Gout Self-Monitoring Aiming to Reach Target Serum Urate (Gout-SMART): Feasibility Study of Supported Self-management of Gout in Secondary Care Patients Requiring Escalation of Urate Lowering Therapy
Phase: NA
Conditions: Gout
Sponsor: University of Edinburgh

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
1 
 
 
 
 
Study Protocol 
Improving the care of Gout –Self-Management Aiming 
to Reach Target urate (Gout-SMART) –feasibility study 
 
 
The University of Edinburgh and/or Lothian Health Board 
ACCORD 
The Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
Protocol authors 
Dr Barbara Kuske, Dr. Owen Cronin, Dr Philip Riches 
Chief Investigator 
Dr Philip Riches 
Sponsor number 
AC17101 
REC Number 
18/SS/0031 
Project registration 
NCT03274063 
Gout Self-Management Aiming to Reach Target (Gout-
SMART) 
Version Number and Date 
Version 7.0 
Wednesday 25/02/2021 
Amendment classification 
and number: 
 
Summary of change(s) 
 
Amendment number 1 
1) Addition of stool and urine samples at baseline for 
faecal and urinary metabolomics and gut microbiota 
characterization using shotgun metagenomic 
sequencing.  
2) Change from use of the Edinburgh Clinical Trials 
Centre (ECTU) to host the GoutSMART webportal to 
the Edinburgh Parallel Computing Centre (EPCC) 
3) Change in the urate meter device used from 
HumaSens to BeneCheck 
4) Editing of PIS and CF version 1.1  (29/3/18) to reflect 
the above – now version 2.0 (30/11/18). 
5) New inclusion of PIS and consent form (V2.1) to 
include control subjects which are first degree, near 
relatives or age- and gender-match non-relative 
controls for once-off stool, urine, dietary and serum 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
2 
 
urate and bioprofile analysis.  
6) Revised study protocol – previously v1.2 (29/3/18), 
now v2.0 (30/11/18) 
7) Additional promotional email of the study for 
Lothian GP v1.0 (30/11/18) 
Amendment number 2 
1) Specification of anthropometric measurements at 
visits added 
2) Addition of 24 hour urine collection and blood 
sample for renal function as paired samples for 
analysis of urate metabolism 
3) Editing of PIS and CF version 2.0 
(30/11/18)_Patients and PIS and CF version 1.0 
(30/11/18)_Controls to reflect the above –now 
versions 3.0  and 2.0 (15/02/19), respectively 
Amendment number 3 
1) Specification of use of SHARE for participant 
recruitment within protocol 
2) Clarification that all referrals will be considered. 
3) Further promotional email for Lothian GP v2.0 
(30/06/19) 
Amendment number 4 
1) Changes to protocol in light of COVID-19 risk 
assessment ; for the 24 and 52 week study visits the 
option of telephone consultations is now included to 
allow continued participation despite requirements 
for social distancing or self-isolation. At these study 
assessments  capillary rather than serum urate will 
be used to assess achievement of urate target, and 
tophus assessment will be made by review of 
submitted images. 
Amendment number 5 
1. Change to study procedures 6.1.1 to allow payment 
of reasonable expenses to participants in the study 
2. Changes to protocol to allow extended participation 
in the study. Changes made to Background and 
rationale, Study design and Endpoint Sections   
Amendment number 6 
1) Changes to protocol to allow recruitment of 
participants into long term monitoring arm of study. 
Changes made to Study design Sections  3.2, Study 
population Section 4.1, Sample size calculation 8.1 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
4 
 
CONTENTS 
 
1 
INTRODUCTION .......................................................................................................... 8 
1.1 
BACKGROUND AND RATIONAL ........................................................................ 8 
2 
STUDY OBJECTIVES .................................................................................................. 9 
2.1 
Objectives ............................................................................................................ 9 
2.1.1 
Primary Objective .............................................................................................. 9 
2.1.2 
Secondary Objectives ....................................................................................... 9 
2.2 
ENDPOINTS ........................................................................................................ 9 
2.2.1 
Primary Endpoint .............................................................................................. 9 
2.2.2 
Secondary Endpoints ........................................................................................ 9 
3 
STUDY DESIGN ......................................................................................................... 10 
3.1 Original Study 
3.2 Extension Phase 
3.3. COVID-19 
4 
STUDY POPULATION ............................................................................................... 14 
4.1 
NUMBER OF PARTICIPANTS ........................................................................... 14 
4.2 
INCLUSION CRITERIA ...................................................................................... 14 
4.3 
EXCLUSION CRITERIA ..................................................................................... 14 
4.4 
CO-ENROLMENT .............................................................................................. 15 
5 
PARTICIPANT SELECTION AND ENROLMENT ...................................................... 15 
5.1 
IDENTIFYING PARTICIPANTS ......................................................................... 15 
5.2 
CONSENTING PARTICIPANTS ........................................................................ 15 
5.3 
Withdrawal of Study Participants ........................................................................ 16 
6 
STUDY PROCEDURES AND ASSESSMENTS ......................................................... 16 
6.1 
STUDY PROCEDURES ..................................................................................... 16 
6.1.1 
Baseline visit ................................................................................................... 16 
6.1.2 
Intervention procedures .................................................................................. 16 
6.1.3 
End-of study visit week 24 ............................................................................... 17 
6.1.4 
Follow-up visit week 52 (and extension week 104,156) ................................... 17 
6.2 
STUDY ASSESSMENTS ................................................................................... 18 
6.2.1 
History and physical examination .................................................................... 18 
6.2.2 
Laboratory assessments ................................................................................. 18 
6.2.3 
App assessments ............................................................................................ 18 
6.2.4 
Questionnaires ................................................................................................ 18 
6.2.5 
Biomarker analysis .......................................................................................... 18 
6.2.6 
Urinary metabolomics ..................................................................................... 19 
6.2.7 
Faecal samples ............................................................................................... 19 
6.3 
STORAGE AND ANALYSIS OF SAMPLES ....................................................... 19 
7 
DATA COLLECTION ................................................................................................. 19 
7.1 
Source Data Documentation .............................................................................. 19 
7.2 
Case Report Forms ............................................................................................ 20 
8 
STATISTICS AND DATA ANALYSIS ........................................................................ 20 
8.1 
SAMPLE SIZE CALCULATION .......................................................................... 20 
8.2 
PROPOSED ANALYSES ................................................................................... 20 
9 
ADVERSE  EVENTS .................................................................................................. 21 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
5 
 
