Effectiveness and Feasibility of a Mobile Health Self-management Intervention for Patients With Rheumatoid Arthritis: the App-based Education and GOal-setting in Rheumatoid Arthritis Trial
Phase: NA
Conditions: Rheumatoid Arthritis
Sponsor: Universitaire Ziekenhuizen KU Leuven

 
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Protocol version 6.3dd 03-11-2022 
 
 
 
 
The usefulness of an educational and 
goal-setting mobile app for 
improving self-efficacy and lifestyle 
factors in patients with rheumatoid 
arthritis. 
PROTOCOL FOR A RANDOMIZED CONTROLLED TRIAL (NO IMP) 
NCT05888181 

 
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Protocol version v6.3 dd 03/11/2022   
 
 
Protocol Acronym/short title: AEGORA: App-based Education and 
Goal-setting in Rheumatoid Arthritis. 
 
 
Version and date of final protocol: v6.3 (03-11-2022) 
 
 
Sponsor: 
 
Name: University Hospitals Leuven (UZ Leuven) 
Address: Herestraat 49, 3000 Leuven 
 
Principal Investigator: 
 
Name: prof. dr. Patrick Verschueren 
Address: Herestraat 49, 3000 Leuven, Belgium 
Telephone: 003216342541 
Fax: 003216342543 
Email: patrick.verschueren@uzleuven.be 
 
 
Sub-investigators: 
 
Name: dr. Cedric Lefevre 
Address: Sint-Lucaslaan 29, 8310 Brugge, Belgium - Herestraat 49, 3000 Leuven, Belgium 
Telephone: 003250365030 - 003216342541 
Fax: 003250365033 - 003216342543 
Email: cedric.lefevre@stlucas.be - cedric.lefevre@uzleuven.be 
 
Name: dr. Michaël Doumen 
Address: Herestraat 49, 3000 Leuven, Belgium 
Telephone: 003216342541 
Fax: 003216342543 
Email: michael.doumen@kuleuven.be 
 
Name: dr. Mieke Devinck 
Address: Sint-Lucaslaan 29, 8310 Brugge, Belgium 
Telephone: 003250365030 
Fax: 003250365033 
Email: mieke.devinck@stlucas.be 
 

 
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Protocol version v6.3 dd 03/11/2022   
 
Confidentiality Statement 
The information in this document is strictly confidential and is available for review to Investigators, 
potential Investigators and appropriate Ethics Committees, Institutional Review Boards or Competent 
Authorities.  No disclosure should take place without written authorization from the Sponsor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Protocol version v6.3 dd 03/11/2022   
 
LIST OF PARTICIPATING SITES 
(as applicable) 
List of Participating Sites 
Principal Investigators 
UZ Leuven 
Prof. Dr. Patrick Verschueren 
Dr. Michaël Doumen 
Dr. Cedric Lefevre 
AZ Sint-Lucas Brugge  
Dr. Mieke Devinck                       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Protocol version v6.3 dd 03/11/2022   
 
SIGNATURES 
 
Protocol title:  The usefulness of an educational and goal-setting mobile app for improving self-
efficacy and lifestyle factors in patients with rheumatoid arthritis. 
The undersigned confirm that the above referenced protocol has been acknowledged and accepted, 
and agree to conduct the Trial in compliance with the approved protocol, and will adhere to: the 
principles outlined in the requirements for the conduct of clinical trials in the EU as provided for in 
Directive 2001/20/EC and any subsequent amendments thereto, the ICH guidelines, the most recent 
version of the Declaration of Helsinki,  the Belgian law of May 7th 2004 regarding experiments on the 
human person (as amended) or the Belgian law of May 7th 2017 related to clinical trials on medicinal 
products for human use (as soon as in effect), the EU General Data Protection Regulation 2016/679 
(GDPR), relevant Belgian laws implementing the GDPR, the Belgian Law of August 22nd 2002 on patient 
rights, and any other regulatory requirements and Standard Operating Procedures (SOPs), as 
applicable. 
The undersigned agree not to disclose the confidential information contained in this document for any 
purpose other than the evaluation or conduct of the Trial, without prior written consent of the 
Sponsor. 
The undersigned also commit to making the findings of the Trial publicly available through publication 
and/or other dissemination tools, in accordance with this protocol and applicable regulations, without 
any unnecessary delay and to provide an honest, accurate and transparent account of the Trial; and to 
explain any discrepancies or deviations from the approved Trial protocol.  
 
Coordinating Investigator 
 
………………………… 
………………………… 
………………………… 
Prof Dr Patrick Verschueren 
Signature 
Date 
 
Principal Investigator (Participating Site) (in case of monocentric Trial, the Principal Investigator is the 
same as the Coordinating Investigator) 
 
………………………… 
………………………… 
………………………… 
………………………… 
………………………… 
………………………… 
 
Name & Title 
Signature 
Date 
 

 
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Protocol version v6.3 dd 03/11/2022   
 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
PI 
Principal Investigator (Participating Site) 
CI 
Coordinating Investigator (Participating Site) 
EC 
Ethics Committee 
ICH 
International Conference on Harmonisation 
GCP 
Good Clinical Practice (latest version of ICH E6) 
PRO 
Patient-Reported Outcome 
RAID 
Rheumatoid Arthritis Impact of Disease 
PCS 
Pain Catastrophizing Scale 
IPAQ-S 
International Physical Activity Questionnaire short form 
PSQI 
Pittsburgh Sleep Quality Index 
DAS28-CRP 
Disease Activity Score with 28 joints, using C-reactive protein 
SDAI 
Simple Disease Activity Index 
RA 
Rheumatoid Arthritis 
T2T 
Treat to target 
DMARD 
Disease-modifying antirheumatic drug 
EULAR 
European League Against Rheumatism 
WHO 
World Health Organization 
(e)CRF 
(electronic) Case Report Form 
AE 
Adverse Event 
GDPR 
General Data Protection Regulation 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
REDCap 
Research Electronic Data Capture 
ITT 
Intention-to-treat 
PP 
 
 
 
 
 
 
 
Per-protocol 

 
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Protocol version v6.3 dd 03/11/2022   
 
Table of contents 
LIST OF PARTICIPATING SITES .................................................................................................................. 4 
SIGNATURES ............................................................................................................................................. 5 
LIST OF ABBREVIATIONS........................................................................................................................... 6 
1. 
Funding and Support ........................................................................................................................ 9 
2. 
Study Synopsis ................................................................................................................................ 10 
3. 
Background and rationale .............................................................................................................. 17 
4. 
Trial objectives and Design ............................................................................................................ 18 
4.1 Trial objectives ......................................................................................................................... 18 
Primary objective ........................................................................................................................... 18 
4.2 Primary endpoints .................................................................................................................... 19 
4.3 Secondary endpoints................................................................................................................ 19 
4.3b Exploratory endpoints ............................................................................................................ 19 
4.4 Trial Design ............................................................................................................................... 20 
4.5 Study diagram .......................................................................................................................... 22 
4.6 Trial Flowchart.......................................................................................................................... 22 
5. 
Selection and withdrawal of subjects ............................................................................................ 23 
5.1 Inclusion criteria ....................................................................................................................... 23 
5.2 Exclusion criteria ...................................................................................................................... 24 
5.3 Expected duration of trial ........................................................................................................ 24 
6. 
Trial Procedures ............................................................................................................................. 24 
6.1 By visit ...................................................................................................................................... 24 
6.2 Laboratory tests ....................................................................................................................... 26 
6.3 Other investigations ................................................................................................................. 26 
7. 
Assessment of efficacy ................................................................................................................... 26 
8. 
Assessment of Safety ..................................................................................................................... 27 
8.1 Specification, timing and recording of safety parameters....................................................... 27 
8.2 Procedures for recording and reporting adverse events (AE) ................................................. 27 
8.3 Treatment stopping rules ......................................................................................................... 27 
9. 
Statistics ......................................................................................................................................... 27 

 
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9.1 Sample size ............................................................................................................................... 27 
9.2 Analysis ..................................................................................................................................... 28 
10. 
Quality assurance ....................................................................................................................... 30 
11. 
Direct access to source data and documents ............................................................................ 31 
12. 
Ethics and regulatory approvals ................................................................................................. 31 
13. 
Data Handling ............................................................................................................................. 32 
14. 
Data Management ..................................................................................................................... 34 
15. 
Translational research ................................................................................................................ 35 
16. 
Publication Policy ....................................................................................................................... 35 
17. 
Insurance/Indemnity .................................................................................................................. 35 
18. 
References .................................................................................................................................. 35 
19. 
Amendment history ................................................................................................................... 39 
 
 
 

 
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Protocol version v6.3 dd 03/11/2022   
 
1. Funding and Support 
Funder 
Type of Financial or Non-Financial Support 
Fonds Wetenschappelijk 
Onderzoek (FWO) 
Co-investigator Michaël Doumen has received a Strategic Basic 
Research grant (grant number 1S85521N) from FWO. Funds 
from this grant will be used in part to support this trial.  
 
 
Support in Kind 
A total of 250 licenses for the unrestricted use of the mobile application Sidekick Health (Iceland) will 
be provided by Pfizer to the research team, to distribute among study participants. These licenses are 
being made available free of charge, and Pfizer’s company name or logo will not be represented in any 
shape or form on information leaflets, study materials or in the interface of the Sidekick Health 
application. Sidekick Health will also make the in-app user data available, considering current GDPR 
rules, only for scientific purposes, without commercial purposes of any kind. 
Role of study sponsor 
University Hospitals Leuven, shall act as sponsor of the Study, as defined in the Law of 2004, and shall 
assume all responsibilities and liabilities in connection therewith and procure the mandatory liability 
insurance coverage in accordance with the Law of 2004. University Hospitals Leuven shall ensure that 
it shall be mentioned in the Protocol, the Informed Consent Forms and in other relevant 
communication with the Study Subjects or the Regulatory Authorities as sponsor of the Study. 
Roles and responsibilities 
The Principal Investigator (PI) is responsible for the conduct of the Trial at his/her Participating Site, 
and for protecting the rights, safety, and well-being of the Trial participants. As such the PI must 
ensure adequate supervision of the Trial conduct at the Participating Site. If any tasks are delegated, 
the PI will maintain a log of appropriately qualified persons to whom he/she has delegated specified 
Trial-related duties. The PI will ensure that adequate training is provided and documented for all Trial 
staff, prior to conducting assigned Trial-related activities.  
It is the Coordinating investigator's (CI’s) responsibility to supervise the general conduct (e.g. Trial 
progress, communication, protocol training and support of the participating sites, annual reporting to 
the Ethics Committee (EC), end of Trial notification(s) and results reporting…) of the Trial. The CI 
fulfils both Investigator and Sponsor responsibilities, as outlined in International Conference on 
Harmonisation – Good Clinical Practice (ICH-GCP) E6(R2) and applicable regulations. 
PI and CI shall each be referred to as «Investigator(s)». 
 
