lay carer; medication and dose, and time given; reason for medication (e.g. pain, nausea, restlessness or noisy breathing); symptom score before and 30 minutes after medication administration; and when symptom control/reduction of the symptom to an acceptable level was achieved. Hospital or hospice admissions during last illness and the actual place of death were also recorded. Approximately 6–8 weeks post bereavement, carers were asked to complete the Family Memorial Symptom Assessment Score – General Distress Index (MSAS-GDI).10,59–61
Carer measurements
Carer measurements were demographic information at baseline; QOLLTI-F questionnaire (at baseline, after the first as-needed SC medication, then every 48 hours thereafter until the patient’s death); whether or not HCP support was sought; and Family MSAS-GDI (a measure of the patient’s symptom distress in the last 7 days of life) at the 6–8 week post-bereavement visit. In the intervention group, the confidence in administering SC medication and competence at intervals after training were recorded.
Health-care professional measurements
Health-care professional measurements were the baseline measurements of attending team structure, primary prescriber and carer trainer.
Safety
The CARiAD study contained a number of safety outcome measures at different stages of the clinical journey taken by the patient, carer and HCPs. Safety outcome measures include the RA tool, competency checklist and significant event reporting (see Report Supplementary Material 2). Significant event reporting included the following: the appropriateness of administration (is administration accompanied by evidence of need?); proportionality (has the correct dose been administered?); side effects both anticipated and not anticipated; drug accountability (do stocks tally?); and carer events (e.g. distress, injury, accidental or purposeful self-administration).
An AE was defined as any untoward medical occurrence in a trial participant (either the patient or the carer) and included incidents that were not necessarily caused by or related to the trial. A SAE was any untoward occurrence that resulted in death, was life-threatening, required inpatient hospitalisation or prolonged existing hospitalisation, resulted in persistent or significant disability/incapacity or was otherwise medically significant.
All AEs and SAEs were captured via the significant event form. SAEs were reported to the PI and sponsor within 24 hours. As this was a study involving patients who were close to the end of their lives, death was an expected outcome. It was recorded and reported to the sponsor but was not considered a SAE if, in the opinion of the PI, it was a natural conclusion to a patient’s life-limiting illness. Owing to the nature of the study, events of death did not require immediate reporting to the DMEC.
Exploratory end points/outcomes for a future definitive trial
Core Outcome Measures for Effectiveness Trials (COMET) in patients close to the end of their life were not available at the time of CARiAD trial planning.2 After scrutiny of available outcome measures, the most likely candidates for primary outcome measures for a future definitive trial of this intervention were Family MSAS-GDI (a measure of overall symptom burden/distress in the last 7 days of life)10,59–61 and QOLLTI-F (a measure of the quality of life of carers looking after someone with a life-threatening illness, incorporating elements of control and self-efficacy).41
In addition, we measured carer confidence using a seven-point Likert scale, in which the carer is asked after administration of every as-needed SC injection to rate their level of confidence in administering this injection (1 = not at all confident, 7 = extremely confident). We planned to give quantitative and qualitative data equal importance and integrate these at the interpretation stage. For more detail on the rationale for choosing the Family MSAS-GDI and QOLLTI-F, see Appendix 2.
Criteria for assessing feasibility as primary outcome measure
All outcome measures were assessed on the same criteria for consistency.
Applicability:
This was assessed by an independent expert panel and was based on feedback from participants (HCPs and carers).
Each measure was assessed by the panel with regard to its relevance and applicability to the population, based on the outcomes of the pilot data collection phase.
The panel will recommend an ‘accept’ or ‘not accept’ status for each outcome based on the criteria below and their expert opinions, and taking into account the RATIONALE (Risk of Bias Justification Table) statements on outcome measures and assessment of bias risks in ultimate reporting.
62,63
Acceptability:
Level of completeness:
This was assessed by the frequency of missing data during the data collection phase. This would require potential primary outcome measures to have > 70% completeness.
An assessment will also be made of the reasons for missing data to establish whether or not anything systematic in the trial design could be adjusted to mitigate for the missing data.
Once the feasibility of the outcomes is established, the design of the definitive trial will consider whether a single or a combined primary outcome of interest is appropriate.
Secondary outcome measures
The potential suitability of the secondary outcomes will be considered, as detailed below.
Time to symptom relief
This outcome measure was collected given the importance of this outcome to carers and patients. It does, however, present significant inherent challenges with potential bias and will not contend as a primary outcome measure for a future definitive trial, unless methodological concerns are resolved. The specific methodological concern is that it will be hard to demonstrate that the measurement of this outcome will be carried out in comparable ways in the two arms of the trials. We acknowledge that these problems arise because the individual who is measuring the outcome (the carer) cannot be blinded to the trial group. The intervention group will have lay carers deciding to dispense treatment, and this could systematically affect their judgement of this outcome.
Sample size
A fully justified sample size was not required; sample size was justified by estimating what sample size a future definitive RCT will need.
