A Randomized Controlled Trial of Electroacupuncture in the Management of Patients With Axial Spondyloarthritis in Singapore (E-AcuSpA)
Phase: NA
Conditions: Spondylarthritis, Axial Spondyloarthritis
Sponsor: Singapore General Hospital

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CLINICAL TRIAL PROTOCOL 
 
PROTOCOL TITLE: 
A randomized controlled trial of electroacupuncture in the management of patients with axial 
Spondyloarthritis in Singapore (E-AcuSpA) 
 
PROTOCOL VERSION:  
2.0 
PROTOCOL DATE:  
17 November 2020 
 
PRINCIPAL INVESTIGATOR:  
Dr Warren Fong, Consultant, Singapore General Hospital 
 
 
CO-INVESTIGATORS: 
A/Prof Koh Hwee Ling, Associate Professor, National University of Singapore 
Prof Truls Ostbye, Professor, Duke-NUS Medical School 
A/Prof Tai Bee Choo, Associate Professor, National University of Singapore 
Dr Tan Chuen Seng, Assistant Professor, National University of Singapore 
Dr Stanley Angkodjojo, Associate Consultant, Singapore General Hospital 
Ms Ang Xiang Ling, TCM Physician, Singapore Thong Chai Medical Institution 
Ms Quek Su-An, TCM Physician, Singapore Thong Chai Medical Institution 
Dr Huang Youyi, Resident, Singapore General Hospital 
Dr Kwan Yu Heng, MD-PhD Candidate, Duke-NUS Medical School 
 
 
 
 
 
 

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Table of Contents 
1 
BACKGROUND AND RATIONALE ................................................................................................ 5 
1.1 
GENERAL INTRODUCTION ................................................................................................................... 5 
1.2 
RATIONALE AND JUSTIFICATION FOR THE STUDY ...................................................................................... 5 
1.2.1 
RATIONALE FOR THE STUDY PURPOSE ................................................................................................... 5 
1.2.2 
RATIONALE FOR STUDY POPULATION .................................................................................................... 6 
1.2.3 
RATIONALE FOR STUDY DESIGN ........................................................................................................... 7 
2 
HYPOTHESIS AND OBJECTIVES .................................................................................................. 7 
2.1 
HYPOTHESIS ................................................................................................................................... 7 
2.2 
OBJECTIVES ................................................................................................................................... 8 
2.3 
POTENTIAL RISKS AND BENEFITS: ...................................................................................................... 13 
2.3.1 
POTENTIAL RISKS .......................................................................................................................... 13 
2.3.2 
POTENTIAL BENEFITS ...................................................................................................................... 13 
3 
STUDY POPULATION ................................................................................................................. 13 
3.1 
LIST THE NUMBER AND NATURE OF SUBJECTS TO BE ENROLLED ................................................................. 13 
3.2 
CRITERIA FOR RECRUITMENT AND RECRUITMENT PROCESS ....................................................................... 13 
3.3 
INCLUSION CRITERIA ...................................................................................................................... 13 
3.4 
EXCLUSION CRITERIA ...................................................................................................................... 13 
3.5 
SUBJECT REPLACEMENT ................................................................................................................... 14 
4 
STUDY DESIGN .......................................................................................................................... 14 
4.1 
RANDOMISATION AND BLINDING ........................................................................................................ 14 
4.2 
STUDY VISITS AND PROCEDURES ....................................................................................................... 14 
4.2.1 
SCREENING VISITS AND PROCEDURES ................................................................................................. 14 
4.2.2 
STUDY VISITS AND PROCEDURES ....................................................................................................... 14 
4.2.3 
FINAL STUDY VISIT: ....................................................................................................................... 17 
4.2.4 
POST STUDY FOLLOW UP AND PROCEDURES .......................................................................................... 17 
4.3 
DISCONTINUATION/WITHDRAWAL ...................................................................................................... 17 
4.3.1 
DISCONTINUATION CRITERIA ............................................................................................................ 17 
4.3.2 
DISCONTINUATION VISIT AND PROCEDURES ......................................................................................... 17 
5 
TRIAL MATERIALS ................................................................................................................... 17 
6 
TREATMENT ............................................................................................................................. 18 
6.1 
SPECIFIC RESTRICTIONS / REQUIREMENTS ........................................................................................... 18 
6.2 
BLINDING .................................................................................................................................... 18 
6.3 
CONCOMITANT THERAPY .................................................................................................................. 18 
7 
SAFETY MEASUREMENTS ......................................................................................................... 18 
7.1 
DEFINITIONS ................................................................................................................................ 18 
7.2 
COLLECTING, RECORDING AND REPORTING OF SERIOUS ADVERSE EVENTS (SAES) TO CIRB ............................ 19 
7.3 
COLLECTING, RECORDING AND REPORTING OF ADVERSE EVENTS (AES) TO THE HEALTH SCIENCES AUTHORITY 
(HSA)  ................................................................................................................................................. 19 
7.4 
SAFETY MONITORING PLAN .............................................................................................................. 20 
7.5 
COMPLAINT HANDLING .................................................................................................................... 20 
8 
DATA ANALYSIS ........................................................................................................................ 20 
8.1 
DATA QUALITY ASSURANCE .............................................................................................................. 20 
8.2 
DATA ENTRY AND STORAGE .............................................................................................................. 20 

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9 
SAMPLE SIZE AND STATISTICAL METHODS ............................................................................. 21 
9.1 
DETERMINATION OF SAMPLE SIZE ...................................................................................................... 21 
9.2 
STATISTICAL AND ANALYTICAL PLANS ................................................................................................. 21 
10 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ..................................................................... 22 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................... 22 
12 
ETHICAL CONSIDERATIONS ..................................................................................................... 22 
12.1 
INFORMED CONSENT....................................................................................................................... 22 
12.2 
CONFIDENTIALITY OF DATA AND PATIENT RECORDS ............................................................................... 22 
13 
PUBLICATIONS ......................................................................................................................... 23 
14 
RETENTION OF TRIAL DOCUMENTS ......................................................................................... 23 
15 
FUNDING AND INSURANCE ....................................................................................................... 23 

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PROTOCOL SIGNATURE PAGE 
 
 
 
Protocol Title: A randomized controlled trial of electroacupuncture in the management of patients with 
axial Spondyloarthritis in Singapore (E-AcuSpA) 
 
 
Protocol Number: 
 
 
Protocol Version/ Date: 2.0, 17 November 2020 
 
 
Sponsor Name: 
 
 
 
Declaration of Investigator 
 
I confirm that I have read the above-mentioned protocol and its attachments. I agree to conduct the 
described trial in compliance with all stipulations of the protocol, regulations and ICH E6 Guideline for 
Good Clinical Practice (GCP). 
 
  
 
 
Principal Investigator Name:  __________________________________________ 
                                                            
 
Principal Investigator Signature:  _______________________________________ 
                                                            
 
Date:  __________________________________________ 
                                                            
 
 
 
 
 
 
 

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1 
BACKGROUND AND RATIONALE 
 
1.1 
General Introduction 
 
Axial Spondyloarthritis (AxSpA) is a chronic debilitating disease which often results in 
severe disability and poor quality of life. Till date, there is no cure for AxSpA and the 
pathophysiology of the disease is still unclear. Based on current treatment guidelines, the 
first line treatment involves nonsteroidal anti-inflammatory drugs (NSAIDs), but this is only 
effective in about one-third of the patients. For patients with persistently active disease 
despite NSAIDs, the next recommended treatment is biologics which cost around $15,000 
per year and is only efficacious in 60% of biologic treated patients. Of these, majority of 
patients will suffer a relapse upon discontinuation of the biologics. NSAIDs and biologics 
are also not without side effects, which includes risk of developing renal impairment and 
peptic ulcer disease, increased risk of cardiovascular disease or increased risk of infection.  
 
In Traditional Chinese Medicine (TCM), AxSpA disease can be classified under Bi 
Syndrome. Acupuncture is commonly used to treat Bi Syndrome in TCM. Acupuncture 
treatment theories include Acupuncture along the 12 Tendon Meridians and Acupuncture 
along the 12 Meridians. The Meridian Tendon is part of the twelve meridians, and it is also 
the system that gather and connect the muscles and joints. The movement of vertebrae along 
the spine creates tension in the muscles, forming lesions or meridian tendon points on the 
back. These tendon points are tangible and detectable signs produced under pathological 
conditions, so it is also called “positive reaction point”, and a small lesion can cause a wide 
range of pain, thus removal of this lesion can cure a wide range of pain. During disease 
development, corresponding positive reaction point (lesion point) will be formed, and they 
can be felt as painful nodules or cords under the finger.  
 
1.2 
Rationale and Justification for the Study 
 
There are anecdotal reports that electroacupuncture provides faster and more sustained pain 
relief compared to manual acupuncture, but there are no randomized trials performed thus 
far comparing the two modes of acupuncture. Previous small studies have shown that 
electroacupuncture might be beneficial in patients with rheumatoid arthritis.  Till date, there 
are no trials looking at the effectiveness of electroacupuncture in patients with AxSpA. 
 
1.2.1 
Rationale for the Study Purpose 
 
TCM is one of the most commonly used complementary and alternative medicine 
modalities. TCM, especially acupuncture, has shown promising results in the management of 
pain, possibly by releasing encephalin. Acupuncture has frequently been promoted for lower 
back pain and osteoarthritis, and rheumatic diseases are, according to survey data, frequently 
treated by acupuncturists. Previous studies have demonstrated efficacy of acupuncture in 
pain relief for various rheumatic diseases, especially osteoarthritis, with minimal side 
effects. For patients with irritable bowel syndrome, acupuncture plus usual care can provide 
additional benefit over usual care alone, and the magnitude of the effect is sustained. Hence, 
acupuncture may be a safe and effective intervention to relieve pain.  
 
 

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Electroacupuncture is a modification of manual acupuncture in which electrical stimulation 
is administered through acupuncture needles, and it has been shown to have better local 
analgesic effects as compared to manual acupuncture. In animal models, electroacupuncture 
has further been shown to down-regulate levels of tumour necrosis factor alpha (TNFα) and 
interleukin-17 (IL-17), both of which are important mediators of inflammation in AxSpA. 
Continuous waves below 30Hz are known as sparse waves, whereas continuous waves 
above 30Hz are called dense waves. The dense-sparse wave is a combination of both, 
alternating between each about every 1.5 seconds, which makes the body less prone to 
adaptive response, thereby resulting in rhythmic tensing and relaxation of the muscles, better 
blood and lymph circulation, improved nutrient uptake of tissues and reduction in 
inflammation and edema. In addition, it can regulate the excitation and inhibition of the 
cerebral cortex, as well as the function of the subcortical autonomic nervous system. 
Therefore, when the endogenous analgesic system or the endogenous pain modulation 
system in the brain is activated, the analgesic effect can be exerted more effectively.  
 
Electroacupuncture has also been shown to provide a stronger and more continuous level of 
stimulation than traditional acupuncture, and produce more rapid and prolonged treatment 
effects. This may be because electrical stimulation of a tissue triggers an increase in the 
movement, especially potassium and sodium ions along the axon of the nerve cell. This 
accelerates the neuronal depolarization, which is responsible for nerve conduction. A 
previous study had shown that electroacupuncture is more effective in alleviating tender 
joints among patients with rheumatoid arthritis as compared to manual acupuncture. With 
electroacupuncture at the corresponding acupoints, we hope to deliver faster and more 
sustained relief of pain compared to manual acupuncture, thus improving the overall quality 
of life of patients with AxSpA. Currently, there are no published studies investigating the 
effectiveness of electroacupuncture for patients with AxSpA, and this study will help to 
address this gap in knowledge. 
 
In this proposal, we aim to assess the clinical effectiveness, safety and cost-effectiveness of 
electroacupuncture as compared to manual acupuncture. We hope the research findings from 
this study will inform policy makers of the impact of a collaborative model of care involving 
electroacupuncture on healthcare delivery in rheumatology. The results of this study will 
provide a robust, real world-based evidence to understand the clinical effectiveness, safety 
and cost-effectiveness of electroacupuncture. For the TCM community, this trial can provide 
stakeholders greater evidence base towards implementation of electroacupuncture into the 
current healthcare system. For rheumatology community, a successful implementation of 
this model of care involving electroacupuncture will allow better management of AxSpA 
and also other chronic diseases such as chronic back pain and osteoarthritis. The long-term 
implications of a successful outcome of this project will provide clinicians in other 
specialties and policy makers confidence to explore electroacupuncture in management of 
patients with other chronic diseases such as diabetes, cancer care and cardiovascular 
diseases. 
 
