Effect of Tight Urate Control in Gouty Arthritis Compared to Usual Care (TICOGA), a Randomised Clinical Trial
Phase: NA
Conditions: Gout
Sponsor: University of Edinburgh

 
 
TICOGA 
 
 
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Study Protocol 
 
Effect of tight urate control in gouty arthritis compared to usual care 
(TICOGA), a randomised clinical trial 
 
Sponsor 
The University of Edinburgh/ Lothian Health Board 
ACCORD 
The Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
Protocol author 
Dr Philip Riches, Rowan Hart 
Chief Investigator 
Dr Philip Riches 
Sponsor number 
AC22077 
REC Number 
IRAS ID 314061 
Project registration 
NCT 05507723 
Tight control in gouty arthritis (TICOGA)  
Version Number and Date 
Version 3.0 
Thursday 07.08.2025 
Amendment History 
 
Amendment 1 
Amendments to protocol; 
1) The control arm has been changed to 'Usual Care' 
from a flare based algorithm of treatment escalation. 
This simplifies conduct of the trial, and ensures the 
cost-effectiveness analysis has a comparator which 
reflects current practice. 
2) Power calculation revised based on experience of 
extension trial, recruitment target reduced to 125 
participants  
3) Qualitative interview component introduced to 
explore participant experience and attitudes in 
greater depth 
4) Outcome measures revised in line with updated 
OMERACT (Outcome Measures in Rheumatology 
Clinical Trials) guidelines for gout trials 
Amendment 2 
Amendments to protocol 
1) Recruitment of patients through patient engagement 
T  COGA
Targeting Tight Control of Gouty Arthritis

 
 
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and display of posters in the community 
2) Amendments to body of text to ensure consistency 
with outcome measures specified in Endpoints  
Section 2.2 (eg use of SF-36/HAQ-DI in place of 
EQ5D5L) 
3) Clarification of methods used to gather data including 
use of RedCAP software to generate an electronic 
patient record, and that this software will be used to 
allow potential participants to express interest in the 
trial. 

 
 
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CONTENTS 
 
1 
INTRODUCTION .......................................................................................................... 8 
1.1 
BACKGROUND AND RATIONAL ........................................................................ 8 
2 
STUDY OBJECTIVES .................................................................................................. 8 
2.1 
Objectives ............................................................................................................ 8 
2.1.1 
Primary Objective .............................................................................................. 8 
2.1.2 
Secondary Objectives ....................................................................................... 8 
2.2 
ENDPOINTS ........................................................................................................ 9 
2.2.1 
Primary Endpoint .............................................................................................. 9 
2.2.2 
Secondary Endpoints ........................................................................................ 9 
3 
STUDY DESIGN ......................................................................................................... 10 
3.1 
Original study ..................................................................................................... 10 
3.2 
COVID -19 ......................................................................................................... 11 
4 
STUDY POPULATION ............................................................................................... 12 
4.1 
NUMBER OF PARTICIPANTS ........................................................................... 12 
4.2 
INCLUSION CRITERIA ...................................................................................... 12 
4.3 
EXCLUSION CRITERIA ..................................................................................... 12 
4.4 
CO-ENROLMENT .............................................................................................. 12 
5 
PARTICIPANT SELECTION AND ENROLMENT ...................................................... 12 
5.1 
IDENTIFYING PARTICIPANTS ......................................................................... 12 
5.2 
CONSENTING PARTICIPANTS ........................................................................ 13 
5.3 
Withdrawal of Study Participants ........................................................................ 13 
6 
STUDY PROCEDURES AND ASSESSMENTS ......................................................... 13 
6.1 
STUDY PROCEDURES ..................................................................................... 13 
6.1.1 
Screening ........................................................................................................ 13 
6.1.2 
Baseline assessment ...................................................................................... 14 
6.1.3 
Baseline Interventions ..................................................................................... 14 
6.1.5 
Final Study visit week 104 ............................................................................... 15 
6.2 
STUDY ASSESSMENTS ................................................................................... 15 
6.2.1 
History and physical examination .................................................................... 15 
6.2.2 
Laboratory assessments ................................................................................. 15 
6.2.3 
App assessments ............................................................................................ 15 
6.2.4 
Questionnaires ................................................................................................ 15 
6.2.5 
Qualitative Interviews ...................................................................................... 15 
6.2.6 
Linkage ........................................................................................................... 16 
6.3 
STORAGE AND ANALYSIS OF SAMPLES ....................................................... 16 
7 
DATA COLLECTION ................................................................................................. 16 
7.1 
Source Data Documentation .............................................................................. 16 
7.2 
Case Report Forms ............................................................................................ 16 
8 
STATISTICS AND DATA ANALYSIS ........................................................................ 16 
8.1 
SAMPLE SIZE CALCULATION .......................................................................... 16 
8.2 
PROPOSED ANALYSES ................................................................................... 17 
9 
ADVERSE  EVENTS .................................................................................................. 17 
10 
OVERSIGHT ARRANGEMENTS ............................................................................... 17 

 
 
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10.1 
INSPECTION OF RECORDS ............................................................................ 17 
11 
GOOD CLINICAL PRACTICE .................................................................................... 17 
11.1 
ETHICAL CONDUCT ......................................................................................... 17 
11.2 
INVESTIGATOR RESPONSIBILITIES ............................................................... 18 
11.2.1 Informed Consent ........................................................................................... 18 
11.2.2 Study Site Staff ............................................................................................... 18 
11.2.3 Data Recording ............................................................................................... 18 
11.2.4 Investigator Documentation ............................................................................. 18 
11.2.5 GCP Training .................................................................................................. 18 
11.2.6 Confidentiality ................................................................................................. 18 
11.2.7 Data Protection ............................................................................................... 18 
12 
STUDY CONDUCT RESPONSIBILITIES ................................................................... 19 
12.1 
PROTOCOL AMENDMENTS ............................................................................. 19 
12.2 
MANAGEMENT OF PROTOCOL NON COMPLIANCE ..................................... 19 
12.3 
SERIOUS BREACH REQUIREMENTS ............................................................. 19 
12.4 
STUDY RECORD RETENTION ......................................................................... 19 
12.5 
END OF STUDY ................................................................................................ 19 
12.6 
CONTINUATION OF TREATMENT FOLLOWING THE END OF 
STUDY .............................................................................................................. 20 
12.7 
INSURANCE AND INDEMNITY ......................................................................... 20 
13 
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS ........................ 20 
13.1 
AUTHORSHIP POLICY ..................................................................................... 20 
13.2 
DISSEMINATION OF RESULTS ....................................................................... 20 
14 
REFERENCES ........................................................................................................... 21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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LIST OF ABBREVIATIONS 
 
