Core outcome measurement set for research and clinical practice in post-COVID-19 condition (long COVID) in children and young people: an international Delphi consensus study "PC-COS Children".

The coronavirus disease 2019 (COVID-19) pandemic substantially impacted different age groups, with children and young people not exempted. Many have experienced enduring health consequences. Presently, there is no consensus on the health outcomes to assess in children and young people with post-COVID-19 condition. Furthermore, it is unclear which measurement instruments are appropriate for use in research and clinical management of children and young people with post-COVID-19. To address these unmet needs, we conducted a consensus study, aiming to develop a core outcome set (COS) and an associated core outcome measurement set (COMS) for evaluating post-COVID-19 condition in children and young people. Our methodology comprised of two phases. In phase 1 (to create a COS), we performed an extensive literature review and categorisation of outcomes, and prioritised those outcomes in a two-round online modified Delphi process followed by a consensus meeting. In phase 2 (to create the COMS), we performed another modified Delphi consensus process to evaluate measurement instruments for previously defined core outcomes from phase 1, followed by an online consensus workshop to finalise recommendations regarding the most appropriate instruments for each core outcome. In phase 1, 214 participants from 37 countries participated, with 154 (72%) contributing to both Delphi rounds. The subsequent online consensus meeting resulted in a final COS which encompassed seven critical outcomes: fatigue; post-exertion symptoms; work/occupational and study changes; as well as functional changes, symptoms, and conditions relating to cardiovascular, neuro-cognitive, gastrointestinal and physical outcomes. In phase 2, 11 international experts were involved in a modified Delphi process, selecting measurement instruments for a subsequent online consensus workshop where 30 voting participants discussed and independently scored the selected instruments. As a result of this consensus process, four instruments met a priori consensus criteria for inclusion: PedsQL multidimensional fatigue scale for "fatigue"; PedsQL gastrointestinal symptom scales for "gastrointestinal"; PedsQL cognitive functioning scale for "neurocognitive" and EQ-5D for "physical functioning". Despite proposing outcome measurement instruments for the remaining three core outcomes ("cardiovascular", "post-exertional malaise", "work/occupational and study changes"), a consensus was not achieved. Our international, consensus-based initiative presents a robust framework for evaluating post-COVID-19 condition in children and young people in research and clinical practice via a rigorously defined COS and associated COMS. It will aid in the uniform measurement and reporting of relevant health outcomes worldwide.

Methodological quality of 100 recent systematic reviews of health-related outcome measurement instruments: an overview of reviews.

PURPOSE: Systematic reviews evaluating and comparing the measurement properties of outcome measurement instruments (OMIs) play an important role in OMI selection. Earlier overviews of review quality (2007, 2014) evidenced substantial concerns with regards to alignment to scientific standards. This overview aimed to investigate whether the quality of recent systematic reviews of OMIs lives up to the current scientific standards. METHODS: One hundred systematic reviews of OMIs published from June 1, 2021 onwards were randomly selected through a systematic literature search performed on March 17, 2022 in MEDLINE and EMBASE. The quality of systematic reviews was appraised by two independent reviewers. An updated data extraction form was informed by the earlier studies, and results were compared to these earlier studies' findings. RESULTS: A quarter of the reviews had an unclear research question or aim, and in 22% of the reviews the search strategy did not match the aim. Half of the reviews had an incomprehensive search strategy, because relevant search terms were not included. In 63% of the reviews (compared to 41% in 2014 and 30% in 2007) a risk of bias assessment was conducted. In 73% of the reviews (some) measurement properties were evaluated (58% in 2014 and 55% in 2007). In 60% of the reviews the data were (partly) synthesized (42% in 2014 and 7% in 2007); evaluation of measurement properties and data syntheses was not conducted separately for subscales in the majority. Certainty assessments of the quality of the total body of evidence were conducted in only 33% of reviews (not assessed in 2014 and 2007). The majority (58%) did not make any recommendations on which OMI (not) to use. CONCLUSION: Despite clear improvements in risk of bias assessments, measurement property evaluation and data synthesis, specifying the research question, conducting the search strategy and performing a certainty assessment remain poor. To ensure that systematic reviews of OMIs meet current scientific standards, more consistent conduct and reporting of systematic reviews of OMIs is needed.

COVID-19 related headaches: epidemiology, pathophysiology, impacts, and management.

