Results Of A Pilot Feasibility Randomized Controlled Trial Exploring The Use Of An Electronic Patient-reported Outcome Measure in The Management Of UK Patients With Advanced Chronic Kidney Disease

ABSTRACT

1. Objectives

The use of routine remote follow-up of patients with chronic kidney disease (CKD) is increasing exponentially. It has been suggested that online electronic patient-reported outcome measures (EPROMs) could be used in parallel, to facilitate real-time symptom monitoring aimed at improving outcomes. We tested the feasibility of this approach in a pilot trial of EPROM symptom monitoring versus usual care in patients with advanced CKD not on dialysis.

2. Design

A 12-month, parallel, pilot randomized controlled trial (RCT) and qualitative substudy. Setting and participants Queen Elizabeth Hospital Birmingham, UK. Adult patients with advanced CKD (estimated glomerular filtration rate ≥6 and ≤15 mL/ min/1.73 m2, or a projected risk of progression to kidney failure within 2 years ≥20%).

3. Intervention

Monthly online ePROM symptom reporting, including automated feedback of tailored self-management advice and triggered clinical notifications in the advent of severe symptoms. Real-time ePROM data were made available to the clinical team via the electronic medical record.

4. Outcomes

Feasibility (recruitment and retention rates, and acceptability/adherence to the ePROM intervention). Health-related quality of life, clinical data (eg, measures of kidney function, kidney failure, hospitalization, death), and healthcare utilization.

5. Results

52 patients were randomized (31% of approached). Case report form returns were high (99.5%), as was retention (96%). Overall, 73% of expected EPROM questionnaires were received. Intervention adherence was high beyond 90 days (74%) and 180 days (65%); but dropped beyond 270 days (46%). Qualitative interviews supported proof of concept and intervention acceptability but highlighted necessary changes aimed at enhancing the overall functionality/scalability of the EPROM system.

6. Limitations

Small sample size.

7. Conclusions

This pilot trial demonstrates that patients are willing to be randomized to a trial assessing ePROM symptom monitoring. The intervention was considered acceptable; though measures to improve longer-term engagement are needed. A full-scale RCT is considered feasible.

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BACKGROUND

Patients with advanced chronic kidney disease (CKD) commonly have a high symptom burden; increasingly so as they progress towards kidney failure.1 2 Uncontrolled symptomology can be a particular source of anxiety and can have a detrimental impact on a patient’s health-related quality of life and outcomes.1–3

Timely detection of symptomatic deterioration is a key component of effective disease management during this period.3 It can be challenging, however, to identify an unexpected decline in kidney function between scheduled clinic appointments, unless a patient self-refers. Unfortunately, some patients self-refer too late because they have difficulty identifying the point at which they may require assistance. Without prompt recognition of advanced symptoms, such patients are at high risk of severe illness, emergency hospitalization, progression to unplanned kidney replacement therapy, and significantly poorer long-term outcomes, including increased mortality. 4–6

Routine systematic capture of symptom data using electronic patient-reported outcome measure (ePROM) measures has been suggested as a low-cost method of supporting symptom monitoring and control.7 EPROM platforms provide patients with access to short online questionnaires that allow them to share self-reported symptom data with their clinical team, often in real-time, to help guide care.8 Systems may be configured to provide patients with tailored self-management advice and to trigger clinical notifications in the advent of sudden deterioration and/or severe symptomology.9–11

In studies involving patients with cancer, ePROM symptom monitoring is associated with enhanced patient-clinician communication; improved patient education and self-efficacy; better symptom control; earlier detection of adverse events; improved patient quality of life; reduced use of accident and emergency services; fewer inpatient hospital episodes; and improved survival; even for ‘computer-inexperienced’ patients.9–17

The efficacy of EPROM symptom monitoring for patients with advanced CKD has not been investigated within a randomized controlled trial (RCT), nor has the feasibility of undertaking such a trial been established. This single-center pilot study aimed to assess the feasibility of undertaking an RCT investigating the use of monthly EPROM reporting compared with usual care in patients with advanced CKD not on dialysis.

