Administrative information
Title {1} | The High-volume Haemodiafiltration vs High-flux Haemodialysis Registry Trial (H4RT): a multi-centre, unblinded, randomised, parallel-group, superiority study to compare the effectiveness and cost-effectiveness of high-volume haemodiafiltration and high-flux haemodialysis in people with kidney failure on maintenance dialysis using linkage to routine healthcare databases for outcomes. |
Trial registration {2a and 2b}. | ISRCTN10997319. Registered on 10th October 2017. Prospectively registered. |
Protocol version {3} | Version 8, 3 May 2022 |
Funding{4} | National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme, project number 15/80/52 |
Author details {5a} | 1 Population Health Sciences, Bristol Medical School, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK 2 Renal unit, Southmead Hospital, North Bristol NHS Trust, Bristol, BS10 5NB, UK 3 Bristol Trials Centre, 1-5 Whiteladies Road, Bristol Medical School, University of Bristol, Bristol, BS8 1NU, UK 4 Research and Innovation, Southmead Hospital, Bristol, BS10 5NB, UK 5 UCL Department of Renal Medicine, Royal Free Hospital, University College London, London, England 6 Renal Unit, Lister Hospital, East and North Hertfordshire NHS Trust, Coreys Mill Lane, Coreys Mill Ln, Stevenage, SG1 4AB, UK 7 Renal Unit, Manchester University Hospitals NHS Trust, Manchester, UK 8 George Institute for Global Health, Sydney, Australia 9 Public and patient involvement representative, Bristol, UK |
Name and contact information for the trial sponsor {5b} | North Bristol NHS Trust, Southmead Hospital, Bristol, UK. BS10 5NB researchsponsor@nbt.nhs.uk |
Role of sponsor {5c} | The sponsor played no part in study design and will play no part in the collection, management, analysis, and interpretation of data. The sponsor is however responsible for overall oversight of the trial. Drafts of all reports will be shared with the Sponsor for approval prior to submission for publication. |
Introduction
Background and rationale {6a}
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The intervention was defined as aiming for a substitution volume of greater than or equal to 21L adjusted for body surface area, equivalent to greater than or equal to 23L convection volume in a typical patient needing 2L of ultrafiltration to reach their target weight.
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The events for inclusion in the composite primary endpoint were chosen on the following bases:
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○ Non-cancer mortality — cancer would not be biologically expected to be affected by convection and cancer is more reliably captured as a cause of death in UK mortality data, compared with cardiovascular and respiratory infection [19].
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Objectives {7}
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All-cause mortality
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Cardiovascular events associated with death
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Cardiovascular events associated with hospital admission
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Infection events associated with death
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Infection events associated with hospital admission
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Health-related quality of life
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Cost-effectiveness
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Environmental impact
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Water quality testing and breaches
Trial design {8}
Methods: participants, interventions and outcomes
Study setting {9}
Eligibility criteria {10}
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Being aged 18 years or over and in receipt of in-centre, maintenance HD or HDF for kidney failure
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Dialysing at least three times a week in a main dialysis or satellite unit
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Having the potential to achieve high-volume HDF
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Lacking capacity to consent
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Having a prognosis of less than 3 months
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Having started maintenance HD or HDF within the preceding 4 weeks
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Having a transition to living kidney donor transplant or home dialysis scheduled within the next 3 months
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Being unsuitable for high-volume HDF for other clinical reasons such as dialysis less than thrice weekly or unlikely to achieve sufficient blood flow rates with current vascular access, or prior intolerance of HDF
Who will take informed consent? {26a}
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Interventions
Explanation for the choice of comparators {6b}
Intervention description {11a}
Criteria for discontinuing or modifying allocated interventions {11b}
Strategies to improve adherence to interventions {11c}
Relevant concomitant care permitted or prohibited during the trial {11d}
Provisions for post-trial care {30}
Outcomes {12}
Primary outcome measure
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All-cause mortality (source: trial data, civil registration and UKRR)
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Non-cancer mortality (source: civil registration)
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Cardiovascular — cause-specific hospitalisation and mortality (source: hospital statistics and civil registration)
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Infection — cause-specific hospitalisation and mortality (source: hospital statistics and civil registration) and reportable infections (MRSA and MSSA) (source: Public Health England to September 2021, UK Health Security Agency from October 2021)
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Health-related quality of life — preference-based quality of life derived from EQ-5D-5L, disease-specific quality of life (Dialysis Symptom Index) and time to recover after each dialysis [4] (source: patient questionnaires)