PURPOSE OF REVIEW: This is an expert overview of the recent literature on the nature, epidemiology, pathophysiology, impact, and management of COVID-19 related headache, in the acute phase of infection and in post-COVID-19 syndrome. RECENT FINDINGS: Headache is one of the commonest symptoms of COVID-19 during acute infection and it is often experienced by individuals who go on to develop long COVID. There is a higher prevalence of headache in individuals with long COVID who contracted the Delta variant than in those who were infected with the Wuhan or Alpha variants. Headaches related to COVID-19 infection are commoner and may be more intense in women.There are indications that presence of headache might indicate a more benign COVID-19 infection and a better chance of survival. However, the impact of COVID-19 related headache could be substantial leading to poor quality of life in individuals affected. Headache that changes in its nature in terms of frequency and severity should be investigated to exclude cerebrovascular complications. There are promising new therapies for its treatment, but further research is needed. SUMMARY: The findings of this review can promote a better understanding of COVID-19 related headache and guide clinicians in the management of patients.

Symptom burden and health-related quality of life in chronic kidney disease: A global systematic review and meta-analysis.

BACKGROUND: The importance of patient-reported outcome measurement in chronic kidney disease (CKD) populations has been established. However, there remains a lack of research that has synthesised data around CKD-specific symptom and health-related quality of life (HRQOL) burden globally, to inform focused measurement of the most relevant patient-important information in a way that minimises patient burden. The aim of this review was to synthesise symptom prevalence/severity and HRQOL data across the following CKD clinical groups globally: (1) stage 1-5 and not on renal replacement therapy (RRT), (2) receiving dialysis, or (3) in receipt of a kidney transplant. METHODS AND FINDINGS: MEDLINE, PsycINFO, and CINAHL were searched for English-language cross-sectional/longitudinal studies reporting prevalence and/or severity of symptoms and/or HRQOL in CKD, published between January 2000 and September 2021, including adult patients with CKD, and measuring symptom prevalence/severity and/or HRQOL using a patient-reported outcome measure (PROM). Random effects meta-analyses were used to pool data, stratified by CKD group: not on RRT, receiving dialysis, or in receipt of a kidney transplant. Methodological quality of included studies was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data, and an exploration of publication bias performed. The search identified 1,529 studies, of which 449, with 199,147 participants from 62 countries, were included in the analysis. Studies used 67 different symptom and HRQOL outcome measures, which provided data on 68 reported symptoms. Random effects meta-analyses highlighted the considerable symptom and HRQOL burden associated with CKD, with fatigue particularly prevalent, both in patients not on RRT (14 studies, 4,139 participants: 70%, 95% CI 60%-79%) and those receiving dialysis (21 studies, 2,943 participants: 70%, 95% CI 64%-76%). A number of symptoms were significantly (p < 0.05 after adjustment for multiple testing) less prevalent and/or less severe within the post-transplantation population, which may suggest attribution to CKD (fatigue, depression, itching, poor mobility, poor sleep, and dry mouth). Quality of life was commonly lower in patients on dialysis (36-Item Short Form Health Survey [SF-36] Mental Component Summary [MCS] 45.7 [95% CI 45.5-45.8]; SF-36 Physical Component Summary [PCS] 35.5 [95% CI 35.3-35.6]; 91 studies, 32,105 participants for MCS and PCS) than in other CKD populations (patients not on RRT: SF-36 MCS 66.6 [95% CI 66.5-66.6], p = 0.002; PCS 66.3 [95% CI 66.2-66.4], p = 0.002; 39 studies, 24,600 participants; transplant: MCS 50.0 [95% CI 49.9-50.1], p = 0.002; PCS 48.0 [95% CI 47.9-48.1], p = 0.002; 39 studies, 9,664 participants). Limitations of the analysis are the relatively few studies contributing to symptom severity estimates and inconsistent use of PROMs (different measures and time points) across the included literature, which hindered interpretation. CONCLUSIONS: The main findings highlight the considerable symptom and HRQOL burden associated with CKD. The synthesis provides a detailed overview of the symptom/HRQOL profile across clinical groups, which may support healthcare professionals when discussing, measuring, and managing the potential treatment burden associated with CKD. PROTOCOL REGISTRATION: PROSPERO CRD42020164737.

Knowledge translation concerns for the CONSORT-PRO extension reporting guidance: a review of reviews.

