Title: Does reducing serum phosphate to normal levels improve clinical outcomes including mortality, cardiovascular events, bone pain or fracture in patients on dialysis? A feasibility study to inform the design of a national multi-centre RCT.
Funder: Department of Health (England)

Abstract: Background: The likelihood of five year survival for a 60 year old dialysis patient (50%) is significantly worse than for breast (88%), prostate (90%) or colon cancer sufferers (56%)7, but robust information about the contributory risk-factors to inform clinician-patient discussions is lacking. Most dialysis patients die from vascular disease4,8, which is statistically associated with high blood phosphate levels1,2. Standard dialysis treatment removes phosphate to only a limited extent. Even with dietary restriction of high phosphate foods and additional medication to bind phosphate in the stomach (reducing its absorption), serum phosphate is difficult to control, so that ~40% of dialysis patients' levels remain above the current opinion-based target range of 0.8–1.8mmol/L6 (which is higher than the normal adult range; 0.8-1.4mmol/L). Although phosphate levels are statistically associated with decreased life span in observational studies1,2 (an effect at least as significant as that of cholesterol), no randomised studies have been performed to prove cause and effect, and the ideal target for control of phosphate in dialysis patients is unknown (unlike cholesterol). Oral phosphate binding medication; is difficult to take (up to 15 tablets daily in some cases)9 has significant gastro-intestinal side-effects so that adherence is generally poor7 is disliked by most patients (large tablets, difficult to swallow) and associated with reduced quality of life measurements10 can cost up to £3,500 per patient (Manchester average £1,608) per annum7. Aims: Before embarking on a national multi-centre study of phosphate control in mortality and cardiovascular event reduction, we need to demonstrate that it is feasible to achieve and maintain normal serum phosphate levels across a representative group of dialysis patients. Therefore the aim of this study is to assess the feasibility of conducting a large multicentre randomised controlled trial of ‘lower range’ versus ‘higher range’ control of phosphate in dialysis patients in the future, investigating hard clinical end-points including mortality. The results of this feasibility study will inform the design and conduct of the later definitive trial. Plan of investigation: This study will examine the feasibility and timescale of recruiting 120 haemodialysis patients from across Greater Manchester, and randomising them to either; serum phosphate 0.8-1.4mmol/L (lower range) serum phosphate 1.8-2.4 mmol/L (higher range). An on-line ‘educate/intervene/inform’ package (Communicare), plus oral phosphate binder tablets, plus nicotinamide tablets will be prescribed in a sequential, pre-specified manner to reduce phosphate and assess the feasibility of achieving these ranges. Patients will be followed for 12 months to monitor stability, separation of groups by serum phosphate, tablet burden/quality of life, symptom scores, and drop-out rate. We anticipate that the higher range group may require minimal intervention. Potential benefit: Will inform design of a large definitive NIHR-Health Technology Assessment of the effect of phosphate on mortality and cardiovascular events in dialysis patients, starting 2014/15. The potential benefits of such a study are: If reduction of phosphate improves life expectancy then both clinicians and patients will be better informed and able to address this issue more certainly and appropriately, despite current drawbacks of phosphate binding medication. The time, inconvenience and expense associated with phosphate control would be justified. If there is no benefit to reducing phosphate to normal then patients may be relieved of the burden of excessive binding medication and side-effects. Savings from reduced prescriptions could be re-directed to develop other methods believed to improve patients’ quality and quantity of life – e.g. increased provision of home dialysis therapies, with benefits to NHS capital/revenue expenditure. 20% saving = £32,000 per 100 patients, £288,000 across Manchester. Either positive or negative results could be beneficial to patients and the NHS.


Research activity codes: 6.7 PHYSICAL;6.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL