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Renal medicine
Protocol
Benefits and harms of high-dose haemodiafiltration versus high-flux haemodialysis: the comparison of high-dose haemodiafiltration with high-flux haemodialysis (CONVINCE) trial protocol
  1. Peter J Blankestijn1,
  2. Kathrin I Fischer2,
  3. Claudia Barth3,
  4. Krister Cromm4,
  5. Bernard Canaud4,5,
  6. Andrew Davenport6,
  7. Diederick E Grobbee7,8,
  8. Jörgen Hegbrant9,
  9. Kit C Roes7,
  10. Matthias Rose2,10,
  11. Giovanni FM Strippoli11,12,
  12. Robin WM Vernooij1,7,
  13. Mark Woodward13,14,15,
  14. G Ardine de Wit7,16,
  15. Michiel L Bots7
  1. 1Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
  2. 2Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Center of Internal Medicine and Dermatology, Department of Psychosomatic Medicine, Berlin, Germany
  3. 3B. Braun Avitum AG, Medical Scientific Affairs, Melsungen, Germany
  4. 4Fresenius Medical Care Deutschland GmbH, Global Medical Office, Bad Homburg v.d.H, Germany
  5. 5Montpellier University, School of Medicine, Montpellier, France
  6. 6Department of Nephrology, University College of London, London, UK
  7. 7Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
  8. 8Julius Clinical, Academic Clinical Research Organisation, Zeist, The Netherlands
  9. 9Department of Nephrology, Clinical Sciences, Lund University, Lund, Sweden
  10. 10Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, USA
  11. 11Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
  12. 12University of Sydney, School of Public Health, Sydney, New South Wales, Australia
  13. 13The George Institute for Global Health, University of Oxford, Oxford, UK
  14. 14The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia
  15. 15Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA
  16. 16Centre for Nutrition, Prevention and Health Services, National Institute of Public Health and the Environment, Bilthoven, The Netherlands
  1. Correspondence to Dr Peter J Blankestijn; P.J.Blankestijn{at}umcutrecht.nl

Abstract

Introduction End-stage kidney disease (ESKD) is a major public health problem affecting more than 2 million people worldwide. It is one of the most severe chronic non-communicable diseases. Haemodialysis (HD) is the most common therapeutic option but is also associated with a risk of cardiovascular events, hospitalisation and suboptimal quality of life. Over the past decades, haemodiafiltration (HDF) has become available. Although high-dose HDF has shown some promising survival advantage compared to conventional HD, the evidence remains controversial. A Cochrane systematic review found, in low-quality trials, with various convective forms of dialysis, a reduction in cardiovascular, but not all-cause mortality and the effects on non-fatal cardiovascular events and hospitalisation were uncertain. In contrast, an individual patient data analysis suggested that high-dose HDF reduced both all-cause and cardiovascular mortality compared to HD. In view of these discrepant results, a definitive trial is required to determine whether high-dose HDF is preferable to high-flux HD. The comparison of high-dose HDF with high-flux HD (CONVINCE) study will assess the benefits and harms of high-dose HDF versus a conventional high-flux HD in adults with ESKD.

Methods and analysis This international, prospective, open label, randomised controlled trial aims to recruit 1800 ESKD adults treated with HD in nine European countries. Patients will be randomised 1:1 to high-dose HDF versus continuation of conventional high-flux HD. The primary outcome will be all-cause mortality at 3 years’ follow-up. Secondary outcomes will include cause-specific mortality, cardiovascular events, all-cause and infection-related hospitalisations, patient-reported outcomes (eg, health-related quality of life) and cost-effectiveness.

Ethics and dissemination The CONVINCE study will address the question of benefits and harms of high-dose HDF compared to high-flux HD for kidney replacement therapy in patients with ESKD with a focus on survival, patient perspectives and cost-effectiveness.

Trial registration number Netherlands National Trial Register (NTR 7138).

  • haemodiafiltration
  • haemodialysis
  • end-stage kidney disease
  • randomised controlled trial
  • protocol
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjopen-2019-033228

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    Strengths and limitations of this study

    • This is the largest randomised trial to assess the efficacy and safety of high-dose haemodiafiltration versus continuation of conventional high-flux haemodialysis in patients with end-stage kidney disease (ESKD).

    • Information will be collected about patient-reported outcomes, particularly health-related quality of life.

    • A cost-effectiveness analysis for the two treatment modalities will be performed.

    • Information about co-medications, given that patients with ESKD have often comorbidities, will be collected during follow-up.

