Title: Pragmatic randomised trial of High Or Standard PHosphAte Targets in End-stage kidney disease - The PHOSPHATE trial
Funder: Department of Health and Social Care

Abstract: THE PROBLEM_x000D_ _x000D_ The kidneys maintain normal phosphate levels in the blood by excreting it into the urine. When kidneys fail, phosphate levels in the blood rise, and doctors believe this may be harmful to blood vessels and the heart. Consequently, most dialysis patients take medicines (up to 15 tablets per day) to lower phosphate. These are known as ‘BINDERS’ because they work by binding phosphate in the intestine before it is absorbed from the diet. Binders have many side effects, and patients struggle to take them. Binders are expensive, costing the NHS up to £5000 per patient per year._x000D_ _x000D_ Despite this, there have NEVER been any trials to test whether lowering blood phosphate with binders makes any difference in improving the health of dialysis patients by keeping the heart and blood vessels healthy, helping them feel better, or improving quality of life._x000D_ _x000D_ _x000D_ THE QUESTION_x000D_ _x000D_ Does lowering blood phosphate with binders reduce angina, heart attack, stroke, circulation problems to the legs including amputation, or death from any of these causes?_x000D_ _x000D_ _x000D_ HOW WILL WE DO THE STUDY?_x000D_ _x000D_ Patients needing dialysis will be asked to participate in a randomised trial. _x000D_ _x000D_ Patients will be assigned to one of two groups: A) Intensive phosphate lowering (towards normal or a blood level less than 1.5 mol/L) or B) Liberal phosphate (blood level 2 to 2.5 mol/L). The intensive group will receive binders to reach a low phosphate; the liberal group will only receive binders if their blood phosphate goes very high (more than 2.5)._x000D_ _x000D_ _x000D_ HOW WILL WE LIMIT THE BURDEN ON NHS PATIENTS?_x000D_ _x000D_ UK Patients taking part in the study will have ONLY ONE STUDY VISIT at the start of the trial. This is possible because information about the health of dialysis patients is routinely collected by the NHS._x000D_ _x000D_ Dialysis patients can register on PatientView (https://patientview.org) to allow them to view their own blood test results. PatientView is active in all kidney units in the United Kingdom. Hospital laboratories send blood test results on all registered patients to the UK Renal Registry (UKRR). The UKRR provides patients with access to their own results via the PatientView website. We will use the PatientView data to monitor phosphate and will recommend changes to binder doses based on these results. The UKRR collects other information about dialysis patients which will also be sent to the trial team._x000D_ _x000D_ The NHS collects information on anyone admitted to hospital (through NHS Digital). From this information we can establish whether patients have had serious illnesses. Using these existing data sources means that we do not need to call patients in for extra study visits. It also means the study will cost less than it might otherwise have done._x000D_ _x000D_ _x000D_ HOW MANY PATIENTS DO WE NEED?_x000D_ _x000D_ 3600 patients would need to participate. Since it may not be possible to enrol so many patients from the UK alone, we have joined forces with colleagues in Canada, Australia and New Zealand. Patients from all three countries may be enrolled in the study. We expect more than half to come from the UK._x000D_ _x000D_ _x000D_ HOW LONG WILL THE TRIAL LAST?_x000D_ _x000D_ 6 Years.

Lay abstract: RESEARCH QUESTION_x000D_ _x000D_ Does lowering serum phosphate in dialysis patients reduce a cardiovascular (CV) events and CV death?_x000D_ _x000D_ _x000D_ BACKGROUND_x000D_ _x000D_ End Stage Kidney Disease (ESKD) results in phosphate retention and hyperphosphataemia, which is associated with worse outcomes including CV events and mortality. Current treatment guidelines recommend lowering phosphate towards normal through dietary restriction, dialysis and medications called ‘binders’ that prevent its dietary absorption from the gut. Binders have been in use for many decades, and 88% of UK dialysis patients require binders to achieve current targets._x000D_ _x000D_ Despite preclinical and observational data suggesting an association of hyperphosphataemia with CV mortality, there is no randomised trial evidence that phosphate lowering improves clinical or patient reported outcomes. Binders cost at least £5000 p.a. per patient; their use contributes to one of the highest pill burdens of any chronic disease (up to 15 binders per day), resulting in high non-adherence and reduced quality of life. There is an urgent need for adequately powered trials to assess the effectiveness of the costly and burdensome practice of phosphate lowering._x000D_ _x000D_ _x000D_ AIMS and OBJECTIVES_x000D_ _x000D_ We will assess the effect of intensive vs. liberal phosphate targets on fatal and non-fatal cardiovascular events and quality of life (HRQoL) in patients receiving dialysis._x000D_ _x000D_ _x000D_ METHODS_x000D_ _x000D_ We will conduct a pragmatic parallel-group randomised controlled superiority trial of intensive (<1.5 mmol/L) vs liberal (2.0-2.5 mmol/L) phosphate targets to determine effectiveness and cost effectiveness of phosphate lowering in patients receiving dialysis._x000D_ _x000D_ Setting_x000D_ Dialysis centres in the UK (56%), Canada (27%), New Zealand and Australia (17%)_x000D_ _x000D_ Population_x000D_ Inclusions_x000D_ - Age = 45 years, or age = 18 years with diabetes_x000D_ - Dialysis dependent > 3 months_x000D_ - Prescribed at least one phosphate binder_x000D_ _x000D_ Intervention:_x000D_ Binders to achieve a phosphate target = 1.5 mmol/L._x000D_ _x000D_ Control:_x000D_ Binders only if serum phosphate > 2.5 mmol/L, with cessation of phosphate binders if phosphate = 2.0 mmol/L._x000D_ _x000D_ Both groups will receive standard dietary advice at the start of the trial, then as needed to achieve target phosphate._x000D_ _x000D_ Outcomes:_x000D_ _x000D_ The primary outcome is the time to the composite of CV mortality or non-fatal CV events including acute coronary syndrome, hospitalisation for unstable angina, coronary revascularisation, stroke, peripheral arterial event or peripheral arterial revascularisation. _x000D_ _x000D_ Key secondary outcomes will include:_x000D_ - Health-Related Quality of Life (EQ5D, SF36)_x000D_ - Cost effectiveness_x000D_ Other secondary outcomes are described in the detailed research plan._x000D_ _x000D_ Sample Size_x000D_ _x000D_ The PHOSPHATE trial will enrol 3600 participants (2000 from the United Kingdom)._x000D_ IMPACT_x000D_ _x000D_ PHOSPHATE will demonstrate whether the current practice of intensive phosphate lowering has clinical benefit or improves quality of life. Clear evidence of benefit is necessary to justify the current scale and consequences of binder prescribing.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL