Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614000871640
Ethics application status
Approved
Date submitted
29/07/2014
Date registered
14/08/2014
Date last updated
8/07/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Interactions between genetics and diuretic medications in the kidney's clearance of uric acid
Scientific title
Gene-diuretic interactions in renal uric acid handling in healthy volunteers: an intervention study
Secondary ID [1] 285076 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Gout 292604 0
Condition category
Condition code
Renal and Urogenital 292915 292915 0 0
Other renal and urogenital disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Single dose of oral frusemide 40mg
Intervention code [1] 289913 0
Other interventions
Comparator / control treatment
Comparison between individuals possessing at least one protective allele at the SLC2A9 SNP rs11942223 or SLC22A11 SNP rs2078267 and those without the protective alleles
Control group
Uncontrolled

Outcomes
Primary outcome [1] 292780 0
Change in FEUA (this is the ratio between the clearance of uric acid and the clearance of creatinine, and is measured by testing serum and urine uric acid and creatinine).
Timepoint [1] 292780 0
180 minutes following oral intake of frusemide 40mg
Secondary outcome [1] 309670 0
Change in serum urate concentration
Timepoint [1] 309670 0
180 minutes following oral intake of frusemide 40mg
Secondary outcome [2] 309823 0
Change in fractional excretion of sodium (this is the ratio between the clearance of sodium and the clearance of creatinine, and is measured by testing serum and urine sodium and creatinine).
Timepoint [2] 309823 0
180 minutes following oral intake of frusemide 40mg
Secondary outcome [3] 309824 0
Change in fractional excretion of potassium (this is the ratio between the clearance of potassium and the clearance of creatinine, and is measured by testing serum and urine potassium and creatinine).
Timepoint [3] 309824 0
180 minutes following oral intake of frusemide 40mg

Eligibility
Key inclusion criteria
a. Age from 18 to 50 years
b. Able to provide written informed consent
c. eGFR>60
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
a. History of gout
b. History of diabetes
c. Fasting capillary glucose >6mmol/L
d. Existing diuretic use
e. Hypokalaemia (serum potassium <3.5mmol/L)
f. Recurrent episodes of vasovagal syncope or fainting
g. Previous intolerance to frusemide

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
We plan to recruit 100 healthy participants without documented gout; 50 participants of Maori or Pacific ancestry, and 50 participants of European Caucasian ancestry. We have chosen to pool Maori and Pacific participants into a single group of Polynesian ancestry, as the allele frequencies for SLC2A9 and SLC22A11 are very similar in these two groups, and our previous data also indicate similar renal responses to hyperuricaemia in Maori and Pacific participants. We have included a one week period of salt restriction prior to the study visit to standardise the renal urate responses to frusemide and reduce variation due to non-genetic factors.

Yu et al (1981) provide a point estimate of the mean FEUA 3 hours after a 40mg frusemide bolus dose (5.5 SD 1.3). Using this estimate of variability the proposed sample size would have 90% power at the 5% significance level to detect a scientifically relevant absolute mean difference of at least 1 FEUA unit between those with (n=30) and without (n=70) the protective SLC2A9 SNP (rs11942223) three hours post frusemide treatment (the primary endpoint). Although there are two co-primary hypotheses in this study (SLC2A9 and SLC22A11), it is proposed that each will be treated independently with no adjustment for multiplicity (ie the critical significance level will be 0.05 for each). In practice recalculation of the sample size with alpha set to 0.05/2 (ie P split between the two primary hypotheses) increases the difference that could be detected by 0.1 - a scientifically trivial amount.

Whilst the primary analysis will be performed on the change from baseline no adequate estimate of the variability of this is available and so the conservative approach of modelling the difference between groups at a single time point was chosen to validate the sample size. Removing between patient variability by using the change from baseline as the dependent variable is likely to offer increased power which should more than offset the very small number of samples which may not be adequately genotyped. Sample size calculations were performed using PASS 2002 (Hintze, J (2006) Kaysville, Utah).

Data will be presented as mean (SD) or median (IQR) for descriptive purposes. Measures of effect will be presented with the appropriate 95% confidence interval.

The primary endpoint will be a comparison of the FEUA response to frusemide in the entire group based on the presence or absence of the rs11942223 protective allele and independently the presence or absence of the rs2078267 protective allele. A mixed models approach to repeated measures (analysis of covariance, ANCOVA) will be employed modelling the change from baseline in FEUA as the dependent variable and including baseline FEUA as a covariate. Time, the presence or absence of the protective allele and their interaction will be modelled independently for each allele. Significant main and/or interaction effects will be explored using the method of Tukey to preserve the overall 5% significance level within each analysis. No adjustment for multiplicity will be performed.

Secondary analyses will include the comparison of the hyperuricaemic response to frusemide between each of the alleles in serum urate concentration, and a comparison of the change in FEUA level between ancestral subgroups. In exploratory analyses the interaction between ancestral subgroup and ethnicity will be explored for each genotype for both FEUA and serum urate concentration.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
8/10/2014
Actual
25/09/2014
Date of last participant enrolment
Anticipated
7/10/2016
Actual
28/10/2015
Date of last data collection
Anticipated
Actual
23/11/2015
Sample size
Target
100
Accrual to date
Final
100
Recruitment outside Australia
Country [1] 6259 0
New Zealand
State/province [1] 6259 0
Auckland

Funding & Sponsors
Funding source category [1] 289681 0
Government body
Name [1] 289681 0
Health Research Council
Country [1] 289681 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
85 Park Rd
Grafton Auckland 1023
Country
New Zealand
Secondary sponsor category [1] 288374 0
None
Name [1] 288374 0
Address [1] 288374 0
Country [1] 288374 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291416 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 291416 0
Ethics committee country [1] 291416 0
New Zealand
Date submitted for ethics approval [1] 291416 0
Approval date [1] 291416 0
24/02/2014
Ethics approval number [1] 291416 0
MEC/05/10/130/AM06

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 50294 0
Prof Nicola Dalbeth
Address 50294 0
Rheumatologist and Professor Room 502-201D Bone and Joint Research Group Department of Medicine Faculty of Medical and Health Sciences University of Auckland 85 Park Rd, Grafton, Auckland 1023
Country 50294 0
New Zealand
Phone 50294 0
+64 (0) 9 3737999 x82568
Fax 50294 0
Email 50294 0
[email protected]
Contact person for public queries
Name 50295 0
Anne Horne
Address 50295 0
Bone and Joint Research Group
Department of Medicine
Faculty of Medical and Health Sciences
University of Auckland
85 Park Rd, Grafton, Auckland 1023
Country 50295 0
New Zealand
Phone 50295 0
+64 (0) 9 3737999 x89787
Fax 50295 0
Email 50295 0
[email protected]
Contact person for scientific queries
Name 50296 0
Nicola Dalbeth
Address 50296 0
Rheumatologist and Professor Room 502-201D Bone and Joint Research Group Department of Medicine Faculty of Medical and Health Sciences University of Auckland 85 Park Rd, Grafton, Auckland 1023
Country 50296 0
New Zealand
Phone 50296 0
+64 (0) 9 3737999 x82568
Fax 50296 0
Email 50296 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseInfluence of genetic variants on renal uric acid handling in response to frusemide: An acute intervention study.2017https://dx.doi.org/10.1136/rmdopen-2016-000424
N.B. These documents automatically identified may not have been verified by the study sponsor.