ACCORD 
Academic and Clinical Central Office for Research & Development - Joint office 
for The University of Edinburgh and Lothian Health Board 
EPCC 
Edinburgh Parallel Computing Centre 
GP 
General Practitioner 
GCP 
Good Clinical Practice 
NHS 
National Health Service 
PI 
Principal Investigator 
PIL 
Participant Information Leaflet 
REC 
Research Ethics Committee 
REDCap 
Research Electronic Data Capture 
RDU 
Rheumatic Diseases Unit 
WGH 
Western General Hospital 
 
 

 
 
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Study title:  
Tight control in gouty arthritis 
Type of study 
Randomised clinical trial 
Trial participants 
Patients with diagnosis of gout requiring urate lowering therapy 
Planned sample 
size 
125 participants 
Follow-up 
duration 
2 years 
Planned trial 
period 
3 years (1 year for recruitment, with 2 years of follow up) 
Primary objective 
Assessment of clinical outcomes with supported self-
management of gout 
Secondary 
objectives 
Measurement of health related quality of life 
Evaluation of cost effectiveness and safety of the approach 
Assessment of treatment adherence 
Assessment of brief diet and exercise questionnaires, and 
compliance with lifestyle advice 
Primary endpoint 
Proportion of participants flare free in 2nd year of trial 
Secondary 
endpoints 
Number of flares of gout in year 1, year 2 and over whole 
course of trial  
Proportion of participants achieving urate levels of ≤0.3mmol/L 
or  ≤0.36mmol/L at week 52 and 104 
Proportion of participants meeting gout remission criteria at 
week 52 and 104 
Medication compliance assessed by patient self-report, and 
prescription collection  
Proportion of participants with tophi at week 52 and 104  
Self-reported quality of life and pain at week 52 and week 104  
Number of days lost at work and number of medical 
appointments or hospital admissions due to gout 
Time to last flare of gout and time to resolution of tophi 
User enagagement with Smartphone app (number of 
reminders needed for each submission) 
Cost-effectiveness and cost-utility analysis 
Activity limitation measured through Haq-DI 
Patient 
understanding 
and 
attitudes 
assessed 
through 
qualitative interview 
Device name 
BeneCheck plus 
Manufacturer 
name 
General Life Biotechnology Co Ltd, Taiwan 
Principle intended 
use 
Supported self-management of gout 
 
 
 
 
 

 
 
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1 
INTRODUCTION 
1.1 BACKGROUND AND RATIONAL 
Gout is the most common cause of inflammatory arthritis with prevalence in the UK estimated 
at 2.5%, and an incidence that is rising globally alongside epidemics of obesity and 
cardiovascular disease. For patients it is characterised by sudden attacks of pain of great 
intensity, and is a cause of reduced quality of life, work absence and disability. For health 
services gout is an increasing cause of emergency attendance, hospital admission, and 
prolonged hospital stays. Recent guidelines have emphasised the importance of maintaining 
urate below target levels in order to achieve long term prevention of gout attacks (Fitzgerald 
2020). Within clinical trials or with sufficient support it is clear that the vast majority of patients 
are able to achieve target serum urate levels, though in routine clinical practice patients rarely 
meet current recommendations.  
 
Suitable monitoring devices for urate self-testing are available and have been reported to 
show excellent reliability in comparison to gold standard laboratory diagnostics (Paraskos J, 
2016). We have developed a supported self-management approach to gout which uses 
results of urate self-monitoring to guide escalation of treatment to target urate levels, with 
communication of results and treatment advice sent through a smartphone application 
(GoutSMART). This approach has been evaluated in a feasibility trial which showed that the 
approach was well tolerated and resulted in high attainment of urate targets by 6 months 
(Riches et al 2022). Exploratory results from this trial suggested that active care participants 
sustained fewer flares; however this needs to be confirmed in a larger trial with flares as the 
primary outcome. Similarly we were able to show that participants assigned to active care 
required fewer GP appointments for review of gout, but we still need to formally evaluate the 
cost-effectiveness of the approach. The GoutSMART application also provides an opportunity 
to educate patients about beneficial lifestyle modifications and encourage their 
implementation with direct feedback through better control of urate levels. Once patients are 
established on effective urate lowering therapy we aim to offer individualised dietary advice to 
participants identified as having elevated consumption of certain foods, and then review 
dietary compliance and its impact on urate levels via frequent urate level testing and repeat 
Food Frequency Questionnaires during a block of intervention.  
 
Although a treat-to-target urate approach to gout is recommended in rheumatology specialty 
clinical guidelines (Hui 2017, Fitzgerald 2020), the approach has not been endorsed by 
primary care practice guidelines (Qaseem 2017) which cite a lack of evidence that such an 
approach is superior to pragmatic escalation of urate lowering therapy based on gout flares. 
We wish to investigate the clinical and cost-effectiveness of our treat-to-target urate approach 
incorporating supported self-management in comparison to a usual care strategy. 
2 
STUDY OBJECTIVES  
2.1 Objectives 
 
2.1.1 Primary Objective 
• 
To assess flare frequency in patients allocated to a treat-to-target urate 
approach incorporating supported self-management, in comparison to a 
pragmatic usual care approach. 
2.1.2 
Secondary Objectives 
• 
To measure health related quality of life. 
• 
To measure proportion of participants achieving resolution of tophi 
• 
To assess treatment adherence by measuring oxypurinol, the active 
metabolite of Allopurinol, as well as by prescription collection rates 