 
 
 

 
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Protocol version v6.3 dd 03/11/2022   
 
2. Study Synopsis  
 
Title of clinical trial 
 
 
The usefulness of an educational and goal-setting 
mobile app for improving self-efficacy and lifestyle 
factors in patients with rheumatoid arthritis. 
Protocol Short Title/Acronym 
 
AEGORA: App-based Education and Goal-setting in 
Rheumatoid Arthritis. 
Sponsor name 
 
University Hospitals Leuven 
Coordinating Investigator 
 
Prof. Dr. Patrick Verschueren 
Medical condition or disease under 
investigation 
 
Rheumatoid arthritis (RA) 
Purpose of clinical trial 
 
To study the usefulness of a mobile application, 
developed through principles of goal-setting and 
gamification, to remotely monitor patient-reported 
outcomes (PROs) and deliver disease-specific patient 
education and lifestyle advice. Specifically, we aim to 
study the effects of this app-based intervention on self-
efficacy, pain catastrophizing, physical activity, and sleep 
quality in patients with RA. To test the usefulness of 
monitoring PROs, participants in the intervention group 
will be asked to complete the Rheumatoid Arthritis 
Impact of Disease (RAID) questionnaire electronically in 
the app, either on a weekly or a monthly basis.  
Primary objective 
 
To investigate whether disease-specific patient 
education, promotion of a healthy lifestyle and remote 
PRO-monitoring, delivered through a mobile application 
based on principles of goal-setting and gamification, can 
improve self-efficacy in patients with RA. Self-efficacy will 
be assessed with the Arthritis Self-Efficacy Scale (ASES).  
Secondary and exploratory objective (s) 
 
Secondary objectives 
- To study if this app-based intervention affects pain 
catastrophizing (either positively or negatively), assessed 
with the Pain Catastrophizing Scale (PCS). Pain 

 
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catastrophizing can be defined as an overly negative 
cognitive-affective orientation toward pain.  
 
Exploratory objectives 
- To study if the intervention’s effects on self-efficacy and 
pain catastrophizing are affected by the interval at which 
participants are asked to report PROs (the RAID 
questionnaire either once per week or once per month). 
 
- To study if this app-based intervention leads to changes 
in physical activity or sleep quality, assessed with the 
International Physical Activity Questionnaire short form 
(IPAQ-S) and Pittsburgh Sleep Quality Index (PSQI), 
respectively. 
 
- To study the feasibility of delivering this intervention 
through a mobile application, by assessing participants’ 
engagement with the app through the proportion of 
completed RAID-questionnaires and user-behavior 
statistics, including the proportion of days with logged 
activities in the app. No incentives for app-use will be 
provided, except those needed in the trial as built-in in 
the app (standard push-messages of the app), in order to 
provide a representative picture of participants’ intrinsic 
and continued motivation. 
 
- To identify baseline predictors of the intervention’s 
effect on ASES, PCS, IPAQ-S and PSQI scores. 
 
- To describe the evolution over time of scores on the 
RAID-questionnaire completed in the app, and its 
association with self-efficacy, physical activity, sleep 
quality, and disease activity assessed at the study visit. 
 
- To describe the evolution of the data that were actively 
logged by participants relating to their diet, physical 
activity, stress (such as minutes spent completing 
relaxation exercises in the application), and sleep, and 
study their association with (changes in) disease activity, 
the RAID, ASES, IPAQ-S, and PSQI.  

 
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Protocol version v6.3 dd 03/11/2022   
 
Study population 
 
Patients diagnosed with rheumatoid arthritis aged 18 
years or older, with a disease duration of 16 weeks or 
more, no exclusions based on sex or therapy. 
Patients will be randomized (1:1) to one of the following 
groups: 
- 
Control group: standard of care (including 
referral to allied health professionals for 
additional education/non-pharmacological 
support as needed), educational leaflet, 
completion of the RAID questionnaire at baseline 
and last study visit. No access to the Sidekick 
Health app, and no completion of the RAID 
questionnaire in between study visits.  
- 
Intervention group: standard of care (including 
referral to allied health professionals for 
additional education/non-pharmacological 
support as needed), educational leaflet and 
access to the Sidekick Health app, including 
completion of the RAID questionnaire via the app 
in between study visits.  
Participants who are randomized to the intervention 
group will be re-randomized in a 1:1-ratio to one of the 
following arms: 
- 
Intervention arm A: intervention with the 
Sidekick Health app as described above, and 
participants will be asked to complete a RAID 
questionnaire in-app once a week.  
- 
Intervention arm B: intervention with the 
Sidekick Health app as described above, and 
participants will be asked to complete a RAID 
questionnaire in-app once a month.  
Trial Design 
 
Investigator-initiated, open-label, parallel-group, 
multicenter randomized controlled trial (without IMP).  
Endpoints 
 
Primary endpoint 
Difference in mean change of total ASES (Arthritis Self-
Efficacy Scale) score from baseline to week 16 ± 2w in the 

 
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intervention group when compared to the control group. 
The ASES is a patient-reported questionnaire consisting 
of 20 items to measure one’s arthritis-specific self-
efficacy across 2 subscales: self-efficacy for managing 
pain (PSE, range 5-50), and self-efficacy for controlling 
other symptoms (OSE, range 6-60). Both scores can be 
summed to derive a total ASES-score (range 11-110).  
Secondary endpoints 
- Difference in mean change of total PCS (Pain 
Catastrophizing Scale) score from baseline to week 16 ± 
2w in the intervention group when compared to the 
control group. The PCS is a patient-reported 
questionnaire with 13 items scored on a 0-4 Likert scale, 
resulting in a total score of 0-52 with sub scores for 
rumination, magnification, and helplessness. Higher 
scores indicate more catastrophic perceptions concerning 
pain.  
Exploratory endpoints 
- Difference in mean change of total ASES score from 
baseline to week 16 ± 2w in the intervention arm with 
weekly RAID questionnaires when compared to the 
intervention arm with monthly RAID questionnaires. 
- Difference in mean change of total PCS score from 
baseline to week 16 ± 2w in the intervention arm with 
weekly RAID questionnaires when compared to the 
intervention arm with monthly RAID questionnaires. 
- Difference in mean change of total IPAQ-S score from 
baseline to week 16 ± 2w in the intervention group when 
compared to the control group. The IPAQ short form is a 
7-item questionnaire enquiring about physical activities 
during the last 7 days. A specific activity score is obtained 
for different domains, each being multiplied with the 
accompanying mean metabolic equivalent (MET) value. 
This leads to a total score corresponding with low, 
moderate, or high physical activity. 
 
- Difference in mean change of total PSQI score from 

 
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baseline to week 16 ± 2w in the intervention group when 
compared to the control group. The PSQI is a patient-
reported questionnaire developed to measure sleep 
quality through 19 items across 7 domains. The resulting 
total score ranges from 0-21, with scores of 5 or higher 
being defined as poor sleep quality.     
- To describe participants’ continued engagement with 
the app and to compare it between the weekly and 
monthly PRO subgroups. Engagement will be defined as:  
* The proportion of RAID questionnaires with at least one 
completed item in the Sidekick app, compared to the 
total number of RAID questionnaires prompted by the 
app for each participant during the study period.  
* User-behavior statistics: Sidekick Health will provide 
pseudonymized logged data from the app. This includes 
“passive” usage information such as the number of times 
participants logged into the app or the number of goals 
that were set, as well as data that were actively logged by 
participants relating to their physical activity, diet, stress 
(such as minutes spent completing relaxation exercises in 
the application), and sleep.  
- Baseline predictors of the intervention’s effect on ASES, 
PCS, IPAQ-S and PSQI scores: candidate predictors 
include demographic characteristics, disease-related 
characteristics (autoantibody status, current and previous 
therapy, disease duration, …), and measures of 
participant engagement (as previously defined).  
 
- The evolution and fluctuation over time of scores on the 
RAID-questionnaire completed in the app, and its 
association with self-efficacy, physical activity, sleep 
quality, and disease activity assessed at the study visit. 
The RAID is a patient-reported questionnaire with 7 items 
scored on a 0-10 numeric rating scale, enquiring about 
the impact of RA on different aspects of physical and 
mental health. Disease activity will be assessed as in 
usual care, with composite scores such as the DAS28-CRP 
and SDAI (both are composed of the number of tender 

 
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joints and swollen joints, patient’s global assessment of 
disease activity on a visual analogue scale VAS, and C‐
reactive protein CRP; the SDAI additionally includes the 
physician’s global assessment of disease activity). 
 
- The association of data actively logged in the app (step 
counts, exercise activities, diet, sleep quality, stress level, 
and energy level) with the validated outcome measures 
RAID, IPAQ-S, PSQI, ASES, and DAS28-CRP.  
 
Sample Size 
 
See page 27-28 for more detailed calculations.  
N = 120. 
For the primary outcome, sample size calculation was 
based on the minimal clinically important difference in the 
ASES-score, and on data from a recently published, large 
prospective study from our research group. Following 
these assumptions, 60 participants are needed in each 
group to detect a clinically meaningful change in ASES 
scores with 80% power and a significance level of 0.05, 
after adjusting for a 10% dropout rate and the possible 
need for non-parametric tests.  
An additional sample size calculation was made for the 
secondary outcome of change in PCS score from baseline 
between the control and intervention group, using the 
proposed minimal clinically important difference in the 
PCS 
score, 
with 
pooled 
data 
from 
the 
PCS 
development/validation studies and a French cohort of 
patients with RA to estimate the population distribution. 
Aiming to exclude any (negative) effect of the intervention 
on change in the PCS score, we chose a non-inferiority 
design for this outcome. Given that the effect of the 
intervention on the PCS score is unknown, we chose the 
aforementioned minimal clinically important difference as 
the non-inferiority margin. Following these assumptions 
and allowing for a 10% dropout rate, a total of 82 
participants need to be included (41 in both the control 
and intervention groups) to demonstrate a non-inferior 
effect of the intervention on the PCS score with 80% 

 
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power, a minimal clinically important margin and a two-
sided significance level of 0.025. When 120 patients are 
included as per the primary outcome, and assuming a 10% 
drop-out rate, we should have 90.2% power to 
demonstrate non-inferiority for this secondary outcome. 
In summary, a total of 120 patients will need to be 
included to assess both the primary outcome of self-
efficacy 
and 
the 
secondary 
outcome 
of 
pain 
catastrophizing with at least 80% power, with 60 
participants in both the control group and the intervention 
group.  
Summary of eligibility criteria 
 
Consecutive participants will be assessed for eligibility at 
the rheumatology outpatient clinic of both participating 
centers. Patients enrolled in the study must meet all of 
the following inclusion criteria:  
1. Are aged 18 years or older. 
2. Have a diagnosis of RA made by a 
rheumatologist, with a minimal disease duration 
of 16 weeks or more. 
3. Be able and willing to give written informed 
consent. 
4. Are able to understand and write Dutch. 
5. Have access to a smartphone with an Android 
(Requires Android 7.0 or later) or Apple iOS 
(Requires iOS 13.0 or later) operating system. 
 
Maximum duration of intervention 
 
16 weeks with a window of 2 weeks. 
Version and date of final protocol 
 
v6.3 (03-11-2022) 
Version and date of protocol amendments 
 
Listed at page 39, 40, 41, 42. 
 
 
 
 

 
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3. Background and rationale 
Rheumatoid arthritis (RA) is the most common form of chronic inflammatory arthritis worldwide, with 
an estimated prevalence of approximately 0.5-1% (1). The condition usually presents with a 
symmetrically distributed pain, swelling and/or redness of the small joints, such as those of the hands 
and feet, and significantly impacts patients’ quality of life, physical functioning, and work participation 
(2). In recent years, shifts to a more intensive and targeted treatment paradigm, the so-called treat-
to-target (T2T) strategy, along with the development of numerous novel disease-modifying 
antirheumatic drugs (DMARDs) have considerably improved outcomes for most patients with RA (3). 
Nevertheless, both international research and recent work from our research group have shown that 
many patients still report unmet needs despite successful treatment, such as ongoing symptoms of 
pain and fatigue, or suboptimal psychosocial wellbeing (4–6). Moreover, many patients with RA are 
confronted with comorbidities that further complicate the management of their disease (7,8). 
Consequently, it is becoming increasingly clear that an adequate management of RA is only possible 
when pharmacological treatment is embedded within a biopsychosocial approach that additionally 
includes attention for aspects of the disease burden that are best addressed non-pharmacologically, 
for instance with lifestyle measures (9). In this regard, a crucial aspect of care is empowering patients 
to gain a better understanding of their disease and to assume a more active role in its management, 
which in turn promotes shared decision-making. An important contributor towards such self-
management behavior is self-efficacy, which can be defined as patients’ confidence in their ability to 
control disease and its consequences, and which has been shown to positively affect various aspects 
of living with RA (10,11). Consequently, self-efficacy was recently put forward by the European League 
Against Rheumatism (EULAR) as both an important facilitator and an outcome of self-management 
strategies for inflammatory arthritis, and several intervention studies have already shown that this is 
not a static personality trait but can be improved with personalised patient education and 
psychological support (12–14).  
In addition to proposing self-efficacy as an outcome, the EULAR-taskforce also defined several 
recommendations for the content of self-management interventions, including patient education and 
lifestyle measures (12). Assuming a healthier lifestyle is not only relevant for the management of RA, 
but also to prevent cardiovascular events, which are known to be more prevalent in patients with RA 
than in the general population (15). Therefore, promoting a healthier lifestyle is crucial to improving 
outcomes of patients with RA and represents an often-underrecognized strategy. For instance, 
although being physically active is known to reduce the risk of cardiovascular events, ample research 
has shown that most patients with rheumatic diseases do not meet the level of physical activity 
recommended by the World Health Organisation (WHO) and EULAR (16,17). In addition, patients’ 
nutritional habits are rarely assessed in clinical practice, despite a recent systematic review suggesting 
that some dietary approaches may improve RA symptoms (18). Finally, sleep has been identified as a 
key contributor to patients’ wellbeing, suggesting that interventions to improve sleep quality could be 
an added value in RA management (19,20).  
One way to deliver self-management interventions that is growing in popularity is by using mobile 
health (mHealth) applications, for instance employing goal-setting strategies and motivational 
principles such as gamification (21,22). Recent advances in the availability of mobile apps and 
smartphones could present an opportunity to provide patients with more personalised education and 
tools to guide and promote disease self-management in their everyday environment (23). However, 
concerns are often raised about the feasibility of using mobile apps to deliver educational or lifestyle-

 
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promoting interventions, with large variations in patient compliance and attrition rates being reported 
in previous studies (24). Moreover, it remains somewhat unclear whether such app-based 
interventions can effectively promote self-efficacy and a healthier lifestyle or might have a negative 
effect by potentially inducing chronic disease behavior and increasing pain catastrophizing tendency. 
This study aims to mitigate these challenges. 
4. Trial objectives and Design 
4.1 Trial objectives 
Primary objective 
To investigate whether disease-specific patient education, promotion of a healthy lifestyle and 
remote PRO-monitoring, delivered through a mobile application based on principles of goal-setting 
and gamification, can improve self-efficacy in patients with RA. Self-efficacy will be assessed with the 
Arthritis Self-Efficacy Scale (ASES). 
Secondary objectives 
- To study if this app-based intervention affects pain catastrophizing (either positively or negatively), 
assessed with the Pain Catastrophizing Scale (PCS). Pain catastrophizing can be defined as an overly 
negative cognitive-affective orientation toward pain.  
 
Exploratory objectives 
- To study if the intervention’s effects on self-efficacy and pain catastrophizing are affected by the 
interval at which participants are asked to report PROs (the RAID questionnaire either once per week 
or once per month). 
 
- To study if this app-based intervention leads to changes in physical activity or sleep quality, 
assessed with the International Physical Activity Questionnaire short form (IPAQ-S) and Pittsburgh 
Sleep Quality Index (PSQI), respectively. 
 
- To study the feasibility of delivering this intervention through a mobile application, by assessing 
participants’ engagement with the app through the proportion of completed RAID-questionnaires 
and user-behavior statistics, including the proportion of days with logged activities in the app. No 
incentives for app-use will be provided, except those needed in the trial as built-in in the app 
(standard push-messages of the app), in order to provide a representative picture of participants’ 
intrinsic and continued motivation. 
 
- To identify baseline predictors of the intervention’s effect on ASES, PCS, IPAQ-S and PSQI scores. 
 
- To describe the evolution over time of scores on the RAID-questionnaire completed in the app, and 
its association with (changes in) self-efficacy, physical activity, sleep quality, and disease activity 
assessed at the study visits. 

 
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- To describe the evolution of the data that were actively logged by participants relating to their diet, 
physical activity, stress (such as minutes spent completing relaxation exercises in the application), 
and sleep, and study their association with disease activity, the RAID, ASES, IPAQ-S, and PSQI.  
4.2 Primary endpoints 
Difference in mean change of total ASES (Arthritis Self-Efficacy Scale) score from baseline to week 16 
± 2w in the intervention group when compared to the control group. The ASES is a patient-reported 
questionnaire consisting of 20 items to measure one’s arthritis-specific self-efficacy across 2 
subscales: self-efficacy for managing pain (PSE, range 5-50), and self-efficacy for controlling other 
symptoms (OSE, range 6-60). Both scores can be summed to derive a total ASES-score (range 11-
110).  
4.3 Secondary endpoints 
Difference in mean change of total PCS (Pain Catastrophizing Scale) score from baseline to week 16 ± 
2w in the intervention group when compared to the control group. The PCS is a patient-reported 
questionnaire with 13 items scored on a 0-4 Likert scale, resulting in a total score of 0-52 with sub 
scores for rumination, magnification, and helplessness. Higher scores indicate more catastrophic 
perceptions concerning pain.  
4.3b Exploratory endpoints 
- Difference in mean change of total ASES score from baseline to week 16 ± 2w in the intervention 
arm with weekly RAID questionnaires when compared to the intervention arm with monthly RAID 
questionnaires. 
- Difference in mean change of total PCS score from baseline to week 16 ± 2w in the intervention arm 
with weekly RAID questionnaires when compared to the intervention arm with monthly RAID 
questionnaires. 
- Difference in mean change of total IPAQ-S score from baseline to week 16 ± 2w in the intervention 
group when compared to the control group. The IPAQ short form is a 7-item questionnaire enquiring 
about physical activities during the last 7 days. A specific activity score is obtained for different 
domains, each being multiplied with the accompanying mean metabolic equivalent (MET) value. This 
leads to a total score corresponding with low, moderate, or high physical activity. 
 
- Difference in mean change of total PSQI score from baseline to week 16 ± 2w in the intervention 
group when compared to the control group. The PSQI is a patient-reported questionnaire developed 
to measure sleep quality through 19 items across 7 domains. The resulting total score ranges from 0-
21, with scores of 5 or higher being defined as poor sleep quality.     
- To describe participants’ continued engagement with the app and to compare it between the 
weekly and monthly PRO subgroups. Engagement will be defined as: 
* The proportion of RAID questionnaires with at least one completed item in the Sidekick app, 
compared to the total number of RAID questionnaires prompted by the app for each participant 

 
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during the study period.  
* User-behavior statistics: Sidekick Health will provide pseudonymized logged data from the app. This 
includes “passive” usage information such as the number of times participants logged into the app or 
the number of goals that were set, as well as data that were actively logged by participants relating 
to their physical activity, diet, stress (such as minutes spent completing relaxation exercises in the 
application), and sleep.  
- Baseline predictors of the intervention’s effect on ASES, PCS, IPAQ-S and PSQI scores: candidate 
predictors include demographic characteristics, disease-related characteristics (autoantibody status, 
current and previous therapy, disease duration, …), and measures of participant engagement (as 
previously defined).  
 
- The evolution and fluctuation over time of scores on the RAID-questionnaire completed in the app, 
and its association with self-efficacy, physical activity, sleep quality, and disease activity assessed at 
the study visit. The RAID is a patient-reported questionnaire with 7 items scored on a 0-10 numeric 
rating scale, enquiring about the impact of RA on different aspects of physical and mental health. 
Disease activity will be assessed as in usual care, with composite scores such as the DAS28-CRP and 
SDAI (both are composed of the number of tender joints and swollen joints, patient’s global 
assessment of disease activity on a visual analogue scale VAS, and C‐reactive protein CRP; the SDAI 
additionally includes the physician’s global assessment of disease activity). 
 
- The association of data actively logged in the app (step counts, exercise activities, diet, sleep 
quality, stress level, and energy level) with the validated outcome measures RAID, IPAQ-S, PSQI, 
ASES, and DAS28-CRP.  
4.4 Trial Design 
This will be an investigator-initiated, prospective, open label, parallel group, multi-center, 
randomized controlled trial (RCT). Participants will be randomized in a 1:1-ratio, using stratified 
(local) randomization by study center (UZ Leuven or AZ Sint-Lucas Brugge), to either a control group 
or an intervention group (n = 120 participants in total, 60 in each group). The randomization schedule 
will be based on center-specific, computer-generated sequences programmed in Research Electronic 
Data Capture (REDCap), ensuring allocation concealment.  
Following randomization, the intervention group will be re-randomized (via computer-generated 
simple randomization in REDCap) into two arms in a 1:1 ratio (n = 30 participants in each arm). 
Participants in intervention arm A will be asked to complete the RAID questionnaire once a week via 
the Sidekick app, compared to once a month in intervention arm B.  
The control group will be followed according to usual care standards. This includes informal 
screening for psychosocial wellbeing and illness perceptions during outpatient clinic visits, with 
referral to specific allied health professionals for additional education or non-pharmacological 
support if needed. The scores derived from questionnaires that form part of the study design can be 

 
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used as a guide for these discussions. As part of standard care, participants in both the control group 
and the intervention group will also receive a standardized educational leaflet about RA (attached as 
additional file), as is already available in the clinic and via the website of patient organization 
ReumaNet.  
In addition to usual care, participants in the intervention group will receive unrestricted, free-of-
charge and unincentivized access to the Sidekick Health application. The application was designed by 
the company Sidekick Health (Iceland) with the support of pharmaceutical company Pfizer for the 
adaptation of the app to the Belgian public, with a design centered particularly around promoting 
behavioral change and a strong focus on gamification techniques. It includes an educational module 
(Appendix A) that was specifically developed for patients with RA in collaboration with 10 
rheumatologists. In addition, the app allows users to record nutritional diaries, subjective sleep 
quality and physical activity (manually or through wearable activity trackers or the smartphone’s 
accelerometer), while also providing several physical and mindfulness-based exercises and the option 
to record PROs such as the RAID questionnaire. Reminders or alerts can be set up and customized by 
the users in the app itself, according to their personal preferences. These logs are stored in the 
application’s designated data cloud, from which all identifiable data will be removed upon 
termination of the account at the end of the study (also see section on Data handling). The 
educational program on the app runs for a period of 16 weeks.  
In all groups, an in-person visit will be scheduled at baseline and after 16 weeks, with a window of 2 
weeks before and 2 weeks after this time point, taking place at the Rheumatology outpatient clinic of 
the participating centers. At the baseline and week 16 ± 2w visits and in all groups, we will collect 
routine clinical data, including clinical examination and readily available blood samples, DAS28-
CRP/SDAI, and HAQ, as well as trial questionnaires in the form of the ASES, PCS, IPAQ-S, and PSQI 
(see 3.5 and 3.6). The following data will only be collected at baseline, also in all groups: RA 
phenotype (RF/ACPA/erosive), disease duration, past and current DMARD-therapy, comorbidities if 
present, educational level, and participants’ demographic characteristics.   
After the week 16 ±2w visit, the study ends, and all participants will be free to continue with the 
Sidekick-application at their leisure, by creating a personal account. As outlined in the section on 
Data Handling, the pseudonymized study account will be terminated at the end of the study, upon 
which all stored personal data will be removed from the application’s data cloud. The 
aforementioned logged data and in-app data will be stored by Sidekick Health on a secure platform 
and provided in pseudonymized form as data for the study (also see section on Data handling), only 
identifiable through participants’ study ID.  
 
 
 

 
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4.5 Study diagram 
 
RAID = Rheumatoid Arthritis Impact of Disease ; q1w = once a week ; q1m = once a month ; DAS28 = Disease Activity Score 
28 joints ; SDAI = Simple Disease Activity Index ; CDAI = Clinical Disease Activity Index ; ASES =: Arthritis Self-Efficacy Scale ;  
IPAQ-S = International Physical Activity Questionnaire short form ; PSQI = Pittsburgh Sleep Quality Index ; HAQ = Health 
Assessment Questionnaire ; RF = rheumatoid factor ; ACPA = anti-citrullinated peptide antibodies ; DMARD = disease-
modifying antirheumatic drugs ; BMI = body mass index 
4.6 Trial Flowchart 
 
Procedures / Assessment 
Screening and 
randomization 
Intervention period 
Visits / Contacts 
Visit 1 
= Baseline 
During intervention 
Visit 2 
= Evaluation of primary 
endpoint 
Timing (weeks) 
Week 0 
 
Week 16 ± 2w 
Informed consent 
X 
 
 
Inclusion / Exclusion criteria 
X 
 
 
Randomization 
X 
 
 
Downloading Sidekick Health app     
X  
 
 
Demographics (age, sex), RF and ACPA status, 
radiographic erosions, disease duration, past and 
current DMARD-therapy, prior DMARD-therapy, 
BMI, smoking status, education level 
X 
 
 
Medical and Surgical history, comorbidities (if 
available in the patient file) 
X 
 
 
Physical examination (including TJC28 and SJC28) 
X 
 
X 

 
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Patient’s global assessment (VAS) 
X 
 
X 
Physician’s global assessment (VAS) 
X 
 
X 
HAQ 
X 
 
X 
Weight / Height / BMI 
X 
 
X 
Blood sampling (CRP) as part of usual care (in clinic 
or through patient’s general practitioner) 
X 
 
X 
ASES 
X 
 
X 
PCS 
X 
 
X 
IPAQ-S 
X 
 
X 
PSQI 
X 
 
X 
RAID (both control- and intervention group) 
X 
 
X 
RAID (via Sidekick Health app, only in intervention 
group): 
- Intervention arm A: weekly 
- Intervention arm B: monthly 
 
 
X 
 
Collecting in-app logged data concerning physical 
activity, sleep, diet, stress management 
 
 
X 
 
 
 
RF = Rheumatoid Factor, ACPA = Anti-citrullinated peptide antibodies, DMARD = disease-modifying antirheumatic drug, BMI 
= body mass index, TJC28 = tender joint count in 28 joints, SJC28 = swollen joint count in 28 joints, VAS = Visual Analogue 
Scale, HAQ = Health Assessment Questionnaire, CRP = C-reactive protein, ASES = Arthritis Self-Efficacy Scale, PCS = Pain 
Catastrophizing Scale, IPAQ-S = International Physical Activity Questionnaire short form, PSQI = Pittsburgh Sleep Quality 
Index, RAID = Rheumatoid Arthritis Impact of Disease 
5. Selection and withdrawal of subjects 
 
5.1 Inclusion criteria 
Patients enrolled in the study must meet all of the following inclusion criteria:  
1. Voluntary written informed consent of the participant or their legally authorized 
representative has been obtained prior to any screening procedures. 
2. Are aged 18 years or older. 
3. Have a diagnosis of RA, diagnosed by a rheumatologist, with a minimal disease duration of 16 
weeks or more. This minimal disease duration was chosen based on conceptual reasons and 
previous work of our research group, suggesting that the dynamic and impactful first weeks 
after diagnosis are not the ideal time window to assess psychosocial outcomes (6). 
4. Are able to understand and write Dutch.  
5. Have access to a smartphone with an Android (requires Android 7.0 or later) or Apple iOS 
(requires iOS 13.0 or later) operating system. 

 
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All participants that are considered for Trial participation, per the above criteria will be documented 
on the Screening Log, including Screen Failures.  
5.2 Exclusion criteria 
Since the study intervention does not include an IMP, no strict exclusion criteria are defined other 
than the abovementioned inclusion criteria. However, participants will be excluded from analyses if 
they do not provide any questionnaire data at either of the two study visits, or, for the intervention 
group, if they fail to use the Sidekick Health application at least once (= dropouts).  
5.3 Expected duration of trial 
As stated above and illustrated in 3.5 and 3.6, the trial will end after the follow-up visit at week 16 
with a window of 2 weeks before and after that timing, or if the participant requests to exit the 
study. The inclusion period will be covering Q3 an Q4 of 2022 (06/2022 – 12/2022) with last possible 
visit performed in Q1 of 2023 (end of 03/2023). Since this study does not involve an IMP, we do not 
expect any study-related adverse events to occur that might necessitate premature termination of 
the study. 
6. Trial Procedures 
 
6.1 By visit 
 
Visit 1 (screening and baseline): 
- Recruitment of eligible participants after informed consent at the Rheumatology outpatient clinic of 
the participating centers.  
- Two-step randomization, as described above, into a control group and an intervention group (1:1), 
which will in turn be re-randomized in a 1:1 ratio into a weekly RAID arm and a monthly RAID arm.  
- Downloading Sidekick Health app (intervention group only). 
- Collection of demographic and disease-related characteristics for included patients: age, sex, RF and 
ACPA status, radiographic erosions, disease duration, current DMARD-therapy, prior DMARD-
therapy, BMI, smoking status, education level. 
- Collection of relevant medical and surgical history and comorbidities.  
- Physical examination, including TJC28 and SJC28, measurement of weight and height. 
- Patient’s and Physician’s global assessment (VAS). 
 