1.2.2 
Rationale for Study Population 
 
AxSpA is a chronic debilitating disease which often results in severe disability and poor 
quality of life. Till date, there is no cure for AxSpA and the pathophysiology of the disease 
is still unclear. Based on current treatment guidelines, the first line treatment involves 
NSAIDs, but this is only effective in about one-third of the patients. For patients with 

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persistently active disease despite NSAIDs, the next recommended treatment is biologics 
which cost around $15,000 per year and is only efficacious in 60% of biologic treated 
patients. Of these, 75-90% of patients will suffer a relapse upon discontinuation of the 
biologics. NSAIDs and biologics are also not without side effects, which includes risk of 
developing renal impairment and peptic ulcer disease, increased risk of cardiovascular 
disease or increased risk of infection. 
 
1.2.3 
Rationale for Study Design 
 
This proposed project is a randomized controlled trial anchored closely using the 
Consolidated Standards of Reporting Trials (CONSORT) guidelines as well as the Standards 
for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) statement for 
acupuncture. This design can provide evidence of effectiveness, which may be important for 
policy- and decision-makers considering TCM as a treatment option for patients with 
AxSpA.  
 
2 
HYPOTHESIS AND OBJECTIVES 
 
2.1 
Hypothesis 
 
Our primary hypothesis is that electroacupuncture may result in better control of disease 
activity in patients with AxSpA as compared to manual acupuncture over 12 weeks. The 
secondary hypothesis is that electroacupuncture may result in greater improvements in other 
clinical and quality of life outcomes as compared to those receiving manual acupuncture 
over 24 weeks. The clinical, quality of life, and economic outcomes over 52 weeks serve as 
exploratory outcomes. We also hypothesize that there is no difference in safety between both 
arms.  
 

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2.2 
Objectives 
 
The objective of this study is to determine the clinical effectiveness, safety and cost-effectiveness of 
electroacupuncture as compared to manual acupuncture in the management of Axial 
Spondyloarthritis (AxSpA) with the following outcomes in Table 1. 
 
Table 1: Type of outcomes and time point 
Types of 
Outcomes 
Descriptions 
Primary 
outcome 
BASDAI score over 12 weeks (as assessed at weeks 0, 3, 6, 9, and 12) 
Secondary 
outcomes 
 
Clinical 
BASDAI score over 24 weeks (as assessed at weeks 0, 3, 6, 9, 12 and 24) 
 
BASFI, BASG, ASAS HI over 12 and 24 weeks (as assessed at weeks 0, 6, 12, and 24) 
 
Quality of life 
Quality of life – ASQoL and EQ-5D over 12 and 24 weeks (as assessed at weeks 0, 6, 12, 
and 24) 
 
Economic Outcomes 
Healthcare resource use 
Rheumatologist’s consultation fees, TCM physician time and salary, costs of acupuncture 
needles and equipment, costs of electroacupuncture unit, costs of imaging, costs of 
laboratory and procedures, AxSpA-related drug costs, AxSpA-related device costs, 
AxSpA-related physiotherapy costs, costs of other outpatient visits, costs of other drugs, 
costs of inpatient visits, costs of emergency department visits over 12 and 24 weeks (as 
assessed at weeks 0, 6, 12, and 24)  
 
Indirect costs 
Patient income and salary, number of days of work missed due to illness (when 
applicable), travel costs, work status (active, inactive, retired) over 12 and 24 weeks (as 
assessed at weeks 0, 6, 12, and 24) 
 
WPAI over 12 and 24 weeks (as assessed at weeks 0, 6, 12, and 24) 
Exploratory 
outcomes 
Clinical 
BASDAI score over 52 weeks (as assessed at weeks 0, 3, 6, 9, 12, 24 and 52) 
 
BASFI, BASG, ASAS HI over 52 weeks (as assessed at weeks 0, 6, 12, 24 and 52) 
 
TCM syndrome score over 12 weeks (as assessed at weeks 0, 3, 6, 9, and 12) 
 
Quality of life 
Quality of life – ASQoL and EQ-5D over 52 weeks (as assessed at weeks 0, 6, 12, 24 and 
52) 
 
Economic Outcomes 
Healthcare resource use 
Rheumatologist’s consultation fees, TCM physician time and salary, costs of acupuncture 
needles and equipment, costs of electroacupuncture unit, costs of imaging, costs of 
laboratory and procedures, AxSpA-related drug costs, AxSpA-related device costs, 
AxSpA-related physiotherapy costs, costs of other outpatient visits, costs of other drugs, 

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costs of inpatient visits, costs of emergency department visits over 52 weeks (as assessed 
at weeks 0, 6, 12, 24 and 52) 
 
 
Indirect costs 
Patient income and salary, number of days of work missed due to illness (when 
applicable), travel costs, work status (active, inactive, retired) over 52 weeks (as assessed 
at weeks 0, 6, 12, 24 and 52) 
 
WPAI over 52 weeks (as assessed at weeks 0, 6, 12, 24 and 52) 
Abbreviation  
ASAS HI: Assessment of SpondyloArthritis international Society Health Index; ASQoL: Ankylosing Spondylitis 
Quality of Life; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis 
Functional Index; BAS-G: Bath Ankylosing Spondylitis Global score; TCM: Traditional Chinese Medicine; WPAI: 
Work Productivity and Activity Impairment 

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Outcome Measurement 
The type of outcome measures and time of assessment are summarized in Table 2 below. Patient 
demographics, past medical history, and current medication use will be collected at enrolment and 
randomisation, which is also the date when patients have their baseline visit with the attending 
rheumatologist. Follow-up at week 3 is selected after the first 5 sessions of acupuncture as the pain-
relieving effects of electroacupuncture are postulated to be of faster onset and better as compared to 
manual acupuncture at this time point and is of clinical relevance to the patient. The week 6 and 12 
visits are selected because participants would have completed their 10 and 20 sessions of 
acupuncture respectively, and most trials in this field assessed the outcomes at this time point. 
Follow-up at week 9 is selected to allow the trending of the trajectory of pain relief. Outcomes at 
week 24 and 52 can be used to assess long term effectiveness of electroacupuncture, which matter 
most to patients. 
 
Primary outcome 
The mean difference in BASDAI score between the 2 groups over 12 weeks (as assessed at weeks 0, 
3, 6, 9, and 12) adjusted for baseline covariate and other potential confounders (as appropriate) is 
the primary outcome in this study. It measures severity of fatigue, spinal and peripheral joint pain, 
localized tenderness and morning stiffness (both qualitative and quantitative).The 0-10 pain 
numerical rating scale (NRS) will be used and it is widely used and validated across many settings 
to assess the disease activity of AxSpA, and has been endorsed by Assessment of SpondyloArthritis 
International Society (ASAS) for the measurement of disease activity. This was selected, as the 
pain-relieving effects of the two different modes of acupuncture will be captured by the BASDAI. 
BASDAI (ranges from 0 to 10) is an English, self-administered disease-specific questionnaire to 
measure disease activity, with higher values indicating more active disease.  
 
Secondary clinical outcomes 
The mean difference in BASDAI score between the 2 groups over 24 weeks (as assessed at weeks 0, 
3, 6, 9, 12 and 24) adjusted for baseline covariate and other potential confounders (as appropriate) 
will serve as one of the secondary clinical outcomes. 
  
The mean difference in clinical parameters including BASFI, BAS-G and ASAS HI between the 2 
groups over 12 and 24 weeks (as assessed at weeks 0, 6, 12, and 24) adjusted for baseline covariate 
and other potential confounders (as appropriate) will serve as the other clinical outcomes for this 
study. These are clinically relevant outcomes measures used in daily practice in the management of 
AxSpA patients and endorsed by ASAS. These patient-reported outcomes will be collected via 
interviews by our research assistant. 
 
BASFI (ranges from 0 to 10) is a disease-specific questionnaire used to measure physical 
functioning, with higher values indicating worse functioning. BAS-G (ranges from 0 to 100) is a 
disease-specific questionnaire to give a global assessment of well-being, with higher score reflecting 
poorer well-being. ASAS HI is a disease-specific questionnaire, with 17 dichotomous items 
(dichotomous response option: “I agree” and “I do not agree”) to assess health status in patients with 
all forms of SpA. The total sum of the ASAS HI ranges from 0-17, with lower scores indicating 
better health status. 
 
Secondary and exploratory quality of life outcomes 
The mean difference in the ASQoL and EQ-5D score between the 2 groups over 12 and 24 weeks 
(as assessed at weeks 0, 6, 12, and 24) adjusted for baseline covariate and other potential 

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confounders (as appropriate) will serve as the secondary quality of life outcomes for this study. 
 
ASQoL is a self-administered patient-derived and disease-specific measure of QoL for AS. It 
consists of 18 items with a “yes” (scored as 1) or “no” (scored as 0) response to each item. All item 
scores are summed to a total score ranging from 0 to 18, with higher scores indicating worse QoL. 
The English version of ASQoL has been shown to be a valid and reliable measure for use in patients 
with axSpA, also in Singapore.  
 
The EQ-5D comprises a descriptive system and a visual analogue scale (VAS). The former assesses 
five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) with 
five possible answers for each item (1= “no”, 2= “slight”, 3= “moderate”, 4= “severe” and 5= 
“unable”/“extreme”). EQ-5D utility scores will then be computed with 0 representing death and 1 
representing full health, using time trade-off valuations from the Singaporean value set. The VAS is 
a vertical “ruler” that records the patient’s self-rated health and extends from 0 (“worst imaginable 
health state”) to 100 points (“best imaginable health state”) for respondents to rate their overall 
health. 
 
Secondary economic outcomes 
AxSpA-related and non-AxSpa-related health care costs will include rheumatologist’s consultation 
fees, TCM physician time and salary, costs of imaging, laboratory and procedures, drug costs, 
assistive devices cost, costs of other outpatient visits, AxSpA-related physiotherapy costs, costs of 
inpatient visits, and costs of visits to emergency departments. Healthcare use and costs will be 
obtained through questionnaires administered to patients. In addition, this information will be 
supplemented by a review of medical records and data retrieval from the electronic databases at 
SGH. Non-health care financial consequences will be captured in the questionnaires by recording 
self-reported travel costs incurred by the patients to receive treatment, patient income and salary, the 
number of days patients missed work due to illness, and work status (active, inactive, retired). The 
mean difference in the healthcare use and costs over 12 and 24 weeks (as assessed at weeks 0, 6, 12, 
and 24) adjusted for baseline covariate and other potential confounders (as appropriate) will serve as 
the secondary economic outcomes for this study. 
 
The WPAI assesses absenteeism, presenteeism, daily activity impairment and work productivity. 
The mean difference in the WPAI outcomes over 12 and 24 weeks (as assessed at weeks 0, 6, 12, 
and 24) adjusted for baseline covariate and other potential confounders (as appropriate) will serve as 
the secondary economic outcomes for this study.   
 
Exploratory outcomes 
The BASDAI, BASFI, BAS-G, ASAS HI, ASQoL, EQ-5D, WPAI outcomes, total AxSpA-related 
and non-AxSpA-related costs over 52 weeks will serve as exploratory outcomes. 
 
TCM syndrome score between the 2 groups over 12 weeks (as assessed at weeks 0, 3, 6, 9, and 12) 
adjusted for baseline covariate and other potential confounders (as appropriate) is one of the 
exploratory outcomes in this study. The score will be calculated based on the severity of symptoms 
observed. Guidelines of symptom differentiation and severity rating are according to the “Guiding 
principles for clinical research of new Traditional Chinese Medicine” (中药新药临床研究指导原
则). All patients are evaluated holistically, and other areas of discomfort, in addition to pain, also 
contribute to the severity of their condition and impact their quality of life. These symptoms can be 
treated by acupuncture and changes in the severity will also serve as an indication on the 

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effectiveness of the different forms of acupuncture in improving their overall condition. 
 
Table 2: Summary of primary, secondary and exploratory outcome measures  
 
Abbreviation  
ASAS HI: Assessment of SpondyloArthritis international Society Health Index; ASQoL: Ankylosing Spondylitis 
Quality of Life; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis 
Functional Index; BAS-G: Bath Ankylosing Spondylitis Global score; TCM: Traditional Chinese Medicine; WPAI: 
Work Productivity and Activity Impairment 
 
Outcomes 
Time  
 
 
Baseline 
Week 3 
Week 6 
Week 9 
Week 12 
Week 24 Week 52 
1. Primary outcome 
 
1.1 BASDAI   
✓ 
✓ 
✓ 
✓  
✓ 
 
2. Secondary outcomes 
 
2.1 Clinical outcomes 
 
2.1.1 BASDAI 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
2.1.2 BASFI 
✓ 
 
✓  
 
✓  
 ✓ 
 
2.1.3 BAS-G 
✓ 
 
✓  
 
✓  
 ✓ 
 
2.1.3 ASAS HI 
✓ 
 
✓  
 
✓  
 ✓ 
 
 
 