10 
OVERSIGHT ARRANGEMENTS ............................................................................... 21 
10.1 
INSPECTION OF RECORDS ............................................................................ 21 
11 
GOOD CLINICAL PRACTICE .................................................................................... 21 
11.1 
ETHICAL CONDUCT ......................................................................................... 21 
11.2 
INVESTIGATOR RESPONSIBILITIES ............................................................... 21 
11.2.1 Informed Consent ........................................................................................... 21 
11.2.2 Study Site Staff ............................................................................................... 22 
11.2.3 Data Recording ............................................................................................... 22 
11.2.4 Investigator Documentation ............................................................................. 22 
11.2.5 GCP Training .................................................................................................. 22 
11.2.6 Confidentiality ................................................................................................. 22 
11.2.7 Data Protection ............................................................................................... 22 
12 
STUDY CONDUCT RESPONSIBILITIES ................................................................... 22 
12.1 
PROTOCOL AMENDMENTS ............................................................................. 22 
12.2 
MANAGEMENT OF PROTOCOL NON COMPLIANCE ..................................... 23 
12.3 
SERIOUS BREACH REQUIREMENTS ............................................................. 23 
12.4 
STUDY RECORD RETENTION ......................................................................... 23 
12.5 
END OF STUDY ................................................................................................ 23 
12.6 
CONTINUATION OF TREATMENT FOLLOWING THE END OF 
STUDY .............................................................................................................. 23 
12.7 
INSURANCE AND INDEMNITY ......................................................................... 24 
13 
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS ........................ 24 
13.1 
AUTHORSHIP POLICY ..................................................................................... 24 
13.2 
DISSEMINATION OF RESULTS ....................................................................... 24 
14 
REFERENCES ........................................................................................................... 24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
6 
 
LIST OF ABBREVIATIONS 
 
ACCORD 
Academic and Clinical Central Office for Research & Development - Joint office 
for The University of Edinburgh and Lothian Health Board 
AE 
Adverse Event 
AR 
Adverse Reaction 
CI 
Chief Investigator 
CRF 
Case Report Form 
EPCC 
Edinburgh Parallel Computing Centre 
GP 
General Practitioner 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
ICF 
Informed Consent Form 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NHS 
National Health Service 
PI 
Principal Investigator 
PIL 
Participant Information Leaflet 
QA 
Quality Assurance 
REC 
Research Ethics Committee 
RDU 
Rheumatic Diseases Unit 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SHARE 
Scottish Health Research Registry 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
WGH 
Western General Hospital 
 
 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
7 
 
 
Study title:  
 
Type of study 
Feasibility study 
Trial participants 
Patients with diagnosis of gout requiring urate lowering therapy 
Planned sample 
size 
60 participants and 60 non-gout controls 
Follow-up 
duration 
1 year for GoutSMART study, further 2 years if participating in 
GoutSMARTER extension 
Planned trial 
period 
2 years (4 years in total with GoutSMARTER extension) 
Primary objective 
Assessment of supported self-management of gout 
Secondary 
objectives 
Measurement of gout flare frequency and health related quality 
of life 
Evaluation of cost effectiveness and safety of the approach 
Assessment of treatment adherence 
Identification of uric acid load in faecal samples and correlation 
with gut microbiome characteristics.  
Assessment of compliance with dietary modification and 
impact on serum urate levels. 
Primary endpoint 
Proportion of participants achieving urate levels of ≤0.3mmol/L 
at 24 weeks 
Secondary 
endpoints 
Proportion of participants achieving urate levels of ≤0.3mmol/L 
at 52wks (and for extension 104wks and 156wks) 
Medication compliance assessed by patient self-report and 
serum oxypurinol 
Number of days of self-reported gout flare  
Size in mm of the largest tophus (index tophus) and number of 
clinically evident tophi  
Self-reported quality of life during/following gout flare evaluated 
using the EQ-5D-5L questionnaire  
Number of days lost at work and number of scheduled and 
unscheduled medical appointments or hospital admissions due 
to gout 
Proportion of patients achieving a dose reduction of urate 
lowering therapy in the extension phase 
Proportion of patients achieving sustained dietary modifications 
and relative reduction of urate lowering therapy in the 
extension phase. 
Device name 
BeneCheck plus 
Manufacturer 
name 
General Life Biotechnology Co Ltd, Taiwan 
Principle intended 
use 
Self-management of gout by patients in the community 
managed by the general practitioner 
 
 
 
 
 
 
 
 
 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
8 
 
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 (Khanna J, 
2012). 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. High levels of serum urate can result in the formation of urate 
crystal deposits under the skin (called tophi) which are a marker of severe disease. These will 
resolve if serum urate levels are held low for a sustained period of time. Tight control of gout 
with a target of urate at or below 0.3mmol/l should achieve disease remission (clearance of all 
crystals from the body), but once this has been achieved recent guidelines suggest that 
keeping urate levels at or below 0.36mmol/l should prevent recurrence of disease. There is no 
consensus on how long tight control of urate is required, nor is there published experience of 
long term disease related outcomes in gout patients that have achieved target urate levels. 
 