    Introduction

    End-stage kidney disease (ESKD) is a major public health problem, affecting more than 2 million people requiring kidney replacement therapy in 2015,1 and the global prevalence of kidney replacement therapy is expected to double by the year 2025, reaching 4.9 million people.2 ESKD is one of the most severe chronic non-communicable diseases worldwide associated with approximately 10%–20% mortality after 1 year.3 The 5-year mortality rate is above that of some of the more common solid organ malignancies, including regional breast cancer, regional colon cancer and kidney cancer.4 5 Kidney replacement therapy is generally required when residual kidney function falls below 10% of the normal value and therapeutic options include haemodialysis (HD), peritoneal dialysis and kidney transplantation. Regenerative medicine, to develop an implantable kidney, is still in the experimental phase and access to kidney transplantation varies between countries. Even in those countries with an active transplant programme, only around 20% of the dialysis population are listed for transplantation.6 Worldwide, HD treatment is the standard of care for the vast majority of patients with ESKD.1 7 However, the risk for fatal and non-fatal cardiovascular events, infections, hospitalisation and reduced quality of life is high among patients treated with HD.7 8 Given the high prevalence and high mortality rates, improvements in the currently available standard HD care are needed.

    High-flux HD is defined as HD using high-flux dialysis membranes and bicarbonate-based dialysate. Over the past decades, haemodiafiltration (HDF),9 an alternative to standard HD, has become available. By adding convective clearance HDF removes middle and large uraemic compounds that accumulate due to kidney failure more effectively than standard high-flux HD. Greater convective exchange increases the clearance of uraemic toxins.10 HDF might also improve survival by increasing the removal of middle-sized uraemic toxins, reducing oxidative stress11 12 and improving intradialytic cardiovascular stability.13 A recent individual patient-level data meta-analysis, including 2753 patients14 15 has shown that, during a median follow-up of 2.5 years, compared to the standard HD, a high-dose HDF (convection volume >23 L/session) reduced the risk of all-cause mortality by approximately 22%, and of cardiovascular disease mortality by 31%,14 the latter mostly due to reduction in coronary heart disease death.16 However, a previous Cochrane systematic review reported that convective dialysis therapies appeared to reduce cardiovascular, but not all-cause, mortality and had uncertain effects on non-fatal cardiovascular events and hospitalisation compared to HD. The quality of evidence was considered low due to methodological limitations and poor reporting of the primary studies. In addition, the majority of trials were not specifically designed to assess the effects of various convection volumes. Thus, patients were not randomised to different targets of convective volumes and were not equally likely to achieve a specific convective volume (ie, healthier patients were more likely to achieve a higher convection volume).15 17–19 Furthermore, there was remarkable heterogeneity in the dialysis interventions across studies, including differences in convective modalities ranging from haemofiltration, HDF with bagged solutions, and online HDF. When HDF was first introduced, small volume convective exchanges were performed with sterile bagged fluid replacement,20 and it was only more recently, following technical advances in dialysis machines21 and production of online ultra-pure dialysis water,9 that higher volume convective exchanges were possible.10 As such, depending on which studies were considered, published meta-analyses report either a beneficial effect for HDF or no benefit compared to conventional high-flux HD.19 22 23

    We report on the design of the CONVINCE study, a randomised controlled trial that evaluates the benefits and harms of a high-dose HDF versus a conventional high-flux HD treatment in adults with ESKD.

    Study objectives

    Based on previous evidence, we hypothesise that high-dose HDF will significantly decrease mortality risk compared to conventional high-flux HD treatment in adults with ESKD. The objectives of our study are:

    1. To evaluate the comparative efficacy of high-dose HDF and high-flux HD on all-cause and cause-specific death, fatal and non-fatal cardiovascular events, all-cause and cause-specific hospitalisations.

    2. To evaluate the effect of high-dose HDF versus high-flux HD on patient-reported outcomes (PROs), particularly health-related quality of life.

    3. To conduct a cost-effectiveness analysis for the two treatment modalities.

    Methods and analysis

    Study population

    Eligible patients will be adults with ESKD treated with high-flux HD compliant with the inclusion and exclusion criteria outlined in table 1. Participants will be recruited in up to nine European countries. As of June 2019, we are active in France, Germany, Hungary, Poland, Portugal, Romania, Spain, The Netherlands and the United Kingdom. Around 70 sites will participate, including both academic and hospital based-dialysis centres, and private dialysis providers (Fresenius Medical Care, B. Braun Avitum and Diaverum).

