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

Sponsor

The University of Queensland (Other)

Overall Status

Recruiting

CT.gov ID

NCT03573089

Collaborator

National Health and Medical Research Council, Australia (Other), Applied Health Research Centre (Other), Cambridge University Hospitals NHS Foundation Trust (Other), University of Otago (Other)

3,600

Enrollment

Locations

Arms

72.7

Anticipated Duration (Months)

65.5

Patients Per Site

0.9

Patients Per Site Per Month

Study Details

Study Description

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	N/A

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.

Study Design

Study Type:

Interventional

Anticipated 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.

Actual Study Start Date :

Dec 10, 2019

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Dec 31, 2025

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Time to a composite endpoint of cardiovascular death or non-fatal major cardiovascular event [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

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 [5 years]
EQ5D-5L will be used to assess patient self-reported quality of life measures.

Other Outcome Measures

Differences in the serum concentrations of phosphate, PTH, calcium, alkaline phosphatase and albumin [Time Frame: 5 years]
Phosphate-lowering medication usage [5 years]
Phosphate-lowering medication self-reported adherence [5 years]
Proportion of patients requiring parathyroidectomy [5 years]
Proportion of patients developing calciphylaxis [5 years]
Gastrointestinal Symptom Rating Scale [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.
Itch/pruritus visual analog scale [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).
Cost-effectiveness analysis: [5 years]
Difference in the incremental cost per Quality Adjusted Life Years gained

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Royal Prince Alfred Hosptial	Camperdown	New South Wales	Australia	2050
2	Nepean Hospital	Kingswood	New South Wales	Australia	2750
3	St George Hospital	Kogarah	New South Wales	Australia	2217
4	Royal North Shore Hospital	Saint Leonards	New South Wales	Australia	2065
5	Western Sydney Renal Service	Westmead	New South Wales	Australia	2145
6	Wollongong Hospital	Wollongong	New South Wales	Australia	2500
7	Sunshine Coast University Hospital	Birtinya	Queensland	Australia	4575
8	Royal Brisbane and Women's Hospital	Brisbane	Queensland	Australia	4006
9	Princess Alexandra Hospital	Brisbane	Queensland	Australia	4110
10	Bundaberg Hospital	Bundaberg	Queensland	Australia	4670
11	Cairns Hospital	Cairns	Queensland	Australia	4870
12	Fraser Coast Renal Service	Hervey Bay	Queensland	Australia	4655
13	Mackay Hospital	Mackay	Queensland	Australia	4740
14	Logan Hospital	Meadowbrook	Queensland	Australia	4131
15	Gold Coast University Hospital	Southport	Queensland	Australia	4215
16	Central and Northern Adelaide Renal and Transplant Service	Adelaide	South Australia	Australia	5000
17	Flinders Medical Centre	Bedford Park	South Australia	Australia	5042
18	Austin Health	Heidelberg	Victoria	Australia	3084
19	Royal Melbourne Hospital	Melbourne	Victoria	Australia	3050
20	St Vincent's Hospital Melbourne	Melbourne	Victoria	Australia	3065
21	Latrobe Regional Hospital	Traralgon	Victoria	Australia	3844
22	Armadale Hospital	Armadale	Western Australia	Australia	6112
23	Hospital de Clinicas Porto Alegre	Porto Alegre	Rio Grande Do Sul	Brazil
24	Foothills Hospital/ U of Calgary	Calgary	Alberta	Canada	T2N 4Z6
25	St. Paul's Hospital	Vancouver	Bristish Columbia	Canada	V6Z 1Y6
26	Dalhousie University	Halifax	Nova Scotia	Canada	B3H 4R2
27	Queen's University	Kingston	Ontario	Canada	K7L 3N6
28	London Health Sciences Centre	London	Ontario	Canada	N6A 5W9
29	Oakville Trafalgar Memorial Hospital	Oakville	Ontario	Canada	L6M 0L8
30	Lakeridge Health	Oshawa	Ontario	Canada	L1G 2B9
31	The Ottawa Hospital	Ottawa	Ontario	Canada	K1H 8L6
32	Scarborough Hospital Network	Scarborough	Ontario	Canada	M1P 2V5
33	St Michael's Hospital	Toronto	Ontario	Canada	M5B 1W8
34	University Health Network - University of Toronto	Toronto	Ontario	Canada	M5G 1L7
35	St. Joseph's Healthcare Hamilton	Toronto	Ontario	Canada	M6R 1B5
36	St. Joseph's Healthcare Toronto	Toronto	Ontario	Canada	M6R 1B5
37	McGill University Health Centre	Montreal	Quebec	Canada	4A 3J1
38	Hopital Maisonneuve Rosemont	Montréal	Quebec	Canada	H1T 2M4
39	CHUM	Montréal	Quebec	Canada	H2W 1T8
40	Jewish General Hospital	Montréal	Quebec	Canada	H3T 1E2
41	Sacre Coeur Hospital	Montréal	Quebec	Canada	H4J 1C5
42	CHU de Quebec Universite Laval	Quebec City	Quebec	Canada	G1V 4G2
43	Auckland City Hospital	Auckland		New Zealand
44	Christchurch Hospital	Christchurch		New Zealand
45	Dunedin Hospital	Dunedin		New Zealand
46	Waikato DHB	Hamilton		New Zealand
47	Hawkes Bay Hospital	Hastings		New Zealand
48	Middlemore Hospital	Otahuhu		New Zealand
49	Waitematā Hospital	Takapuna		New Zealand
50	Northland DHB	Whangarei		New Zealand
51	Cambridge University Hospitals NHS Foundation Trust	Cambridge	Cambridgeshire	United Kingdom
52	University Hospitals Plymouth NHS Trust	Plymouth	Devon	United Kingdom
53	NHS Lanarkshire	Airdrie	North Lanarkshire	United Kingdom
54	South Tees Hospitals NHS Foundation Trust	Middlesbrough	North Yorkshire	United Kingdom
55	University Hospitals Sussex NHS Foundation Trust	Brighton	Sussex	United Kingdom