A new paradigm of care for patients is required. Providing patients with the means to measure 
their own levels of serum urate would reduce the requirement for review appointments 
needed to guide escalation of therapy to achieve target, and possibly reinforce patient 
adherence to treatment. Suitable monitoring devices for urate self-testing are already 
available and have been reported to show excellent reliability in comparison to gold standard 
laboratory diagnostics (Paraskos J, 2016). Within our unit there is already experience in the 
use of applications for smart phones facilitating patient feedback of self-testing results, and 
the interactive nature of this approach provides additional opportunity for providing support to 
patients at time of need. This could help establish a patient led approach to gout 
management, similar to the ‘treat to target’ approach adopted in the management of diabetes. 
 
We also aim to understand the contribution of the gut microbiome to the pathogenesis of gout. 
Little is known about the factors that contribute to uric acid and purine availability within the 
gut lumen. Some preliminary evidence (Guo Z, et al. 2016) has suggested that gut bacteria 
resident in patients with gout is different than controls. We would like to challenge and 
develop this hypothesis by quantifying the availability of purine and urate metabolites within 
the gut as well as the metabolic potential of gut microbes known to play a role in uric acid and 
purine metabolism. This section of the study may pave the way for future development of anti-
microbial, dietary modification or probiotic agents that may contribute to reducing uric acid 
availability within the gut and the burden of gout in the wider population.  
 
It has long been suggested that certain lifestyle factors including dietary factors impact the 
risk of hyperuricaemia and gout. The British Society for Rheumatology Guidelines for 
Management of Gout (Hui M, et al. 2017) includes that all patients with gout should be 
encouraged to follow a well-balance diet low in fat and added sugars, high in vegetables and 
fibres specifically advising the avoidance of sugar-sweetened soft drinks containing fructose, 
high-purine foods and reducing alcohol intake. However, implementing this knowledge and 
routinely including this step in the management of patients with gout is challenging due to a 
variety of factors including limited time resources in primary care. The GoutSMART 
application provides the opportunity to educate patients of beneficial lifestyle modifications 
and encourage implementation with direct feedback through control of urate levels and 
regular review by the healthcare professional, Lifestyle changes may ultimately allow the use 
of lower doses of urate lowering therapy. During an extension phase, we aim to offer 
individualised dietary advice based on a Food Frequency Questionnaire for those patients 
with 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.  

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
9 
 
2 
STUDY OBJECTIVES  
2.1 Objectives 
 
2.1.1 Primary Objective 
 
To assess supported self-management of gout using an application on a 
smart phone and self-testing of serum urate. 
2.1.2 
Secondary Objectives 
 
To measure gout flare frequency and health related quality of life. 
 
To assess treatment adherence measuring oxypurinol, the active metabolite 
of Allopurinol 
 
To evaluate the cost-effectiveness and safety of the approach by gathering 
data including hospital and GP visits and work absenteeism, and adverse 
events. 
 
Identification of uric acid load in faecal samples and correlation with gut 
microbiome characteristics. 
 
To assess feasibility of implementation, compliance and impact of dietary 
modification on serum urate levels. 
2.2 ENDPOINTS 
2.2.1 Primary Endpoint 
 
Proportion of participants achieving urate level≤ 0.30mml/L at 24 weeks.  
2.2.2 Secondary Endpoints (assessed at week 24 and 52, and for extension 
study also at week 104 and 156) 
 
Proportion of participants achieving urate level ≤0.3mmol/l and ≤0.36mmol/l 
 
Prospectively gathered number of days of self-reported gout flare over course 
of study 
 
Size in mm of the largest tophus at baseline (index tophus)  
 
The number of clinically evident tophi  
 
Prospectively gathered self-reported quality of life during/following gout flare 
evaluated using the EQ-5D-5L questionnaire over course of study 
 
Prospectively gathered data on days lost at work due to gout flare over 
course of study 
 
Prospectively gathered number of scheduled and unscheduled medical 
appointments/ hospital admissions due to gout over course of study 
 
Self report of number of doses of medication omitted in preceding 2 weeks 
will be collected at all study visits 
 
Plasma oxypurinol levels will be measured at study visits where possible 
 
Proportion of patients achieving a dose reduction of urate lowering therapy 
in the extension phase whilst maintaining target urate levels. 
 
Proportion of patients achieving sustained dietary modifications with 
reduction of urate levels, and/or further reduction of urate lowering therapy 
dose in the extension phase. 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
10 
 
3 
STUDY DESIGN 
3.1 Original study 
 
This is a feasibility study. A total of approximately 60 patients will be recruited from 
rheumatology clinics or rheumatology on-call services in NHS Lothian. Participants will be 
randomized to the intervention group in a 2:1 ratio. Based on baseline renal function and 
serum urate levels, and in line with local protocol, an individual treatment plan will be drawn 
up for all participants with the goal to achieve serum urate level of ≤0.30mm/L. A sample from 
a 24 hour urine collection and paired serum creatinine and urate sample from each participant 
will be analysed for urate metabolites. The treatment plan will be communicated to the patient 
and their general physician.  
 