    View this table:
    Table 1

    Inclusion and exclusion criteria for enrolment in CONVINCE

    Study design

    The CONVINCE study is an international, prospective, randomised, controlled trial. Allocation to high-flux HD and high-dose HDF will be concealed by central randomisation, with a 1:1 ratio. A block randomisation scheme, stratified by centre, will be conducted.

    Study intervention

    The experimental intervention will be a high-dose HDF with online production of substitution fluid and ultrapure dialysis fluid. Substitution fluid should be infused in postdilution mode.8 In case of different substitution modality (pre, mid or mixed dilution) a correction factor (2 to 1.5 times higher than in post dilution mode respectively) will be applied to match the performance as detailed in online supplementary appendix 1. High-dose HDF is defined as a convection volume of ≥23 L (range ±1 L). Previous studies have shown that it is also possible to achieve these convection volumes in older patients with comorbidities.24 25 In cases where the target convection volume (≥23 L/ session; range ±1 L) is not initially achieved, then steps should be undertaken in an effort to achieve the target convection volume which may require a stepwise adjustment of dialysis prescription to achieve this target over 2–3 weeks (online supplementary appendices 1-3 and table 2).25 26 If the target convection volume still cannot be reached after these steps, then the highest volume possible should be used. Convection volume, and reasons why the target could not be reached, should be recorded into the electronic study case record form (eCRF). Centres are required to check dialysis water quality to ensure that all patients dialyse with ultra-pure water (online supplementary appendix 4).

    View this table:
    Table 2

    Achieving convection volume ≥23 L/treatment session

    The control group will receive high-flux HD using high-flux dialysis membranes and ultrapure bicarbonate-based dialysis fluid as standard of dialysis care.

    Co-interventions

    During follow-up, patients might receive (in a non-randomised fashion) additional co-interventions, including blood pressure modifying medication, medication used for managing co-morbid conditions and complications of chronic kidney disease, including diabetes, ischaemic heart disease and heart failure, as part of usual care. Additionally, erythropoiesis stimulating agents (ESAs), iron preparations, drugs for treatment of hyperkalaemia, phosphate binders, vitamin D and vitamin D analogues, parathyroid hormone (PTH) antagonists and extracorporeal anticoagulants might be applied, as these are considered part of routine clinical care.

    Study procedures

    Patient visits start at the time of randomisation, followed by monthly visits for the first 12 months and then 3 monthly from 12 months up to 36 months. After randomisation, patients will continue thrice weekly dialysis and have regular safety and dialysis efficacy assessments, as described in table 3. After initial study entry assessments, data will be collected and study specific activities will be performed every 3 months until the end of the study, apart from the Patient Health Assessment (PHA) questionnaire which is to be completed monthly for the first 12 months of the study.

    View this table:
    Table 3

    Schedule of the activities in CONVINCE

    Study measurements

    After an initial screening visit to determine subject eligibility, suitable patients will be asked to take part in the study and provide written informed consent. Patients who fail to meet the study entry criteria will not be rescreened. Once entered into the study each participant recruited into the study will be given a unique study number. Data will be collected during routine clinical practice, including year of birth, gender, ethnicity, relevant medical history, lifestyle information (smoking, alcohol use, work status and use of informal care) concomitant medication and current medical conditions, including cause of ESKD and date of ESKD diagnosis. In keeping with routine clinical practice, pretreatment and post-treatment weight, along with systolic and diastolic blood pressure and heart rate, will be measured once before, and once after, the dialysis session in a sitting position during all visits. Height of the participant will be recorded at screening only. Vascular access flow assessments should be recorded at least twice a year.

    During all follow-up visits, information will be collected on drugs for treatment of hyperkalaemia, phosphate binders, vitamin D and vitamin D analogues, PTH antagonists, ESAs and medication used to treat serious adverse events. During the screening visit, a physical performance test will be taken covering nine tasks to assess multiple domains of physical function, simulating activities of daily living. The physical performance test will be performed by dialysis centre staff or members of the research team.27

    Laboratory measurements

    During the study entry visit, at the 6, 12 and 18-month review visits, and end of the trial the following laboratory values will be recorded before dialysis: haemoglobin, sodium, potassium, calcium, phosphate, creatinine, urea, magnesium, PTH, C-reactive protein and residual renal function (urine sampling). Local laboratory procedures will be followed to perform these measurements. After dialysis, urea and creatinine will be recorded. Single-pool Kt/V urea will be calculated and recorded together with the calculation method. All assessments will be performed by a local laboratory and are part of standard assessments (ie, routine clinical practice) for dialysis participants. If centres do not routinely collect all of the data items, those items will then be recorded in the eCRF as not routinely collected.