Careful consideration was given to the size of effect that we could potentially see for the Family MSAS-GDI and QOLLTI-F in a potential future definitive trial. There was no definitive statement of what a minimal clinically important difference would be for either of these measures in this context; therefore, we had to make an assumption that was informed by both HCPs and public contributors. It may be that these estimates are considered too conservative/small; however, for the pilot trial we wanted to ensure that we had captured enough precision within any estimates to be confident of capturing any potential indication of a signal. Using a smaller effect size to ensure adequate precision when investigating at this stage would not preclude the use of a larger effect size (and possibly resultant smaller sample), if it were considered more appropriate when designing a definitive study.
Assuming an important difference of 0.4 [standard deviation (SD) = 1)] on the Family MSAS-GDI, a sample of about 216 participants would be required to achieve 90% power to detect a difference of this size with a significance level of 0.05 using a two-sided test. Equivalently, a sample of about 550 participants would be required to detect a difference of 0.5 points (SD = 2) using the QOLLTI-F.
Using the larger of these estimates for the feasibility trial, we assumed approximately 9% of the main trial size, give an 80% confidence interval to exclude a clinically important difference, required approximately 25 participants in each group.64 Sim and Lewis65 recommend a sample size of approximately 50–55 to ensure robust estimates of the variance. Using estimates of dropouts, we predicted that we needed to approach 200 potential participants to achieve 100 randomised participants, with 50 completers (‘completer’ is defined as a dyad who completed all of the study measures from baseline to follow-up at 6–8 weeks post bereavement). Therefore, we needed to approach 5.5 dyads per month from each of the three sites and randomise 2.7 dyads per month from each of the three sites to meet our recruitment target. Assuming that we would recruit equally between the three sites, we needed to approach 66 dyads, randomise 33–34 and would have had 16–17 dyads available per site for analysis (see ).
Detailed considerations
The 2013 Office for National Statistics data66 showed that 8.6% of all deaths in those aged > 15 years are home deaths caused by neoplasms. Deaths caused by neoplasms were seen as a useful proxy for expected deaths. Therefore, the three recruitment sites had the following numbers of home deaths caused by neoplasms available per annum: BCUHB, 653; CVUHB, 349; and GCS, 517.
Lay carers of patients who are cared for at home in their last days of life
Drawing on the collective clinical experience of the study team, we knew that it is rare for a patient to successfully fulfil their wish to die at home if they did not have the support of a lay carer. This was because most health and care services (and specifically in the sites that we propose to recruit from) could not provide 24/7 care in a patient’s own home. That said, the best data available on this topic came from a recent quasi-experimental study examining palliative care interventions at home. It noted that of 953 patients who expressed a preference to die at home, 72.2% had an informal carer.67 It is worth noting that the study did not record where patients who were unable to identify an informal carer actually died, or if previously unidentified lay carers in the patient’s circle stepped in to support their wish to die at home.
The pilot trial
For the pilot trial we proposed to approach 200 dyads (66 or 67 at each site). Therefore, even if only 72.2% of the patients had an identified carer, the numbers of dyads in the three sites that could be eligible were as follows: BCUHB, 471; CVUHB, 251; and GCS, 373. It is also worth noting that all of the participants in the focus group indicated they would take part in a trial if invited (caution: selection bias). Of these, on very conservative calculation, 100 dyads would consent to participate (33 or 34 at each site). The percentage recruited in the Australian study was much higher: 97.6% of those approached consented to participate. In total, 50 of those dyads would be in the intervention group (receiving training) and 50 dyads would be in the usual-care group (i.e. 16 or 17 per group per site), with, again on very conservative calculation, 25 in each group (50 in total) completing the trial (i.e. 8 or 9 per group per site). In total, 50 completers were needed for the analysis (i.e. 25% of those initially approached for participation).
Statistical methods
Statistical analysis
The primary analysis was concentrated on the feasibility metrics and adherence outcomes based on defined thresholds (). There was limited preliminary analysis of intervention outcomes. Point and 95% confidence interval estimates were calculated and used to estimate the variability and direction of effect to further inform the sample size calculation for a definitive study.
Summary statistics of all outcomes were used to inform the approximate models of analysis that would be used in a full trial. The results of the feasibility trial were used to inform the most appropriate analysis models (e.g. the number of episodes in which as-needed medication was used and proportion of participants who never required as-needed medication). A preliminary analysis of the outcomes was completed using an intention-to-treat approach. All analysis that was undertaken was prespecified in a statistical analysis plan that was written and agreed before data collection was completed.
As this was a feasibility trial, there was no imputation of missing data. Missing data were considered as a criterion for assessing the suitability of measures. Descriptive statistics were produced for each of the outcome measures to evaluate the appropriateness of the measures for inclusion in a definitive RCT.
Progression to a full trial
Clear progression rules were defined to determine whether or not an application for a future substantive trial that was powered to study clinical effectiveness and cost-effectiveness should proceed. Our progression rules related to the following measure that we considered important to feasibility: reaching our target (16–17) for the number of patients recruited per site.
We also established clear assessment criteria for establishing the acceptability of the potential primary outcome measures.
explains sample size calculations and summarises the objectives, action plan and criteria for progression to a full trial.
Objectives, action plan and criteria for progression to a full trial
Summary of any changes to the study protocol
Version 1 was approved by the funder (October 2016) and detailed the whole CARiAD study (including the work-up phase/expert consensus workshops). The workshops had concluded and the results were incorporated in the trial processes and materials. Version 2 focused on the trial (with embedded qualitative study), which was due to commence in October 2017. Further amendments were made in response to REC comments (July 2017) to clarify details of the qualitative methods (June 2018) to reflect the decision to unblind RNs and the affect on trial processes (August 2018) and to make general corrections to trial processes and reflect the extended trial period (November 2018). The current protocol is version 6 (27 November 2018).
Governance
Trial governance procedures adhere to the NIHR guidelines and include a trial management group, an independent TSC and an independent DMEC. SAEs will be reported to the TSC and DMEC in line with NIHR guidance.68 The current version of the trial protocol can be accessed via the NIHR project web page.47
Ethics and regulatory considerations
The current version of the trial protocol details safety outcome measures, REC review, regulatory arrangements, quality assurance and quality control, data handling and publication policy.47
Public contribution
Public contribution formed an integral part of the CARiAD trial and was part of each stage from development to dissemination. Our reporting of public contribution in the CARiAD trial is based on the GRIPP2 (Guidance for Reporting Involvement of Patients and the Public) (short form) checklist (version 2).69 A summary, presented in the GRIPP2 (short form) format, is shown in . This is followed by a more detailed account, organised in accordance with the GRIPP2 (short form) structure.
Summary of public contribution in the CARiAD trial
Aim
In this study, the aim of public contribution was to collaboratively involve patients as co-applicants and partners at all stages of the study, with the intention of improving the design and conduct of the study and ensuring that it was informed by experiences of giving injections to loved ones dying at home, and to involve public contributors with appropriate experience to ensure that there was full understanding of the needs of research participants.
Methods
A range of methods were used for public contribution at different stages throughout the study. These included the following:
The initial decision to develop the CARiAD trial resulted from the Palliative and End of Life Care Priority Setting Partnership report, which incorporated the views of 1403 people across the UK, which placed great emphasis on empowerment of family carers and symptom management during the last days of life.
11The study design was heavily informed by the work-up stages, which comprised two group consultations with carer groups (suggestions on consent mechanisms, drug safety, training and ongoing support were incorporated into the study design), one telephone consultation with a bereaved carer (JO’C) who had given SC medications to her late husband and one telephone consultation with a nurse who had trained a carer to give SC medication to a relative and had supported them in doing so.
The CARiAD trial had two public contributors as co-applicants to the study (BF and JO’C) who contributed to the submitted application, including providing the lay summary. Following this, one of the public contributors (JO’C) attended and contributed significantly to the CARiAD REC meeting.
Trial materials, including the topic guides for the qualitative interviews, were produced with the input of the public contributors. Public contributors also took part in expert consensus workshops and formed part of the TSC.
The public contributors strongly supported the study dissemination. One of the public contributor co-applicants (JO’C) presented the results of the CARiAD study at a national palliative care conference.
Public contribution was of an extremely high standard in this study and public contributors formed an integral part of the research team. When public contributors were able to attend meetings in person, measures were taken for considerate inclusion, such as access, briefing, refreshments and travel provision and expenses. The two public contributor team members/co-applicants were supported in the role directly both by the CARiAD team and by their respective groups (Sue Ryder Hospice and North Wales Cancer Network).
Results
The outcomes of public contribution in the early stages of the study included a better-designed study, particularly based on input during the study work-up phase. This added to, altered or confirmed a number of study design elements. Throughout the study, the study team were better informed through the sustained and active public contribution in meetings and developed a stronger sense of bereaved carers’ perspectives on the appropriateness of the approaches considered.
In more practical ways, it was an enormous advantage to have the presence and participation of Julie O’Connor at the NHS REC meeting. This gave the REC a sense of the meaning of the study and how it may be perceived by bereaved carers, and reassured them that the study intervention could be welcomed by carers. The public contribution improved the quality of a number of the public-facing documents, such as the qualitative topic guide and the study close-out documentation for carers. We identified no negative outcomes from public contribution.
A more indirect outcome that may have been influenced by participating in this study is that one of the public contributors (JO’C) has decided to embark on a new career in end-of-life care.
Reflections
Overall, public contribution influenced this study to a great extent. At all stages, the study was kept on track by ongoing and active public participation. The study team learnt a lot and changed a lot. We were guided through a very sensitive and potentially distressing study and steered towards appropriate and acceptable approaches. Not only was the instructive, beneficial and reassuring for the team but it also resulted in more of the right approaches being used to ensure that the study proceeded with respect and consideration for the study participants at a very difficult, and important, time of their lives.