 
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- Participants in both the control and intervention groups will be asked to complete the following 
questionnaires considering self-efficacy (ASES), patient-reported outcomes (RAID), daily functioning 
(HAQ), pain catastrophizing (PCS), physical activity (IPAQ-S) and sleep quality (PSQI). Questionnaires 
will be completed in MyNexuzHealth (an online patient communication platform used by the 
University Hospitals Leuven Belgium) or, if not possible, in a pen-and-paper form at the outpatient 
clinic. 
• 
Self-efficacy: The ASES is a patient-reported questionnaire (25) consisting of 20 items to 
measure one’s arthritis-specific self-efficacy across 2 subscales: self-efficacy for managing 
pain (PSE, range 5-50), and self-efficacy for controlling other symptoms (OSE, range 6-60). 
Both scores can be summed to derive a total ASES-score (range 11-110). 
• 
Patient-reported outcomes: The RAID questionnaire is a patient-derived differentially 
weighted 7-item tool assessing pain, functional disability, fatigue, sleep, coping, physical and 
emotional well-being.  
• 
Daily functioning: The HAQ is a self-administered questionnaire, that assesses the ability in 
performing daily life activities and measures the functional impact of rheumatoid arthritis 
(26). The HAQ is routinely collected at the rheumatology outpatient clinic at University 
Hospitals Leuven. 
• 
Pain catastrophizing: The PCS is a patient-reported questionnaire with 13 items scored on a 
0-4 Likert scale, resulting in a total score of 0-52 with subscores for rumination, 
magnification, and helplessness (27). Higher scores indicate more catastrophic perceptions 
concerning pain. 
• 
Physical activity: The IPAQ short form is a 7-item questionnaire enquiring about physical 
activities during the last 7 days (28). A specific activity score is obtained for different 
domains, each being multiplied with the accompanying mean metabolic equivalent (MET) 
value. This leads to a total score corresponding with low, moderate or high physical activity.   
• 
Sleep quality: The PSQI is a patient-reported questionnaire developed to measure sleep 
quality through 19 items across 7 domains (29). The resulting total score ranges from 0-21, 
with scores of 5 or higher being defined as poor sleep quality. 
- Disease activity will be monitored in both participant groups with the DAS28-CRP and SDAI scores, 
using internationally validated cut-offs. DAS28-CRP is a composite score that combines a patient’s 
global assessment of disease activity, a clinical examination with counts of painful and swollen joints, 
and CRP as an inflammatory laboratory parameter (30). SDAI is an analogous composite score that 
additionally includes the physician’s/evaluator’s global assessment of disease activity and has its own 
validated cut-offs (31). These examinations are part of routine care.  
- Results of both clinical data and the obtained questionnaires will be extracted from the electronic 
medical patient file used in UZ Leuven and other participating centers (KWS) or, if not possible, from 
the completed pen-and-paper forms. 

 
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Intervention phase (between baseline and week 16 ± 2w visit) 
While using the SideKick Health app, patients in the intervention group will have the opportunity to 
actively log data relating to their diet, physical activity, sleep quality, stress (such as minutes spent 
completing relaxation exercises in the application), vital signs, and fill out short questionnaires, for 
example the RAID questionnaire, integrated in the application. Among these, only completion of the 
RAID questionnaire is actively stimulated and expected as part of the study, all other functions can be 
used on a voluntary basis.  
As stated before, one arm of the intervention group will be asked to complete the RAID 
questionnaire on a weekly basis, the other one will do this on a monthly basis. During this phase of 
the study user behavior statistics will also be collected as described above (number of times the app 
was used, how often certain questions were answered, …). 
Visit 2 (week 16 ± 2) 
- Participants in both the control and intervention groups will be asked to again complete the 
previously outlined questionnaires considering self-efficacy (ASES), patient-reported outcomes 
(RAID),  physical disability (HAQ), pain catastrophizing (PCS), physical activity (IPAQ-S), and sleep 
quality (PSQI). Questionnaires will be completed in MyNexuzHealth or in pen-and-paper form at the 
outpatient clinic if not available. In addition, disease activity will again be assessed as part of routine 
care by way of the DAS28-CRP and SDAI scores. 
- The study will end after this visit. The participants will be free to continue with the Sidekick-
application at their leisure, or alternatively, to terminate the account. Upon termination of the 
account, all stored personal data will be removed from the application’s data cloud (also see section 
on Data handling). 
6.2 Laboratory tests 
Laboratory tests obtained for this study will be limited to those collected as part of routine care in 
hospital or by the patient’s general practitioner, for instance the collection of CRP to calculate 
DAS28-CRP and SDAI scores. No additional laboratory tests will be conducted for the purposes of this 
study. 
6.3 Other investigations 
Other than any investigations required as part of routine care, no additional investigations will be 
carried out for this study.  
7. Assessment of efficacy 
Efficacy of this app-based educational, monitoring, and lifestyle intervention will be studied by 
assessing changes in self-efficacy (ASES), physical activity (IPAQ-S) and sleep quality (PSQI), while the 
intervention’s effect on pain catastrophizing will be studied in a non-inferiority setting to exclude any 

 
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(negative) effects of systematic PRO-registration on pain perceptions. As stated in the sections on 
Trial Objectives and Design, the primary endpoint will be the difference in mean change of total 
ASES-score from baseline to week 16 ± 2w in the intervention group when compared to the control 
group, while the intervention’s effect on pain catastrophizing was chosen as a secondary endpoint. 
Sample size calculations were based on obtaining 80% power for both the primary and the secondary 
endpoint, as outlined in section 9. 
In addition to the information obtained from the questionnaires, we will also study participants’ 
continued engagement with the app and its possible effects on intervention efficacy as an 
exploratory endpoint, as described above.  
8. Assessment of Safety 
8.1 Specification, timing and recording of safety parameters 
Clinical examination will be conducted as prescribed in the normal procedures of standard of care. 
Results of blood samples to calculate the DAS28-CRP and SDAI scores, will only be used if already 
available, no extra blood samples will be taken for the study.  
8.2 Procedures for recording and reporting adverse events (AE) 
Since the study intervention does not include an IMP, recording and reporting of adverse events is 
not applicable for this study.  
8.3 Treatment stopping rules 
Not applicable for this study.  
9. Statistics 
9.1 Sample size 
For the primary outcome, we opted for a superiority design aiming to reject the null hypothesis that 
there would be no difference between the intervention and control groups in the change of the total 
ASES-score from baseline to week 16. Sample size calculation was based on the previously proposed 
minimal clinically important difference in the ASES-score, corresponding with a change of 5.5 on 
either the pain or other symptoms subscale (13,25). Moreover, in a recently published, large 
prospective study from our research group, including 379 patients with RA, the mean (± SD) self-
efficacy for pain (PSE) was 31.8 (± 8.9) and self-efficacy for other symptoms (OSE) was 42.6 (± 9.4) 
(32). Based on a minimal clinically important difference of 5.5 and population SD of 9.4, an effect size 
of approximately 0.59 was assumed. Additionally, based on previous research and outpatient clinic 
attendance experience, we expect dropout rate to be maximally 10% (13,24,33). Following these 
assumptions and in the setting of a superiority trial, 52 participants are needed in each group to 
detect a clinically meaningful difference in either PSE or OSE with 80% power and a significance level 

 
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of 0.05, while allowing for a 10% dropout rate.  
It should be noted that the ASES score was not fully normally distributed in our aforementioned 
prospective study, implying that non-parametric tests might be needed to analyze the primary 
outcome. Following a general rule of thumb, sample size was thus increased by 15% to account for 
the loss of power these non-parametric tests would imply(34). Consequently, a total of 120 
participants are needed (60 in each group) for the analysis of the primary outcome, with 80% power 
and a significance level of 0.05.  
An additional sample size calculation was conducted for the secondary outcome of change in PCS score 
from baseline in the intervention group compared to the control group. Based on pooled data from 
the PCS development/validation studies and a French cohort of patients with RA, the population 
weighted mean (SD) PCS score is estimated at 20.3 (SD 12.3) (27,35,36). Thus, a clinically important 
difference in the PCS score, previously proposed as greater than 38% change (27,37), would 
correspond to a change in total PCS score of greater than 7.7/52. Aiming to exclude any (negative) 
effect of the intervention on change in the PCS score, we chose a non-inferiority design for this 
outcome. Given that the effect of the intervention on the PCS score is unknown, we chose the 
aforementioned minimal clinically important difference of 7.7 as the non-inferiority margin. In other 
words, non-inferiority will be confirmed if the upper bound of the 95% CI for the intervention’s effect 
on PCS remains within a minimal clinically important margin(38). Following these assumptions and 
allowing for a 10% dropout rate, a total of 82 participants need to be included (41 in both the control 
and intervention groups) to demonstrate a non-inferior effect of the intervention on the PCS score 
with 80% power, a minimal clinically important margin and a two-sided significance level of 0.025. 
When 120 patients are included as per the primary outcome, and assuming a 10% drop-out rate, we 
should have 90.2% power to demonstrate non-inferiority for this secondary outcome. 
Sample size calculations were conducted via R version 4.2.1, using the packages pwr and epiR (see 
Appendix B). In summary, a total of 120 patients will need to be included to assess both the primary 
outcome and the secondary outcome with at least 80% power, including 60 participants in both the 
control group and in the intervention group.  
As described above, the intervention group will then again be randomized in a 1:1-ratio to assess the 
exploratory outcomes. The trial will thus not be powered for the exploratory analyses. 
9.2 Analysis 
Analyses will be carried out according to the intention-to-treat (ITT) principle, implying that 
participants will be analyzed based on the group they were originally assigned to.  
In this study, the ITT population will consist specifically of all patients in the intervention group who 
effectively downloaded and installed the Sidekick application at the baseline visit, and all patients 
assigned to the control group. As stated above, participants in the intervention group will be re-
randomized to intervention arm A or B, constituting two additional ITT populations that will only be 
analyzed exploratorily.  