    Dialysis specific measurements

    Information will be collected during screening, 6 monthly review visit, 12 monthly review visit, 18 monthly review visit and at the end of trial visit on type of dialyser, blood flow rate through the extracorporeal circuit, session time, anticoagulation (type and dosage), type of vascular access and net ultrafiltration volume (=sessional weight loss). For high-dose HDF patients, we will collect data on achieved convection volume, substitution volume and the number of treatment sessions not performed as high-dose HDF in the previous 3 months.

    Study outcomes

    The primary outcome will be all-cause mortality. Secondary outcomes will be cardiovascular events which comprise:

    • Cause specific mortality (at least cardiovascular and non-cardiovascular death; others with high frequency may be added).

    • Acute coronary syndrome.

    • Myocardial infarction (STEMI/NSTEMI).

    • Unstable angina pectoris.

    • Congestive heart failure.

    • Coronary artery bypass graft.

    • Percutaneous transluminal coronary angioplasty and/or stenting.

    • Transient ischaemic attack.

    • Cerebral vascular accident.

    • Therapeutic carotid procedure (endarterectomy and/or stenting).

    • Vascular intervention of peripheral arterial ischaemia (revascularisation, percutaneous transluminal angioplasty and/or stenting using physician reporting based of standard consensus definitions)28–32 (online supplementary appendix 5).

    • Hospitalisation for infection related causes.32

    • Any hospitalisation of more than 24 hours.

    If a participant drops out (eg, due to kidney transplantation, switching to another dialysis modality or transferring out of the participating centre), effort will be made to collect information on his/her vital status until the end of the study follow-up.

    Assessment of patient-reported outcomes

    To determine whether high-dose HDF improves patients’ self-reported outcomes (PROs), patients will be asked to complete the PHAs (box 1). These assessments were compiled following a construct-based approach. In due consideration of international initiatives, such as Standardised Outcomes in Nephrology (SONG)33 and International Consortium for Health Outcomes Measurements (ICHOM),34 and results of interviews with patients and healthcare professionals, we determined domains and symptoms most relevant to patients with ESKD. Based on these, validated questionnaires covering the respective health domains were compiled to the Patient Health Assessment sets. The PHA sets vary in coverage of included health domains. Whereas the baseline assessment is the most comprehensive, only a subset of domains are included in the monthly assessment (box 1).

    Box 1

    List of the patient reported outcomes (PROs questionnaires in CONVINCE)

    Patient health assessments

    The Patient Health Assessment Screening (PHA-Screening) is a comprehensive instrument to assess key sociodemographic information, study targeted information about the medical history, their treatment expectation and their perceived health status. This assessment will also include instruments to evaluate factors which may contribute to the outcome prediction model (ie, perceived stress, self-efficacy, social support). Instruments included in the initial assessment tools are:

    • Sociodemographic variables & treatment information.

    • PROMIS Fatigue 6-item customised short form.

    • Time to recovery module.

    • Modified Kidney Disease Quality of Life (KDQOL) symptom checklist.

    • Health transition items (2 items of the SF-36).

    • PROMIS Physical Function 4-item short form (part of the PROMIS Profile-29).

    • PROMIS Cognitive Abilities 4-item customised short form.

    • PROMIS Pain Interference 4-item short form (part of the PROMIS Profile-29).

    • PROMIS Pain Intensity one item (part of the PROMIS Profile-29).

    • PROMIS Anxiety 4-item short form (part of the PROMIS Profile-29).

    • PROMIS Depression 4-item short form (part of the PROMIS Profile-29).

    • PROMIS Ability to participate in social roles and activities 4-item short form (part of the PROMIS Profile-29).

    • PROMIS Sleep disturbance 4-item short form (part of the PROMIS Profile-29).

    • Perceived Stress Questionnaire 5-item short form.

    • 5-item sub-set of the General Self-Efficacy Scale.47

    • MOS Social Support Scale 4-item short form.

    The Patient Health Assessment Quarterly (PHA-Quarterly) is a comprehensive assessment of the participants health status, which includes the core instruments of the screening instruments:

    • PROMIS Fatigue 6-item customised short form.

    • Time to recovery module.

    • modified KDQOL symptom checklist.

    • 2 Health transition items (SF-36)–modified.

    • PROMIS Physical Function 5-item short form (part of the PROMIS Profile-29).

    • PROMIS Cognitive Abilities 4-item customised short form.

    • PROMIS Pain Interference 4-item short form (part of the PROMIS Profile-29).

    • PROMIS Pain Intensity 1-item (part of the PROMIS Profile-29).

    • PROMIS Anxiety 4-item short form (part of the PROMIS Profile-29).

    • PROMIS Depression 4-item short form (part of the PROMIS Profile-29).

    • PROMIS Ability to participate in social roles and activities 4item short form (part of the PROMIS Profile-29).

    • PROMIS Sleep disturbance 4-item short form (part of the PROMIS Profile-29).

    The Patient Health Assessment Monthly (PHA-Monthly) will monitor the health status monthly with a parsimonious assessment of key health domains, including fatigue, physical function, depression, social participation and items asking about the recovery time. Instruments included for the monthly assessment are:

    • Modified transition question (SF-36).

    • PROMIS Physical Function 3-item short form (part of the PROMIS Profile-29).

    • PROMIS Fatigue 3-item short form (part of the PROMIS Profile-29).

    • Two items time to recovery module.

    • PROMIS Depression 3item short form (part of the PROMIS Profile-29).

    • PROMIS Ability to participate in social roles and activities 3-item short form (part of the PROMIS Profile-29).

    Based on the technical infrastructure and the availability of PROMIS item banks in participating countries (availability of translations) computer-adaptive tests (CATs) might replace the respective PROMIS short forms.

    Most health domains will be assessed by use of PROMIS measures35 which are based on modern test theory methods. The PROMIS item banks allow to apply customised short forms as well as computer-adaptive tests, aiming for higher measurement precision, while reducing respondent burden.

    In addition, we will apply the SF-12 version 236 to assess overall health-related quality of life, and the PHQ-937 to assess depression.

    The Patient Health Assessment sets will be applied at screening (PHA-Screening) and every 3 months (PHA-Quarterly). During the first 12 months, patients will complete a short assessment (PHA-Monthly) on a monthly base in between the scheduled visits.

    Cost–utility analysis and budget-impact analysis

    The economic evaluation will consist of a cost–utility analysis to express efficiency in terms of costs per Quality Adjusted Life Year (QALY). Incremental costs and effects of both treatments will be compared and Incremental Cost Utility Ratios will be estimated. The cost–utility analysis takes a societal perspective, implying that healthcare costs, patient and family costs and productivity costs are included. Healthcare use of patients in both groups will be monitored in the eCRF and via patient questionnaires. Patient and family costs, including informal care, and productivity losses are collected through patient questionnaires. These questionnaires consists of relevant parts of the institute of Medical Technology Assessment (iMTA) Productivity Cost Questionnaire (iPCQ), to capture productivity losses associated with ESKD or its treatment,38 and the iMCQ, for healthcare use outside the hospital and for patient and family costs.39 QALYs will be estimated by use of the EQ-5D-5L questionnaire.40 The EQ-5D-5L is a questionnaires that covers five domains of quality of life (ie, mobility, selfcare, usual activities, pain/discomfort and anxiety/depression) each with five levels of functioning (no problems, some problems, moderate problems, severe problems, extreme problems). The EQ-5D-5L describes 3125 (55) unique health states, with associated values to be used for QALY calculations.41 Based on trial data, probabilistic sensitivity analyses with 5000 bootstrap replications will be applied to estimate the Incremental Cost Effectiveness Ratio (ICER) and to plot cost-effectiveness planes and acceptability curves. In addition to the economic evaluation, budget impact analyses will be constructed for the different countries that participate in the trial, using country specific perspectives, depending on the health system of the country.

    Monitoring data and safety

    An independent Data and Safety Monitoring Board (DSMB), comprising two nephrologists and one biostatistician, has been established to monitor the progress of the study and ensure that the safety of participants enrolled in the study is not compromised. Details of the composition, meetings, roles, responsibilities and processes of the DSMB will be documented in the DSMB charter. The independent DSMB will review primary outcome and safety data at regular intervals. Reports and recommendations (continue, amend or stop the study, based on cumulative findings) will be reported to the Project Coordinator, who is responsible for informing the General Assembly (online supplementary appendix 6).