This review of reviews aimed to appraise the use of the CONSORT-PRO Extension as an evaluation tool for assessing the reporting of patient-reported outcome (PROs) in publications, and to describe the reporting of PRO research across reviews. We also outlined how variation in such evaluations impacts knowledge translation and may lead to potential misuse of the CONSORT-PRO Extension. We systematically searched Medline, Pubmed and CINAHL from 2013 to 2025 March 2021 for reviews of the completeness of reporting of PRO endpoints according to CONSORT-PRO criteria. Two reviewers extracted details of each review, the percentage of included studies that addressed each CONSORT-PRO item, and key recommendations from each review. Fourteen reviews met inclusion criteria, and only six of these used the full CONSORT-PRO checklist with minimal justified modifications. The remaining eight studies made significant or unjustified adjustments to the CONSORT-PRO Extension. Review studies also varied in how they scored multi-component CONSORT-PRO items. CONSORT-PRO items were often unreported in trial reports, and certain CONSORT-PRO items were reported less often than others. The reporting of statistical approaches to dealing with missing PRO data were poor in RCTs included in all 14 review articles. Studies reviewing PRO publications often omitted recommended CONSORT-PRO items from their evaluations, which may cause confusion among readers regarding how best to report their PRO research according to the CONSORT-PRO extension. Many trials published since CONSORT-PRO's release did not report recommended CONSORT-PRO items, which may lead to misinterpretation and consequently to research waste.

Ethical Considerations for the Inclusion of Patient-Reported Outcomes in Clinical Research: The PRO Ethics Guidelines.

Importance: Patient-reported outcomes (PROs) can inform health care decisions, regulatory decisions, and health care policy. They also can be used for audit/benchmarking and monitoring symptoms to provide timely care tailored to individual needs. However, several ethical issues have been raised in relation to PRO use. Objective: To develop international, consensus-based, PRO-specific ethical guidelines for clinical research. Evidence Review: The PRO ethics guidelines were developed following the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network's guideline development framework. This included a systematic review of the ethical implications of PROs in clinical research. The databases MEDLINE (Ovid), Embase, AMED, and CINAHL were searched from inception until March 2020. The keywords patient reported outcome* and ethic* were used to search the databases. Two reviewers independently conducted title and abstract screening before full-text screening to determine eligibility. The review was supplemented by the SPIRIT-PRO Extension recommendations for trial protocol. Subsequently, a 2-round international Delphi process (n = 96 participants; May and August 2021) and a consensus meeting (n = 25 international participants; October 2021) were held. Prior to voting, consensus meeting participants were provided with a summary of the Delphi process results and information on whether the items aligned with existing ethical guidance. Findings: Twenty-three items were considered in the first round of the Delphi process: 6 relevant candidate items from the systematic review and 17 additional items drawn from the SPIRIT-PRO Extension. Ninety-six international participants voted on the relevant importance of each item for inclusion in ethical guidelines and 12 additional items were recommended for inclusion in round 2 of the Delphi (35 items in total). Fourteen items were recommended for inclusion at the consensus meeting (n = 25 participants). The final wording of the PRO ethical guidelines was agreed on by consensus meeting participants with input from 6 additional individuals. Included items focused on PRO-specific ethical issues relating to research rationale, objectives, eligibility requirements, PRO concepts and domains, PRO assessment schedules, sample size, PRO data monitoring, barriers to PRO completion, participant acceptability and burden, administration of PRO questionnaires for participants who are unable to self-report PRO data, input on PRO strategy by patient partners or members of the public, avoiding missing data, and dissemination plans. Conclusions and Relevance: The PRO ethics guidelines provide recommendations for ethical issues that should be addressed in PRO clinical research. Addressing ethical issues of PRO clinical research has the potential to ensure high-quality PRO data while minimizing participant risk, burden, and harm and protecting participant and researcher welfare.

Patient and clinician opinions of patient reported outcome measures (PROMs) in the management of patients with rare diseases: a qualitative study.

BACKGROUND: Rare diseases may be life-threatening or chronically debilitating conditions. Patient care needs are often complex and challenging to coordinate and deliver effectively. Rare diseases and their clinical management may therefore substantially impact on patients' health-related quality of life (HRQOL). The use of patient-reported outcome measures (PROMs) may complement clinical assessments by elucidating patients' perspectives on their health status and care priorities. This study explored the opinions of patients and clinicians on the use of PROMs in the management of patients with rare diseases in routine clinical practice. METHODS: A total of 15 semi-structured one-to-one interviews were conducted with four patients with primary sclerosing cholangitis (PSC); five renal transplant recipients; and six PSC doctors from University Hospitals Birmingham (UHB) NHS Foundation Trust. A focus group session was also conducted with 10 clinical staff members (doctors, nurses and other allied health professionals from UHB). The suitability and acceptability of the Chronic Liver Disease Questionnaire (CLDQ) and the Short Form 12 (SF12) were assessed by patients with PSC and their doctors while the Paediatric quality of life inventory Transplant Module (PedsQL-TM) and the EuroQoL-5 dimensions (EQ. 5D) were evaluated by the renal transplant recipients and their doctors. The discussions were audio recorded and transcribed verbatim. Coding of the transcripts was done using the Nvivo 11 Plus software. Thematic analysis was conducted to identify the main themes and subthemes. RESULTS: Four themes were identified, namely: (i) potential benefits of PROMs in the management of rare diseases; (ii) views on selected questionnaires; (iii) practical considerations for implementation; and (iv) potential facilitators and barriers of implementation. Patients and clinicians suggested that the use of ePROMs may facilitate patient-centred care by promoting patient-clinician communication, highlighting aspects of HRQOL that are important to patients and encouraging patient involvement in their care. They also felt that the disease-specific CLDQ and PedsQL-TM were more relevant than the generic SF12 and EQ-5D. CONCLUSIONS: Patients with rare diseases often experience impaired HRQOL. The use of an ePROM system may enhance the routine management of patients with rare diseases.

Key methodological considerations for usability testing of electronic patient-reported outcome (ePRO) systems.

INTRODUCTION: Recent advances in information technology and improved access to the internet have led to a rapid increase in the adoption and ownership of electronic devices such as touch screen smartphones and tablet computers. This has also led to a renewed interest in the field of digital health also referred to as telehealth or electronic health (eHealth). There is now a drive to collect these PROs electronically using ePRO systems. METHOD: However, the user interfaces of ePRO systems need to be adequately assessed to ensure they are not only fit for purpose but also acceptable to patients who are the end users. Usability testing is a technique that involves the testing of systems, products or websites with participants drawn from the target population. Usability testing can assist ePRO developers in the evaluation of ePRO user interface. The complexity of ePRO systems; stage of development; metrics to measure; and the use of scenarios, moderators and appropriate sample sizes are key methodological issues to consider when planning usability tests. CONCLUSION: The findings from usability testing may facilitate the improvement of ePRO systems making them more usable and acceptable to end users. This may in turn improve the adoption of ePRO systems post-implementation. This article highlights the key methodological issues to consider and address when planning usability testing of ePRO systems.

General practitioners' views on use of patient reported outcome measures in primary care: a cross-sectional survey and qualitative study.

BACKGROUND: Patient reported outcome measures (PROMs) are increasingly used to assess impact of disease and treatment on quality of life and symptoms; however, their use in primary care is fragmented. We aimed to understand how PROMs are currently being used in primary care, the barriers and facilitators of this use and if appropriate how it might be optimised. METHODS: Cross-sectional survey and semi-structured interviews among general practitioners (GPs) in England. GPs' opinions were explored using an electronic, self-completed questionnaire disseminated to 100 GPs via an online doctors' community and semi-structured qualitative interviews with 25 GPs. RESULTS: Most GPs surveyed (77/100; 77%) reported using one or more PROM, primarily to aid clinical management (n = 66) or as screening/diagnostic tools (n = 62). Qualitative interviews highlighted challenges in identifying and selecting PROMs; however, some GPs valued PROMs for shared decision making and to direct patient discussions. The interviews identified key barriers to PROM use including: time constraints; insufficient knowledge; lack of integration into clinical systems; and PROMs being mandated without consultation or explanation. Evidence of the benefit of PROMs is required to promote uptake and use of PROMs in primary care. CONCLUSION: Implementation of PROMs in primary care requires integration with clinical systems, a bottom-up approach to PROM selection and system design involving meaningful consultation with patients and primary care clinicians and training/support for use.