2.2 Quality of life outcomes 
 
2.2.1 ASQoL 
✓ 
 
✓ 
 
✓  
✓  
 
2.2.2 EQ-5D 
✓ 
 
✓ 
 
✓  
✓  
 
2.3 Economic outcomes 
 
 
 
2.3.1 Costs 
✓ 
 
✓ 
 
✓  
✓  
 
2.3.2 WPAI 
✓ 
 
✓ 
 
✓  
✓  
 
3. Exploratory outcomes 
 
3.1 Clinical outcomes 
 
3.1.1 BASDAI 
 
  
 
  
 
  
 ✓ 
3.1.2 BASFI 
 
 
 
 
 
  
 ✓ 
3.1.3 BAS-G 
 
 
  
 
 
  
 ✓ 
3.1.4 ASAS HI 
 
 
  
 
 
  
 ✓ 
3.1.5 TCM 
syndrome  
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
 
 
 
 
 
 
3.2 Quality of life outcomes 
 
3.2.1 ASQoL 
 
 
 
 
 
  
 ✓ 
3.2.2 EQ-5D 
 
 
 
 
 
  
 ✓ 
3.3 Economic outcomes 
 
3.3.1 Costs 
 
 
 
 
  
 
✓ 
3.3.2 WPAI 
 
 
 
 
  
 
✓ 

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2.3 
Potential Risks and Benefits:  
 
2.3.1 
Potential Risks 
 
Potential adverse effects of acupuncture and electroacupuncture include fainting, bent or 
broken needle, local pain, slight bleeding and skin infections. If any of these symptoms 
occur, they will be advised to contact study personnel. These symptoms will be evaluated 
and reviewed by the PI who will determine if these symptoms are related to acupuncture.  
 
2.3.2 
Potential Benefits 
 
There is no assurance that participants will benefit from this study. However, their 
participation may contribute to the medical knowledge about the use of TCM in particular 
electroacupuncture in the management of AxSpA. 
 
3 
STUDY POPULATION 
 
3.1 
List the Number and Nature of Subjects to be Enrolled 
 
A total of 100 patients with 50 patients per group will be recruited. There is no subject 
restriction based on race or gender of the subject. 
 
3.2 
Criteria for Recruitment and Recruitment Process 
 
Patients with a clinical diagnosis of AxSpA and fulfil the inclusion criteria will be recruited 
from outpatient clinics by the attending rheumatologist. In the case whereby the PI is also the 
attending physician, he will directly make first contact and ask for informed consent. If not, a 
study team member will ask for informed consent. The study will be performed in accordance 
with the guidelines and with the approval of the SingHealth Centralised Institutional Review 
Board. 
 
3.3 
Inclusion Criteria 
 
We aim to recruit adult patients with AxSpA who have spinal pain and active disease despite 
standard medical therapy. Patients are eligible for the study if they are 21 years of age or 
older; have AxSpA, diagnosed according to the 2009 Assessment of Spondyloarthritis 
International Society (ASAS) criteria; have active disease based on Bath AS Disease Activity 
Index (BASDAI) score ≥4 on a 11-point Numerical Rating Scale (NRS); have failed 2 
sequential NSAIDs (including COX-2 inhibitor) at maximal tolerated doses for ≥ 4 weeks in 
total. Patients who are on current treatment with concomitant biological therapy (e.g. tumour 
necrosis factor inhibitor therapy, anti-interleukin 17) or non-biologic disease-modifying 
antirheumatic drugs (DMARDs) (e.g. methotrexate (MTX) or sulfasalazine (SSZ) or 
leflunomide (LEF)) at study entry must be on the drug for ≥12 weeks and at stable dose for ≥4 
weeks prior to randomisation. Patients taking systemic corticosteroids have to be on stable 
dose of ≤ 10mg/day prednisolone or equivalent for at least two weeks before randomisation.  
 
3.4 
Exclusion Criteria 
 
We will exclude patients who are pregnant or breastfeeding, have bleeding disorders, have 
blood-borne communicable diseases (e.g. hepatitis B, hepatitis C, human immunodeficiency 

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virus, etc), have implantable electrical device (e.g. pacemaker), as well as patients suffering 
from impaired skin sensation or serious skin lesions along the vertebrae. 
 
3.5 
Subject Replacement 
 
Subjects who drop out will not be replaced. 
 
4 
STUDY DESIGN 
4.1 
Randomisation and Blinding 
 
Patients will be randomly allocated to receive electroacupuncture or manual acupuncture on a 
1:1 basis via random permuted block randomization. 
 
4.2 
Study Visits and Procedures 
 
4.2.1 
Screening Visits and Procedures 
 
As BASDAI and spinal pain score are routinely used during outpatient sessions to measure 
patient disease activity and pain level, there will be no specific screening visits and 
procedures for this study. The PI will assess the eligibility for each participant before 
enrolment.  
 
4.2.2 
Study Visits and Procedures 
 
Usual rheumatological care, which will be given to all patients in this trial, comprises of 
medications (e.g. NSAIDs, DMARDs or biologics) and regular monitoring for other 
complications that may arise from AxSpA such as cardiac events and maintenance of bone 
health. In this trial, the attending rheumatologist will see each patient at regular time points 
(Figure 1) from the start of randomization till trial termination at week 52. Extra visits will 
be arranged if needed e.g. for titration of medications or to address monitoring of 
complications of disease. The attending rheumatologist will prescribe a variety of treatments 
inclusive of medications such as NSAIDs and physiotherapy. At each session, the attending 
rheumatologist will monitor the disease activity through a validated patient-reported 
outcome instrument. Further investigations such as imaging or laboratory tests will be 
ordered depending on the clinical judgment of the attending rheumatologist and the 
guidelines stipulated. The rheumatologist will be allowed to prescribe the full range of 
treatment usually used, including biologics, as per treatment guidelines.  
 