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Indirect effects: routinely measured/prescribed and recorded anaemia disorder management (haemoglobin levels and erythropoiesis-stimulating agent dose), mineral bone disorder management (calcium, phosphate and PTH levels and phosphate binder dose) and nutritional status (albumin level) (source: UKRR and data extracts from electronic health records)
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Cost-effectiveness from an NHS perspective (source: UKRR, hospital statistics for in-patient and out-patient activity and patient questionnaires for primary care, community and residential care)
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Impact on the environment, including locally purified water, manufactured saline and plastic consumables
Procedures | Data | Screening | Baseline | Treatment phase | Event based | |
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Face-to-face visit 1 | Follow-up (min = 32 month, max = 91 months) No visits | |||||
Linkage | Patient questionnaire (6 monthly) | |||||
Eligibility assessment | √ | |||||
Informed consent | √ | |||||
Randomisation | √ | |||||
Demographics | Age, sex, ethnicity, marital status, education level, smoking history | √ | ||||
Clinical (1) | Primary renal disease, date first seen by a nephrologist, co-morbidities, dietary restrictions, 24-h urine volume | √ | ||||
Clinical (2) | RRT treatment history, prescribed medication (including erythropoiesis-stimulating agents and phosphate binders) | √ | √ | |||
Physical assessment (1) | Height, heart rate | √ | ||||
Physical assessment (2) | Weight, systolic and diastolic blood pressure | √ | √ | |||
Resource use (1) | Day case and inpatient hospital admissions (including surgical procedures performed) | √ | √ | |||
Resource use (2) | Nursing home/residential home days/hospice days, other hospital out-patient services and primary care and community services in the last 6 months | √ | √ | |||
Laboratory tests | Creatinine, urea, Kt/V, urea reduction ratio, albumin, haemoglobin, haematocrit, mean corpuscular volume, sodium, potassium, bicarbonate, corrected calcium, phosphate, C-reactive protein, intact parathyroid hormone, total cholesterol. (From the date of the study visit or the closest date prior to the study visit) | √ | √ | |||
Patient reported | EQ-5D-5L and DSI and time to recovery [31] | √ | √ | |||
SAE reporting | √ |
Participant timeline {13}
Sample size {14}
Recruitment {15}
Assignment of interventions: allocation
Sequence generation {16a}
Concealment mechanism {16b}
Implementation {16c}
Assignment of interventions: blinding
Who will be blinded {17a}
Procedure for unblinding if needed {17b}
Data collection and management
Plans for assessment and collection of outcomes {18a}
Demographics/social | Age, sex, ethnicity, marital status, education level, smoking history |
Clinical | Primary renal disease, date first seen by a nephrologist, renal replacement therapy history, co-morbidities, prescribed medication (including erythropoiesis-stimulating agents and phosphate binders), 24-h urine volume (within the 6 weeks preceding randomisation) |
Resource use | Day case and inpatient hospital admissions (including surgical procedures), nursing home/residential home days/hospice days, other hospital out-patient services, and primary care and community services in the last 6 months |
Laboratory | Creatinine, urea, Kt/V, urea reduction ratio, albumin, haemoglobin, haematocrit, mean corpuscular volume, sodium, potassium, bicarbonate, corrected calcium, phosphate, C-reactive protein, intact parathyroid hormone, total cholesterol (from the date of the study visit or the closest date prior to the study visit) |
Physical assessment | Height, weight, blood pressure, heart rate |
Patient reported | EQ-5D-5L, Dialysis Symptom Index and time to recovery [31] |
Data items | Source | |
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Routine laboratory data | Creatinine, urea, Kt/V, urea reduction ratio, albumin, haemoglobin, haematocrit, mean corpuscular volume, sodium, potassium, bicarbonate, corrected calcium, phosphate, C-reactive protein, intact parathyroid hormone, total cholesterol | UKRR |
Cardiovascular and infection hospital admission data | Cardiovascular: nonspecific chest pain (102); congestive heart failure, non-hypertensive (108); coronary atherosclerosis (101); other circulatory diseases (117); acute myocardial infarction (100); peripheral and visceral atherosclerosis (114); chronic ulcer of skin (199); Gangrene (248); aortic, peripheral and visceral arterial disease (115); transient cerebral ischemia (112); cardiac arrest and ventricular fibrillation (107); pulmonary heart disease (103); other and ill-defined cerebrovascular disease (111); acute cerebrovascular disease (109) Infection: pneumonia (122); septicemia (except in labour) (2); pleurisy, pneumothorax, pulmonary collapse (130); aortic and peripheral arterial emboli (116); tuberculosis (1); mycoses (4); HIV infection (5); encephalitis (77); meningitis (76); shock (249); skin and subcutaneous tissue infection (197); fever of unknown origin (246); infective arthritis and osteomyelitis (201); bacterial infection, unspecified site (3); other inflammatory conditions of the skin (198); other infections, including parasitic (8); influenza (123); urinary tract infections (159); genitourinary symptoms and ill-defined conditions (163) | Hospital Statistics (HES, PEDW, ISD), |
Mortality data | Non-cancer mortality (i.e. all causes of death excluding chapter II causes in ICD-10) | NHS Spine tracing, UKRR, Hospital Statistics, Civil Registration |
Patient-reported outcomes | EQ-5D-5L, DSI and time to recovery (following dialysis) [31] | Patient questionnaire administered 6 monthly |
RRT use | Frequency, machine, dialyser, dialysis times and consumables used | Annual census (extracted from the renal IT system) |
Other hospital admissions | Day case and inpatient hospital admissions (including surgical procedures performed) | Hospital Statistics (HES, PEDW, ISD) |
Patient-reported healthcare use | Nursing home/residential home days/hospice days, and primary care, community services and medication usage in the last 6 months | Patient questionnaire administered 6 monthly |
Blood stream infections | Methicillin-resistant Staphylococcus aureus, methicillin-sensitive Staphylococcus aureus, Clostridium difficile, and Escherichia coli, as the report by mandate to PHE/the UKHSA | Reported to PHE/UKHSA and shared with UKRR |