 
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Per protocol (PP) analyses will be carried out as sensitivity analyses, including only those patients 
who completed the follow-up visit.  
The variables described above in sections 4-6 will be extracted from the electronic medical patient 
file that is employed in all participating centers (KWS). Additionally, user behavior statistics and data 
actively logged by the patients in the app will be collected and provided for analysis in 
pseudonymized form by Sidekick Health. The primary and secondary outcome data of this study will 
be collected via questionnaires on the MyNexuzHealth app, or if not possible in pen-and-paper 
format at the outpatient clinic. All study-related information will be assembled and prepared for 
further analysis in an electronic CRF developed in REDCap. P-values <0.05 will be considered as 
statistically significant for all analyses. Missing data will be handled with multiple imputation by 
chained equations when data can be assumed to be missing at random. Descriptive statistics for 
baseline participant characteristics will be provided as means (± SD), medians (IQR) or proportions 
depending on data distribution.  
Primary endpoint 
The difference in mean change of total ASES (Arthritis Self-Efficacy Scale) score from baseline to 
week 16 ± 2w in the intervention group when compared to the control group will be evaluated with 
an unpaired t-test or Wilcoxon rank sum test depending on distribution of the ASES-score. As a 
sensitivity analysis, we will additionally assess the difference between groups in week 16 scores using 
ANOVA adjusted for the baseline score. Furthermore, differences in the pain and other symptoms 
subscales of the ASES will be presented separately. 
 
Secondary endpoints 
- The difference in mean change of total PCS score from baseline to week 16 ± 2w in the intervention 
group will be compared to that in the control group, using an unpaired t-test or Wilcoxon rank sum 
test depending on distribution of the PCS score. As a sensitivity analysis, we will additionally assess 
the difference between groups in week 16 scores using ANOVA adjusted for the baseline score. 
Exploratory endpoints 
- The difference in mean change of total ASES score from baseline to week 16 ± 2w in the 
intervention arm with weekly RAID questionnaires will be compared to that in the intervention arm 
with monthly RAID questionnaires, using an unpaired t-test or Wilcoxon rank sum test depending on 
distribution of the ASES-score. As a sensitivity analysis, we will additionally assess the difference 
between groups in week 16 scores using ANOVA adjusted for the baseline score. 
- The difference in mean change of total PCS score from baseline to week 16 ± 2w in the intervention 
arm with weekly RAID questionnaires will be compared to that in the intervention arm with monthly 
RAID questionnaires, using an unpaired t-test or Wilcoxon rank sum test depending on distribution of 

 
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the PCS score. As a sensitivity analysis, we will additionally assess the difference between groups in 
week 16 scores using ANOVA adjusted for the baseline score. 
- The difference in mean change of total IPAQ-S score from baseline to week 16 ± 2w in the 
intervention group when compared to the control group will be evaluated with an unpaired t-test or 
Wilcoxon rank sum test depending on distribution of the IPAQ-S score. As a sensitivity analysis, we 
will additionally assess the difference between groups in week 16 scores using ANOVA adjusted for 
the baseline score. 
 
- The difference in mean change of total PSQI score from baseline to 16 ± 2w in the intervention 
group when compared to the control group will be evaluated with an unpaired t-test or Wilcoxon 
rank sum test depending on distribution of the PSQI score. As a sensitivity analysis, we will 
additionally assess the difference between groups in week 16 scores using ANOVA adjusted for the 
baseline score. 
- Participant engagement with the app will be analyzed descriptively as 1) the proportion of RAID 
questionnaires with at least one completed item in the Sidekick app, compared to the total number 
of RAID questionnaires prompted by the app for each participant during the study period; and 2) 
several user behavior statistics as described elsewhere. Additionally, participant engagement will be 
compared between the weekly and monthly RAID groups with unpaired t-tests or Mann-Whitney-U 
tests depending on data distribution.  
 
- Candidate predictors of a favorable effect of using the Sidekick app on self-efficacy, sleep and 
physical activity will be studied exploratively with (multiple) linear regression. 
 
- The evolution over time of the RAID scores  at baseline, provided in the app (intervention group 
only) and at week 16 ± 2w, and their association with other outcomes including ASES, IPAQ-S, PSQI 
and DAS28-CRP/SDAI scores, will be described with linear mixed effects regression models. 
 
- The association of data actively logged in the app (step counts, exercise activities, sleep quality, 
stress level, and energy level) with (changes in) the validated outcome measures RAID, IPAQ-S, PSQI, 
ASES, and DAS28-CRP/SDAI collected at baseline and week 16 ± 2w will be reported as Spearman or 
Pearson correlation coefficients depending on data distribution.  
10. 
Quality assurance 
Data collection tools and source document identification: 
Source data will be collected and recorded in the study participants’ files/medical records. They will 
be kept on a secured location at all times. The collection and processing of source data (from 
subjects enrolled in this study) will be limited to those data that are necessary to fulfill the objectives 

 
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of the study. These data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and regulations. 
Appropriate technical and organizational measures to protect the data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be put 
in place. Personnel whose responsibilities require access to personal data agree to keep the data 
confidential. 
Documentation of source data is necessary for the evaluation and validation of clinical findings, 
observations and other activities during a clinical study. Source documentation serves to substantiate 
the integrity of study data, confirms observations that are recorded and confirms the existence of 
study participants. Furthermore, source documentation must be available for the following to 
confirm data collected in the e-CRF: subject identification, eligibility, and study identification; study 
discussion and date of informed consent; dates of visits; results of safety and efficacy parameters as 
required by the protocol and date of study completion and reason for withdrawal from the study, if 
applicable. Data collection is the responsibility of the clinical study staff at the site under the 
supervision of the investigator. The investigator will maintain complete and accurate documentation 
for the study. All source documents will be reviewed by the clinical team to ensure that they are 
accurate and complete. 
As defined in section 1.52 of the ICH Guideline for Good Clinical Practice (ICH E6) source documents 
may include: original documents, data and records (e.g., hospital records, clinical and office charts, 
laboratory notes….). 
11. 
Direct access to source data and documents 
The investigator will permit trial-related audits, IEC review and regulatory inspection, providing direct 
access to all related source data / documents.     
E-CRF’s and all source documents, including progress notes and copies of laboratory and medical test 
results must be available at all times for review by the data manager, auditor and inspection by 
health authorities (e.g. EMA, FDA). The accuracy of the data will be verified by review of the source 
documents sponsor’s clinical trial monitor. 
12. 
Ethics and regulatory approvals 
The trial will be conducted in compliance with the principles of the Declaration of Helsinki (current 
version), the principles of GCP and in accordance with all applicable regulatory requirements. This 
protocol and related documents will be submitted for review to Ethics Committee and to the Federal 
Agency for medicinal products for Clinical Trial Authorization. 
The Study can and will be conducted only on the basis of prior informed consent by the Subjects, or 
their legal representatives, to participate in the Study. The Participating Site shall obtain a signed 

 
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informed consent form (ICF) for all patients prior to their enrollment and participation in the Study in 
compliance with all applicable laws, regulations and the approval of the (local) Ethics Committee, if 
required. The Participating Site shall retain such ICFs in accordance with the requirements of all 
applicable regulatory agencies and laws. The ICF for this study includes a dedicated section to inform 
participants that they will be presented with general Terms and Conditions upon downloading the 
application.  
The Investigator and the Participating Site shall treat all information and data relating to the Study 
disclosed to Participating Site and/or Investigator in this Study as confidential and shall not disclose 
such information to any third parties or use such information for any purpose other than the 
performance of the Study. The collection, processing and disclosure of personal data, such as patient 
health and medical information is subject to compliance with applicable personal data protection 
and the processing of personal data (Regulation (EU) 2016/679 also referred as the General Data 
Protection Regulation ("GDPR") and the Belgian Law of July 30 2018 on the protection of natural 
persons with regard to the processing of personal data). 
Any personal data shall be treated as confidential at all times including during collection, handling 
and use, and that the personal data (including in any electronic format) shall be stored securely at all 
times and with all technical and organizational security measures that would be necessary for 
compliance with data protection legislation. The Sponsor shall take appropriate measures to ensure 
the security of all personal data and guard against unauthorized access to or disclosure of or loss or 
destruction while in its custody. 
The personal data of study participants will be encoded, which means that they can only be related 
to an identifiable person by means of a unique code. The unique code will only be in the possession 
of the members of the study team who are in direct contact with the study participants. In no event 
will the coded personal data include personal identifiers, including any Study participant’s initials. 
Such coded personal data can only be traced or linked back by said study team members and said 
study team members shall treat these codes as strictly confidential. 
13. 
Data Handling 
Data collection tools and source document identification 
The Terms and Conditions in the informed consent form (ICF) also apply to the storage and handling 
of personal data, specifically account registration information, user-logged data and user behavior 
data.  
According to these general Terms and Conditions, account registration information, data logged by 
users in the SidekickHealth application, and user behavior data are stored in the Google Cloud SQL 
service on behalf of GoodlifeMe, the SidekickHealth manufacturer. Google does not have access to 
this information for any other reason than to store it. Account registration information includes a 
user’s name, email and chosen password, as well as information about their height, weight, age, 

 
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gender and profile picture if app users choose to supply this. To protect the personal email address 
of the user, we will label the individual patient account with a unique code (coded study email 
address) that will also serve as the study identification code for that individual in the eCRF. This code 
will be matched with the unique patient identification number in the KWS (EAD number) and kept in 
a separate file only available to the local study team. Logged data includes only the information 
actively logged by the user relating to their diet, physical activity, stress (such as minutes spent 
completing relaxation exercises in the application), vital signs, and questionnaires entered into the 
application. User behavior data include specific information about how participants use the 
application, such as how often the app is used, to what extent the educational modules have been 
accessed, how often certain lifestyle information is uploaded, to what extent patients have used a 
wearable together with the app etc… Upon deletion of the Sidekick account, or when the user has 
not logged any activity in the application for a period of two years, all personally identifiable data is 
deleted from the Google Cloud SQL service. 
Other than user behavior data and actively logged data, no data derived by or entered into the 
Sidekick application will be collected or stored as part of this study. Demographic, clinical and 
questionnaire-derived source data will be collected and recorded in the study participants’ 
files/medical records. They will be kept on a secured location at all times. The collection and 
processing of source data (from subjects enrolled in this study) will be limited to those data that are 
necessary to fulfill the objectives of the study. These data will be collected and processed with 
adequate precautions to ensure confidentiality and compliance with applicable data privacy 
protection laws and regulations. Appropriate technical and organizational measures to protect the 
data against unauthorized disclosures or access, accidental or unlawful destruction, or accidental loss 
or alteration will be put in place. Personnel whose responsibilities require access to personal data 
agree to keep the data confidential. 
Documentation of source data is necessary for the evaluation and validation of clinical findings, 
observations and other activities during a clinical study. Source documentation serves to substantiate 
the integrity of study data, confirms observations that are recorded and confirms the existence of 
study participants. Furthermore, source documentation will be available for the following to confirm 
data collected in the e-CRF: subject identification, eligibility, and study identification; study discussion 
and date of informed consent; dates of visits; and date of study completion and reason for early 
discontinuation of study or withdrawal from the study, if applicable. Data collection is the 
responsibility of the clinical study staff at the site under the supervision of the investigator. The 
investigator will maintain complete and accurate documentation for the study. All source documents 
will be reviewed by the clinical team to ensure that they are accurate and complete. 
As defined in section 1.52 of the ICH Guideline for Good Clinical Practice (ICH E6) source documents 
may include: original documents, data and records (e.g., hospital records, clinical and office charts, 
laboratory notes….). 