All participants will have a smart phone application developed by IT specialists in the EPCC 
uploaded to their smart phones. Control participants will have a limited version of the 
GoutSMART application installed with background information about gout and providing a 
means for participants to enter details of gout flare frequency and quality of life through the 
trial. Subjects in the intervention group 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 
incorporating advice on urate monitoring and medication titration. Participants will be 
prompted to check their serum urate on two separate days and enter the results into the 
GoutSMART application. The application will respond by a) a suggestion to increase urate 
lowering therapy or b) to stay on the current dose of allopurinol. If the patient needs to 
increase allopurinol there will be an automatic reminder two weeks after any increased dose 
of urate lowering therapy prompting the patients to test their own urate levels on two separate 
days and submit updated readings 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 until 3 consecutive target 
readings have been obtained. 6 months is given until review reflecting current practice. 
 
The main outcome will be urate levels at week 24, with a secondary outcome being urate 
levels at week 52. Where participants are able to attend hospital then both serum and 
capillary urate will be obtained and the serum urate will be used as the study outcome, 
however we anticipate that a capillary urate only will be obtained in participants required to 
self-isolate or maintain social distancing during the coronavirus pandemic and this will be 
used to determine the urate level at week 24 and 52 for affected participants. To assess 
treatment compliance drug metabolite levels will be tested from serum samples obtained at 
week 24 and 52 visits where possible, and by self report in all participants. All patients will be 
assessed for tophi at baseline by clinical exam, and again at week 24 and 52. This will be by 
examination if participants are able to attend hospital, or by review of submitted images where 
attendance at hospital is not appropriate due to coronavirus restrictions. All participants will be 
asked once per month to record flares, measurements of quality of life, number of hospital 
and GP visits as well as days off work via the application. The study is designed for a total 
(post-randomization) duration of 52 weeks. Subjects who withdraw or disengage before the 
24 week visit will not be considered to have completed the study. 
 
For the gut microbial aspect of this study, eligible participants will fill in an online semi-
quantitative food frequency questionnaire (FFQ, Scottish Collaborative Group – see Zgaga et 
al, PLOSone 2012). Patients will also provide an early morning urine sample for urinary 
metabolomic analysis and a fresh faecal sample for subsequent faecal metabolomics and 
shotgun metagenomics. To provide suitable controls, patients will be asked whether they are 
happy that a family member be contacted to provide control samples for this analysis. In this 
case, first or secondary sex-matched controls without gout will be contacted by the study 
team for a once-off visit (Medical history, bloods – serum urate LFTs, renal function, FFQ and 
urine and stool samples). Patients can opt out of having a family member involved if they wish 
in which case local controls (age-similar and sex matched) will be recruited from the staff of 
the University of Edinburgh. 
 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
11 
 
 
Figure 1: Study Design
PI identifies patient diagnosed with gout 
and requiring escalation of ULT. 
Individual treatment plan agreed. 
Discusses study and provides PIL.
Patients invited to RDU for eligibility  assessment and consented to study. Baseline  blood 
tests for uric acid/oxypurinol levels and renal/liver function and finger prick test performed. 
Uric acid levels controlled
Not-eligible.
Randomise.  
24 week assessment in clinic. Blood samples taken for U&E, LFTs, urate, 
oxypurinol. Finger prick test performed. 
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
Control
Intervention
Uric acid levels not controlled. 
Eligible.
Letter to GP & 
patient 
Treatment plan continues as 
set out by PI. Restricted 
GoutSMART app installed on 
phone to record secondary 
study outcomes. Patients 
provided with further supply 
of medication
56 week assessment in clinic. Blood samples taken for U&E, LFTs, urate, 
oxypurinol. Finger prick test performed. . 
RDU clinicians identify patients with 
gout requiring escalation of ULT. 
Individual treatment plan agreed. PI/ SI 
discuss study via telephone and send 
PIL.
 
 
3.2 Extension phase 
 
Urate-lowering therapy requires a long term commitment from the patient and health care 
provider. We know that levels of medication adherence in gout are unusually low (Dehlin M, 
2017 and Briesacher BA, 2008). A recent randomised controlled trial comparing specially 
trained nurses leading care versus usual care in the UK, showed that with dedicated 
surveillance and monitoring, the use of urate lowering therapy is significantly higher at 1 and 2 
years in the nurse-led compared to the usual care group (Doherty M, 2018). The GoutSMART 
approach may provide an alternative means for patients to monitor their disease and increase  
awareness of the role and importance of long-term urate lowering therapy for disease control 
thereby increasing adherence. At the 12 month study visit all participants will be invited to 
participate in a 2 year extension to the study which will evaluate long term compliance with 
medication along with clinical outcomes. Additional participants will be invited to take part in 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
12 
 
this long term monitoring arm of the study and will be randomised 1:1 to active monitoring or 
routine care.  All participants taking part in this extension study will have their medication 
optimised using the GoutSMART approach to ensure that their urate level is at target of 
0.3mmol/l or less.   
 
For participants in the active care arm of the study ongoing monitoring of self-reported urate 
will be performed until participants meet criteria for disease remission. For the purposes of 
this study we will define disease remission to have been achieved if all three of the following 
outcomes have been achieved: 
 
1) Resolution of clinically evident tophi 
2) Urate levels at or below 0.3mmol/l over preceding 12 months (with minimum of 3 
separate readings obtained in different months. 
3) Resolution of gout flares (self-reported) for 12 months 
 
When remission has been achieved by these criteria then participants will be given the option 
to reduce their dose of allopurinol in line with current best practise guidelines which suggest 
that maintaining urate below 0.36 mmol/l is sufficient to maintain remission, and that long term 
urate levels should not be held below 0.18mmol/l.  
 