Patient and Clinician Perspectives on Electronic Patient-Reported Outcome Measures in the Management of Advanced CKD: A Qualitative Study.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) can substantially affect patients' health-related quality of life. Electronic patient-reported outcome measures (ePROMs) may capture symptoms and health-related quality of life and assist in the management of CKD. This study explored patient and clinician views on the use of a renal ePROM system. STUDY DESIGN: Qualitative study. SETTING & PARTICIPANTS: 12 patients with stage 4 or 5 CKD (non-dialysis dependent); 22 clinicians (6 CKD community nurses, 1 clinical psychologist, 10 nephrologists, 3 specialist registrars, and 2 renal surgeons) in the United Kingdom. ANALYTICAL APPROACH: Semi-structured interviews and focus group discussion during which patients received paper versions of the Kidney Disease Quality of Life-36 and the Integrated Patient Outcome Scale-Renal to exemplify the type of content that could be included in an ePROM. Thematic analysis of interview transcripts. RESULTS: 4 themes were identified: (1) general opinions of PROMs, (2) potential benefits and applications of an ePROM system, (3) practical considerations for the implementation of ePROMs, and (4) concerns, barriers, and facilitators. Patients were willing to complete ePROMs on a regular basis as part of their care despite clinician concerns about patient burden. Patients assessed the questionnaires favorably. Clinicians suggested that the extent of adoption of renal ePROM systems in routine clinical settings should be based on evidence of significant impact on patient outcomes. Clinicians were concerned that an ePROM system may raise patient expectations to unrealistic levels and expose clinicians to the risk for litigation. Patients and clinicians identified potential benefits and highlighted issues and concerns that need to be addressed to ensure the successful implementation of the renal ePROM system. LIMITATIONS: Transferability of the findings may be limited because only English-speaking participants were recruited to the study. CONCLUSIONS: A renal ePROM system may play a supportive role in the routine clinical management of patients with advanced CKD if the concerns of clinicians and patients can be sufficiently addressed.

The impact of patient-reported outcome (PRO) data from clinical trials: a systematic review and critical analysis.

BACKGROUND: Patient-reported outcomes (PROs) are commonly collected in clinical trials and should provide impactful evidence on the effect of interventions on patient symptoms and quality of life. However, it is unclear how PRO impact is currently realised in practice. In addition, the different types of impact associated with PRO trial results, their barriers and facilitators, and appropriate impact metrics are not well defined. Therefore, our objectives were: i) to determine the range of potential impacts from PRO clinical trial data, ii) identify potential PRO impact metrics and iii) identify barriers/facilitators to maximising PRO impact; and iv) to examine real-world evidence of PRO trial data impact based on Research Excellence Framework (REF) impact case studies. METHODS: Two independent investigators searched MEDLINE, EMBASE, CINAHL+, HMIC databases from inception until December 2018. Articles were eligible if they discussed research impact in the context of PRO clinical trial data. In addition, the REF 2014 database was systematically searched. REF impact case studies were included if they incorporated PRO data in a clinical trial. RESULTS: Thirty-nine publications of eleven thousand four hundred eighty screened met the inclusion criteria. Nine types of PRO trial impact were identified; the most frequent of which centred around PRO data informing clinical decision-making. The included publications identified several barriers and facilitators around PRO trial design, conduct, analysis and report that can hinder or promote the impact of PRO trial data. Sixty-nine out of two hundred nine screened REF 2014 case studies were included. 12 (17%) REF case studies led to demonstrable impact including changes to international guidelines; national guidelines; influencing cost-effectiveness analysis; and influencing drug approvals. CONCLUSIONS: PRO trial data may potentially lead to a range of benefits for patients and society, which can be measured through appropriate impact metrics. However, in practice there is relatively limited evidence demonstrating directly attributable and indirect real world PRO-related research impact. In part, this is due to the wider challenges of measuring the impact of research and PRO-specific issues around design, conduct, analysis and reporting. Adherence to guidelines and multi-stakeholder collaboration is essential to maximise the use of PRO trial data, facilitate impact and minimise research waste. TRIAL REGISTRATION: Systematic Review registration PROSPERO CRD42017067799.

Assessing the impact of healthcare research: A systematic review of methodological frameworks.