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METHODS

1. Reporting

This study is reported by the Consolidated Standards of Reporting Trials checklist for reporting a pilot/feasibility trial.18

2. Study design

RePROM (Renal ePROM) was a single-center, open-label, two-arm randomized controlled pilot/feasibility trial and qualitative substudy. The trial was registered with ISRCTN (ISRCTN12669006) and the UK NIHR Portfolio (CPMS ID: 36497); and the protocol has been published.19

3. Study changes

Owing to changes in clinical practice at the host research site, made in response to the COVID-19 pandemic, the study received approval from the Health Research Authority for early closure of follow-up (2 April 2020). This meant that follow-up was truncated for some participants and that recruitment of healthcare professionals (HCPs) to the qualitative substudy had to be suspended.

4. Study setting

The trial was undertaken within the Birmingham Clinical Trials Unit (BCTU) and Centre for Patient-Reported Outcomes Research at the University of Birmingham and the Queen Elizabeth Hospital Birmingham (QEHB) within the UK National Health Service (NHS) University Hospitals Birmingham Foundation Trust.

5. Patient and public involvement

Development of the study design was informed by a series of meetings held with our Patient Advisory Group (AB, SO’B, GP, KS, RV, and JW), established in 2016, which included people with lived experience of CKD. Members were also involved in the ePROM intervention codesign group20 and trial management group.

6. Study oversight

An independent steering committee was convened to provide guidance to the trial management group and to review feasibility data during the trial.

7. Study population

Eligible participants were adult (≥18 years old) patients under the care of the kidney services at QEHB, who met the trial definition of advanced CKD (estimated glomerular filtration rate (eGFR) ≥6 and ≤15 mL/min/1.73 m2, or a projected risk of progression to kidney failure within 2 years ≥20% using the four-variable Tangri renal risk equation21). Participants were excluded if they met any of the following criteria: patients unwilling to use the EPROM intervention; patients who, in the opinion of the consenting professional, could not speak, read or write English sufficiently well to complete the ePROM unaided; an episode of acute kidney injury (defined by international guidelines)22 within the last 3 months; patients meeting the trial definition of kidney failure (receiving dialysis, or scheduled to start, in the next 2 weeks, had received (or had a scheduled date to receive) a kidney transplant; or an eGFR ≤5 mL/min/1.73 m2 ); patients with a terminal illness that, in the opinion of the clinician assessing eligibility, was likely to lead to the death of the patient within 6 months of starting participation in the study.

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8. Recruitment and randomization

Members of the kidney research team at QEHB screened for potentially eligible study participants using the inclusion/exclusion criteria. Those considered eligible were provided with a patient information sheet and allowed to consider participation. For patients wishing to take part in the pilot trial (and optional qualitative substudy), consent, enrolment, and baseline data collection were conducted face-to-face in the clinic. Randomization was provided via a web-based system developed by BCTU. Participants were randomized at the level of the individual in a 1:1 ratio to usual care (control arm) or usual care supplemented with monthly online symptom reporting using the ePROM system (experimental arm). Minimization was used to achieve a balance between the 2-year risk of progression to kidney failure (<40%, vs ≥40%, based on the four-variable Tangri renal risk equation21); self-reported computer experience (regular use of a computer, tablet, or smartphone at least weekly, vs less than weekly); and patient-reported ethnicity (‘white’ vs ‘non-white’).

9. Intervention

Participants allocated to the ePROM intervention arm were asked to complete and submit monthly symptom questionnaires using an online system and received an automated reminder to do so. In addition, patients were allowed to submit any number of additional ‘ad hoc’ questionnaires at any time outside of the scheduled monthly reporting dates. The development and functionality of the ePROM system have been described in detail elsewhere.20 In summary, on questionnaire submission, automated self-management advice was provided to patients based on their responses; questionnaire data was integrated into the QEHB electronic medical record and made available to HCPs in real time; and a system algorithm triggered an automated notification which was sent to both the patient and the clinical team in the event of a severe and current symptom report. Participants allocated to the control arm received the usual care. It was not possible to blind clinicians or participants due to the nature of the intervention.

