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Trial registered on ANZCTR


Registration number
ACTRN12611000791932
Ethics application status
Approved
Date submitted
19/07/2011
Date registered
28/07/2011
Date last updated
26/03/2021
Date data sharing statement initially provided
30/11/2018
Date results information initially provided
30/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The CKD-FIX Trial: Controlled trial of slowing of Kidney Disease progression From the Inhibition of Xanthine oxidase
Scientific title
A randomised, double-blind, controlled trial to assess the effect of xanthine oxidase inhibitor, allopurinol, on the glomerular filtration rate (eGFR) in patients with stage 3-4 Chronic Kidney Disease.
Secondary ID [1] 262659 0
Nil
Universal Trial Number (UTN)
Trial acronym
CKD-FIX trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Kidney Disease stages 3 and 4 268365 0
Condition category
Condition code
Renal and Urogenital 268499 268499 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomised to either allopurinol or matching placebo after informed consent. The starting dose will be 1 tablet daily of allopurinol (100mg) for 4 weeks. If tolerated, the dose will be increased to 2 tablets daily for another 4 weeks. If tolerated the dose will be further increased to 3 tablets daily thereafter. The maximally tolerated dose (1 or 2 or 3 tablets daily will be continued during the remaining follow up period (total follow up of 104 weeks).
Intervention code [1] 267005 0
Treatment: Drugs
Comparator / control treatment
Participants will be randomised to either allopurinol or matching placebo (indistinguishable from the active treatment but containing no active ingredients) after informed consent. The starting dose will be 1 placebo tablet daily(100mg) for 4 weeks. If tolerated, the dose will be increased to 2 tablets daily for another 4 weeks. If tolerated the dose will be further increased to 3 tablets daily thereafter. The maximally tolerated dose (1 or 2 or 3 tablets daily will be continued during the remaining follow up period (total follow up of 104 weeks).
Control group
Placebo

Outcomes
Primary outcome [1] 269242 0
Change in estimated glomerular filtration rate (eGFR) at 104 weeks. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation will be used to estimate eGFR.
Timepoint [1] 269242 0
104 weeks
Secondary outcome [1] 279202 0
reduction in GFR greater than or equal to 40% from baseline
Timepoint [1] 279202 0
104 weeks
Secondary outcome [2] 279203 0
progression to End Stage Kidney Disease requiring dialysis or kidney transplantation; (i.e. if the participant commences dialysis or requires a transplant in the trial follow-up period of 104 weeks).
Timepoint [2] 279203 0
104 weeks
Secondary outcome [3] 279204 0
change in Cystatin C-based eGFR
Timepoint [3] 279204 0
104 weeks
Secondary outcome [4] 279205 0
all-cause death
Timepoint [4] 279205 0
104 weeks
Secondary outcome [5] 279206 0
composite of reduction in GFR greater than or equal to 40% from baseline, ESKD, and death from any cause,
Timepoint [5] 279206 0
104 weeks
Secondary outcome [6] 279207 0
blood pressure The average of three blood pressure readings is calculated by adding the three systolic or diastolic readings together and dividing by 3
Timepoint [6] 279207 0
104 weeks
Secondary outcome [7] 279208 0
Degree of proteinuria, measured via spot urine collection
Timepoint [7] 279208 0
104 weeks
Secondary outcome [8] 279209 0
fatal or non-fatal cardiovascular events during course of follow-up period of 104 weeks
Timepoint [8] 279209 0
104 weeks
Secondary outcome [9] 279210 0
all-cause hospitalisation - assessed by the collection of data from serious adverse events, Medical Benefits Scheme and Pharmaceutical Benefits Scheme, and the Health Costs Questionnaire
Timepoint [9] 279210 0
104 weeks
Secondary outcome [10] 279211 0
quality of life, as assessed using the Short-Form 36 health survey (self-report)
Timepoint [10] 279211 0
At 12 months and 24 months
Secondary outcome [11] 308676 0
Serum uric acid concentration
Timepoint [11] 308676 0
104 weeks
Secondary outcome [12] 308677 0
Cost-effectiveness and economic analyses
Timepoint [12] 308677 0
104 weeks
Secondary outcome [13] 308678 0
Adverse events (especially adverse drug reactions such as severe cutaneous adverse reactions- Erythema Multiforme, Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, minor skin rash, hypersensitivity syndrome, aplastic anaemia, thrombocytopenia)
Timepoint [13] 308678 0
104 weeks
Secondary outcome [14] 354579 0
reduction in GFR greater than or equal to 30% from baseline,
Timepoint [14] 354579 0
104 weeks
Secondary outcome [15] 354580 0
composite of reduction in GFR greater than or equal to 30% from baseline, ESKD, and death from any cause,
Timepoint [15] 354580 0
104 weeks

Eligibility
Key inclusion criteria
1. Adult (age greater than or equal to 18 years) 2. CKD stage 3 or 4 (eGFR 15 to 59 mL/min/1.73 m2) 3. Random urine albumin to creatinine ratio greater or equal to 30mg/mmol OR Evidence of progression of CKD (decrease in eGFR greater than or equal to 3.0 mL/min/1.73 m2 during the preceding 12 months, calculated as the difference between the first and last tests, based on minimum of 3 blood tests with each test done at least 4 weeks apart).