 
 
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• 
To evaluate the cost-effectiveness and safety of the approach by gathering 
data including hospital and GP visits and work absenteeism, and adverse 
events. 
• 
To assess feasibility of implementation, compliance and impact of lifestyle 
modification. 
2.2 ENDPOINTS 
2.2.1 Primary Endpoint 
• 
Proportion of participants flare free in 2nd year of trial.  
2.2.2 Secondary Endpoints  
• 
Number of flares in year 1, and year 2 of study and total flares experienced 
over the 104 week course of the study.  
• 
Proportion of participants flare free in 1st year of trial. 
• 
Patient global assessment of health and pain (both all cause and due to gout) 
at week 52 and 104 and opportunistically during gout flare 
• 
Time to final flare of gout 
• 
Proportion of participants achieving urate level ≤0.3mmol/l and ≤0.36mmol/l 
at week 52 and 104 
• 
Proportion of participants with tophi at week 52 and week 104. The number of 
clinically evident tophi and size of largest baseline tophus (index tophus) at 
week 52 and week 104 
• 
Proportion of participants achieving remission criteria for gout at week 52 and 
104 
• 
Quality of life evaluated using  Medical Outcomes Study Questionnaire Short 
Form 36 at week 52 and 104. 
• 
Activity limitation evaluated using HAQ-DI questionnaire at week 52 and 104 
• 
Number of days lost at work due to gout flare at week 52 and 104 
• 
Number of scheduled and unscheduled medical appointments/ hospital 
admissions both all cause and due to gout assessed at week 52 and 104 
through questionnaire and data linkage. 
• 
Cost-effectiveness (cost per flare avoided) and cost-utility (cost per quality-
adjusted life year (QALY) gained) will be determined within the trial using 
healthcare resource use data (from questionnaires and medical records 
obtained through data linkage) including both all healthcare resource use and 
resource use attributable directly to gout.  
• 
Wider societal costs such as carers leave, personal time travelling to/from GP 
appointments and work absenteeism will be measured by questionnaire and 
again broken down into total costs and gout attributable costs (utilising the 
Work Productivity and Activity Impairment Questionnaire: General Health 
V2.0) at week 52 and 104 and opportunistically during the trial after reports of 
flares. 
• 
Self report of number of doses of medication omitted in preceding week, and 
prescription collection rates will be evaluated at week 52 and 104 
• 
Number of reminders received per submission on GoutSMART app 
• 
Patient attitudes and understanding assessed through qualitative interview 

 
 
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3 
STUDY DESIGN 
3.1 Original study 
 
A total of approximately 125 participants will be recruited. We anticipate that most participants 
will be identified following referral to rheumatology outpatient or on-call services in NHS 
Lothian, or through NHS Lothian’s gout liaison service.   Additional patients may indicate their 
willingness to participate directly in response to study advertisements.   
 
Based on baseline renal function and flare frequency, an individual treatment plan will be 
drawn up for all participants which will set a ceiling on the maximum dose of allopurinol to be 
used within the trial and determine the need for flare prophylaxis with colchicine. Participants 
will be randomized to the intervention group in a 1:1 ratio. 
 
All participants will have a smart phone application (GoutSMART) uploaded to their smart 
phones. Usual care participants will have a limited version of the GoutSMART application 
installed which includes background information about gout and provides a means for 
participants to maintain diaries of gout flares and quality of life. Subjects in the usual care arm 
of the study will be managed by their GP in line with usual practice. Subjects in the treat-to-
target arm will be taught to self-test serum urate using a BeneCheck Plus hand held device 
and provided with test strips. A full version of the GoutSMART application will be installed with 
the features mentioned above but also the facility to record a urate diary. Participants will be 
prompted to check their serum urate and enter the results into the GoutSMART application. 
Participants reporting a urate level >0.3mmol/l will be advised to increase the dose of 
allopurinol by 100mg or 50mg depending on renal function, up to the maximum dose of 
allopurinol specified in their treatment plan. No change will be advised in those whose urate 
levels are already at target. If the patient needs to increase allopurinol there will be an 
automatic reminder after two weeks prompting the patients to submit updated self-test results 
which will be handled in the same way as described above. Conversely for participants 
achieving target levels this will be acknowledged and a request to resubmit readings will be 
sent on a monthly basis. 
 
The primary outcome will be the proportion of participants that are flare free in the second 
year of participation in the trial. Secondary outcomes will include number of flares in year 1, 
year 2 and over entire trial period, time to last flare, resolution of tophi, urate levels at year 1 
and year 2, quality of life measures, compliance measures, and measures of healthcare 
resource utilisation and societal impact. All reviews will be performed remotely with capillary 
urate used to assess urate levels at study close to allow social distancing in view of the 
coronavirus pandemic. To assess treatment compliance drug metabolite levels will be tested 
from urine samples obtained at week 52 and week 104 visits, and by review of prescription 
collection. Presence of tophi will be assessed by review of submitted images and patient self-
report. All participants will be asked once per month to record flares via the application. The 
study is designed for a total (post-randomization) duration of 104 weeks. Subjects who 
withdraw or disengage before the final visit will not be considered to have completed the 
study. 
Cost-effectiveness (cost per flare avoided) and cost-utility (cost per quality-adjusted life year 
(QALY) gained) will be determined within the trial using healthcare resource use data 
(questionnaires and medical records obtained through data linkage), primary outcome data 
and responses to the SF-36. The economic evaluation will assess the cost-effectiveness and 
cost-utility of treat-to-target with ULT compared to outcomes in the usual care arm. This will 
take the form of an incremental cost-utility analysis to estimate cost per QALY and an 
incremental cost-effectiveness analysis to estimate the cost per gout flare avoided over 24 
months follow-up. The base-case analysis will be from an NHS and Personal Social 
Services perspective, with an additional analysis from a societal perspective taking into 
account productivity losses. The analysis will be report both all healthcare utilisation costs 
and gout attributable costs.  
 