BACKGROUND: Increasingly, researchers need to demonstrate the impact of their research to their sponsors, funders, and fellow academics. However, the most appropriate way of measuring the impact of healthcare research is subject to debate. We aimed to identify the existing methodological frameworks used to measure healthcare research impact and to summarise the common themes and metrics in an impact matrix. METHODS AND FINDINGS: Two independent investigators systematically searched the Medical Literature Analysis and Retrieval System Online (MEDLINE), the Excerpta Medica Database (EMBASE), the Cumulative Index to Nursing and Allied Health Literature (CINAHL+), the Health Management Information Consortium, and the Journal of Research Evaluation from inception until May 2017 for publications that presented a methodological framework for research impact. We then summarised the common concepts and themes across methodological frameworks and identified the metrics used to evaluate differing forms of impact. Twenty-four unique methodological frameworks were identified, addressing 5 broad categories of impact: (1) 'primary research-related impact', (2) 'influence on policy making', (3) 'health and health systems impact', (4) 'health-related and societal impact', and (5) 'broader economic impact'. These categories were subdivided into 16 common impact subgroups. Authors of the included publications proposed 80 different metrics aimed at measuring impact in these areas. The main limitation of the study was the potential exclusion of relevant articles, as a consequence of the poor indexing of the databases searched. CONCLUSIONS: The measurement of research impact is an essential exercise to help direct the allocation of limited research resources, to maximise research benefit, and to help minimise research waste. This review provides a collective summary of existing methodological frameworks for research impact, which funders may use to inform the measurement of research impact and researchers may use to inform study design decisions aimed at maximising the short-, medium-, and long-term impact of their research.

Factors that influence the selection of conservative management for end-stage renal disease - a systematic review.

Background: Most patients with end-stage renal disease (ESRD) are managed with dialysis and less commonly kidney transplantation. However, not all are suitable for or desire either of these renal replacement therapies. Conservative management (CM) is an option. However, the selection of CM is often not easy for patients and clinicians. The aim of this systematic review is to identify the key factors that influence the selection of CM for ESRD. Methods: Medline, Embase, PsychINFO, and CINAHL Plus were systematically searched from inception to 10 September 2021. Titles/abstracts and full texts were independently screened by two reviewers. Reference lists of included articles were searched. An update search via PubMed was conducted on 10 August 2023. A narrative synthesis of review findings was conducted. Results: At the end of the screening process, 15 qualitative and 8 survey articles were selected. Reference checking yielded no additional relevant studies. Main themes were: (i) Patient-specific factors; (ii) Clinician-specific factors; (iii) Organisational factors; and (iv) National and international factors. Patient-specific factors were awareness and perceptions of CM and dialysis, beliefs about survival, preferred treatment outcomes and influence of family/caregivers and clinicians. Clinician-specific factors included perceptions of CM as 'non-intervention', perceptions of clinician role in the decision-making process, and confidence and ability to initiate sensitive treatment discussions. Relationships with and involvement of other healthcare professionals, time constraints, and limited clinical guidance were also important factors. Conclusions: An improvement in the provision of education regarding CM for patients, caregivers, and clinicians is essential. Robust studies are required to generate crucial evidence for the development of stronger recommendations and guidance for clinicians.

Patient and public involvement and engagement in the development of innovative patient-centric early phase dose-finding trial designs.

BACKGROUND: In light of the FDA's Project Optimus initiative, there is fresh interest in leveraging Patient-reported Outcome (PRO) data to enhance the assessment of tolerability for investigational therapies within early phase dose-finding oncology trials. Typically, dose escalation in most trial designs is solely reliant on clinician assessed adverse events. Research has shown a disparity between patients and clinicians when assessing whether an investigational therapy is tolerable, leading to the recommendation of potentially intolerable doses for further investigation in subsequent trials. It is also increasingly recognized that patient and public involvement and engagement (PPIE) plays a pivotal role in enriching trial design and conduct. However, to our knowledge, no PPIE has explored the optimal integration of PROs in the development of advanced statistical trial designs within early phase dose-finding oncology trials. METHODS: A virtual PPIE session was held with nine participants on 18th October 2023 to discuss the incorporation of PROs within a dose-finding trial design. This cross disciplinary session was developed and led by a team of statisticians, clinical specialists, qualitative experts, and trial methodologists. Following the session, in-depth perspectives were provided by two patient advocates who actively engaged in the PPIE session. We discuss the importance of PPIE in shaping advanced dose-finding trial designs, share insights from patients on integrating PROs to inform treatment tolerability, and present a template for meaningful patient involvement in trial design development. RESULTS: Participants generally supported the introduction of PROs within dose-finding trials but showed some apprehensiveness as to how PROs may reduce the size of the recommended dose (and potentially efficacious effect). Some participants shared that they may be reluctant to record the real severity of their symptoms via PROs if it would mean that they would have to discontinue treatment. They discussed that PROs could be used to assess tolerability rather than toxicity of a dose. CONCLUSIONS: Amplifying patient voice in the development of patient-centric dose-finding trial designs is now essential. This paper offers an exemplary illustration of how trialists and methodologists can effectively incorporate patient voice in the future development of advanced dose-finding trial designs.

