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Trial registered on ANZCTR


Registration number
ACTRN12619000915156
Ethics application status
Approved
Date submitted
12/06/2019
Date registered
1/07/2019
Date last updated
20/06/2024
Date data sharing statement initially provided
1/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
High urate levels in the transition to gout
Scientific title
The development of gout in people with asymptomatic hyperuricemia: a 5-year prospective cohort study
Secondary ID [1] 298411 0
None
Universal Trial Number (UTN)
Trial acronym
TIGER (Transitions In Gout Research) study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Gout 313118 0
Cardiovascular disease 313121 0
Kidney disease 313122 0
Hyperuricemia 313123 0
Condition category
Condition code
Inflammatory and Immune System 311595 311595 0 0
Other inflammatory or immune system disorders
Cardiovascular 311746 311746 0 0
Other cardiovascular diseases
Metabolic and Endocrine 311747 311747 0 0
Metabolic disorders
Musculoskeletal 311748 311748 0 0
Other muscular and skeletal disorders
Renal and Urogenital 311749 311749 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
This is a prospective cohort study of people with asymptomatic hyperuricemia. Participants will attend a baseline study visit where clinical data will be collected, blood samples will be obtained, and an ultrasound scan performed. Participants will then be followed for 5 years to identify factors associated with the development of symptomatic gout. During the 5 year follow-up period participants will be contacted every 6 months to assess gout development. If participants develop gout during the 5 year follow-up period they will attend a second study visit, where the baseline assessments will be repeated. If participants do not develop gout, they will continue in the study and attend a final study visit at 5 years where the baseline assessments will be repeated.
Intervention code [1] 314657 0
Early Detection / Screening
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 320299 0
The proportion of participants who develop gout who have baseline evidence of crystal deposition on ultrasound imaging
Timepoint [1] 320299 0
Evidence of crystal deposition on ultrasound imaging will be assessed at the baseline visit.

Gout development will be assessed every 6 months for five years from baseline via phone call follow-ups or by contacting the researcher at the time new joint pain or swelling develops.
Primary outcome [2] 320300 0
The time taken to develop gout in participants who have baseline evidence of crystal deposition on ultrasound imaging
Timepoint [2] 320300 0
Evidence of crystal deposition on ultrasound imaging will be assessed at the baseline visit.

Gout development will be assessed every 6 months for five years from baseline via phone call follow-ups or by contacting the researcher at the time new joint pain or swelling develops.
Secondary outcome [1] 371102 0
Clinical, genetic and biological factors (assessed via the collection of whole blood, serum and urine samples) associated with the development of crystal deposition on ultrasound imaging (Exploratory Outcome).
Timepoint [1] 371102 0
Clinical, genetic and biological factors, as well as ultrasound assessment for crystal deposition will be assessed at the baseline visit and again at a final visit after five years.
Secondary outcome [2] 371103 0
Clinical, genetic and biological factors (assessed via the collection of whole blood, serum and urine samples) associated with the development of gout (Exploratory Outcome).
Timepoint [2] 371103 0
Clinical, genetic and biological factors will be assessed at a baseline visit and at a final five year visit.

Gout development will be assessed every 6 months for five years from baseline via phone call follow-ups or by contacting the researcher at the time new joint pain or swelling develops.
Secondary outcome [3] 371104 0
Predictive role of ultrasound evidence of crystal deposition in the development of medical co-morbidities, specifically cardiovascular disease and kidney disease. Medical comorbidities will be assessed by one-on-one interviews with participants during study visits (using yes/no questions) and confirmed via access to their medical records (Exploratory Outcome).
Timepoint [3] 371104 0
Ultrasound evidence of crystal deposition will be assessed at the baseline visit and the development of medical co-morbidity will be assessed every 6 months for five years.

Eligibility
Key inclusion criteria
1. Current serum urate level of greater than or equal to 8 mg/dl
2. No current or previous clinical symptoms of gout (including flares or clinically apparent tophi)
3. Able to provide informed consent, according to requirements of local IRB/ethics committee
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. eGRF < 30 mL/min/1.73 m² or on renal replacement therapy
2. Serious illness with poor prognosis less than 5 years
3. Plans to shift out of area in the next 5 years
4. Previous synovial fluid analysis showing MSU crystals
5. The presence of subcutaneous tophi
6. Taking urate lowering therapy (e.g. allopurinol, probenecid, benzbromarone, febuxostat), canakinumab, or colchicine.

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
The primary aim of this study is to determine whether those people who already have a high risk of gout due to elevated serum urate concentrations (i.e. serum urate (=8 mg/dL) at baseline visit are at increased risk of developing gout (according to the 2015 ACR/EULAR criteria) over 5 years if they have evidence of crystal deposition.
The primary analysis will focus on follow-up data. The development of gout will be examined using standard logistic regression techniques (Proc Logistitic, SAS v 9.4, SAS Institute Inc) to estimate the discriminability of ultrasound evidence of MSU crystal deposition (as a continuous variable) to predict the presence/absence of gout using a standard receiver operating curve (ROC) approach with the results expressed as area under the ROC curve (AUC) with 95% confidence interval and tested to determine whether the observed AUC differs from that attributable to chance (ie AUC > 0.05). The model will include study site stratification in secondary analysis. Optimal cutoff points for MSU crystal deposition score (and its components) that are likely to be of clinical relevance will be determined from investigation of sensitivity/specificity at each score (Youden’s index).
The primary analysis will analyze gout as defined by the 2015 ACR/EULAR gout classification criteria. In a sensitivity analysis, participants who are lost to follow-up but have gout documented in medical records or gout medications dispensed will be included in the analysis of gout cases.
Multivariable linear regression analysis will be used to determine the independent predictors of change (end of study-baseline) in OMERACT ultrasound score. Following best practice the choice of independent variables will not be on the basis of bivariate comparisons nor iterative model building techniques rather models will be constructed based on expert clinical knowledge of likely associations. Since these models are considered hypothesis generating final model choice will be on the basis of biological plausibility, parsimony and goodness of fit.

An original computed sample size of 904 was estimated to allow analysis of significant transition from hyperuricaemia to symptomatic gout and assumed a 5-year incidence of gout of 9.9%. The original study intent was to determine whether there was a significant increased odds of developing gout in those with MSU crystal deposition compared to those without. The influence of the global COVID pandemic on study site and participant recruitment, reappraisal that a continuous ultrasound assessment of MSU crystal deposition is now available, and the observation that the incidence of gout in the cohort to date (as at 21st March 2024) is actually 11.8% (95% CI 8.3, 16.5) in an average of 2.4 years follow up has necessitated a reappraisal of the study methods of analysis and sample size justification. Importantly this reappraisal has been informed by the overall rate of gout observed in the study cohort but did not include analysis of MSU crystal deposition data.
Pragmatically, recruitment will be completed with approximately 250 participants of whom 28 are known to have gout with an average follow-up of 2.4 years (range 0.01-4.61 years). Additional cases of gout are assumed to continue to accrue at the same rate as observed in the study to date ie 4.9 (95% CI 3.3, 7.0) new classifications of gout per 100 patient years of follow-up. It is anticipated that total proportion of participants who have developed gout in five years will have increased to 23% (58 participants develop gout overall).
A sample of 58 participants with gout and 192 (ie total N=250) without gout achieves 90% power to detect a difference of 0.14 between the area under the ROC curve (AUC) under the null hypothesis of 0.50 and an AUC under the alternative hypothesis of 0.64 using a two-sided z-test at a significance level of 0.050. The data are continuous responses. The AUC is computed between false positive rates of 0.00 and 1.00. The ratio of the standard deviation of the responses in the negative group to the standard deviation of the responses in the positive group is 1.00. (PASS 16 Power Analysis and Sample Size Software (2018). NCSS, LLC. Kaysville, Utah, USA, ncss.com/software/pass.) A difference in AUC of 0.18 (ie AUC ROC curve for MSU crystal deposition =0.68) could be detected with a 12% incidence of gout. A total of 58 participants with gout would enable multivariable analysis with at most 6 independent variables (rule of 10 events per independent variable) to be performed.
This change was made after enrolment of 238 participants.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
31/07/2019
Actual
31/07/2019
Date of last participant enrolment
Anticipated
31/08/2024
Actual
Date of last data collection
Anticipated
31/08/2029
Actual
Sample size
Target
250
Accrual to date
245
Final
Recruitment outside Australia
Country [1] 21562 0
New Zealand
State/province [1] 21562 0
Auckland, Christchurch, Wellington
Country [2] 21563 0
France
State/province [2] 21563 0
Lille
Country [3] 21564 0
United States of America
State/province [3] 21564 0
Los Angeles
Country [4] 21565 0
Spain
State/province [4] 21565 0
Alicante
Country [5] 21567 0
Lithuania
State/province [5] 21567 0
Kaunas
Country [6] 26390 0
China
State/province [6] 26390 0
Qingdou