Participants that were assigned to usual care will have their care optimised using the 
GoutSMART approach until they have achieved a urate at or below the target of 0.3mmol/l, 
but in line with usual clinical practise will have no further titration of their medication or 
outpatient clinical review after this point. Outcomes will be reviewed at 12 months, 24 months, 
and 36 months as part of the extension study. 
 
In addition, all patients in the active care arm will be invited to participate in a dietary 
modification substudy during the extension phase. Those in whom aspects of dietary 
discordance with current BSR guidelines have been identified utilising the Food Frequency 
Questionnaire, will be offered an individualised plan of dietary modifications to be 
implemented over a period of time lasting up to three months. Regular measurements of urate 
levels and diet feedback will monitor progress. 
 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
13 
 
Figure 2: Study Design Extension Phase
Patients invited to participate in extension phase. 
Patient opts out.
52 week assessment in clinic (virtual). Blood samples taken for U&E, LFTs, urate, 
oxypurinol. Finger prick test performed. 
Control Group
Intervention Group
Discharge to GP with treatment 
plan and with or without routine 
rheumatology follow-up. 
All participants have 
allopurinol adjusted to target 
urate level using GoutSMART
app. Once target is achieved 
then. No ongoing monitoring 
offered. Study outcomes 
recorded at +52 and 
+104weeks. 
Consent taken.
Patient  does not 
meet
remission criteria
Offered to lower allopurinol
dose every two weeks until 
remission maintenance 
urate levels reached.
Patient opts in.
Patient  meets
remission criteria
Follows self (including flare)  
management with urate
readings and recording of 2⁰ 
outcomes. 
Study +52 and +104 week assessment 
Continues self-
management as per 
original study 
(including flare self-
management) or 
until remission 
criteria met .
Management plan formulated
(substudy participation offered)
All participants have close monitoring of 
urate levels to remission target using 
GoutSMART app.
 
 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
14 
 
3.3 COVID -19 
 
Any research activity continues to be effected by the current 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. In practice this will require 
adaptations in most activities. 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.  
4 
STUDY POPULATION 
4.1 NUMBER OF PARTICIPANTS 
We aim to recruit approximately 60 participants. Recruitment will remain open until sufficient 
numbers of recruited participants has been reached. Additional participants satisfying the 
same inclusion and exclusion criteria (but without any urate threshold requirement) will be 
recruited into the extension study to ensure sufficient power is maintained ). An equal number 
of control participants will be recruited for the purposes of the gut microbiota analysis. 
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. 
 
Confirmed clinical diagnosis of gout as per ACR/EULAR criteria (Neogi T, 2015). 
 
Physician recommendation that initiation or escalation of urate lowering therapy 
(Allopurinol or Febuxostat) is required guided by further monitoring of serum urate 
levels. 
 
No previous adverse reaction to Allopurinol or Febuxostat. 
 
Serum urate >0.36mm/L. 
 
Patient has a smart phone and is able to use application. 
 
For the gut microbiota part of this study control participants must be: 
 
Adult male or female aged ≥18 years. 
 
Evidence of a personally signed and dated informed consent document indicating that 
the subject (or a legally acceptable representative) has been informed of all aspects 
of the study. 
For the extension study 
 
Patient has completed week 52 of original study 
 
Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all aspects of the extension study. 
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 where therapy cannot be escalated 
further 
 
Severe renal failure (eGFR <30) or established liver disease 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
15 
 
 
Current prescription of medication known to interact with xanthine oxidase inhibitors 
such as azathioprine or mercapto-purine. 
For the gut microbiota part of this study - subjects are excluded from the control group if 
any of the previous or following are present: 
 
Have a history of gout 
 
Taking urate lowering therapy 
 
Have a history of inflammatory bowel disease or colorectal cancer 
 
Have had oral antibiotics in the previous 3 months 
 
Have had a total colectomy previously 
 
Have suffered an infective gastro-intestinal illness in the previous 6 weeks. 
 
No face to face visits or samples will be arranged for participants that have ever 
tested positive for, or had symptoms suggestive of, COVID-19  
4.4 CO-ENROLMENT 
Co-enrolment will not be allowed in any circumstances. 
 
5 
PARTICIPANT SELECTION AND ENROLMENT 
5.1 IDENTIFYING PARTICIPANTS 
Participants will be identified by the principal investigator or the sub-investigator following 
assessment by the NHS Lothian Rheumatology service. It is anticipated that most participants 
will be identified following routine and acute-care referrals to NHS Lothian Rheumatology 
services by the participants’ general practitioner or secondary care physicians, however any 
appropriate referral will be considered including referrals from out with NHS Lothian. 
Additional participants will be sought through SHARE - The Scottish Health Research 
Register which is a register of adults and children aged 11 and over who are willing to be 
invited to take part in medical research. 
Posters raising awareness of the study will be placed in the rheumatology outpatient 
department, and in Acute receiving units at Western General Hospital and Royal Infirmary of 
Edinburgh. An email will be sent to General Practitioners in NHS Lothian inviting referral of 
suitable patients to the rheumatology service. 
In the case of control participants for the microbiota analysis, patients can opt in or out of 
having a family member as a control participant. If the patient agrees, he/she will be asked to 
pass the Patient Information Leaflet (PIL – control version) to their relative who will be invited 
to contact the study team if they are interested in participation. Family members can be first 
degree or second degree relatives of the same sex. In the event that no family member is 
suitable or willing to be involved then an age-similar, sex-matched control may be recruited 
from the staff of the University of Edinburgh, the  Western General Hospital or SHARE.  
 