The aim of dose-finding oncology trials is to make sure a treatment is safe, understand its side effects, and recommend the right dose (or doses) for future clinical trials. Traditionally, a patient's tolerance to treatment is assessed by doctors who evaluate toxicities (side-effects) using established grading guidelines. Research has shown that doctors might not identify all the side effects that patients actually experience during a trial.There is growing interest in the introduction of patient-reported outcomes (PROs) within dose-finding trials. PROs are reports of a patient's health and well-being experiences which come directly from the patient themselves, usually assessed using a questionnaire.In a dose-finding trial, we start with a low dose of a drug and increase it until too many patients have severe side effects. The highest safe dose is then investigated in a later phase trial.   We are suggesting a new way to do these trials. We want to look at both what doctors see as severe side effects and what patients say. This enables us to recommend a dose that balances both perspectives. We would also like to ask patients what level of risk they are comfortable with regarding severe side effects.In this paper, we highlight the importance of involving patients in creating advanced dose-finding trial designs, particularly with PROs to help decide whether a dose is tolerable for patients. We also share findings of a patient and public involvement and engagement session and provide a guide for meaningful patient involvement in developing trial designs.

Protocol for the development of a core outcome set for clinical trials in primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a progressive immune-mediated liver disease, for which no medical therapy has been shown to slow disease progression. However, the horizon for new therapies is encouraging, with several innovative clinical trials in progress. Despite these advancements, there is considerable heterogeneity in the outcomes studied, with lack of consensus as to what outcomes to measure, when to measure and how to measure. Furthermore, there has been a paradigm shift in PSC treatment targets over recent years, moving from biochemistry-based endpoints to histological assessment of liver fibrosis, imaging-based biomarkers and patient-reported outcome measures. The abundance of new interventional trials and evolving endpoints pose opportunities for all stakeholders involved in evaluating novel therapies. To this effect, there is a need to harmonise measures used in clinical trials through the development of a core outcome set (COS). METHODS AND ANALYSIS: Synthesis of a PSC-specific COS will be conducted in four stages. Initially, a systematic literature review will be performed to identify outcomes previously used in PSC trials, followed by semistructured qualitative interviews conducted with key stakeholders. The latter may include patients, clinicians, researchers, pharmaceutical industry representatives and healthcare payers and regulatory agencies, to identify additional outcomes of importance. Using the outcomes generated from the literature review and stakeholder interviews, an international two-round Delphi survey will be conducted to prioritise outcomes for inclusion in the COS. Finally, a consensus meeting will be convened to ratify the COS and disseminate findings for application in future PSC trials. ETHICS AND DISSEMINATION: Ethical approval has been granted by the East Midlands-Leicester Central Research Ethics Committee (Ref: 24/EM/0126) for this study. The COS from this study will be widely disseminated including publication in peer-reviewed journals, international conferences, promotion through patient-support groups and made available on the Core Outcomes Measurement in Effectiveness Trials (COMET) database. TRIAL REGISTRATION NUMBER: 1239.

Potentially modifiable factors associated with health-related quality of life among people with chronic kidney disease: baseline findings from the National Unified Renal Translational Research Enterprise CKD (NURTuRE-CKD) cohort.

