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Trial registered on ANZCTR


Registration number
ACTRN12620001005943p
Ethics application status
Submitted, not yet approved
Date submitted
11/08/2020
Date registered
6/10/2020
Date last updated
6/10/2020
Date data sharing statement initially provided
6/10/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Measuring how allopurinol is removed by peritoneal dialysis
Scientific title
A pilot study to determine the impact of peritoneal dialysis on oxypurinol and urate handling in patients with gout
Secondary ID [1] 302003 0
Nil known
Universal Trial Number (UTN)
U1111-1256-6830
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Gout 318560 0
Chronic kidney disease 318561 0
Condition category
Condition code
Musculoskeletal 316574 316574 0 0
Other muscular and skeletal disorders
Renal and Urogenital 316575 316575 0 0
Kidney disease

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
The study will observe the handling (pharmacokinetics) of oxypurinol (the active metabolite of allopurinol) in patients who are receiving peritoneal dialysis. The patients will have had a prior diagnosis of gout are already prescribed allopurinol therapy. The duration of the observation will be 24 hours.

The typical (nromal) daily PD schedule is to retain the dialysate for 4 hours before exchanging for fresh fluid. This is repeated by the subject 3 times during the day. The 4th exchange of the daily is retained overnight for 12 hours. Given this schedule, we will collect seven blood samples of 3 mL over a single day at the following times;
• Immediately prior to the daily dose of allopurinol and the first dialysis bag exchange of the day (typically in the morning)
• At the half-way point and at the end of the first dialysate dwell, just prior to draining and exchange (i.e. approximately 2 and 4 hours after the dose for a 4 hour dwell time)
• At the half-way point and at the end of the second dialysate dwell, just prior to draining and exchange (i.e. approximately 6 and 8 hours for a 4 hour dwell time)
• At the half-way point of the third dialysate dwell, just prior to draining and exchange (i.e. approximately 10 for a 4 hour dwell time)
• At the end of the fourth dialysate dwell, just prior to draining and exchange (i.e. 24 hours for a 12 hour dwell time)

Waste dialysate will be collected and the volume measured, with a correction for ultrafiltration. Oxypurinol and urate concentrations will be measured in the dialysate bag to determine the the excretion rate of both.

For patients with residual renal function, 24 urine timed urine samples (0-4, 4–8, 8–24 hours - complete catch) will be collected to determine the renal clearances of oxypurinol, creatinine and urate.
Intervention code [1] 318287 0
Not applicable
Comparator / control treatment
There is no control group. Comparisons will be made of the AUC0-24h to the predicted AUC0-24h for an equivalent weight patient who is not receiving PD. The predicted AUC will be determined using an oxypurinol model.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 324707 0
Observed change in oxypurinol plasma concentration over 24 hours
Timepoint [1] 324707 0
Plasma concentrations of oxypurinol observed at the following times after the patients usual morning dose of allopurinol; 0, 2, 4, 6, 8, 10 and 24 hours post-dose.
Primary outcome [2] 325058 0
Dialysate oxypurinol cumulative amount excreted over the 24h study peroid.
Timepoint [2] 325058 0
Dialysate oxypurinol concentrations (and volume) will be measured at the time of each dialysate bag exchange at 4, 8, 12 and 24 (4 bags over 24 hours).
Primary outcome [3] 325059 0
Urine oxypurinol cumulative amount excreted over the 24h study peroid.
Timepoint [3] 325059 0
Urine will be collected continuously over the 24 hour study period (volume and oxypurinol concentrations are measured at 3hr, 6hr and 24 hr)
Secondary outcome [1] 385438 0
Observed change in urate plasma concentration over 24 hours
Timepoint [1] 385438 0
Plasma concentrations of urate observed at the following times after the patients usual morning dose of allopurinol; 0, 2, 4, 6, 8, 10 and 24 hours post-dose.
Secondary outcome [2] 386711 0
Dialysate urate cumulative amount excreted over the 24h study peroid.
Timepoint [2] 386711 0
Dialysate urate concentrations (and volume) will be measured at the time of each dialysate bag exchange at 4, 8, 12 and 24 (4 bags over 24 hours).
Secondary outcome [3] 386714 0
Urine urate cumulative amount excreted over the 24h study peroid.
Timepoint [3] 386714 0
Urine will be collected continuously over the 24 hour study period (volume and urate concentrations are measured at 3hr, 6hr and 24 hr)

Eligibility
Key inclusion criteria
A peritoneal dialysis patient with a prior diagnosis of gout receiving allopurinol therapy will be eligible for inclusion.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants who are unable or unwilling to give written informed consent, who are taking concurrent losartan, probenecid, or benzbromarone, who are undergoing treatment for peritonitis, or who use an automated peritoneal dialysis set up will be excluded.

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
This is a small pharmacokinetic pilot study. A formal sample size calculation is therefore not possible. We intend to recruit 10 peritoneal dialysis patients. This will provide sufficient data to address our research aims.

Oxypurinol pharmacokinetics will be analysed using standard non-compartmental methods. Pharmacokinetic parameters such as maximum and minimal plasma concentrations, half-life, area-under the plasma concentration time curve, total plasma clearance, dialysate clearance and renal clearance will be estimated. The percentage of oxypurinol clearance attributed to peritoneal dialysis will be determined by comparing dialysate clearance to total clearance. The AUC0-24h will be compared to the expected AUC0-24h for an equivalent weight patient who is not receiving PD at various levels of renal function . The dose-response response of the allopurinol in relation to urate-lowering effect in peritoneal dialysis will be explored using non-linear mixed effects modelling in the software NONMEM.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 22821 0
New Zealand
State/province [1] 22821 0
Otago, Southland, Canterbury

Funding & Sponsors
Funding source category [1] 306424 0
Charities/Societies/Foundations
Name [1] 306424 0
Otago Medical Research Foundation Laurenson Award
Address [1] 306424 0
P.O. Box 5726
Dunedin 9054
New Zealand
Country [1] 306424 0
New Zealand
Primary sponsor type
Individual
Name
Professor Robert Walker
Address
Otago Medical School
University of Otago
PO Box 56
Dunedin, NZ 9054
Country
New Zealand
Secondary sponsor category [1] 306935 0
Individual
Name [1] 306935 0
Dr Daniel Wright
Address [1] 306935 0
School of Pharmacy
University of Otago
PO Box 56
Dunedin, NZ 9054
Country [1] 306935 0
New Zealand

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 306620 0
Health and Disability Ethics Committee (HDEC)
Ethics committee address [1] 306620 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington, NZ, 6140
Ethics committee country [1] 306620 0
New Zealand
Date submitted for ethics approval [1] 306620 0
11/08/2020
Approval date [1] 306620 0
Ethics approval number [1] 306620 0

Summary
Brief summary
Gout is very common in people with chronic kidney disease including individuals on dialysis. Gout is due to high concentrations of urate in the body and treatment is aimed at lowering urate by blocking it's formation using allopurinol. Oxypurinol, the active product of allopurinol, is normally removed by the kidneys and the dose of allopurinol is modified according to kidney function. However, we do not know how well oxypurinol is removed by peritoneal dialysis. This means that often the dose of allopurinol is insufficient to reduce the body’s urate concentration to prevent further episodes of gout.
It is important to maintain the right concentration of oxypurinol to properly lower uric acid concentrations to prevent further gout. At present, there is no good data to help accurately prescribe the correct dose of allopurinol to safely reduce uric acid concentrations. We hypothesise that the majority of oxypurinol is eliminated by peritoneal dialysis and the current doses used are insufficient to optimally treat gout. Allopurinol is usually prescribed once a day, therefore we would like to carefully measure just how much oxypurinol is removed over a 24 hour period of peritoneal dialysis. By measuring the concentrations of oxypurinol in the blood, as well as in the dialysate and in the urine collected over the 24 hour period, we can accurately predict the amount being removed both by peritoneal dialysis and residual kidney function. At the same time we will measure the urate concentrations. To be effective in stopping gout urate concentrations need to be below 0.36umol/l. This will allow us to work out the correct dose to safely lower uric acid concentrations and prevent further attacks of gout.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 104494 0
Dr Daniel Wright
Address 104494 0
School of Pharmacy
University of Otago
PO Box 56,
Dunedin, New Zealand, 9056
Country 104494 0
New Zealand
Phone 104494 0
+64 211515671
Fax 104494 0
Email 104494 0
dan.wright@otago.ac.nz
Contact person for public queries
Name 104495 0
Prof Robert Walker
Address 104495 0
School of Medicine
University of Otago
PO Box 56,
Dunedin, New Zealand, 9056
Country 104495 0
New Zealand
Phone 104495 0
+64 34740999
Fax 104495 0
Email 104495 0
rob.walker@otago.ac.nz
Contact person for scientific queries
Name 104496 0
Dr Daniel Wright
Address 104496 0
School of Pharmacy
University of Otago
PO Box 56,
Dunedin, New Zealand, 9056
Country 104496 0
New Zealand
Phone 104496 0
+64 211515671
Fax 104496 0
Email 104496 0
dan.wright@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not permitted under our intended ethics application (since individuals are potentially identifiable)
What supporting documents are/will be available?
No other documents available
Summary results
No Results