Pragmatic Randomised Trial of High Or Standard PHosphAte Targets in End-stage Kidney Disease (PHOSPHATE)

Study Overview
=================
Brief Summary
-----------------
During end-stage kidney disease, clinical guidelines suggest reducing elevated phosphate levels in the blood. However, the effect of lowering blood phosphate levels on important patient-centred outcomes has never been tested. This trial will evaluate whether compared to high levels, lowering blood phosphate levels would reduce death or major events due to heart disease, improve physical health, and be cost-effective.

Detailed Description
-----------------
Hyperphosphataemia is highly prevalent in patients with end-stage kidney disease (ESKD) and associated with increased mortality risk. The Clinical Practice Guidelines suggest lowering elevated phosphate levels towards the normal range (level 2C suggestion). However, trial data demonstrating that treatments that lower serum phosphate will improve patient-centred outcomes are lacking. The primary objective is to test the hypothesis that compared to a liberal serum phosphate concentration target of 2.0 to 2.5 mmol/L, intensive lowering of serum phosphate towards the normal level (≤1.50 mmol/L) with phosphate binders reduces the risk of fatal or non-fatal major cardiovascular events in ESKD patients receiving dialysis. The secondary objectives are to test the hypothesis that intensive lowering of serum phosphate towards the normal level with phosphate binders would improve physical health, fatigue, health-related quality of life, patient satisfaction, and pruritus; and be cost-effective. In this pragmatic, multinational, randomised controlled large simple trial, a total of 3600 adult ESKD patients receiving dialysis will be randomised either to intensive (≤1.50 mmol/L) or liberalized (2.0-2.5 mmol/L) serum phosphate target. The choice and dose of phosphate binders will be at the treating physician's discretion and local practice to achieve and maintain serum phosphate concentration within the required target range according to randomisation. The primary endpoint is the composite endpoint of cardiovascular death, non-fatal major cardiovascular or peripheral arterial events. The secondary outcome measures will be individual components of the primary composite endpoint, all-cause death, and utility-based quality of life EQ5D-5L.

Official Title
-----------------
An Investigator-initiated, International, Multi-centre, Prospective, Randomized, Open-label, Parallel-group, Superiority, and Pragmatic Large Simple Trial (LST) to Determine Whether the Currently Recommended Strategy of Intensive Reduction of Serum Phosphate Concentration Towards the Normal Level Results in Significant Patient-centred Benefits in End-stage Kidney Disease (ESKD) Patients Receiving Dialysis.

Conditions
-----------------
Kidney Failure, Chronic, Hyperphosphatemia

Intervention / Treatment
-----------------
* Drug: Liberal phosphate target
* Drug: Intensive phosphate target


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥45 years, or Age ≥18 years with diabetes, ESKD on haemodialysis or peritoneal dialysis, for at least 3 months, Currently prescribed at least one phosphate-lowering medication at any dose Able to provide informed consent Exclusion Criteria: Elective kidney transplantation scheduled, Concomitant major illness / comorbidity that may result in death in the next 6 months in the view of the treating physician, Participation in an interventional study that is likely to affect serum phosphate concentration.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Liberal phosphate target<br>Liberal serum phosphate target of 2.0 to 2.5 mmol/L. | Drug: Liberal phosphate target<br>* All phosphate-lowering medications in use at baseline will be discontinued. Phosphate-lowering medications will be prescribed only if serum phosphate concentration exceeds 2.50 mmol/L. The choice and dosages of phosphate-lowering medications will be at the discretion of treating physicians and/or participants.<br>|
| Experimental: Intensive phosphate target<br>Intensive serum phosphate target of ≤1.50 mmol/L. | Drug: Intensive phosphate target<br>* This will be achieved by prescribing phosphate-lowering medications aimed to intensively lower serum phosphate concentration towards normal level (≤1.50 mmol/L). The choice and dosages of phosphate-lowering medications will be at the discretion of treating physicians and/or participants.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to a composite endpoint of cardiovascular death or non-fatal major cardiovascular event | Time to a composite endpoint of cardiovascular death, non-fatal myocardial infarction or coronary revascularization, stroke, or peripheral arterial event. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to individual components of the primary composite endpoint, |  | 5 years | 
| Time to all-cause death |  | 5 years | 
| Utility-based quality of life EQ5D-5L | EQ5D-5L will be used to assess patient self-reported quality of life measures. | 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Renal dialysis, Randomised controlled trial, Bone markers, Cardiovascular risk factors, Phosphate lowering agent, End stage kidney disease, Hyperphosphatemia