10. Outcomes

As this was a pilot trial there was no single primary outcome measure. The primary aims of the study were to pilot the trial protocol and assess the feasibility of undertaking a full-scale RCT exploring the use of EPROMs in the management of advanced CKD. The feasibility outcomes included the following: the proportion of eligible participants approached to take part in the trial; the proportion of eligible participants who took part in the trial; recruitment rate: the proportion of participants randomized/screened; the proportion of participants randomized/approached; the proportion of participants who completed the trial (retention); and the proportion of participants who adhered to the ePROM intervention.

This pilot trial was not powered to detect differences in outcome measures but provided an opportunity to ensure that there were no issues with the completion of the outcome data and proposed outcome measures for the main RCT. The following outcome data were collected:

►Health-related quality of life, using the paper version of the EuroQol five-dimension, five-level, questionnaire (EQ-5D-5L). The EQ-5D-5L is a reliable/ validated generic measure of health status/utility commonly used internationally in cost-effectiveness and ePROM research.10 23

► Clinical data, including serum creatinine, calcium, phosphate, bicarbonate, albumin, eGFR, albumin-to-creatinine ratio, blood pressure, and, for participants with diabetes: glucose and glycated hemoglobin.

► Event data: progression to kidney failure, contacts with HCPs in secondary care (outpatient clinics and accident and emergency), inpatient hospitalization, death.

► Additional healthcare resource use data were also collected at each study visit.

All data were collected at baseline and 3, 6, 9, and 12 months (assessment window ±3 weeks).

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11. Sample size

As this was a pilot trial, no formal sample size calculation was performed. Following recommendations for pilot studies, 30 patients or more are typically required to obtain estimates of the parameters needed for sample size estimation.24 25 To allow for a 10% drop-out and loss to follow-up, this pilot trial aimed to recruit at least 33 participants in each group, a total of 66 participants. This would allow the recruitment and retention rates to be estimated with 95% CI maximum widths of 20% and 25%, respectively.

12. Statistical analysis

Analysis of feasibility and clinical outcomes was based on all participants screened and recruited. For each binary outcome, the number and percentage are reported along with an exact binomial 95% CI. Estimates of differences between groups are presented as relative risks obtained from log-binomial regression models. These estimates were unadjusted due to the low number of observed events. For continuous outcomes, the means and 95% CIs are reported. Estimates of differences between groups are presented as differences in means adjusted for minimization variables and, for longitudinal outcomes, the corresponding baseline values. All estimates of differences are presented with 95% CIs. No p values are reported as no hypothesis testing was performed. Analysis was conducted using SPSS software, V.26 (IBM), and SAS software, V.9.4 (SAS Institute). Participants were analyzed in the intervention group to which they were randomized, and all participants were included in whether or not they received the allocated intervention (intention to treat). The study dataset and statistical analysis plan are available on request.

13. Qualitative substudy

The qualitative substudy aimed to explore patient and HCP thoughts/experiences regarding the RePROM trial processes and intervention. Semistructured interviews were conducted by the lead author according to predefined topic guides (online supplemental appendix), but there was sufficient scope to explore novel themes where appropriate. All interviews were digitally recorded, and professionally transcribed and the transcripts were anonymized. Transcript data were entered into a specialist software package (Dedoose, V.8.3.35) to aid the organization and analysis of the data. All data were analyzed by the lead author using conventional content analysis.26 Interview transcripts were examined in depth by DK, before first cycle coding, in which content was coded around positive and negative perceptions regarding the intervention, as well as suggested system changes.

DISCUSSION

In this single-center open-label randomized study, we examined the feasibility of randomizing patients with advanced CKD to monthly EPROM reporting with real-time feedback of data or to usual care. We found that the majority of study indicators supported the feasibility of a full-scale RCT: patient eligibility rate (proportion of screened patients eligible) 63%; recruitment rate (of patients approached) 31%; case report form returns 99.5%; and retention 96%. In total, 52 patients were randomized (monthly recruitment rate=4.3), representing 79% of the recruitment target sample size (N=66). This level of recruitment would position the study in the top quartile of performance based on a review of recruitment and retention across 151 RCTs funded by the UK Health Technology Assessment Programme.27 Moreover, overall adherence to the intervention was good, with patients returning 73% of expected EPROM questionnaires, although not always in the specified time windows. We have, therefore, demonstrated that it is possible to randomize and follow-up patients with high levels of data completion through to 12 months and that an RCT is feasible.

Within our study, we found the observed pattern of EPROM reporting did not correspond with our a priori expectations. Relatively few patients submitted their questionnaires within our prespecified compliance window (72 hours on either side of the scheduled submission date). Triangulation with qualitative data suggested that it was unlikely that this observation was related to issues around the acceptability of the intervention: all participants indicated positive engagement with the system. Moreover, overall questionnaire return rates were high. Several patients reported a failure to receive email reminders, or that emails were sent to junk folders, which may have contributed to out-of-window submissions: where patients relied on memory, rather than external prompts. Several patients suggested adding a mobile text reminder option, which they felt would be more reliable. It was our initial intention to include such an option, unfortunately, this was not possible within the existing patient portal framework. This feature will be made available as a priority within the next iteration of the system.

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Our overall findings around feasibility align with similar research conducted in oncology. The feasibility of trial-based exploration of EPROM efficacy in this area has been well established and several trials completed internationally, in the USA,10 France11, and in the UK.28 Within kidney research, while the feasibility of routine collection of EPROMs in clinical practice has been supported,29 30 there has been relatively little research around trial feasibility until recently. The ‘symptom monitoring with feedback trial’, is a registry-based pilot cluster RCT among Australian and New Zealand adults with end-stage kidney disease managed on hemodialysis; due for completion in 2020/2021.31 Early findings from the pilot study suggest feasibility and acceptability when implementing ePROMs with feedback to clinicians in Australian hemodialysis centers, supporting progress to a follow-on multicentre RCT. 32

Previous ePROM trials have commonly included a primary outcome based on health-related quality of life, for example, measured using the EQ-5D.10 Based on our study population data, it would require a total of 348 participants to detect a clinically meaningful 0.07 reduction in EQ-5D-5L index33 (SD=0.18, p=0.05, 90% power, adjusting for 20% attrition). This sample size appears achievable based on the successful implementation of previous UK-led kidney trials with similar (or greater) sample size requirements.34 35

While the study intervention was well received by patients and demonstrated proof of concept, several suggested improvements may enhance longer-term engagement with the system, for example, simplification of the interface and, in particular, improvements to the reminder functionality; incorporation of automated dietary advice; and the inclusion of additional questionnaire items around the psychological impacts associated with CKD. In addition, it was suggested that the use of the intervention within a multicentre trial may necessitate system-level modifications to ensure compatibility with different IT infrastructures at other hospitals. Work conducted within a UK oncology setting has shown that it is possible to integrate a single EPROM system across multiple NHS trusts, each with unique IT platforms, but that repeated integration at each separate site often takes considerable time and resources.9 Our own experience of linking an ePROM to an existing hospital-based patient portal was mixed. Positives included the in-built security aspects, which some patients particularly valued, and also the ability to share data within the electronic medical record relatively easily. Negatives included functionality issues around the interface and the lack of some important features, for example, text reminders and smartphone compatibility. In addition, issues with sign-up to the patient portal for some patients meant that study staff could not approach them to take part in the trial without first arranging access to the patient portal, which created a substantial barrier to recruitment.

Looking ahead to the roll-out of an EPROM system within a multicentre trial, and also considering future potential implementation in clinical practice, the use of a single hospital patient portal as the foundation platform may hinder effective scale-up. Any ePROM system would ideally require full integration with the electronic healthcare record at each site, and also a unified interface, to maximize the likelihood of success and utility. In a recent renal stakeholder summit aimed at developing a UK ePROM roadmap—involving patients, HCPs, academics, and funders/renal organizations (including the Renal Association, British Renal Society, Kidney Care UK, National Kidney Federation, Kidney Research UK)— the development of a single online ePROM gateway/dashboard was identified as a key priority.36 Such a dashboard would provide patients with a simple and consistent point of entry and allow them the flexibility to configure the platform to their liking, for example, around how reminders were configured/delivered, how their data and clinical advice were presented, or which primary/ secondary care providers would have permissions to access their symptom information. Back-end development of application programming interfaces would then allow permitted healthcare providers to securely ‘pull’ appropriate data into their electronic medical record, regardless of their underlying system architecture.

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Strengths and limitations

This is the first UK study conducted in a CKD population that has explored the feasibility of EPROM capture/ feedback with real-time integration within the electronic medical record. Our findings will help guide the design of a future RCT aimed at exploring efficacy and cost-effectiveness. As this was a pilot study, no inferences can be made about the intervention’s therapeutic efficacy. Nevertheless, clinical data around eGFR, risk of progression to kidney failure, and healthcare utilization show trends towards improvement in the intervention arm, suggesting further research is warranted.

The attrition rate for this study was larger than expected, owing to a higher proportion of patients progressing to kidney failure than anticipated (38% of patients randomized, vs 20% predicted). While this demonstrated the effectiveness of our recruitment strategy, which targeted patients with advanced CKD at risk of progression, the sample size for a future trial may need to be adjusted accordingly to account for this observation depending on the exact nature of the primary outcome.

During the qualitative process analysis, it was not possible to conduct dual-coding or triangulation, this should be taken into account when interpreting the findings.

The prespecified data analysis plan for this pilot study did not stipulate the capture of the reason for starting dialysis, only the start date and type of dialysis were recorded.

Finally, a sizeable proportion of patients who were approached during study recruitment declined participation owing to concerns around internet access/computer inexperience. While, anecdotally, reports suggest that patients have become much more comfortable with the use of digital healthcare necessitated during the COVID-19 pandemic, any future RCT should focus on broadening study accessibility and reducing the possibility of digital exclusion by (1) ensuring the use of a simple user-friendly platform, with adequate training/support in place at the outset and (2) potentially providing an offline, for example, paper-based, PRO option.

CONCLUSIONS

This UK single-center, open-label, randomized controlled pilot study has demonstrated that it is feasible to conduct a trial incorporating online ePROM symptom reporting, with high rates of data completion. Based on patient feedback and system data, improvements to our EPROM intervention should be implemented to enhance functionality, long-term engagement, and scalability before a multicentre RCT.

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19 Kyte D, Bishop J, Brettell E, et al. Use of an electronic patient-reported outcome measure in the management of patients with advanced chronic kidney disease: the RePROM pilot trial protocol. BMJ Open 2018;8:e026080.

20 Kyte D, Anderson N, Auti R, et al. Development of an electronic patient-reported outcome measure (ePROM) system to aid the management of patients with advanced chronic kidney disease. J Patient Rep Outcomes 2020;4:1–9.

21 Tangri N, Stevens LA, Griffith J, et al. A predictive model for progression of chronic kidney disease to kidney failure. JAMA 2011;305:1553–9.

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36 UK Renal Association. Electronic patient-reported outcomes (ePROs) for the kidney patient community. electronic patient-reported outcomes (ePROs) for the kidney patient community, 2020. Available: https://wwwyoutubecom/ watch?v=JgG61Vouctk&feature=youtube

Derek Kyte,1,2 Nicola Anderson,2,3 Jon Bishop,4 Andrew Bissell,5 Elizabeth Brettell,4 Melanie Calvert,2,6,7,8,9 Marie Chadburn,4 Paul Cockwell,3 Mary Dutton,3 Helen Eddington,3 Elliot Forster,3 Gabby Hadley,3 Natalie J Ives,4 Louise J Jackson,10 Sonia O'Brien,5 Gary Price,5 Keeley Sharpe,5 Stephanie Stringer,3 Rav Verdi,5 Judi Waters,5 Adrian Wilcockson4

1 School of Applied Health & Community, University of Worcester, Worcester, UK

2 Centre for Patient Reported Outcomes Research, Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

3 University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

4 Birmingham Clinical Trials Unit (BCTU), Institute of Applied Health Research, University of Birmingham, Birmingham, UK

5 Patient Advisory Group, Centre for Patient-Reported Outcomes Research, Institute of Applied Health Research, University of Birmingham, Birmingham, UK

6 Birmingham Health Partners Centre for Regulatory Science and Innovation, University of Birmingham, Birmingham, UK

7 National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK

8 National Institute for Health Research (NIHR) Applied Research Collaboration (ARC) West Midlands, University of Birmingham, Birmingham, UK

9 National Institute for Health Research (NIHR) Surgical Reconstruction and Microbiology Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK

10 Health Economics Unit, Institute of Applied Health Research, University of Birmingham, Birmingham, UK