 
 
 

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Recruitment and 
Randomisation 
5 Manual acupuncture 
(Week 1-3) 
5 Electroacupuncture 
(Week 1-3) 
Visit 1 (Week 3) 
5 Electroacupuncture 
(Week 3-5) 
5 Manual acupuncture 
(Week 3-5) 
Visit 2 (Week 6) 
5 Electroacupuncture 
(Week 7-9) 
Visit 3 (Week 9) 
5 Electroacupuncture 
(Week 9-11) 
Visit 4 (Week 12) 
Visit 5 (Week 24) 
Visit 1 (Week 3) 
Visit 2 (Week 6) 
5 Manual acupuncture 
(Week 7-9) 
Visit 3 (Week 9) 
5 Manual acupuncture 
(Week 9-11) 
Visit 4 (Week 12) 
Visit 5 (Week 24) 
Electroacupuncture arm (45 patients) 
 Manual acupuncture arm (45 patients) 
 
 
 
 
 
Figure 1: Flowchart to illustrate research methodology and timelines 
 
Both arms will involve the TCM physician in the management of patients with AxSpA in 
addition to the usual rheumatological care. The clinical interventions carried out by the TCM 
physicians include, but is not limited to, counselling of patients regarding their illness from 
the TCM perspective, diagnosing based on TCM clinical syndromes and prescribing 
acupuncture treatment (electroacupuncture or manual acupuncture) accordingly. The 
recommended acupuncture treatment will consist of a total of 20 sessions (or 2 courses) in 
total. Each course of treatment will consist of 10 acupuncture sessions held over 5 weeks. 
The patient will take a break of 5-7 days in between each course of acupuncture. The TCM 
physicians will be allowed to make minor adjustment to the acupuncture points in view of 
the differing constitution of the patients as per the holistic treatment philosophy of TCM.  
 
Manual acupuncture  
Patients will receive usual rheumatologic care. In this study, the main acupoints will be 
Jingjin points (meridian sinews) along the Bladder meridian of Foot – Taiyang (足太阳经筋
Electroacupuncture arm (50 patients) 
Manual acupuncture arm (50 patients) 
Visit 6 (Week 52) 
Visit 6 (Week 52) 

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筋病灶点), such as Shenshuci (肾俞次), as well as Jingjin points (meridian sinews) at 
transverse process from L2 to L4 (腰2 至腰4 横突), iliac crest (髂嵴) and spinous process 
from S1 to S4 (骶1 至骶4 棘突). Secondary acupoints for the various syndromes and 
symptoms are listed below. 
 
Secondary acupoints for syndromes: 
1. Blockage due to dampness and heat (湿热痹阻证): Main acupoints PLUS Quchi (LI11 曲
池), Yinlingquan (SP9 阴陵泉) acupoints would also be chosen.  
2. Blockage due to dampness and coldness ( 寒湿痹阻证): Main acupoints PLUS 
Yaoyangguan (DU3 腰阳关)，Yinlingquan (SP9 阴陵泉)acupoints would also be chosen. 
3. Blockage due to stagnated blood (瘀血痹阻证):  Main acupoints PLUS Sanyinjiao (SP6 
三阴交), Geshu (BL 17 膈俞) acupoints would also be chosen. 
4. “Yang” deficiency in kidneys and “Du” meridian (肾督阳虚证): Main acupoints PLUS 
Mingmen (DU4 命门), Yaoyangguan (DU3 腰阳关) acupoints would also be chosen. 
5. Deficiency in the liver and kidneys (肝肾不足证): Main acupoints PLUS Ganshu (BL18
肝俞), Sanyinjiao (SP6 三阴交) acupoints would also be chosen. 
 
Secondary acupoints for symptoms: 
1. Neck pain: Main points PLUS secondary points PLUS Fengchi (GB20 风池), Jianjing 
(GB21 肩井), Dazhui (DU14 大椎) 
2. Thoracic pain: Main points PLUS secondary points PLUS Dazhu (BL11 大杼), Shenzhu 
(DU12 身柱), Zhiyang (DU9 至阳) 
3. Lumbar pain: Main points PLUS secondary points PLUS Dachangshu (BL25 大肠俞), 
Yaoyan(EX-B7 腰眼) , Weizhong (BL40 委中)  
4. Sacrum pain: Main points PLUS secondary points PLUS Ciliao (BL32 次髎) 
5. Knee paint: Main points PLUS secondary points PLUS Yinlingquan (SP9 阴陵泉), 
Yanglingquan (GB34 阳陵泉), Weizhong (BL40 委中) 
6. Ankle Pain: Main points PLUS secondary points PLUS Taixi (KI3 太溪), Kunlun (BL60 
昆仑), Qiuxu (GB40 丘墟)  
 
Acupuncture will be performed after disinfecting the acupuncture points. Depending on the 
acupuncture points, 0.25-0.30 mm × 25-75 mm sterile acupuncture needle will be used, with 
patient lying prone. Depending on the acupuncture points, we will insert the needles 10-50 
mm, and will use rotating manipulation or lifting-thrusting manipulation to achieve de qi (a 
compositional sensation including soreness, numbness, distention and heaviness).  
 
Electroacupuncture 
In addition to the procedures described in the manual acupuncture group, for patients in the 
electroacupuncture group, the electroacupuncture unit will be connected to 1-3 pairs of 
acupoints on the same side of body after “de qi” is obtained. At the beginning, all adjustment 
dials and knobs of the electroacupuncture unit are to be set at 0 (no stimulation). The dense-
sparse wave is selected before the power switched on. Paired electrodes are to be connected 
to points on the same side of the body and should not cross the spine to prevent current from 
reaching the heart. Current will be applied to acupuncture points in order of top to bottom 
(superior to inferior), medial to lateral. After connecting the electrodes to the needle, current 

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intensity will be increased slowly to avoid sudden shock to the patients. The current used is 
based on the tolerance of each patient, with the intensity at a range from 2 to 5. For patients 
who report weak or no sensation at the point of stimulation, the electrical flow can be 
increased gradually, or the apparatus switched off for 1-2 minutes and then restarted. 
Needles with electrical stimulation will be retained for 30 min.  
 
4.2.3 
Final Study Visit 
 
The final study visit will be at 52 weeks after baseline visit. 
4.2.4 
Post Study Follow up and Procedures 
 
There will be no post study follow up and procedures. However, subjects will be advised to 
contact study personnel if there is occurrence of adverse event. 
   
4.3 
Discontinuation/Withdrawal 
 
4.3.1 
Discontinuation Criteria 
 
Study treatment will be discontinued and the subjects withdrawn from the trial if the 
investigator determines that continuing it would result in significant safety risk for the 
subject. The following circumstances require study treatment discontinuation: 
• 
Withdrawal of informed consent. 
• 
Study closure. 
 
4.3.2 
Discontinuation Visit and Procedures 
 
Subjects may withdraw voluntarily from participation in the study at any time. Subjects may 
also withdraw voluntarily from receiving the study intervention for any reason.  
 