 
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Case report forms 
CRFs are provided for each subject in electronic format. The study data will be transcribed on a regular 
basis by study personnel from the source documents onto an e-CRF in a pseudo-anonymized manner 
and transmitted in a secure manner to the Chief Investigator within the timeframe agreed upon 
between Chief Investigator and the sites.  
Worksheets may be used for the capture of some data to facilitate completion of the e-CRF. Any such 
worksheets (including but not limited to copies of the e-CRF) will become part of the study participant's 
source documentation. All data relating to the study must be recorded in e-CRFs prepared by the 
investigator. Data must be entered into e-CRFs in English. Designated site personnel must complete 
the e-CRF as soon as possible after a subject visit, and the forms should be available for review. 
The investigator will ensure that data are recorded on the e-CRFs as specified in the study protocol and 
in accordance with the instructions provided. 
All e-CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. Proper audit trails are available to demonstrate the validity of the trial data. A 
copy of the completed e-CRFs will be archived at the study site. 
Data handling and record keeping 
The investigator will maintain a certified copy of e-CRFs and all source documents that support the 
data collected from each study participant, as well as all study documents as specified in ICH/GCP 
Section 8, Essential Documents for the Conduct of a Clinical Trial, and all study documents as specified 
by the applicable regulatory requirement(s). The investigator will take measures to prevent accidental 
or premature destruction of these documents. 
If data need to be transferred, this will be performed via a secured method of transfer taking into 
account all applicable security arrangements and regulations. Receiving party will agree to keep the 
transferred data confidential at all times. Data will not be transferred outside of the EEA.  
14. 
Data Management 
The investigator will maintain a certified copy of e-CRFs and all source documents that support the 
data collected from each study participant, as well as all study documents as specified in ICH/GCP 
Section 8, Essential Documents for the Conduct of a Clinical Trial, and all study documents as specified 
by the applicable regulatory requirement(s). The investigator will take measures to prevent accidental 
or premature destruction of these documents. 
If data need to be transferred, this will be performed via a secured method of transfer taking into 
account all applicable security arrangements and regulations. Receiving party will agree to keep the 
transferred data confidential at all times. Data will not be transferred outside of the EEA.  
The Sponsor is responsible for archiving study-specific documentation (such as but not limited to 
protocol, potential amendments, final report and database) according to ICH-GCP. Source data and 
Site-specific study documents (such as, but not limited to, ICF) will be archived locally on site according 
to local practice and guidelines for at least 20 years. Archived data may be held on electronic record, 

 
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provided that a backup exists and that hard copies can be obtained, if required. Destruction of essential 
documents will require authorization from the Sponsor. 
Archiving at the end of the trial will be organized by the sponsor and done centrally. 
15. 
Translational research 
No biological material will be collected/shipped/stored/used for the study. Lab results obtained as 
part of routine care will be extracted from the electronic medical patient file (KWS) or via laboratory 
reports of the participants’ general practitioner.  
16. 
Publication Policy 
It is anticipated that the results of the overall Study shall be published in a multi-center publication, 
involving the data of all clinical sites participating in the Study. 
Sponsor shall have the right to delay the projected publication for a period of up to three (3) months 
from the date of first submission to the Sponsor in order to enable the Sponsor to take steps to protect 
its intellectual property rights and know-how.  
Publications will be coordinated by the Investigator of Sponsor. Authorship to publications will be 
determined in accordance with the requirements published by the International Committee of Medical 
Journal Editors and in accordance with the requirements of the respective medical journal. 
17. 
Insurance/Indemnity 
In accordance with the Belgian Law relating to experiments on human persons dated May 7, 2004, 
Sponsor shall assume, even without fault, the responsibility of any damages incurred by a Study Patient 
and linked directly or indirectly to the participation to the Study, and shall provide compensation 
therefore through its insurance. 
18. 
References 
1. 
Alamanos Y, Voulgari P v., Drosos AA. Incidence and Prevalence of Rheumatoid Arthritis, 
Based on the 1987 American College of Rheumatology Criteria: A Systematic Review. Semin 
Arthritis Rheum. 2006;36(3):182–8.  
2. 
Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. The Lancet. 2016;388(10055):2023–
38.  
3. 
Smolen JS, Landewé RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, et al. 
EULAR recommendations for the management of rheumatoid arthritis with synthetic and 

 
Page 36 of 44 
 
Protocol version v6.3 dd 03/11/2022   
 
biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 
2020;79(6):685–99.  
4. 
Michaud K, Pope J, van de Laar M, Curtis JR, Kannowski C, Mitchell S, et al. Systematic 
Literature Review of Residual Symptoms and an Unmet Need in Patients With Rheumatoid 
Arthritis. Arthritis Care Res (Hoboken). 2021;73(11):1606–16.  
5. 
van der Elst K, Verschueren P, de Cock D, de Groef A, Stouten V, Pazmino S, et al. One in five 
patients with rapidly and persistently controlled early rheumatoid arthritis report poor well-
being after 1 year of treatment. RMD Open. 2020;6(1):e001146.  
6. 
Doumen M, de Cock D, Pazmino S, Bertrand D, Joly J, Westhovens R, et al. Psychosocial 
burden predicts sustained remission in early rheumatoid arthritis: unraveling the complex 
interplay of wellbeing and disease activity. Arthritis Care Res (Hoboken) [Internet]. 2021 Dec 
20;Online:ahead of print. Available from: https://doi.org/10.1002/acr.24847 
7. 
Stouten V, Pazmino S, Verschueren P, Mamouris P, Westhovens R, de Vlam K, et al. 
Comorbidity burden in the first three years after diagnosis in patients with rheumatoid 
arthritis, psoriatic arthritis or spondyloarthritis: A general practice registry-based study. RMD 
Open. 2021;7:e001671.  
8. 
Stouten V, Westhovens R, de Cock D, van der Elst K, Pazmino S, Bertrand D, et al. Having a co-
morbidity predicts worse outcome in early rheumatoid arthritis despite intensive treatment: a 
post hoc evaluation of the pragmatic randomized controlled CareRA trial. Rheumatology 
(Oxford). 2021;60:3699–708.  
9. 
Taylor PC, van de Laar M, Laster A, Fakhouri W, Quebe A, de la Torre I, et al. Call for action: 
incorporating wellness practices into a holistic management plan for rheumatoid arthritis—
going beyond treat to target. RMD Open. 2021;7(3):e001959.  
10. 
Bandura A. Self-efficacy: toward a unifying theory of behavioral change. Psychol Rev. 
1977;84(2):191–215.  
11. 
Jackson T, Xu T, Jia X. Arthritis self-efficacy beliefs and functioning among osteoarthritis and 
rheumatoid arthritis patients: A meta-analytic review. Rheumatology (Oxford). 
2020;59(5):948–58.  
12. 
Nikiphorou E, Santos EJF, Marques A, Böhm P, Bijlsma JWJ, Daien CI, et al. 2021 EULAR 
recommendations for the implementation of self-management strategies in patients with 
inflammatory arthritis. Ann Rheum Dis [Internet]. 2021;80(10):1278–85. Available from: 
https://ard.bmj.com/content/80/10/1278 

 
Page 37 of 44 
 
Protocol version v6.3 dd 03/11/2022   
 
13. 
Ndosi M, Johnson D, Young T, Hardware B, Hill J, Hale C, et al. Effects of needs-based patient 
education on self-efficacy and health outcomes in people with rheumatoid arthritis: A 
multicentre, single blind, randomised controlled trial. Ann Rheum Dis. 2016;75(6):1126–32.  
14. 
Garnefski N, Kraaij V, Benoist M, Bout Z, Karels E, Smit A. Effect of a cognitive behavioral self-
help intervention on depression, anxiety, and coping self-efficacy in people with rheumatic 
disease. Arthritis Care Res (Hoboken). 2013;65(7):1077–84.  
15. 
England BR, Thiele GM, Anderson DR, Mikuls TR. Increased cardiovascular risk in rheumatoid 
arthritis: mechanisms and implications. BMJ [Internet]. 2018 Apr 23;361:k1036. Available 
from: http://www.bmj.com/content/361/bmj.k1036.abstract 
16. 
Peters MJL, Symmons DPM, McCarey D, Dijkmans BAC, Nicola P, Kvien TK, et al. EULAR 
evidence-based recommendations for cardiovascular risk management in patients with 
rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis. 
2010;69(2):325–31.  
17. 
O’Dwyer T, Rafferty T, O’Shea F, Gissane C, Wilson F. Physical activity guidelines: is the 
message getting through to adults with rheumatic conditions? Rheumatology (Oxford). 
2014;53(10):1812–7.  
18. 
Philippou E, Petersson SD, Rodomar C, Nikiphorou E. Rheumatoid arthritis and dietary 
interventions: Systematic review of clinical trials. Nutr Rev. 2021;79(4):410–28.  
19. 
Løppenthin K, Esbensen BA, Jennum P, Østergaard M, Tolver A, Thomsen T, et al. Sleep quality 
and correlates of poor sleep in patients with rheumatoid arthritis. Clin Rheumatol. 
2015;34(12):2029–39.  
20. 
Westhovens R, van der Elst K, Matthys A, Tran M, Gilloteau I. Sleep problems in patients with 
rheumatoid arthritis. Journal of Rheumatology. 2014;41(1):31–40.  
21. 
Seppen BF, den Boer P, Wiegel J, ter Wee MM, van der Leeden M, de Vries R, et al. 
Asynchronous mhealth interventions in rheumatoid arthritis: Systematic scoping review. JMIR 
Mhealth Uhealth. 2020;8(11):e19260.  
22. 
van Riel P, Alten R, Combe B, Abdulganieva D, Bousquet P, Courtenay M, et al. Improving 
inflammatory arthritis management through tighter monitoring of patients and the use of 
innovative electronic tools. RMD Open. 2016;2(2):1–9.  
23. 
Doumen M, Westhovens R, Pazmino S, Bertrand D, Stouten V, Neys C, et al. The ideal 
mHealth-application for rheumatoid arthritis: qualitative findings from stakeholder focus 
groups. BMC Musculoskelet Disord. 2021;22(1):746.  

