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

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.

Overview

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.

Interventions

• Drug Liberal phosphate target
  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.
• Drug Intensive phosphate target
  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.

Primary outcome measures

• Time to a composite endpoint of cardiovascular death or non-fatal major cardiovascular event [Time frame: 5 years]

Secondary outcome measures (3)

• Time to individual components of the primary composite endpoint, [Time frame: 5 years]
• Time to all-cause death [Time frame: 5 years]
• Utility-based quality of life EQ5D-5L [Time frame: 5 years]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United Kingdom · 43 centers

• Cambridge University Hospitals NHS Foundation Trust — Cambridge
• University Hospitals Plymouth NHS Trust — Plymouth
• Dorset County Hospital NHS Foundation Trust — Dorchester
• South Tyneside And Sunderland NHS Foundation Trust — Sunderland
• East and North Hertfordshire NHS Trust — Stevenage
• East Kent Hospitals University NHS Foundation Trust — Canterbury
• NHS Greater Glasgow and Clyde — Glasgow
• James Paget University Hospitals NHS Foundation Trust — Great Yarmouth
• … and 35 more centers

Canada · 30 centers

• Foothills Hospital/ U of Calgary — Calgary
• Alberta Health Services — Edmonton
• St. Paul's Hospital — Vancouver
• Vancouver General Hospital — Vancouver
• Dalhousie University — Halifax
• Queen's University — Kingston
• London Health Sciences Centre — London
• Oakville Trafalgar Memorial Hospital — Oakville
• … and 22 more centers

Australia · 23 centers

• Royal Prince Alfred Hosptial — Camperdown
• Nepean Hospital — Kingswood
• St George Hospital — Kogarah
• Royal North Shore Hospital — Saint Leonards
• Western Sydney Renal Service — Westmead
• Wollongong Hospital — Wollongong
• Sunshine Coast University Hospital — Birtinya
• Royal Brisbane and Women's Hospital — Brisbane
• … and 15 more centers

New Zealand · 8 centers

• Auckland City Hospital — Auckland
• Christchurch Hospital — Christchurch
• Dunedin Hospital — Dunedin
• Waikato DHB — Hamilton
• Hawkes Bay Hospital — Hastings
• Middlemore Hospital — Otahuhu
• Waitematā Hospital — Takapuna
• Northland DHB — Whangarei

Brazil · 5 centers

• BRA Santa Casa de Misericórdia de Ponta Grossa — Ponta Grossa
• Sociedade Hospitalar Angelina Caron — Campina Grande
• Hospital de Clinicas Porto Alegre — Porto Alegre
• Fundacao Felice Rosso - Hospital Felicio Rocho — Barro Preto
• Hospital Alemao Oswaldo Cruz — São Paulo

Israel · 4 centers

• Hadassah University — Jerusalem
• Shaare Zedek Medical Centre — Jerusalem
• Meir Hospital — Kfar Saba
• Sheba Hospital — Ramat Gan

France · 1 center

• AURA Paris Plaisance — Paris

Thailand · 1 center

• Ramathibodi Hospital — Bangkok

Publications

• Edmonston D, Isakova T, Dember LM, Waymyers S, Andersen D, Chan KE, Chakraborty H, Wolf M. Higher versus Lower Phosphate Targets for Patients Undergoing In-Center Hemodialysis: A Randomized Controlled Trial. J Am Soc Nephrol. 2025 Dec 1;36(12):2445-2455. doi: 10.1681/ASN.0000000765. Epub 2025 Jul 10. PMID 40638247
• Natale P, Green SC, Ruospo M, Craig JC, Vecchio M, Elder GJ, Strippoli GF. Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD). Cochrane Database Syst Rev. 2025 Jun 27;6(6):CD006023. doi: 10.1002/14651858.CD006023.pub4. PMID 40576086
• Fajol A, Faul C. The Pathologic Actions of Phosphate in CKD. Kidney360. 2025 Apr 17;6(6):1040-1049. doi: 10.34067/KID.0000000820. PMID 40241437
• Fernandez L, Klein J. Vascular Calcification and CKD: Challenges, Emerging Targets, and Future Perspectives. Clin J Am Soc Nephrol. 2025 Nov 1;20(11):1630-1633. doi: 10.2215/CJN.0000000733. Epub 2025 Apr 16. No abstract available. PMID 40238244
• Edmonston D. Tight Phosphate Control in ESKD Patients Is Warranted: CON. Kidney360. 2024 Dec 13;6(6):895-897. doi: 10.34067/KID.0000000000000401. No abstract available. PMID 39671553

Identifiers

NCT: NCT03573089 · AKTN 17.02

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