 
 
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Figure 1: Study Design
PI identifies patient through attendance 
in RDU. Provides PIL. And confirms 
interest in participation
Patients contacted by RDU for eligibility  assessment and consent to study. Finger prick 
urate test. Baseline  blood tests for urate/renal/liver  function checked/requested if not 
available.
Uric acid levels controlled
Not-eligible.
Randomise 1:1   
52 week assessment  by phone. Fingerprick urate test.
Patients taught to self-test serum urate and 
provided with  BeneCheck Device. Full 
GoutSMART app installed on phone to 
provide supported self-management and 
recording of secondary outcomes. Patients 
provided with sufficient treatment to allow 
dose escalation as indicated by results
Treat-to-flare
Treat-to-target
Uric acid levels not controlled. 
Eligible.
Letter to GP & 
patient 
Restricted GoutSMART app 
installed on phone to record 
flare diary. Patients provided 
with initial supply of 
medication
104 week assessment  by phone. Finger prick test performed of urate level. 
PI identifies patients through Gout 
Liaison service. Patient identifies 
themselves in response to advert. GP  
invites patient to participate in study. 
PIL and interest slip sent out.
Interest slip returned
Flare prophylaxis and maximum dose allopurinol
agreed. GoutSMART application installed.
 
 
3.2 COVID -19 
 
Research activity continues to be effected by the COVID-19 pandemic. Any research activity 
will be carried out in compliance with prevailing Scottish and UK Government instructions and 
guidance as well as the local R&D regulations. This includes continuous risk assessments to 
minimize the exposure to COVID-19 to any participant, in particular those who are required to 
socially distance, self-isolate or shield. All scheduled review will be carried out via telephone 
rather than face to face unless clinically indicated. Consent may not be taken in person but 
the information is provided prior to a review, discussed via telephone and the participant 
asked to sign consent in their home forwarding the documents via email or post or online 
using REDCap software.  

 
 
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4 
STUDY POPULATION 
4.1 NUMBER OF PARTICIPANTS 
We aim to recruit approximately 125 participants. Recruitment will remain open until sufficient 
numbers of recruited participants has been reached.  
4.2 INCLUSION CRITERIA 
Subjects must meet all of the following inclusion criteria to enter the study: 
• 
Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all aspects of the study. 
• 
Adult male or female aged ≥18 years. 
• 
Patient has sustained at least one flare of gout in the previous 12 months. 
• 
Confirmed clinical diagnosis of gout as per ACR/EULAR criteria (Neogi T, 2015). 
• 
Serum urate >0.36mm/L. 
• 
Patient has a smart phone and is able to use the GoutSMART application. 
• 
Patient willing to take urate lowering treatment 
• 
Patient is an NHS Lothian patient 
4.3 EXCLUSION CRITERIA 
Subjects with any of the following criteria will not be accepted into the study: 
• 
Subject is unable to follow consent 
• 
Patient on maximum urate lowering therapy or where therapy cannot be escalated 
further due to intolerance. Adverse reaction to either allopurinol or febuxostat. 
• 
End stage renal failure (eGFR <15) or previous kidney transplant 
• 
Current prescription of medication known to interact with xanthine oxidase inhibitors 
such as azathioprine or mercapto-purine. 
4.4 CO-ENROLMENT 
Co-enrolment may be allowed in purely observational studies, but will not be allowed for any 
clinical trial involving an investigational medical product. 
 
5 
PARTICIPANT SELECTION AND ENROLMENT 
5.1 IDENTIFYING PARTICIPANTS 
We anticipate that most participants will be identified by the principal investigator or the sub-
investigator following referral to rheumatology outpatient or on-call services in NHS Lothian, 
or through NHS Lothian’s gout liaison service which identifies NHS Lothian patients that have 
attended unscheduled care services with acute flares of gout, or have recently been 
prescribed allopurinol by their primary care physician. Participants may also be identified 
through attendance at locally held patient information events for gout, or be invited to find out 
more about the trial through articles published in local media. The GoutSMART website will 
have a link to the secure REDCap database, (Harris et al., 2009; Harris et al., 2019) where 
participants can express their interest online. Data submitted via REDCap will be stored on 
secure, University of Edinburgh managed servers. Potential participants that have been 
identified by NHS Lothian’s rheumatology service, or who have identified themselves as 
interested in participation, will be invited to participate directly by the study team, or will self-
identify through the REDCap database. General practitioners who wish their patients to 
participate in the study can refer the patient in for outpatient assessment or signpost patients 
towards online information about the trial. General practices that express an interest in 
recruiting patients into the study will be designated as Participant Identification Centres and 
would then be invited to contact potential participants directly.   
Posters raising awareness of the study will be placed in the rheumatology outpatient 
department, and in Unscheduled Care services in NHS Lothian. Further posters may be 

 
 
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displayed with the approval of the relevant authority in primary care healthcare facilities or 
suitable community locations. These will direct patients to the GoutSMART trial website which 
hosts a link to the Research Electronic Data Capture (REDCap) database. An email will be 
sent to General Practitioners in NHS Lothian inviting referral of suitable patients to the 
rheumatology service. Potential participants who fail screening due to low urate levels will be 
considered for re-screening within 6 weeks of initial screening based on a repeat urate test.  
 
5.2 CONSENTING PARTICIPANTS 
Written and informed consent will be obtained by the principal investigator or the sub-
investigator prior to any study-related procedures being undertaken. Verbal and written 
participant information will be presented to the participant detailing the nature of the study, the 
implications and constraints of the protocol; the known side effects and any risks involved in 
taking part. It will be clearly stated that the participant is free to withdraw from the study at any 
time for any reason and without prejudice to future care, and with no obligation to give the 
reason for withdrawal. The participant will be allowed as much time as wished to consider the 
information, and the opportunity to question the Investigator, the GP or other independent 
parties to decide whether they will participate in the study. Written Informed consent will then 
obtained by means of the participant dated signature and dated signature of the person who 
presented and obtained the informed consent. Consent will be obtained either during a face to 
face visit, or to minimise COVID-19 exposure, consent may be obtained following a telephone 
review, or consent may be obtained online via REDCap. If filled out online, the participant will 
have a chance to contact the research team about any queries about the trial, patient 
information, or consent form.. The participant may sign the PIL at home and send this 
physically or electronically via REDCap back to the researcher.  A copy of the signed 
Informed Consent will be given to the participants, and the original or scanned copy of the 
original be retained at the study site. Alternatively the participant will sign a copy of the 
consent form electronically on REDCap and a copy of this form will be donwnloaded for 
inclusion in the participants study file. 
5.3 Withdrawal of Study Participants 
Participants are free to withdraw from the study at any point or a participant can be withdrawn 
by the Investigator. Withdrawal by the investigator will be considered when participants are 
non-compliant with study procedures. At least two attempts will be made to contact the 
participant to ascertain whether the participant wishes to continue the study. 
 
If withdrawal occurs, the primary reason for withdrawal will be documented in the participant’s 
case report form, if possible. The participant will have the option of withdrawal from  
(i) all aspects of the trial but continued use of data collected up to that point 
(ii) all aspects of the trial with removal of all previously collected data.   
(iii) all aspects of the trial with removal of previously collected and stored participant samples. 
6 
STUDY PROCEDURES AND ASSESSMENTS 
6.1 STUDY PROCEDURES 
6.1.1 Screening 
Screening will be performed remotely for all participants that have indicated interest in the 
study either directly, or by return of an interest slip. At this review all inclusion/exclusion 
criteria will be assessed including confirmation of gout diagnosis, history of gout flares, and 
willingness to take urate lowering therapy. Blood results will be reviewed for measures of 
urate, renal and liver function within the last 12 months. For patients in whom necessary 
baseline blood tests are available the baseline assessment and randomisation can be 
completed remotely using REDCap’s randomisation module. If blood test results are not 
available then the patient will be invited to attend the rheumatology department to have these 
parameters assessed in line with normal clinical care. Similarly if in the course of the trial 
patients are identified as needing switched to Febuxostat they will be invited to attend hospital 
for updated renal, liver function and urate biochemistry check. 
 

 
 
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6.1.2 Baseline assessment 
The baseline assessment may be completed remotely, or alternatively may be completed at a 
face to face visit. Written, informed consent to participate in the study will be obtained. Basic 
anthropometric measurements (weight, height) will be obtained from medical records or 
estimated by participants, and the presence or absence of tophi documented. A medical and 
medication history will be obtained with access to the participants emergency care summary. 
Based on the baseline renal function a maximum dose of allopurinol will be agreed in line with 
local guidelines. Flare prophylaxis with continuous colchicine for 6 months will be 
recommended for participants with a history of ≥3 flares in the preceding 6 months. A letter 
will be sent to the participants general practitioner detailing the treatment plan, where 
appropriate the recommendation for 6 months supply of colchicine flare prophylaxis, and 
recommending that both 100mg and 300mg allopurinol tablets be taken as directed by the 
study team. All participants will install the GoutSMART app onto their phones and will be 
automatically randomised in a 1:1 ratio to usual care or treatment-to-target. Participants will 
be randomised using the REDCap randomisation module. 
 
Participants will fill in a baseline questionnaire at the baseline visit, unless there are time 
constraints, in which the survey will be sent to them to complete at home via REDCap. 
Questions will include details on previous gout flares within the last year, gout disease 
duration, lifestyle factors, and healthcare resource use. Work productivity will be measured 
using the Work Productivity & Activity Impairment – General Health (WPAI:GH) questionnaire, 
Quality of life will be measured using the Short-Form 36 (SF-36) and Health Assessment 
Questionnaire Disability Index (HAQ-DI). 
 
6.1.3 Baseline Interventions 
 
Participants allocated to usual care will be supplied with either emergency or continuous use 
colchicine as determined in their treatment plan. In addition those who are commencing 
allopurinol will be given a supply of 2 months allopurinol 100mg daily, with those already 
prescribed allopurinol continuing on their current dose. Participants allocated to treatment-to-
target will be given supplies of both 100mg and 300mg allopurinol tablets to facilitate dose 
titration based on their urate levels. Participants allocated to treatment-to-target will also be 
provided with a Benecheck urate meter and lancets/test strips and taught how to perform a 
urate finger prick test. 
 
All participants will have the GoutSMART application installed on their phones, and be shown 
how to use the application to allow direct communication between the research staff and the 
participant. All participants will be given access to online resources providing background 
information on the causes of gout, the likely progression of symptoms, strategies for dealing 
with acute attacks of gout and the role of urate in gout. All participants will be prompted once 
per month to update a flare diary through the GoutSMART application. Participants will 
receive daily reminders to complete these updates, and if this is still not completed by day 7 
the trial team will be notified. Adjudication of flares will be performed by trial staff, based on 
the submitted diaries and in line with the 2018 criteria of Gaffo et al.  
 
Participants in the intervention group will receive their treatment plan in the same fashion and 
will be provided with the BeneCheck hand-held device, taught to perform the serum urate 
finger prick self-test and shown how to enter this information into the application. Participants 
will be sent automatic reminders two weeks after any increased dose of urate lowering 
therapy to test their own urate levels and submit updated readings. If urate levels remain 
above target the participant will be advised to increase the dose of urate lowering by 100mg 
or 50mg increments in patients with renal impairment (up to the pre-specified maximum dose 
of allopurinol). If up-titration is recommended, a reminder to test again will be sent after a 
further two weeks. Conversely, for participants achieving target levels, acknowledgement will 
be sent and a request to resubmit readings will be scheduled monthly.  
 
Any participant that requires escalation of therapy in the course of the trial will be recalled to 
have updated renal and liver function tests in line with normal clinical practice. 
 