If voluntary withdrawal occurs, the subject will be asked to continue scheduled evaluations, 
complete an end of study evaluation, and be given appropriate care under medical 
supervision until the symptoms of any adverse event resolve or the subject’s condition 
becomes stable. In addition, the investigators must determine the primary reason for a 
subject’s withdrawal and record this information on the medical record. 
 
5 
TRIAL MATERIALS 
 
The TCM modality for treatment used here will be electroacupuncture and manual 
acupuncture, which is specially implemented by our experienced collaborators at Thong 
Chai Medical Institution. The recommended acupuncture treatment will consist of a total of 
20 sessions (or 2 courses) in total. Each course of treatment will consist of 10 acupuncture 
sessions held over 5 weeks of 30 minutes each. Special queues will be set up with the TCM 
partner to reduce dropout rates due to long queues at the TCM site. To avoid potential 
contamination of the study results, the rheumatologist, nurses and allied health professionals 
will be reminded to treat the patients in both interventional and control arms in a consistent 
manner. All adverse reactions as shown will be entered in a registry by a panel of experts 
consisting of rheumatologists and TCM physician with regards to its severity. All research-
related electronic data will be password locked and stored together with the study survey or 
paper documents in a locked cabinet in the PI’s office at SGH. All patient information will 
be kept strictly confidential, following policies in SingHealth. 

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6 
TREATMENT 
 
6.1 
Specific Restrictions / Requirements  
 
The rheumatologist will see these patients at baseline, week 6, week 12, week 24 and week 
52, and whenever required. Patients will not visit any other TCM physician nor seek 
alternative therapy for the first 24-week of the study. As per usual medication-dispensing 
advice, we will counsel on the importance of medication adherence. As it is likely that the 
patients will not be upfront about their visit to the TCM physicians from previous data, the 
research assistant will also query about their use of other TCM at specified data collection 
points. We will analyze as per intention to treat (ITT) protocol to minimize the potential bias 
associated with not following assigned treatment.  
 
6.2 
Blinding 
 
The Principal Investigator is blinded to the treatment allocation in the first 12 weeks. There 
will be no blinding of study participants nor other study staff.  
 
6.3 
Concomitant therapy 
 
All medications (prescription and over the counter), vitamin and mineral supplements, and / 
or herbs taken by the participant will be documented. 
 
7 
SAFETY MEASUREMENTS 
 
7.1 
Definitions 
 
An adverse event (AE) refers to any untoward event or medical occurrence in a patient or 
clinical investigation subject that: 
• does not necessarily have a causal relationship with the treatment 
• reveals any defect in any medical device  
• concerns any adverse effect arising from the use of thereof  
 
Adverse effect refers to any debilitating, harmful, toxic or detrimental effect that the medical 
device has been found to have or to be likely to have on the body or health of humans when 
such a medical device is used by or administered to humans.  
 
An adverse event (AE) can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the intervention 
or use of a medical device, whether or not related to the intervention or medical device. 
 
A serious adverse event (SAE) is any untoward medical occurrence as a result of human 
biomedical research which: 
• results in or contributes to death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing hospitalisation 
• results in or contributes to persistent or significant disability/incapacity 
• results in or contributes to a congenital anomaly/birth defect 

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• results in the transmission of a communicable disease 
• 
results in any misidentification or mix-up of any type of human biological material, 
gamete or embryo 
• 
results in such other events as may be prescribed 
 
7.2 
Collecting, Recording and Reporting of Serious Adverse Events (SAEs) to Centralised 
Institutional Review Board (CIRB)  
 
Only related SAEs (definitely/ probably/ possibly) will be reported to CIRB, in accordance 
with the reporting requirement and timeline stated on CIRB website. Related SAEs are SAEs 
with a reasonable possibility that they may have been caused by participation in the research.  
 
The investigator is responsible for informing CIRB after first knowledge that the case 
qualifies for reporting. Follow-up information will be actively sought and submitted as it 
becomes available.  
 
Related AEs will not be reported to CIRB.  However, the investigator will keep record of such 
AEs cases at the Study Site File. 
 
7.3 
Collecting, Recording and Reporting of Adverse Events (AEs) to the Health Sciences Authority 
(HSA) 
 
The occurrence of any AE that is associated with use of the medical device, which led to one 
of the following outcomes, will be reported to HSA, in accordance with the reporting 
requirement and timeline stated on HSA website: 
• caused a serious threat to public health 
• death of a patient, user or other person 
• serious deterioration in state of health, user or other person 
• no death or serious injury, but might lead to death or serious injury of a patient, user or 
other person if the event recurs 
 
Any event or other occurrence relating to a medical device represents a serious threat to public 
health if one or more of the following occur: 
• the event or other occurrence is a hazard arising from a systematic failure of the 
medical device that becomes known to the manufacturer, importer or wholesaler of the 
medical device 
• the event or other occurrence may lead to death of, or a serious injury to, a patient, a 
user of the medical device or any other person 
• the probable rate of occurrence of or degree of severity of harm caused by the hazard 
was not previously known or anticipated by the product owner of the medical device 
• it becomes necessary for the product owner of the medical device to take prompt 
action (including the recall of the medical device) to eliminate or reduce the risk of the 
hazard 
 
A serious deterioration in state of health can include: 
• life-threatening illness or injury 
• permanent impairment of a body function or permanent damage to a body structure 
• a condition necessitating medical or surgical intervention to prevent permanent 
impairment of a body function or permanent damage to a body structure 

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7.4 
Safety Monitoring Plan 
 
The data and safety review will be conducted every twelve months. All AEs such as skin 
injuries and infections will be monitored for safety.  
 
All study AEs will be recorded on the Adverse Event data collection form with the following 
information: 
1. 
AE term 
2.           Severity grade (mild, moderate, severe) 
3. 
Its relationship to the study intervention  
4. 
Its duration (start and end dates or if continuing at final examination) 
5. 
Description of AE and subsequent treatment, if any 
6.           Whether it constitutes as SAE 
7. 
Outcome 
8.           Date which Site Principal Investigator or project team members were aware of AE 
 
The study will be stopped if any SAE occurs. The IRB and HSA will be consulted, and if it is 
determined that the SAE was not related to study intervention, the study may be continued. 
 
If the adverse event is determined to be related to study intervention, the nature of the 
relationship between the adverse event and the medical device will be elucidated. IRB and 
HSA will be consulted regarding further enrolment. 
 
7.5 
Complaint Handling  
 
The PI will review all complaints and discuss with the study team about the follow-up action 
when there is complaint. 
 