Background: Many non-modifiable factors are associated with poorer health-related quality of life (HRQoL) experienced by people with chronic kidney disease (CKD). We hypothesize that potentially modifiable factors for poor HRQoL can be identified among CKD patients, providing potential targets for intervention. Method: The National Unified Renal Translational Research Enterprise Chronic Kidney Disease (NURTuRE-CKD) cohort study recruited 2996 participants from nephrology centres with all stages of non-dialysis-dependent CKD. Baseline data collection for sociodemographic, anthropometric, biochemical and clinical information, including Integrated Palliative care Outcome Scale renal, Hospital Anxiety and Depression score (HADS) and the 5-level EuroQol-5D (EQ-5D-5L) as HRQoL measure, took place between 2017 and 2019. EQ-5D-5L dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) were mapped to an EQ-5D-3L value set to derive index value. Multivariable mixed effects regression models, adjusted for known factors affecting HRQoL with recruitment region as a random effect, were fit to assess potentially modifiable factors associated with index value (linear) and within each dimension (logistic). Results: Among the 2958/2996 (98.7%) participants with complete EQ-5D data, 2201 (74.4%) reported problems in at least one EQ-5D-5L dimension. Multivariable linear regression identified independent associations between poorer HRQoL (EQ-5D-3L index value) and obesity (body mass index ≥30.0 kg/m2, ß -0.037, 95% CI -0.058 to -0.016, P = .001), HADS depression score ≥8 (ß -0.159, -0.182 to -0.137, P < .001), anxiety score ≥8 (ß -0.090, -0.110 to -0.069, P < .001), taking ≥10 medications (ß -0.065, -0.085 to -0.046, P < .001), sarcopenia (ß -0.062, -0.080 to -0.043, P < .001) haemoglobin <100 g/L (ß -0.047, -0.085 to -0.010, P = .012) and pain (ß -0.134, -0.152 to -0.117, P < .001). Smoking and prescription of prednisolone independently associated with problems in self-care and usual activities respectively. Renin-angiotensin system inhibitor (RASi) prescription associated with fewer problems with mobility and usual activities. Conclusion: Potentially modifiable factors including obesity, pain, depression, anxiety, anaemia, polypharmacy, smoking, steroid use and sarcopenia associated with poorer HRQoL in this cohort, whilst RASi use was associated with better HRQoL in two dimensions.

Protocol for a mixed-methods study to develop and feasibility test a digital system for the capture of patient-reported outcomes (PROs) in patients receiving chimeric antigen receptor T-cell (CAR-T) therapies (the PRO-CAR-T study).

INTRODUCTION: Chimeric antigen receptor (CAR) T-cell therapies are novel, potentially curative therapies for haematological malignancies. CAR T-cell therapies are associated with severe toxicities, meaning patients require monitoring during acute and postacute treatment phases. Electronic patient-reported outcomes (ePROs), self-reports of health status provided via online questionnaires, can complement clinician observation with potential to improve patient outcomes. This study will develop and evaluate feasibility of a new ePRO system for CAR-T patients in routine care. METHODS AND ANALYSIS: Multiphase, mixed-methods study involving multiple stakeholder groups (patients, family members, carers, clinicians, academics/researchers and policy-makers). The intervention development phase comprises a Delphi study to select PRO measures for the digital system, a codesign workshop and consensus meetings to establish thresholds for notifications to the clinical team if a patient reports severe symptoms or side effects. Usability testing will evaluate how users interact with the digital system and, lastly, we will evaluate ePRO system feasibility with 30 CAR-T patients (adults aged 18+ years) when used in addition to usual care. Feasibility study participants will use the ePRO system to submit self-reports of symptoms, treatment tolerability and quality of life at specific time points. The CAR-T clinical team will respond to system notifications triggered by patients' submitted responses with actions in line with standard clinical practice. Feasibility measures will be collected at prespecified time points following CAR T-cell infusion. A qualitative substudy involving patients and clinical team members will explore acceptability of the ePRO system. ETHICS AND DISSEMINATION: Favourable ethical opinion was granted by the Health and Social Care Research Ethics Committee B(HSC REC B) (ref: 23/NI/0104) on 28 September 2023. Findings will be submitted for publication in high-quality, peer-reviewed journals. Summaries of results, codeveloped with the Blood and Transplant Research Unit Patient and Public Involvement and Engagement group, will be disseminated to all interested groups. TRIAL REGISTRATION NUMBER: ISCTRN11232653.

Recommendations to address respondent burden associated with patient-reported outcome assessment.

Patient-reported outcomes (PROs) are increasingly used in healthcare research to provide evidence of the benefits and risks of interventions from the patient perspective and to inform regulatory decisions and health policy. The use of PROs in clinical practice can facilitate symptom monitoring, tailor care to individual needs, aid clinical decision-making and inform value-based healthcare initiatives. Despite their benefits, there are concerns that the potential burden on respondents may reduce their willingness to complete PROs, with potential impact on the completeness and quality of the data for decision-making. We therefore conducted an initial literature review to generate a list of candidate recommendations aimed at reducing respondent burden. This was followed by a two-stage Delphi survey by an international multi-stakeholder group. A consensus meeting was held to finalize the recommendations. The final consensus statement includes 19 recommendations to address PRO respondent burden in healthcare research and clinical practice. If implemented, these recommendations may reduce PRO respondent burden.