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Participants will be reviewed in person or by telephone at week 52, with in person review 
preferred for participants with tophi. A finger prick urate test will be performed. The patient 
flare diaries generated by the GoutSMART application will be reviewed and the number of 
adjudicated flares recorded. Any adverse advents recorded. All participants will be asked to 
record the number of doses of medication missed in the preceding 2 weeks, and have 
prescription uptake reviewed. Quality of life scores will be evaluated using the SF-36 and 
HAQ-DI questionnaires integrated within the Week 52/104 data collection sheet. The number 
of days lost at work due to gout flares and the number of scheduled and unscheduled medical 
appointments/ hospital admissions due to gout will be collected following review of hospital 
records and through patient self-report. Any adverse events will be recorded.  
6.1.5 Final Study visit week 104 
Participants will be given their final study review in person or by telephone at week 104, with 
in person review preferred for participants with tophi. A finger prick urate test will be 
performed. The patient flare diaries generated by the GoutSMART application will be 
reviewed and the number of adjudicated flares recorded. All participants will be asked to 
record the number of doses of medication missed in the preceding 2 weeks, and have 
prescription uptake reviewed. Quality of life scores will be evaluated using the SF-36 and 
HAQ-DIquestionnaires. The number of days lost at work due to gout flares and the number of 
scheduled and unscheduled medical appointments/ hospital admissions due to gout will be 
collected following review of hospital records and through patient self-report. Any adverse 
advents recorded. All participants will record a finger prick urate at their final study visit using 
the Benecheck meter. 
 
A letter will be written to the GP of all participants summarising the disease course and 
management and proposing further management advice in line with usual clinical practice. 
Participants who have not yet achieved control of their serum urate by week 104 will be 
offered further follow up in the gout clinic in line with usual practice. 
 
6.2 STUDY ASSESSMENTS 
6.2.1 History and physical examination 
A focussed history will be carried out at the specified time points. We will be recording the 
presence of tophi and take measurements of the largest tophus using supplied callipers at 
baseline and year 1 and 2 visits. Details of the duration of disease, frequency and pattern of 
flares will be recorded. Weight and height will be recorded from hospital records or self-report 
at baseline and weight again at year 1 and year 2. 
6.2.2 Laboratory assessments 
Serum FBC, U&Es, LFTs, urate will be collected by venepuncture where needed as part of 
the normal clinical care of the participants. 
6.2.3 App assessments 
The smart phone application will collect the following data over the 104 weeks of the study 
• 
Number of days of self-reported gout flare, updated monthly through study 
• 
Diary of self-reported urate results 
6.2.4 Questionnaires 
We will use the SF-36, HAQ-DI and Work Productivity and Activity Impairment Questionnaire: 
General Health V2.0 to evaluate health outcomes. Study specific questionnaires will be 
completed at week 52, week 104 and an abbreviated version of this questionnaire after gout 
flares. 
6.2.5 Qualitative Interviews  
Patients will be invited to take part in a single semi-structured interview exploring their 
understanding of gout and its treatment according to a draft interview schedule and at a 
mutually convenient time during their participation in the trial. The interviews will be conducted 
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meeting AES 256-bit encryption standard. Transcripts of the interview will be prepared using 
NHS approved transcription software (G2) and these transcripts will be stored on secure 
servers within NHS Lothian for thematic analysis. Travel expenses will be provided to 
participants choosing to take part in this aspect of the study. 
6.2.6 Linkage 
In order to evaluate the full heath economic impact of gout we will contact Public Health 
Scotland, NHS Lothian primary care pharmacy team or other NHS organisations to identify 
participant use of healthcare resources through ‘data linkage’. This will be linked to the 
participant  CHI number and we expect this information to be available within 6 months of 
study close.  
 
6.3 STORAGE AND ANALYSIS OF SAMPLES 
Where serum biochemistry samples are needed for U&Es, LFTS or urate these will be 
analysed and stored by local NHS Lothian laboratories. Samples will be discarded as per 
local protocols. 
7 
DATA COLLECTION 
Data will be collected at baseline, week 52 and 104 visits as well as via the smart phone 
application on a monthly basis. Data will also be collected opportunistically if participants 
submit a flare in the GoutSMART app. A shortened version of the study review questionnaires 
will be sent one week after the start date that a participant has submitted a flare.   Data will be 
collected by the principal investigator and the sub-investigators. The use of REDCap software 
will be the main source of collecting and storing trial data, though paper copies of 
questionnaires are also available should the participant wish them. We will use the SF36 and 
HAQ-DI to evaluate health outcome. To maximise completeness of data collection, every 
effort will be made to contact participants who have failed to attend scheduled visits, submit 
requested information via the smart phone application or return questionnaires. Participants 
will be contacted by telephone on at least two occasions. 
 
7.1 Source Data Documentation 
Source documents will be the patient’s electronic patient record, electronic data entered into 
the smart phone application and participant questionnaires completed either on paper or on 
REDCap. 
. 
7.2 Case Report Forms 
An electroniccase report form will be generated for each patient and kept on secure web 
servers for REDCap, managed by the University of Edinburgh. Any paper documents will be 
stored in a locked facility at the Rheumatic Diseases Unit at the Western General Hospital 
Edinburgh. 
8 
STATISTICS AND DATA ANALYSIS 
8.1 SAMPLE SIZE CALCULATION 
This clinical trial is intended to establish the clinical-effectiveness of a supported self-
management approach, when compared to pragmatic flare based treatment escalation.  
The numbers chosen are based on the outcomes observed in our extension trial in which we 
observed 7.7% of participants sustained flares in the second year of follow up, compared to 
33.3% of usual care participants. Based on these values 90% power (alpha 0.05) can be 

 
 
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achieved with a sample size of 100. Similarly for a quality of life analysis based on feasibility 
trial self-management pain scores of 1.44 +/- 0.57 compared to 1.86 in usual care a sample 
size of 98 yields 90% power to detect an effect of this size. We will aim to recruit 125 
participants assuming 20% drop out rate over the course of 2 years (compared to 10% drop 
out over 1 year in the feasibility trial) 
  