    Sample size

    The recent meta-analysis suggests a 2.5-year mortality rate of 40%14 which is in line with multiple other sources, including the United States Renal Data System,42 Dialysis Outcomes and Practice Patterns Study43 and the aforementioned Cochrane systematic review.19 We anticipate an expected risk reduction of 25%. The sample size calculation is driven by the assumed target HR, a two-sided type 1 error of 5% and specification of 90% power. This means that for a HR of 0.75, 515 events need to be observed. Given the above assumptions on the 2.5-year mortality rate, and an estimated average follow-up of approximately 2.5 years, an estimated number of participants of 900 (HR 0.75) per group will need to be recruited. Thus, the total sample size will be 1800 participants to be randomised. We intend to recruit 400 from academic and hospital based-dialysis centres and 1400 from private dialysis providers.

    Data analysis

    Before the anticipated end of the study a final statistical analysis plan will be drafted and agreed on by CONVINCE General Assembly. The primary analysis will be according to the principle of intention-to-treat using a Cox proportional Hazard regression model to estimate the HR for death from any cause adjusting for the major prognostic factors. Statistical analyses will be conducted that will account for postrandomisation events (such as treatment switches and kidney transplants) through causal models to arrive at adequate estimates of the difference between treatments. Finally, analyses, using interaction terms, to identify important subgroups of participants (particularly suited for high-dose HDF or the reverse) will be undertaken. Prespecified subgroup analyses by age (<50, 50–65, >65 years), sex, residual renal function (<200 mL/day, 200–1000 mL/day and >1000 mL/day), diabetes, cardiovascular disease,26–30 a serum albumin ≤40 g/L, vascular access and dialysis vintage (<2 years, 2–5 years and >5 years) will be performed for exploratory purposes. Assumptions and fits of the statistical models will be evaluated using standard approaches.

    The analyses of cause-specific deaths, total cardiovascular disease and hospitalisations will be as for the primary endpoint. PROs analyses will involve general linear models and generalised estimating equations of changes since baseline, after a transformation to approximate normality if required. This will be adjusted for the major prognostic factors, as for the primary endpoint, plus the baseline value of the index variable.

    Interim analysis

    Two formal interim analyses are planned using the Haybittle-Peto stopping criterion,44 45 but subject to the opinion of the DSMB. This states that we should stop the trial at any interim analysis where the absolute value of the estimated treatment effect is bigger than three times its SE. Using this criterion, the final analysis can still be evaluated at the chosen level of significance (5% two-sided), without imposing any important degree of error.

    Ethical considerations

    The study will be conducted in full conformance with the principles of the ‘Declaration of Helsinki’ (64th World Medical Association (WMA) General Assembly, Fortaleza, Brazil, October 2013)46 or with the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the participant. A written informed consent will be obtained in accordance with the Declaration of Helsinki, laws and regulations, the General Data Protection Regulation Data Protection Directive (Regulation 2016/679) and local regulations. The Investigator will prepare the informed consent form and provide the documents to the independent ethics committees for approval.

    Patient or public involvement

    Patients were not involved in the design and development of the protocol. We have informed key stakeholders, including international patient associations about our study prior to patient enrolment. The findings of our study will be discussed with patients, healthcare professionals, policymakers and the public during the course and at the end of our study.

    Ethics and dissemination

    On the basis of current evidence, the optimal HD modality for the management of patients with ESKD remains unclear. The CONVINCE study has been designed to determine the benefits and harms of high-dose HDF versus high-flux HD in people with ESKD. Patient perspectives along with a cost-effectiveness analysis will also be performed. The study has potential to deliver an answer on the vexing question as to which intervention gives the best patient relevant outcomes and is most cost-effective. We anticipate CONVINCE to be ‘landmark’ study, leading to an expected conclusive ‘end of discussion’ report.

    Ethics statements

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    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Correction notice The text has been corrected to "5-item sub-set of the General Self-Efficacy Scale by Schwarzer, R., & Jerusalem, M. (1995)"

    • Contributors PJB and MB conceived the study. PJB, KIF, CB, KC, BC, AD, DEG, JH, KR, MR, GFMS, RWMV, MW, AAW and MLB contributed to protocol development. PJB and MB drafted the protocol. PJB, KIF, CB, KC, BC, AD, DEG, JH, KR, MR, GFMS, RWMV, MW, AAW and MLB contributed to refinement of the study protocol and approved the final manuscript.

    • Funding This investigator-initiated project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 754803. The governance is given in online supplementary appendix 6.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.