For diagnosis of CKD and determination of eGFR decline, eGFR estimates by either MDRD or CKD-EPI equation can be used according to the local practice.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Past history of clinically established gout, according to the 2015 ACR/EULAR
gout classification criteria,
2. History of hypersensitivity to allopurinol,
3. Kidney transplant recipients,
4. Concurrent treatment with azathioprine, 6-mercaptopurine, theophylline,
cyclophosphamide, cyclosporine, probenecid, phenytoin, or chlorpropamide,
5. Indication for allopurinol, including history of tophus or tophi on clinical
examination or imaging study, uric acid nephropathy, uric acid nephrolithiasis
or urolithiasis,
6. Current non-skin cancer malignancy,
7. Unresolved acute kidney injury in last 3 months,
8. Current pregnancy, breast feeding,
9. Any uncontrolled psychological illness or condition which interferes with their
ability to understand or comply with the requirements of the study,
10. Elective or imminent initiation of maintenance dialysis or kidney
transplantation expected in the next 6 months.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Screening will occur when subjects come for their usual visit to their treating physician. The patient will have an initial consultation with a study renal physician to discuss study participation. This will include a preliminary eligibility check. Randomisation will occur on the day that trial consent is obtained or within 1 month of consent being obtained. This will include a check to ensure that the patient is still eligible. Randomisation will be conducted utilising a web-based database to allocate the patient to a trial arm using dynamically allocated methods. Medication kits will be numbered and allocated on randomsiation. The medication treatment allocation lists will be prepared by the unblinded trial statistician, and will be programmed into the central web-based randomisation system. This will maintain the allocation concealment for all users of the randomisation system and those handling the medication, including participant, phyisican, study nurse, pharmacist and central clinical research associate.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratification will occur for study centre, CKD stage (stage 3 vs. stage 4), albuminuria (random urine ACR greater or equal to 60 mg/mmol vs. less than 60 mg/mmol), and presence/absence of diabetes mellitus.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
A randomised, double-blind, placebo-controlled trial
Phase
Phase 3 / Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
The primary analysis of change in eGFR will be based on a linear mixed-effects regression model. Change from baseline in the other outcome measures with continuous data (uric acid, blood pressure, proteinuria) will be analysed by the same method. These analyses are based on several assumptions (normally distributed errors and random effects, linear change) which will be tested on blinded data. Where assumptions are not met, appropriate modifications will be made to the models. Binary endpoints will be analysed using the chi-square test with frequencies and percentages per treatment arm and odds-ratios or other measures of treatment effect reported along as summary measures. Treatment differences between subgroups defined by age, CKD stage, proteinuria, diabetes status, cause of CKD (diabetic nephropathy vs. non-diabetic kidney disease vs. polycystic kidney disease), use of diuretics, renin-angiotensin-aldosterone system (RAAS) blockade (ACE inhibitor or ARB vs. no RAAS blockade), gender, racial origin, BMI, and presence of metabolic syndrome, will be assessed via tests for interaction using regression models appropriate for the type of outcome. The predictors of adverse events will be analysed by multinomial logistic regression. The predictors of CKD progression (dependent variable slope of eGFR decline) will be analysed by multivariate linear regression. The predictors of response to uric acid-lowering therapy will be analysed by multinomial logistic regression.

Assuming an annual decline in eGFR of 3 mL/min/1.73 m2,113 loss to follow-up of 5%, drop-in and drop-out rates of 5% (from the treatment arm to the control arm and in the opposite direction), 310 patients per arm or 620 patients in total will have 90% power to demonstrate a 20% attenuated decline in eGFR (change in eGFR of 1.2 +/- 4.0 mL/min/1.73 m2) after 2 years of follow up.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/03/2012
Actual
21/03/2014
Date of last participant enrolment
Anticipated
31/12/2016
Actual
29/12/2016
Date of last data collection
Anticipated
31/01/2019
Actual
22/01/2019
Sample size
Target
620
Accrual to date
Final
369
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 2555 0
The Canberra Hospital - Garran
Recruitment hospital [2] 2556 0
John Hunter Hospital Royal Newcastle Centre - New Lambton
Recruitment hospital [3] 2558 0
Nepean Hospital - Kingswood
Recruitment hospital [4] 2559 0
Prince of Wales Hospital - Randwick
Recruitment hospital [5] 2562 0
Westmead Hospital - Westmead
Recruitment hospital [6] 2563 0
Wollongong Hospital - Wollongong
Recruitment hospital [7] 2564 0
Gold Coast Hospital - Southport
Recruitment hospital [8] 2565 0
Hervey Bay Hospital - Pialba
Recruitment hospital [9] 2566 0
Logan Hospital - Meadowbrook
Recruitment hospital [10] 2567 0
Nambour General Hospital - Nambour
Recruitment hospital [11] 2568 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [12] 2569 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [13] 2570 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [14] 2571 0
Royal Hobart Hospital - Hobart
Recruitment hospital [15] 2572 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [16] 2573 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [17] 2574 0
The Alfred - Prahran
Recruitment hospital [18] 2575 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [19] 2576 0
Western Hospital - Footscray
Recruitment hospital [20] 2577 0
Sunshine Hospital - St Albans
Recruitment hospital [21] 2578 0
Williamstown Hospital - Williamstown
Recruitment hospital [22] 2579 0
Sunbury Day Hospital - Sunbury
Recruitment hospital [23] 2581 0
Simon Roger Gosford Renal Research - Gosford
Recruitment hospital [24] 13411 0
St George Hospital - Kogarah
Recruitment hospital [25] 13412 0
Toowoomba Hospital - Toowoomba
Recruitment hospital [26] 13413 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [27] 13647 0
Melbourne Renal Research Group Pty Ltd - Reservoir
Recruitment postcode(s) [1] 4257 0
2145
Recruitment postcode(s) [2] 4258 0
3168
Recruitment postcode(s) [3] 4260 0
4102
Recruitment postcode(s) [4] 4261 0
5000
Recruitment postcode(s) [5] 4262 0
6009
Recruitment postcode(s) [6] 8237 0
2606 - Woden
Recruitment postcode(s) [7] 8239 0
2750 - Penrith
Recruitment postcode(s) [8] 8240 0
2031 - Randwick
Recruitment postcode(s) [9] 8242 0
2500 - Wollongong
Recruitment postcode(s) [10] 8243 0
4215 - Southport
Recruitment postcode(s) [11] 8244 0
4655 - Pialba
Recruitment postcode(s) [12] 8245 0
4131 - Meadowbrook
Recruitment postcode(s) [13] 8246 0
4560 - Nambour
Recruitment postcode(s) [14] 8247 0
5042 - Bedford Park
Recruitment postcode(s) [15] 8248 0
7000 - Hobart
Recruitment postcode(s) [16] 8249 0
3084 - Heidelberg
Recruitment postcode(s) [17] 8250 0
3004 - Melbourne
Recruitment postcode(s) [18] 8251 0
3011 - Footscray
Recruitment postcode(s) [19] 8252 0
3021 - St Albans
Recruitment postcode(s) [20] 8253 0
3016 - Williamstown
Recruitment postcode(s) [21] 8254 0
3429 - Sunbury
Recruitment postcode(s) [22] 8256 0
2250 - Gosford
Recruitment postcode(s) [23] 26013 0
2217 - Kogarah
Recruitment postcode(s) [24] 26014 0
4350 - Toowoomba
Recruitment postcode(s) [25] 26015 0
6150 - Murdoch
Recruitment postcode(s) [26] 26323 0
3073 - Reservoir
Recruitment outside Australia
Country [1] 3738 0
New Zealand
State/province [1] 3738 0

Funding & Sponsors
Funding source category [1] 267483 0
Government body
Name [1] 267483 0
National Health and Medical Research Council
Country [1] 267483 0
Australia
Funding source category [2] 302247 0
Government body
Name [2] 302247 0
Health Research Council
Country [2] 302247 0
New Zealand
Primary sponsor type
University
Name
Australasian Kidney Trials Network (University of Qld)
Address
Australasian Kidney Trials Network, Centre for Health Services Research
Faculty of Medicine, The University of Queensland
Level 5, Translational Research Institute
37 Kent Street, Woolloongabba
Brisbane Qld 4103 Australia
Country
Australia
Secondary sponsor category [1] 266524 0
None
Name [1] 266524 0
Address [1] 266524 0
Country [1] 266524 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 269445 0
Metro South HREC
Ethics committee address [1] 269445 0
Metro South Hospital and Health Service HREC
Princess Alexandra Hospital
Centres for Health Research Centres for Health Research
Level 7 Translational Research Institute
37 Kent Street
WOOLLOONGABBA QLD 4102
Ethics committee country [1] 269445 0
Australia
Date submitted for ethics approval [1] 269445 0
01/10/2011
Approval date [1] 269445 0
08/01/2014
Ethics approval number [1] 269445 0
HREC/13/QPAH/685
Ethics committee name [2] 294291 0
ACT Health Human Research Ethics Committee
Ethics committee address [2] 294291 0
PO Box 11 Woden ACT 2606
Ethics committee country [2] 294291 0
Australia
Date submitted for ethics approval [2] 294291 0
05/02/2014
Approval date [2] 294291 0
05/03/2014
Ethics approval number [2] 294291 0
ETH.2.14035
Ethics committee name [3] 294292 0
Bellberry Hyman Research Ethics Committee
Ethics committee address [3] 294292 0
129 Glen Osmond Road
Eastwood
SA 5063
Ethics committee country [3] 294292 0
Australia
Date submitted for ethics approval [3] 294292 0
13/06/2014
Approval date [3] 294292 0
17/10/2014
Ethics approval number [3] 294292 0
2014-02-074
Ethics committee name [4] 294293 0
Royal Adelaide Hospital Human Research Ethics Committee
Ethics committee address [4] 294293 0
Royal Adelaide Hospital
North Terrace
Adelaide
SA 5000
Ethics committee country [4] 294293 0
Australia
Date submitted for ethics approval [4] 294293 0
31/10/2013
Approval date [4] 294293 0
20/12/2013
Ethics approval number [4] 294293 0
HREC/13/RAH/501
Ethics committee name [5] 294294 0
Human Research Ethics Committee (Tasmania) Network
Ethics committee address [5] 294294 0
University of Tasmania
Private Bag 1
Hobart
TAS 7001
Ethics committee country [5] 294294 0
Australia
Date submitted for ethics approval [5] 294294 0
30/05/2014
Approval date [5] 294294 0
01/08/2014
Ethics approval number [5] 294294 0
H0014160
Ethics committee name [6] 294295 0
Sir Charles Gairdner Group Human Research Ethics Committee
Ethics committee address [6] 294295 0
Level 2 A Block
Hospital Ave
Nedlands
WA 6009
Ethics committee country [6] 294295 0
Australia
Date submitted for ethics approval [6] 294295 0
14/10/2014
Approval date [6] 294295 0
05/12/2014
Ethics approval number [6] 294295 0
2014-072
Ethics committee name [7] 294296 0
Health and Disability Ethics Commitees
Ethics committee address [7] 294296 0
Ministry of Health
C/- MEDSAFE Level 6 Deloitte House
10 Brandon Street
PO Box 5013
Wellington NZ 6011
Ethics committee country [7] 294296 0
New Zealand
Date submitted for ethics approval [7] 294296 0
27/08/2013
Approval date [7] 294296 0
25/10/2013
Ethics approval number [7] 294296 0
13/NTA/144

Summary
Brief summary
Chronic kidney disease (CKD), defined as an eGFR <60 ml/min/1.73 m2 and/or the presence of kidney damage (albuminuria or proteinuria) for at least 3 months, is a major public health problem affecting approximately 1.6 million Australian adults. Of these affected individuals, approximately 930,000 have stages 3-4 CKD (eGFR 15-60 mL/min/1.73 m2). CKD patients have a greatly increased risk of adverse renal and cardiovascular (CV) outcomes, even in its early stages. CKD patients are at increased risk of progression to end-stage kidney disease (ESKD). The incidence of ESKD is increasing in Australia by 6% per annum. Apart from an increased risk of ESKD, the presence of CKD is one of the most potent known risk factors for cardiovascular disease (CVD), such that individuals with CKD are more likely to die, mostly from CVD, than survive to the point of needing dialysis or kidney transplantation. A reduction in eGFR <60 ml/min/1.73 m2 is associated with increased risks of all-cause and CV mortality.
The CKD-FIX trial aims to critically examine the efficacy and safety of allopurinol as an agent to slow the progression of chronic kidney disease (CKD).
Trial website
http://www.aktn.org.au/
Trial related presentations / publications
https://www.nejm.org/doi/full/10.1056/NEJMoa1915833
Public notes

Contacts
Principal investigator
Name 32894 0
Prof David Johnson
Address 32894 0
Princess Alexandra Hospital Renal Department ARTS building (31) Princess Alexandra Hospital, 199 Ipswich Road, WOOLLOONGABBA QLD 4102 Australia
Country 32894 0
Australia
Phone 32894 0
+61 7 3176 5080
Fax 32894 0
Email 32894 0
[email protected]
Contact person for public queries
Name 16141 0
Laura Robison
Address 16141 0
Australasian Kidney Trials Network, Centre for Health Services Research
Faculty of Medicine, The University of Queensland
Level 5, Translational Research Institute
37 Kent Street, Woolloongabba
Brisbane Qld 4103 Australia
Country 16141 0
Australia
Phone 16141 0
+61 7 3443 7067
Fax 16141 0
+61 7 3176 5663
Email 16141 0
[email protected]
Contact person for scientific queries
Name 7069 0
Prof David Johnson
Address 7069 0
Princess Alexandra Hospital
Renal Department
ARTS building (31)
Princess Alexandra Hospital,
199 Ipswich Road,
WOOLLOONGABBA QLD 4102
Country 7069 0
Australia
Phone 7069 0
+61 7 3176 5080
Fax 7069 0
Email 7069 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data that underlie the results reported in the primary publication, after de-identification (text, tables, figures and appendices). Medicare and all other administrative data will not be available.
When will data be available (start and end dates)?
Beginning 2 years after the publication of all pre-specified analyses. There is no set end date for data sharing.
Available to whom?
Researchers with a methodologically sound proposal that has been approved by the AKTN Data Sharing Committee.
Available for what types of analyses?
To achieve the aims in the approved proposal.
How or where can data be obtained?
Proposals should be directed to [email protected]. To gain access, data requestors will need to sign a data access agreement. The AKTN Data Sharing Committee will assess proposals based on the following criteria: sound science, benefit-risk balancing and research team expertise. The data will be available in a digital repository supported by The University of Queensland but without investigator support other than deposited metadata.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes June 25, 2020 N Engl J Med 2020; 382:2504-2513 D... [More Details]
Plain language summaryNo What was the research question? Medical researche... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseFatty liver and chronic kidney disease: Novel mechanistic insights and therapeutic opportunities.2016https://dx.doi.org/10.2337/dc15-1182
EmbaseEffects of allopurinol on the progression of chronic kidney disease.2020https://dx.doi.org/10.1056/NEJMoa1915833
N.B. These documents automatically identified may not have been verified by the study sponsor.