8.2 PROPOSED ANALYSES 
The primary outcome of the study will be the proportion of participants that are flare free in the 
second year of trial participation. Categorical outcomes will be analysed using the Chi-square 
test of independence, or Fishers Exact test for where expected values in any cell of the 
contingency table are less than 5, with results displayed as frequency (percentages). For 
these analyses an intention to treat analysis will be performed with participants that have 
dropped out of the study being included as failing to reach target, or non-compliant with 
medication respectively. Normally distributed continuous study outcomes will be analysed 
using a T test with results displayed as mean ± standard deviation (SD). A Mann Whitney U 
test (MWU) will be applied when the variables are not normally distributed, with results given 
as median (interquartile range IQR). Comparison of number of flares, along with other count 
data such as number of GP visits will be performed using a 2 sample Poisson rate test. A 
nominal value of significance of p<0.05 will be used for secondary outcomes however given 
the number of secondary outcomes these will be acknowledged as exploratory. Statistical 
analysis will be performed using Minitab version 17 (Minitab Inc., Pennsylvania, US). 
9 
ADVERSE  EVENTS 
Adverse side effects from allopurinol and febuxostat are rare, with the commonest 
side effect being of skin rash. All participants will be informed of potential side effects 
of their treatment in line with usual clinical practice and be able to contact the study 
team directly to discuss any concerns. The participants’ usual primary care physician 
will be notified simultaneously with details of any medication change to ensure that 
the primary care records remain accurate and to minimize the risk of drug 
interactions. 
10 
OVERSIGHT ARRANGEMENTS 
10.1 INSPECTION OF RECORDS 
Investigators and institutions involved in the study will permit trial related monitoring and 
audits on behalf of the sponsor, REC review, and regulatory inspection(s). In the event of 
audit or monitoring, the Investigator agrees to allow the representatives of the sponsordirect 
access to all study records and source documentation. In the event of regulatory inspection, 
the Investigator agrees to allow inspectors direct access to all study records and source 
documentation. 
11 
GOOD CLINICAL PRACTICE 
11.1 ETHICAL CONDUCT 
The study will be conducted in accordance with the principles of the International Conference 
on Harmonisation Tripartite Guideline for Good Clinical Practice (ICH GCP). 

 
 
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11.2 INVESTIGATOR RESPONSIBILITIES 
The Investigator is responsible for the overall conduct of the study at the site and compliance 
with the protocol and any protocol amendments. Responsibilities may be delegated to an 
appropriate member of study site staff.   
11.2.1 Informed Consent 
The Investigator is responsible for ensuring informed consent is obtained before any protocol 
specific procedures are carried out. The decision of a participant to participate in clinical 
research is voluntary and should be based on a clear understanding of what is involved. 
Participants must receive adequate oral and written information – appropriate Participant 
Information and Informed Consent Forms will be provided. The oral explanation to the 
participant will be performed by the Investigator or qualified delegated person, and must cover 
all the elements specified in the Participant Information Sheet and Consent Form. 
The participant must be given every opportunity to clarify any points they do not understand 
and, if necessary, ask for more information. The participant must be given sufficient time to 
consider the information provided.  It should be emphasized that the participant may withdraw 
their consent to participate at any time without loss of benefits to which they otherwise would 
be entitled. 
The participant will be informed and agree to their medical records being inspected by 
regulatory authorities and representatives of the sponsor(s). 
The Investigator or delegated member of the trial team and the participant will sign and date 
the Informed Consent Form(s) to confirm that consent has been obtained. The participant 
willreceive a copy of this document and a copy filed in the Investigator Site File (ISF) and 
participant’s medical notes (if applicable). 
 
11.2.2 Study Site Staff 
The Investigator must be familiar with the protocol and the study requirements.  It is the 
Investigator’s responsibility to ensure that all staff assisting with the study are adequately 
informed about the protocol and their trial related duties. 
11.2.3 Data Recording 
The Principal Investigator is responsible for the quality of the data recorded in the CRF at 
each Investigator Site. 
11.2.4 Investigator Documentation 
The Principal Investigator will ensure that the required documentation is available in local 
Investigator Site Files (ISFs).  
11.2.5 GCP Training 
All researchers will be expected to have undertaken GCP training in order to understand the 
principles of GCP.GCP training status for all investigators will be indicated in their CVs.  
11.2.6 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records must be identified in a 
manner designed to maintain participant confidentiality. All records must be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the participant. The Investigator and study site staff involved with this study may 
not disclose or use for any purpose other than performance of the study, any data, record, or 
other unpublished, confidential information disclosed to those individuals for the purpose of 
the study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
11.2.7 Data Protection 
All Investigators and study site staff involved with this study must comply with the 
requirements of the Data Protection Act 1998 with regard to the collection, storage, 

 
 
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processing and disclosure of personal information and will uphold the Act’s core principles. 
Access to collated participant data will be restricted to individuals from the research team 
treating the participants, representatives of the sponsor(s) and representatives of regulatory 
authorities. 
Computers used to collate the data will have limited access measures via user names and 
passwords. 
Published results will not contain any personal data that could allow identification of individual 
participants. 
12 
STUDY CONDUCT RESPONSIBILITIES 
12.1 PROTOCOL AMENDMENTS 
Any changes in research activity, except those necessary to remove an apparent, immediate 
hazard to the participant in the case of an urgent safety measure, must be reviewed and 
approved by the Chief Investigator.  
Amendments will be submitted to a sponsor representative for review and authorisation 
before being submitted in writing to the appropriate REC, and local R&D for approval prior to 
participants being enrolled into an amended protocol. 
12.2 MANAGEMENT OF PROTOCOL NON COMPLIANCE 
Prospective protocol deviations,i.e.protocol waivers,will not be approved by the sponsors and 
therefore will not be implemented, except where necessary to eliminate an immediate hazard 
to study participants. If this necessitates a subsequent protocol amendment, this should be 
submitted to the REC, and local R&D for review and approval if appropriate. 
Protocol deviations will be recorded in a protocol deviation log and logs will be submitted to 
the sponsors every 3 months. Each protocol violation will be reported to the sponsor within 3 
days of becoming aware of the violation.  All protocol deviation logs and violation forms 
should be emailed to QA@accord.scot 
Deviations and violations are non-compliance events discovered after the event has occurred.  
Deviation logs will be maintained for each site in multi-centre studies.  An alternative 
frequency of deviation log submission to the sponsors may be agreed in writing with the 
sponsors. 
 