Study participants in both the GoutSMART, as well as the microbiome part of the project who 
fail screening will be considered for re-screening within one month of initial screening. 
Subjects of the microbiome control group will be considered for re-screening up to 3 months 
from initial screening. 
 
All patients of the GoutSMART active and control arm completing the study at week 52 will be 
invited to participate in the extension study.  
 
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 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
16 
 
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. A copy of the signed Informed Consent will be 
given to the participants. The original signed form will be retained at the study site.  
 
Patients invited to participate in the extension  phase of the study will be provided with written 
information about the extension via email or in the post with at least 48 hrs time to read the 
information pior to there week 52 review. Consent will be obtained either during the face to 
face visit. To minimise COVID-19 exposure, consent may be obtained following a telephone 
review. The participant may sign the PIL at home and email or post this back to the 
researcher.     
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 Baseline visit 
Written and informed consent will be obtained. A history will be taken, basic anthropometric 
measurements taken (blood pressure, weight, waist circumference) and physical examination 
be performed. Full medication history will be obtained from participants. Blood samples will be 
taken for measurement of urate, full blood count, renal and liver function and oxypurinol 
levels. A finger prick testing for urate levels will be carried out. Participants will be asked to 
collect urine over a period of 24hrs to hand into the lab as soon as feasible after the baseline 
visit. A blood sample for creatinine and urate will be taken at that point for paired analysis with 
urine.  Eligible subjects will be randomised at a 1:2 ratio to usual care or supported self-
management using a web-based randomisation tool. 
 
For the purposes of the microbiome analysis, patients will provide a once off stool and urine 
sample at baseline in addition to filling an online food frequency questionnaire. For control 
subjects for the microbiome analysis, participants will attend on one occasion to provide 
written informed consent, medical history review, FFQ, blood samples for urate, renal and 
liver function and oxypurinol levels. In addition they will provide an early morning urine sample 
and a fresh faecal sample. They will also be asked to collect urine over the 24hour period and 
a paired serum renal function and urate blood sample will be taken when handing the 
collection in. No further follow-up visits are planned. 
 
No payment shall be made for participation in the study but compensation for costs of travel 
to the Western General Hospital shall be offered to control participants up to a value of £30 
 
6.1.2 Intervention procedures 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
17 
 
Based on the baseline renal function and serum urate levels, and in line with local protocols, 
an individual treatment plan will be drawn up for all participants in both groups. This includes 
a management plan for a potential episode of gout-flare and offering of flare prophylaxis. The 
treatment plan will be sent to the general practitioner and the patient copied in. All participants 
will be examined at baseline and the number and size of tophi (if present) will be recorded. 
All participants will have the GoutSMART application installed on their phones, and be taught 
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 importance of controlling serum urate levels. All 
participants will be prompted once per month to enter information about their disease severity 
including the number of days of flare per month, health related quality of life during and after 
flares, number of days lost at work and the number of health care appointments attended. 
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 (including that of the plan set during baseline clinic consultation) to test their own 
urate levels and submit updated readings. If urate levels remain above target, written advice 
to increase the dose of urate lowering will be sent to the patient and supervising physician 
advising up-titration of therapy, with this confirmed also by text message. 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 sent on a monthly basis until three consecutive target readings have been 
obtained. Six months are allowed to ensure that all participants have the opportunity to 
escalate to maximum therapy and potentially switch to alterative urate lowering therapy if 
required. 
6.1.3 End-of study visit week 24 
Participants will be invited to the RDU clinic, or alternatively if hospital attendance is not 
appropriate due to recommendations to self-isolate or maintain social distancing due to the 
coronavirus pandemic then this assessment will be made by telephone. The patient diaries 
generated by the GoutSMART application will be reviewed and any adverse advents 
recorded. Participants will complete a questionnaire on their experience with standard care or 
the testing device and the smart phone application. All participants will be asked to record the 
number of doses of medication missed in the preceding 2 weeks. A physical examination will 
be performed to assess the size and number of tophi, or submitted images will be reviewed 
Finger prick and/or serum urate will be measured along with blood tests of full blood count, 
renal and liver function tests and oxypurinol levels. A letter will be written to the GP of all 
participants summarising the disease course and management throughout the past 24 weeks 
and proposing further management advice. All participants will retain access to the smart 
phone application and be asked to enter information about the disease course on a monthly 
basis until week 52. 
6.1.4 Follow-up visit week 52 (and for extension study week 104 and 156) 
Participants will be invited to the RDU clinic for review of secondary outcomes, or alternatively 
if hospital attendance is not appropriate due to recommendations to self-isolate or maintain 
social distancing due to the coronavirus pandemic then this assessment will be made by 
telephone. The patient diaries generated by the GoutSMART application will be reviewed and 
any adverse advents recorded. All participants will be asked to record the number of doses of 
medication missed in the preceding 2 weeks. A physical examination will be performed to 
assess the size and number of tophi or submitted images will be reviewed. Finger prick and/or 
serum urate will be measured along with blood tests of renal and liver function tests and 
oxypurinol levels. 
 
All participants completing the study at week 52 will be offered participation of the extension 
phase of the study. Written information will have been provided prior to their week 52 review 
about the extension. Consent will be gained from those choosing to participate in the 
extension phase. A treatment plan will be formulated for all participants. Participants of the 
intervention arm in remission will be offered to reduce the dose of their urate lowering 
medication and self-reassess every two weeks (update urate levels, entering disease activity 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
18 
 
data) until remission maintenance is achieved. Feedback will be provided in the usual 
GoutSMART application manner. Participants of the control arm will continue as per routine 
care. Once remission maintence is achieved monthly urate reading will be requested. The 
participant will be asked to enter additional urate readings and QoL information during flares. 
 