8 
DATA ANALYSIS 
 
8.1 
Data Quality Assurance 
 
The PI and study team members will perform the data monitoring. The review will be 
conducted every twelve months. The research coordinator will key in the data into REDCap. 
Data checks such as data correlation and cross tabulation will be carried out before 
commencement of data analysis. 
 
8.2 
Data Entry and Storage 
 
The research coordinator will key in the data into REDCap. Data will be password encrypted 
and only anonymised data will be exported for analysis. No identifiable data of the subjects 
will be shared with another party, nor the third-party sponsor. 

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9 
SAMPLE SIZE AND STATISTICAL METHODS 
 
9.1 
Determination of Sample Size  
 
The sample size is estimated based on a repeated measures trial design with one pre- and four 
post-intervention (3, 6, 9 and 12 weeks) measurements. Assuming a mean difference of 0.75 
with a SD of 2, a correlation of 0.6, a power of 80% and a two-sided level of significance of 
5%, a minimum sample size of 80 would be required. Further accounting for 20% attrition, the 
total sample size would be 100 or 50 per group.  
 
9.2 
Statistical and Analytical Plans 
 
All patient data will be analyzed using intention-to-treat approach. The demographic and 
baseline clinical characteristics of participants will be summarized using mean and standard 
deviation (or median and interquartile range where appropriate) for continuous variables, and 
count and percentage for categorical variables. Linear mixed effect models will be 
implemented to determine the effect of intervention on the primary and secondary outcomes, 
taking into account possible intra-subject correlation between the repeated measures. These 
models will further be adjusted for the respective baseline covariate and other potential 
confounders as appropriate. The effect of intervention on the primary and secondary outcomes 
will be quantified based on the mean difference and its associated 95% confidence interval. 
All analyses will be conducted based on the principle of intention-to-treat assuming a two-
sided test at the 5% level of significance. To analyze safety of the intervention, we will 
present the adverse events that occurred in frequency and percentages within the one-year 
period for both intervention and control arms. 
 
Cost-effectiveness analyses (CEA) will be performed from healthcare system and societal 
perspectives. The outcome of interest for CEA is the incremental cost effectiveness ratio 
(ICER), calculated by dividing the difference in total costs by the difference in the outcome 
between the two arms. Costs from the healthcare system perspective will include direct cost of 
medical care such as the cost of electroacupuncture, drug and physician time. Cost of TCM 
physician will be estimated based on the salaries of the TCM physicians. Costs from the 
societal perspective will include direct cost of medical care as well as indirect cost such as 
loss of work productivity (secondary economic outcomes).  
 
The outcome measure is the cumulative quality-adjusted life years (QALY) over the study 
period; thus, the ICER for CEA represents the cost per QALY gained. Cumulative QALY for 
each study arm will be calculated using area under the curve by summing the areas of the 
geometrical shapes obtained by linearly interpolating between utility scores at the 5 follow-up 
time points, with adjustment of baseline utility value if baseline differences exist between 
study arms. Utility scores will be measured using EQ-5D. To generate confidence intervals of 
the ICERs, non-parametric bootstrapping (random sampling with replacement) will be 
conducted. Sensitivity analysis will be conducted to evaluate the influence of uncertainties in 
the variables and assumptions employed on the analysis results. 
 

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10 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
The investigator(s)/institution(s) will permit study-related monitoring, audits and/or IRB 
review and regulatory inspection(s), providing direct access to source data/document. 
 
11 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
The PI and study team members will perform the data monitoring. The review will be 
conducted every twelve months. The research coordinator will key in the data into REDCap. 
Data checks such as data correlation and cross tabulation will be carried out before 
commencement of data analysis. 
 
12 
ETHICAL CONSIDERATIONS 
 
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with the Good Clinical Practice and the 
applicable regulatory requirements. 
 
This final Clinical Trial Protocol, including the final version of the Participant Information 
Sheet and Consent Form, must be approved in writing by the CIRB, prior to enrolment of any 
patient into the study. 
 
The principle investigator is responsible for informing the CIRB of any amendments to the 
protocol or other study-related documents, as per local requirement. 
 
12.1 Informed Consent 
 
Consent process will take place in the clinic consultation room when the potential participant 
comes for his/her consultation. The consent process will take place in the outpatient clinic 
consultation room. The place chosen is suitable because it is a closed and private environment 
with only the PI, potential participant and research coordinator present. When the potential 
participant is identified, the PI will explain the study to the potential participant and invite 
him/her to participate in the study. The PI will answer all questions and the participant will be 
given ample time to consider. He/She need not agree on participation immediately. 
Participants are informed that participation to the study is voluntary and they have the rights 
not to participate.  
 
12.2 Confidentiality of Data and Patient Records 
 
The electronic records will be stored in a PC (with password encryption) in REDCap in the 
locked office in the Department of Rheumatology & Immunology. Paper records will 
similarly be stored in the locked office in the Department of Rheumatology & Immunology. 
All data will be decoded from subject's identity. Only the PI, designated coordinator and 
designated biostatistician will have access to the identifiable data. Data will be password 
encrypted and only anonymised data will be exported for analysis. No identifiable data of the 
subjects will be shared with another party, nor the third-party sponsor. Mr Kwan will access 
the data in the compound of Singapore General Hospital only and data will be de-identified 
before sharing. Also, only de-identified research data will be sent to Dr Tan Chuen Seng and 

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Prof Tai Bee Choo for data analysis. 
 
13 
PUBLICATIONS 
 
All authors will review publication for study findings. The PI will decide on authorship for 
publication. 
 
14 
RETENTION OF TRIAL DOCUMENTS 
 
Records for all participants, including CRFs, all source documentation (containing evidence 
to study eligibility, history and physical findings, laboratory data, results of consultations, 
etc.) as well as IRB records and other regulatory documentation will be kept in the locked 
office in the Department of Rheumatology & Immunology. The records will be accessible for 
inspection and copying by authorized authorities. When the study is complete, data will be 
stored for 7 years as per SingHealth guidelines. 
 
15 
FUNDING and INSURANCE 
 
This trial is supported by philanthropic funding under the Reverie Rheumatology Research 
Fund. The Hospital does not make any provisions to compensate study participants for 
research related injury. However, compensation may be considered on a case-by-case basis 
for unexpected injuries due to non-negligent causes. These costs will be covered using the 
insurance for clinical trials (Ministry of Health Clinical Trial Insurance) conducted in 
SingHealth.