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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
1/07/2019
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
Gender
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 computed sample size will allow analysis of significant transition from hyperuricaemia to crystal deposition to symptomatic gout and was based on the following data and assumptions:
a. Our recent meta-analysis of individual participant data showed the 5 year incidence of gout for people with urate greater than or equal to 0.48mmol/L to be 9.9% (95% CI 8.1, 11.7), with similar estimates in men and women. Therefore at 5 years the percentage of patients who have gout will be 9.9%, and 90.1% of the cohort will remain gout free after 5 years.
b. Analysis of all published studies indicate that 25% of people with serum urate greater than or equal to 0.48mmol/L have imaging evidence of MSU crystal deposition.
c. Assuming 90% power at the 5% significance level (without continuity correct/arcsine transformation), 723 patients in total can detect a difference between 2% gout in the arm without deposition and 7.9% in the arm with deposition (odds ratio 4.2 for gout in the presence of deposition). Assuming 25% loss to follow-up, the proposed sample size required is 904 participants.
This sample size is conservative (based on lowest reported incidence of gout and without considering state transitions).

The primary analysis will focus on follow-up data. The development of gout will be examined using standard logistic regression techniques to estimate the odds of gout for those with ultrasound evidence of MSU crystal deposition at baseline relative to those without crystal deposition. Models will be adjusted for established gout risk factors and will include study site stratification. A propensity score for gout will be developed in the entire cohort and entered as a covariate in the model. A similar approach to the determining whether the time to the development of gout is different for those with and without ultrasound evidence of MSU crystal deposition at baseline will be completed using Cox proportional hazards models for the time to develop gout.

Analysis of baseline data will include a description of baseline ultrasound findings and associations with clinical results, a descriptive analysis of the perceptions about hyperuricemia, and the impact of ABCG2 genotype on MSU crystal deposition in the presence of hyperuricemia.

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 in Australia
Recruitment state(s)
SA,WA
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
Versailles, Lyon, Lille, Paris
Country [3] 21564 0
United States of America
State/province [3] 21564 0
Washington, D.C
Country [4] 21565 0
Spain
State/province [4] 21565 0
Alicante
Country [5] 21566 0
Norway
State/province [5] 21566 0
Oslo
Country [6] 21567 0
Lithuania
State/province [6] 21567 0
Kaunas
Country [7] 21568 0
Ireland
State/province [7] 21568 0
Dublin
Country [8] 21569 0
United Kingdom
State/province [8] 21569 0
Nottingham

Funding & Sponsors
Funding source category [1] 302958 0
Government body
Name [1] 302958 0
Health Research Council of New Zealand
Address [1] 302958 0
Level 3 - ProCARE Building
Grafton Mews
110 Stanley Street
Grafton
Auckland 1010
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
n.dalbeth@auckland.ac.nz
Contact person for public queries
Name 93923 0
Prof 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
n.dalbeth@auckland.ac.nz
Contact person for scientific queries
Name 93924 0
Prof 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
n.dalbeth@auckland.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
It is undecided whether this data will be available at this time.
What supporting documents are/will be available?
Study protocol
How or where can supporting documents be obtained?
Type [1] 2518 0
Study protocol
Citation [1] 2518 0
The study protocol will be submitted for publication in a medical journal later this year.
Link [1] 2518 0
Email [1] 2518 0
Other [1] 2518 0
Attachment [1] 2518 0
Summary results
No Results