 
Page 38 of 44 
 
Protocol version v6.3 dd 03/11/2022   
 
24. 
Druce KL, Dixon WG, McBeth J. Maximizing Engagement in Mobile Health Studies: Lessons 
Learned and Future Directions. Rheumatic Disease Clinics of North America. 2019;45(2):159–
72.  
25. 
Barlow JH, Williams B, Wright CC. The reliability and validity of the arthritis self-efficacy scale 
in a UK context. Psychol Health Med. 1997;2(1):3–17.  
26. 
Bruce B, Fries J. The Stanford health assessment questionnaire: dimensions and practical 
applications. Health Qual Life Outcomes. 2003;1:20.  
27. 
Sullivan MJL, Bishop SR, Pivik J. The Pain Catastrophizing Scale: Development and Validation. 
Psychol Assess. 1995;7(4):524–32.  
28. 
Craig C, Marshall A, Sjostrom M, Bauman A, Booth M, Ainsworth B, et al. International 
Physical Activity Questionnaire: 12-Country Reliability and Validity. Med Sci Sports Exerc 
[Internet]. 2003;35(8):1381–95. Available from: https://journals.lww.com/acsm-
msse/Fulltext/2003/08000/International_Physical_Activity_Questionnaire_.20.aspx 
29. 
Buysse D, Reynolds C, Monk T. The Pittsburgh sleep quality index: a new instrument for 
psychiatric practice and research. Psychiatry Res. 1989;28:193–213.  
30. 
Prevoo M, van ’t Hof M, Kuper H, van Leeuwen M, van de Putte L, van Riel P. Modified disease 
activity scores that include twenty-eight-joint counts. Development and validation in a 
prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 
1995;38:44–8.  
31. 
Smolen JS, Breedveld FC, Schiff MH, Kalden JR, Emery P, Eberl G, et al. A simplified disease 
activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford). 
2003;42(2):244–57.  
32. 
Doumen M, de Cock D, Pazmino S, Bertrand D, Joly J, Westhovens R, et al. Treatment 
response and several patient-reported outcomes are early determinants of future self-efficacy 
in rheumatoid arthritis. Arthritis Res Ther. 2021;23(1):269.  
33. 
Stouten V, Westhovens R, Pazmino S, de Cock D, van der Elst K, Joly J, et al. Effectiveness of 
different combinations of DMARDs and glucocorticoid bridging in early rheumatoid arthritis: 
Two-year results of CareRA. Rheumatology (Oxford). 2019;58(12):2284–94.  
34. 
Lehmann EL. Nonparametrics: Statistical Methods Based on Ranks. Springer New York, NY; 
2006. 76–81 p.  
35. 
Osman A, Barrios FX, Gutierrez PM, Kopper BA, Merrifield T, Grittmann L. The pain 
catastrophizing scale: Further psychometric evaluation with adult samples. J Behav Med. 
2000;23(4):351–65.  

 
Page 39 of 44 
 
Protocol version v6.3 dd 03/11/2022   
 
36. 
Penhoat M, Saraux A, le Goff B, Augereau P, Maugars Y, Berthelot JM. High pain 
catastrophizing scores in one-fourth of patients on biotherapy for spondylarthritis or 
rheumatoid arthritis. Joint Bone Spine [Internet]. 2014;81(3):235–9. Available from: 
http://dx.doi.org/10.1016/j.jbspin.2013.10.004 
37. 
Bhatia A, Kara J, Janmohamed T, Prabhu A, Lebovic G, Katz J, et al. User engagement and 
clinical impact of the manage my pain app in patients with chronic pain: A real-world, multi-
site trial. JMIR Mhealth Uhealth. 2021;9(3).  
38. 
Althunian TA, de Boer A, Groenwold RHH, Klungel OH. Defining the noninferiority margin and 
analysing noninferiority: An overview. Br J Clin Pharmacol. 2017;83(8):1636–42.  
  
19. 
Amendment history 
 
Amendment  no. 
Protocol version 
no.  
Date issued  
Author(s) of 
changes 
Details of 
changes made 
1 
V1.0 
19-09-2021 
Cedric Lefevre 
First draft 
2 
V1.1 
03-10-2021 
Jo Joly 
New lay-out, 
working out of 
the study design, 
adding flow-chart 
to study design 
3 
V2.0 
02-11-2021 
Michaël Doumen 
New, layout, new 
study objectives 
and endpoints, 
adding statistical 
methodology, 
data handling, 
ethics and 
regulatory 
approvals. 
4 
V2.1 
18-11-2021 
Delphine 
Bertrand, Patrick 
Verschueren, 
Recalculating 
sample size, fine-
tuning study 

 
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Protocol version v6.3 dd 03/11/2022   
 
Sofia Pazmino 
Lucio 
design,  updating 
study flow chart. 
5 
V3.0 
21-11-2021 
Cedric Lefevre 
Implementing al 
considered 
changes in 
versions V2.1 and 
V2.2. 
6 
V3.1 
26-11-2021 
Jo Joly 
Advice 
considering 
changing sample 
size, data 
handling and 
study flowchart.  
7 
V3.2 
11-12-2021 
Cedric Lefevre 
Adaptation trial 
flowchart with 
deletion of the 
unscheduled 
visit, correction 
of trial periods, 
adaptation lay-
out. 
8 
V4.0 
17-01-2022 
Cedric Lefevre, 
Patrick 
Verschueren, Jo 
Joly 
Correcting time 
intervals, 
correcting 
sample size, 
correcting small 
errors, adding 
part about data 
handling, refining 
lay-out. 
9 
V4.1 
23-01-2022 
Cedric Lefevre, 
Michaël Doumen, 
Patrick 
Verschueren. 
Extending trial to 
32 weeks with 
cross-over design 
considering the 
control group, 
adding third visit 

 
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Protocol version v6.3 dd 03/11/2022   
 
moment, 
updating list of 
abbreviations, 
adapting sample 
size, making new 
study diagram, 
concordance 
between study 
synopsis and the 
whole document. 
10 
V5.0 
20-02-2022 
Cedric Lefevre, 
Michaël Doumen 
The third 
evaluation 
moment at week 
32 was dropped, 
the study will 
again end at 
week 16 as 
stated before. 
The intervention 
group will be cut 
in half with one 
group getting the 
RAID 
questionnaire 
weekly, the other 
one monthly, 
sample size was 
adjusted for this. 
The FFQ was 
dropped as it 
could not provide 
a quantitative 
result and was 
deemed too 
extensive to 
complete.  
11 
V6.0 
24-02-2022 
Michaël Doumen 
Extensive 
formatting, 

 
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Protocol version v6.3 dd 03/11/2022   
 
including changes 
to the title. 
Adaptation of 
secondary and 
exploratory 
endpoints, 
including 
adaptation of the 
sample size 
calculations and 
consequent 
changes in the 
randomization 
procedure.  
12 
V6.1 
12-03-2022 
Patrick 
Verschueren, 
Cedric Lefevre, 
Michaël Doumen 
Correcting minor 
incompatibilities, 
considering CDAI 
and SDAI for 
measuring 
disease activity, 
change of the 
protocol acronym 
to AEGORA: App-
based Education 
and Goal-setting 
in Rheumatoid 
Arthritis. 
13 
V6.2 
08-09-2022 
Michaël Doumen 
Fine-tuning 
minor 
incompatibilities.  
14 
V6.3 
03-11-2022 
Michaël Doumen, 
Patrick 
Verschueren, Jo 
Joly 
Addressing 
comments of 
Ethical 
Committee 
 
 
 

 
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Appendix A. Short overview of educational content in Sidekick app 
 
 
 
 
 
 

 
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Appendix B. R script for sample size calculations 
 
library(pwr) 
library(epiR) 
#---- Primary outcome: ASES 
d <- 5.5/9.4 
power <- pwr.t.test(d = d, sig.level = 0.05, power = 0.80, type = "two.sample", alternative = 
"two.sided") 
samplesize <- round(power$n * 2) 
 
# Accounting for 10% drop-out 
samplesize <- samplesize*1.10 
 
# Accounting for possible need for non-parametric tests 
samplesize <- round(samplesize*1.15) 
 
#---- Secondary outcome: PCS (non-inferiority) 
power <- epi.ssninfc(treat = 20.3, control = 20.3, sd = 12.3, delta = 7.7, n = NA, r = 1,  
                     power = 0.80, alpha = 0.025) 
 
# Accounting for 10% drop-out 
samplesize <- power$n.total*1.10 
 
# Calculation of power with 120 participants and 10% drop-out (= 108): 
power <- epi.ssninfc(treat = 20.3, control = 20.3, sd = 12.3, delta = 7.7, n = 108, r = 1,  
                     power = NA, alpha = 0.025)