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

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ClinicalTrials.gov Identifier: NCT03573089
Recruitment Status : Not yet recruiting
First Posted : June 29, 2018
Last Update Posted : March 25, 2019
Sponsor:
Collaborators:
National Health and Medical Research Council, Australia
Applied Health Research Centre
Cambridge Clinical Trials Unit
Information provided by (Responsible Party):
The University of Queensland

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.

Condition or disease Intervention/treatment Phase
Kidney Failure, Chronic Hyperphosphatemia Drug: Liberal phosphate target Drug: Intensive phosphate target Not Applicable

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 3600 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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.
Estimated Study Start Date : July 1, 2019
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Liberal phosphate target
Liberal serum phosphate target of 2.0 to 2.5 mmol/L.
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.

Experimental: Intensive phosphate target
Intensive serum phosphate target of ≤1.50 mmol/L.
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 :
  1. Time to a composite endpoint of cardiovascular death or non-fatal major cardiovascular event [ Time Frame: 5 years ]
    Time to a composite endpoint of cardiovascular death, non-fatal myocardial infarction or coronary revascularization, stroke, or peripheral arterial event.


Secondary Outcome Measures :
  1. Time to individual components of the primary composite endpoint, [ Time Frame: 5 years ]
  2. Time to all-cause death [ Time Frame: 5 years ]
  3. Utility-based quality of life EQ5D-5L [ Time Frame: 5 years ]
    EQ5D-5L will be used to assess patient self-reported quality of life measures.


Other Outcome Measures:
  1. Differences in the serum concentrations of phosphate, PTH, calcium, alkaline phosphatase and albumin [ Time Frame: Time Frame: 5 years ]
  2. Phosphate-lowering medication usage [ Time Frame: 5 years ]
  3. Phosphate-lowering medication self-reported adherence [ Time Frame: 5 years ]
  4. Proportion of patients requiring parathyroidectomy [ Time Frame: 5 years ]
  5. Proportion of patients developing calciphylaxis [ Time Frame: 5 years ]
  6. Gastrointestinal Symptom Rating Scale [ Time Frame: 5 years ]
    The Gastrointestinal Symptom Rating Scale (GSRS) is a 15-item instrument designed to assess the symptoms associated with common GI disorders. It has five subscales (reflux, diarrhea, constipation, abdominal pain and indigestion). Subscale scores range from 1-7 and higher scores represent higher symptom burden i.e. more discomfort.

  7. Itch/pruritus visual analog scale [ Time Frame: 5 years ]
    The Pruritis 5-D scale contains five domains: duration, degree, direction, disability and distribution. The scores of each of the five domains are achieved separately and then summed together to obtain a total 5-D score. 5-D scores can potentially range between 5 (no pruritus) and 25 (most severe pruritus).

  8. Cost-effectiveness analysis: [ Time Frame: 5 years ]
    Difference in the incremental cost per Quality Adjusted Life Years gained



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥45 years, or Age ≥18 years with diabetes,
  2. ESKD on haemodialysis or peritoneal dialysis, for at least 3 months,
  3. Currently prescribed at least one phosphate-lowering medication at any dose

Exclusion Criteria:

  1. Elective kidney transplantation scheduled,
  2. Concomitant major illness / comorbidity that may result in death in the next 6 months in the view of the treating physician,
  3. Participation in an interventional study that is likely to affect serum phosphate concentration.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03573089


Contacts
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Contact: Ron Wald +1 416-867-3703 WaldR@smh.ca
Contact: Thomas Hiemstra +44 1223 3 36817 tfh24@cam.ac.uk

Sponsors and Collaborators
The University of Queensland
National Health and Medical Research Council, Australia
Applied Health Research Centre
Cambridge Clinical Trials Unit
Investigators
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Principal Investigator: Sunil Badve The University of Queensland
Principal Investigator: Ron Wald St. Michael's Hospital, Toronto
Principal Investigator: Thomas Hiemstra University of Cambridge

Additional Information:
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Responsible Party: The University of Queensland
ClinicalTrials.gov Identifier: NCT03573089     History of Changes
Other Study ID Numbers: 17.02
First Posted: June 29, 2018    Key Record Dates
Last Update Posted: March 25, 2019
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie the results reported in the primary publication, after deidentification (text, tables, figures and appendices) will be available for individual participant data meta-analysis.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: Beginning 2 years and ending 5 years following main publication. Proposals may be submitted up to 5 years following article publication. After 5 years, the data will be available in our University's data warehouse but without investigator support other than deposited metadata.
Access Criteria: An independent review board will assess proposals based on the following criteria: sound science, benefit-risk balancing and research team expertise.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by The University of Queensland:
Renal dialysis
Randomised controlled trial
Bone markers
Cardiovascular risk factors
Phosphate lowering agent
End stage kidney disease
Hyperphosphatemia
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency
Kidney Failure, Chronic
Hyperphosphatemia
Urologic Diseases
Phosphorus Metabolism Disorders
Metabolic Diseases
Renal Insufficiency, Chronic