For those opting into the dietary lifestyle intervention arm, a personal management plan with 
dietary adjustments where appropriate will be formulated based on the Food Frequency 
Questionnaire which each participant will fill in at baseline. Participants will be asked to 
perform weekly urate measurements, weight measurements and report on flares via the app. 
Feedback will be provided by the research team at least weekly for the first 4 weeks, then 
monthly for three months. Participants will be asked to fill in the Food Frequency 
Questionnaire at extension baseline, monthly for three months and at the end of study. 
 
A letter will be written to the GP of all participants summarising the disease course and 
management and proposing further management advice including the information of 
continued participation in trial if agreed. Participants opting out of participation of the 
extension phase who have achieved target levels of serum urate will be discharged back to 
care by their primary care physician. Participants who have not yet achieved control of their 
serum urate by week 52 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 and physical examination will be carried out at the specified time points. 
This includes basic anthropometrics weight, height, waist circumference and blood pressure. 
We will be recording the presence of tophi and take measurements of the largest tophus. 
Details of the duration of disease, frequency and pattern of flares will be recorded. 
6.2.2 Laboratory assessments 
Serum FBC, U&Es, LFTs, urate and oxypurinol levels will be collected by venepuncture. 
6.2.3 App assessments 
The smart phone application will collect the following data monthly over the 52 weeks of the 
study 
 
Number of days of self-reported gout flare 
 
Self-reported quality of life during/following gout flare evaluated using the EQ-
5D-5L questionnaire  
 
Number of days lost at work due to gout flare 
 
Number of scheduled and unscheduled medical appointments/ hospital 
admissions due to gout 
6.2.4 Questionnaires 
We will use the EQ-5D® standardized instruments EQ-5D-5L to evaluate health outcomes. 
Study specific questionnaires will be completed at week 24, week 52, week 104, and week 
156 visits. 
Participants will fill an online version of the Scottish Collaborative Group food frequency 
questionnaire (FFQ) – see Zgaga et al, PLOSone 2012. This comprises a semi-quantitative 
measure of approximately 150 commonly consumed food items. The questionnaire will also 
be used for the extension substudy at week 52 and week 3 months and end of study for the 
extension phase. Participants of the substudy will also fill in a short dietary compliance report.  
6.2.5 Biomarker analysis 
Participants will be asked to provide an additional sample of about 50ml of venous blood at 
the baseline visit. In most cases the blood sample will be taken on this single occasion only, 
but selected participants who have previously consented may be approached and asked to 
provide an additional blood sample if there is a technical problem with processing the original 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
19 
 
sample. The sample will be used for DNA extraction and serum will be separated and stored 
for biochemical analysis. Analysis of candidate genes thought to be involved in the 
pathogenesis and response to treatment of gout will be performed using standard 
methodology. The genes to be studied will include variants identified in the analysis of the 
Febuxostat versus Allopurinol Streamlined Trial (FAST study) that are found to be associated 
with response to treatment with urate lowering therapy. 
6.2.6 
Urinary metabolomics 
Fresh urinary samples will be provided in a standard universal container. Samples will be the 
first void on the morning that the sample is provided.  
6.2.7 
Faecal samples 
Fresh and formed faecal samples will be provided by participants ideally on the day of 
measurement. Participants will be provided with instructions and equipment to safely and 
effectively collect and deliver the sample to the research staff. 
 
6.3 STORAGE AND ANALYSIS OF SAMPLES 
Routine serum biochemistry samples for U&Es, LFTS, urate and oxypurinol will be analysed 
and stored by local NHS Lothian laboratories. Samples will be discarded as per local 
protocols. 
For biomarker analysis, DNA extraction will be performed in the research laboratories at the 
Centre for Genomics and Experimental Medicine, at the Institute of Genetics & Molecular 
Medicine according to standard procedures. The DNA samples will be stored frozen in these 
facilities or in another suitable storage facility. It is anticipated that the samples and 
associated clinical information will be stored indefinitely to allow replication of future genetic 
studies identifying variants involved in the pathogenesis and response to treatment of gout. 
For urinary metabolomic analysis, urinary samples will be centrifuged and aliquoted into 2mls 
containers. These will be stored at -80 degrees Celsius at the research laboratories of the 
Centre for Genomics and Experimental Medicine, at the Institute of Genetics & Molecular 
Medicine. 
Formed stool samples will also be delivered by study staff to the research laboratories of the 
Centre for Genomics and Experimental Medicine, at the Institute of Genetics & Molecular 
Medicine. Here, DNA extraction will be performed on arrival according to a standardized 
protocol and samples will be aliquoted before being frozen at -80 degrees Celsius. Urinary 
samples will subsequently be analysed en masse to quantify levels of metabolites related to 
purine and uric acid metabolism. Likewise, faecal water will be used to quantify levels of 
metabolites related to purine and uric acid metabolism. DNA extracted from faecal samples 
will also be used to characterise the gut microbiome using shotgun metagenomic sequencing.  
7 
DATA COLLECTION 
Data will be collected at baseline, week 24 and 52 visits as well as via the smart phone 
application on a monthly basis. Data will be collected by the principal investigator and the 
sub-investigators. We will use the EQ-5D® standardized instruments EQ-5D-5L 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. 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
20 
 
7.2 Case Report Forms 
A paper case report form will be generated for each patient and kept 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 is a feasibility study which is intended to establish whether the proposed self-
management approach can be realised in practice, and if so to inform the design of a larger 
study that would look to establish the cost-effectiveness of this approach.  
The numbers chosen are based on previous audits in primary care performed which revealed 
that only 24% of gout patients reached a target of 0.30mmol/l of serum urate when receiving 
standard care by GPs who were given an algorithm for management of gout beforehand. We 
have assumed that about 25% of patients assigned to routine care will achieve the target of 
0.3mmol/l in the control group. We are anticipating that we will achieve target levels of urate 
in 75% of patients in the intervention group which though ambitious is still well below the 92% 
achieved in a recent UK study (Rees, F. 2013). Based on these estimates a sample size of 
n=34 in the intervention group and n=17 in the control group (2:1 randomisation) provides 
82% power to detect an effect of 25% in the control group and 75% in the intervention group 
(assuming a two-sided 5% significance level), after taking into account a 15% drop-out rate.  
For the extension study we have assumed that 90% of participants in the Smart care arm of 
the study remain adherent to therapy, compared with only 50% in the usual care arm. These 
figures are conservative compared to 95% compliance reported in Doherty et al (2018) and 
36.8% medicine possession ratio reported in Briesacher et al (2008). A sample size of 20 in 
each allocation yields 81% power, and 30 in each treatment allocation 94% power to detect 
such a difference. Due to observed drop outs from the feasibility study and restrictions in 
recruiting participants during the COVID pandemic we will recruit additional participants into 
the extension phase of the study to ensure sufficient power is achieved. 
8.2 PROPOSED ANALYSES 
The primary outcomes of the study will be the proportion of participants achieving urate level 
≤0.3mmol/l at 24 weeks in participants receiving supported self-management compared to 
those receiving usual care. Comparison of proportions will be performed 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).The 
proportion of participants achieving serum urate level ≤0.3mmol/l at all subsequent 
assessments will be analysed in the same fashion. Patients with undetectable levels of 
oxypurinol will be deemed to be non-compliant and a similar analysis will compare the 
proportion of participants in each treatment allocation that are non-compliant. 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. 
 
Continuous outcome measures include the size in mm of the largest tophus at baseline (index 
tophus) measured at 52 weeks, and the number of clinically evident tophi evaluated at 52 
weeks. Further continuous outcomes include the number of days lost at work due to gout 
flare, number of scheduled and unscheduled medical appointments/ hospital admissions, self 
report of number of doses of medication omitted in 2 weeks prior to study visits at week 24 
and 52. Two-tailed independent student t-tests will be applied for between group comparisons 
of normally distributed data. Results will be 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). Although a nominal value of 
significance of p<0.05 for these exploratory measures will be adopted, given the number of 
secondary outcomes listed a Bonferroni correction will be applied and reported alongside 
each result. 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
21 
 
Although health reported quality of life data will be gathered this is exploratory data that will 
not be analysed directly but be used to inform the design of a larger health economic study. 
Statistical analysis will be performed using Minitab version 16 (Minitab Inc., Pennsylvania, 
US) or the Statistical Package for Social Services version 19 (SPSS IBM Corp, NY State, 
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). 
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. 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
22 
 
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, 
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.  

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
23 
 
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 of3 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.   
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. 
 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
24 
 
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 feasibility study will be published in their own right, 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). The immediate goal of the study 
however, is to inform the design of a fully powered randomised controlled study into the utility 
of this approach. If this study should in turn 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 
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 
Briesacher, B.A. et al. (2008) Comparison of drug adherence rates among patients with seven 
different medical conditions. Pharmacotherapy. 28:437-43. 
 
Dehlin, M. et al. (2017) Factors associated with initiation and persistence of urate-lowering 
therapy. Arthritis Res Ther. 19:6.  
 

Gout SMART 
 
 
   Protocol v7.0 25.02.21 
NCT 03274063 
25 
 
Doherty, M. et al. (2018) Efficacy and cost-effectiveness of nurse-led care involving 
education and engagement of patients and a treat-to-target urate-lowering strategy versus 
usual care for gout: a randomised controlled trial. Lancet 2018; 392: 1403–12 
 
Guo Z, et al. (2016). Intestinal Microbiota Distinguish Gout Patients from Healthy Humans. 
Sci Rep. 2016 Feb 8;6:20602 
 
Hui, M, et al. (2017). The British Society for Rheumatology Guideline for the Management of 
Gout. Rheumatology. 56:e1 –e20. 
 
Khanna D, F. J. (2012). American College of Rheumatology Guidelines for Management of 
Gout. Part 1: Systematic Nonpharmacologic and Pharmacologic Therapeutic Approaches to 
Hyperuricaemia. Arthritis Care & Research , 1431-46. 
Khanna D, F. J. (2012). American College of Rheumatology Guidelines for Management of 
Gout. Part 2: Therapy and Anti-inflammatory Prophylaxis of Acute Gout Arthritis. Arthritis 
Care & Research , 1447-61. 
Paraskos J, B. Z. (2016). An analytical comparison between point-of-care uric acid testing 
meters. Expert Rev Mol Diagn , 16(3):373-82. 
Rees, F. (2013). Patients with gout adhere to curative treatment if informed appropriately: 
proof-of-concept observational study. Ann.Rheum.Dis., 72(6), 826-830. 
Zgaga L, Theodoratou E, Kyle J, Farrington SM, Agakov F, et al. (2012) The Association of 
Dietary Intake of Purine-Rich Vegetables, Sugar-Sweetened Beverages and Dairy with Plasma 
Urate, in a Cross-Sectional Study. PLoS ONE 7(6): e38123.