Funding & Sponsors
Funding source category [1] 302958 0
Government body
Name [1] 302958 0
Health Research Council of New Zealand
Country [1] 302958 0
New Zealand
Primary sponsor type
University
Name
The University of Auckland
Address
Medicine
85 Park Road
Grafton
Auckland 1023
Country
New Zealand
Secondary sponsor category [1] 302991 0
None
Name [1] 302991 0
Address [1] 302991 0
Country [1] 302991 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303513 0
Health and Disability Ethics Committee
Ethics committee address [1] 303513 0
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 303513 0
New Zealand
Date submitted for ethics approval [1] 303513 0
27/11/2018
Approval date [1] 303513 0
18/12/2018
Ethics approval number [1] 303513 0
MEC/05/10/130/AM16

Summary
Brief summary
This study aims to determine whether ultrasound evidence of urate crystal deposition is a necessary precondition for the development of gout and to understand the pathological mechanisms responsible for the transition from asymptomatic crystal deposition to gout. This five year prospective study, led from Auckland, New Zealand, will involve the recruitment of over 900 participants across multiple international sites. Eligible participants will attend a baseline study visit which will include recording of demographic information, a physical exam, assessment of clinical risk factors, and assessment of health related quality of life, activity limitations, illness perception and pain. Whole blood, serum and urine samples will be collected for biochemical and genetic testing. Bilateral radiographs of the feet will be obtained and an ultrasound assessment of the feet and knees will be performed to assess for crystal deposition, bone erosion and features of soft tissue inflammation. Participants will be followed up six-monthly to determine whether they have developed symptoms of new joint pain or swelling. Participants will attend a second visit after 5 years, or earlier if they develop gout, where these outcomes will be re-assessed.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 93922 0
Prof Nicola Dalbeth
Address 93922 0
The University of Auckland
Room 502-201D
85 Park Road
Grafton
Auckland 1023
Country 93922 0
New Zealand
Phone 93922 0
+64 09 923 2568
Fax 93922 0
Email 93922 0
[email protected]
Contact person for public queries
Name 93923 0
Nicola Dalbeth
Address 93923 0
The University of Auckland
Room 502-201D
85 Park Road
Grafton
Auckland 1023
Country 93923 0
New Zealand
Phone 93923 0
+64 09 923 2568
Fax 93923 0
Email 93923 0
[email protected]
Contact person for scientific queries
Name 93924 0
Nicola Dalbeth
Address 93924 0
The University of Auckland
Room 502-201D
85 Park Road
Grafton
Auckland 1023
Country 93924 0
New Zealand
Phone 93924 0
+64 09 923 2568
Fax 93924 0
Email 93924 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
It is undecided whether this data will be available at this time.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
2518Study protocolThe study protocol will be submitted for publication in a medical journal later this year.  



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseWhere should we set the start of gout?.2023https://dx.doi.org/10.1016/j.jbspin.2022.105509
N.B. These documents automatically identified may not have been verified by the study sponsor.