12.3 SERIOUS BREACH REQUIREMENTS 
A serious breach is a breach which is likely to effect to a significant degree: 
(a) the safety or physical or mental integrity of the participants of the trial; or 
(b) the scientific value of the trial. 
If a potential serious breach is identified by the Chief investigator, Principal Investigator or 
delegates, the co-sponsors (seriousbreach@accord.scot) must be notified within 24 hours. It 
is the responsibility of the co-sponsors to assess the impact of the breach on the scientific 
value of the trial, to determine whether the incident constitutes a serious breach and report to 
research ethics committees as necessary.  
12.4 STUDY RECORD RETENTION 
All study documentation will be kept for a minimum of 3 years from the protocol defined end of 
study point. When the minimum retention period has elapsed, study documentation will not be 
destroyed without permission from the sponsor. 
12.5 END OF STUDY 
The end of study is defined as the last participant’s last visit.   

 
 
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The Investigators or the co-sponsor(s) have the right at any time to terminate the study for 
clinical or administrative reasons.  
The end of the study will be reported to the REC, and R+D Office(s) and co-sponsors within 
90 days, or 15days if the study is terminated prematurely. The Investigators will inform 
participants of the premature study closure and ensure that the appropriate follow up is 
arranged for all participants involved. End of study notification will be reported to the co-
sponsors via email to resgov@accord.scot. 
A summary report of the study will be provided to the REC within 1 year of the end of the 
study. 
 
12.6 CONTINUATION OF TREATMENT FOLLOWING THE END OF STUDY 
All participants will continue on treatment following the end of study in line with usual clinical 
practice. 
 
12.7 INSURANCE AND INDEMNITY 
The co-sponsors are responsible for ensuring proper provision has been made for insurance 
or indemnity to cover their liability and the liability of the Chief Investigator and staff. 
The following arrangements are in place to fulfil the co-sponsors' responsibilities: 
• 
The Protocol has been designed by the Chief Investigator and researchers 
employed by the University and collaborators.  The University has insurance in 
place (which includes no-fault compensation) for negligent harm caused by poor 
protocol design by the Chief Investigator and researchers employed by the 
University. 
• 
Sites participating in the study will be liable for clinical negligence and other 
negligent harm to individuals taking part in the study and covered by the duty of care 
owed to them by the sites concerned.  The co-sponsors require individual sites 
participating in the study to arrange for their own insurance or indemnity in respect 
of these liabilities. 
• 
Sites which are part of the United Kingdom's National Health Service will have the 
benefit of NHS Indemnity. 
• 
Sites outwith the United Kingdom will be responsible for arranging their own 
indemnity or insurance for their participation in the study, as well as for compliance 
with local law applicable to their participation in the study. 
13 
REPORTING, PUBLICATIONS AND NOTIFICATION OF 
RESULTS 
13.1 AUTHORSHIP POLICY 
Ownership of the data arising from this study resides with the study team. For all papers 
arising from the study the Principal Investigator, and the person who drafted the paper will 
decide on authorship order and the corresponding author role. Selection of additional authors 
will remain in line with the criteria of the International Committee of Medical Journal Editors 
(ICMJE) and that of the Journal to which the article is submitted. 
13.2 DISSEMINATION OF RESULTS 
The results of the trial will be published, and details of the experience gained disseminated to 
physicians with an interest in gout attending European and American specialist networking 
meetings (European Crystal Network and G-CAN (Gout, Hyperuricaemia and Crystal-
Associated Disease Network). If this study should be successful then this would represent a 
substantial development in the delivery of better care in an area of long unmet need. In theory 
the approach could be adopted very easily, and since the intention is to develop an approach 

 
 
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that requires less intervention but provides better care, it is to be anticipated that this would 
find favour with policy makers and service users alike. A full cost analysis will be provided in 
order to facilitate adoption of the approach by policy makers. All participants will be informed 
of the results of the research by letter. 
14 
REFERENCES 
 
FitzGerald JD. (2020). 2020 American College of Rheumatology Guideline for the 
Management of Gout Arthritis Care Res (Hoboken);72(6):744-760 
 
Gaffo AL. (2018). Brief Report: Validation of a Definition of Flare in Patients With Established 
Gout. Arthritis Rheumatol;70(3):462-467. 
 
Harris, P.A., Taylor, R., Minor, B.L., Elliott, V., Fernandez, M., O’Neal, L., McLeod, L., 
Delacqua, G., Delacqua, F., Kirby, J. and Duda, S.N. (2019). The REDCap consortium: Building 
an international community of software platform partners. Journal of Biomedical 
Informatics, 95(1), p.103208. doi:https://doi.org/10.1016/j.jbi.2019.103208. 
Harris, P.A., Taylor, R., Thielke, R., Payne, J., Gonzalez, N. and Conde, J.G. (2009). Research 
electronic data capture (REDCap)—A metadata-driven methodology and workflow process 
for providing translational research informatics support. Journal of Biomedical Informatics, 
42(2), pp.377–381. doi:https://doi.org/10.1016/j.jbi.2008.08.010. 
 
Hui, M, et al. (2017). The British Society for Rheumatology Guideline for the Management of 
Gout. Rheumatology. 56:e1 –e20. 
 
Paraskos J, B. Z. (2016). An analytical comparison between point-of-care uric acid testing 
meters. Expert Rev Mol Diagn, 16(3):373-82. 
Qaseem A. (2017). Management of Acute and Recurrent Gout: A Clinical Practice Guideline 
From the American College of Physicians. Ann Intern Med. 2017;166(1):58-68. 
 
Riches PL (2022). Evaluation of supported self-management in gout (GoutSMART): a 
randomised controlled feasibility trial. Lancet Rheumatol. (published online March 24) 
https://doi.org/10.1016/S2665-9913(22)00062-5