Very Low Dose, add-on Prednisolone in Patients With Newly Diagnosed Rheumatoid Arthritis: a Randomised Placebo-controlled Study
Phase: PHASE4
Conditions: Rhematoid Arthritis
Sponsor: Chinese University of Hong Kong

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Very low dose, add-on prednisolone in patients with newly diagnosed rheumatoid arthritis: a 
randomised placebo-controlled study 
 
 
Research in context: 
(i) What is the existing evidence before this study based on an up-to-date literature search? 
State clearly whether research on a similar topic has been/is being carried out. Outline the 
research approaches in other studies and highlight their deficiencies and the research gap. 
 
There are conflicting views from international guidelines on the use of glucocorticoids (GC) 
as bridging therapy in patients with newly diagnosed rheumatoid arthritis (RA). While GC, 
typically at a dose of prednisolone ≥5mg daily, is definitely effective in controlling RA disease 
activity, it is associated with dose-dependent toxicities. There are emerging evidence 
supporting prednisolone dose <5mg daily is not associated with significant infection risk or 
bone loss. Recent real-world registry data also suggest very low dose GC are cardiovascular 
safe in short and long term. Two GC tapering studies provided indirect evidence that very low 
dose GC could help RA disease control. However, the therapeutic effect of very low dose GC 
(prednisolone dose <5mg daily) as bridging therapy has not been formally investigated. 
Therefore, we plan to conduct the first randomised placebo-controlled trial evaluating the 
efficacy and safety of very low dose add-on GC in patients with newly diagnosed RA. 
 
(ii) How will this study add value to existing evidence to improve patient care, population 
health, 
influence clinical practice and/or health services management, or inform health policy in Hong 
Kong and elsewhere? 
 
The results of our study will provide immediate evidence supporting the use of very low dose 
GC as bridging therapy while initiating conventional synthetic disease modifying anti-
rheumatic drugs, which remain the first-line treatment for all patients with newly diagnosed 
RA. The proposed low dose prednisolone prescription can be directly applied to daily clinical 
care. The aim is to offer rapid symptomatic relief, abolish inflammation promptly and treat RA 
to the target of disease remission. This coincides with the contemporary treatment strategies of 
RA which have been well proven to be pivotal for improving patient long-term outcomes. 
Disability of RA patients will be minimized. Their quality of life and productivity can be 
restored as early as possible. Expensive advanced therapies with variable access in different 
health-care settings can be reserved for refractory cases. The treatment algorithm of the study 
can be adopted by future RA management recommendations. The ultimate goal will be to 
improve patient health and reduce the overall socio-economic burden of the disease. 
 
b(ii). Introduction: 
Rheumatoid arthritis (RA) is a common chronic inflammatory arthritis affecting 0.35% of the 
population in Hong Kong (1). Uncontrolled arthritis can lead to pain, disability and decreased 
quality of life. We also found that the disease carried substantial socioeconomic costs (2). The 
contemporary management strategies have considerably improved the long-term outcomes of 
RA but come with toxicity and cost issues. Local and international treatment recommendations 
are largely similar, involving early initiation of conventional synthetic disease-modifying anti-
rheumatic drugs (csDMARDs) and prompt up-titration of medications if tight disease control 

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cannot be achieved (3-6). The major discrepancy between guidelines concerns the use of 
glucocorticoids (GCs) before csDMARDs become fully effective – as a bridging therapy. 
 
GCs were introduced in the 1950s, and have been widely available in all health-care settings. 
Despite its safety concerns, GC stands as a potent anti-inflammatory drug useful for prompt 
and reliable relief of RA symptoms. While it is agreed that long-term usage is harmful, GC is 
still commonly prescribed especially at the initial presentation of active disease while awaiting 
the effect of csDMARDs (7). In our recent retrospective study using real-world local territory-
wide data, 37.7% of patients with early RA (mean disease duration 0.7 year) were on GC (8). 
Intriguingly, the latest RA management recommendations from the American College of 
Rheumatology (ACR, updated in 2021) and European Alliance of Associations for 
Rheumatology (EULAR, updated in 2022) are divergent in terms of GC bridging therapy (5, 
6). ACR conditionally recommended the initiation of csDMARD without short-term GC (over 
with GC) for patients with active disease, meanwhile acknowledging that shortterm GC is often 
needed for symptom alleviation. It also strongly recommended against using GC for longer 
than 3 months. On the contrary, EULAR recommended that short-term (not more than 3 months) 
GC should be considered when initiating csDMARD but should also be tapered and 
discontinued as quickly as clinically feasible, given the robust evidence of efficacy of a 
combination of csDMARD with GC (9). Similarly, while the Hong Kong Society of 
Rheumatology  ecommended that bridging GC might be considered when starting csDMARDs, 
the latest update of the Asia Pacific League of Associations of Rheumatology RA treatment 
recommendation did not mention the usage of GC in addition to csDMARD monotherapy (3, 
4). Despite the distinctly different recommendation statements, all authorities clearly 
acknowledged the therapeutic effect as well as toxicity of GC, and emphasized minimization 
of the dose and duration of use. 
 
Among the extensive list of side effects, increased cardiovascular disease (CVD) risks 
associated 
with GC use is of particular concern. CVD is the most common comorbidity and the leading 
cause of mortality in patients with RA (10). The excess CVD risk in RA is mediated by the 
underlying chronic systemic inflammation, increased prevalence of traditional cardiovascular 
risk factors, and the use of various pharmacotherapeutic agents including GC and arguably 
JAK inhibitors (11). GC increases the risk of CVD by adversely affecting blood pressure, sugar 
metabolism and lipid profile. On the other hand, knowing the key inflammatory cytokines in 
RA, for example, TNF-alpha and IL-6 also promote atherosclerosis, GC may be able to exert 
some cardiovascular protective effect via suppression of these cytokines at transcription level 
(12-14). In addition, nuclear factor-kappa B (NF-κB) has been revealed to be a pivotal upstream 
source for these pro-inflammatory signals involved in the pathogenesis of both RA and 
atherosclerosis, and GC is a known potent inhibitor of NF-κB expression (15-17). Given the 
toxicities associated with GC are dose-dependent, finding a safe threshold dose and duration 
of GC use in RA is of great clinical interest. 
 
A previous observational study of 779 patients with RA showed that the risk of all-cause and 
CVD mortality increased progressively when the daily dose of prednisolone was above 7.5 mg 
(18). We have recently performed a population-based retrospective cohort study using real-
world data and recruited 12,233 RA patients with 105,826 patient-years of follow-up (19). The 
salient findings of our study are that prednisolone <5 mg daily was not associated with major 
adverse cardiovascular events (MACE) after adjusting for time-varying conventional risk 
factors, inflammatory markers and other medications, while prednisolone ≥5 mg daily doubled 

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the risk of future incident MACE, when compared with no GC use. Our findings are in line 
with the another recent large study using the CorEvitas registry in the United State, which 
reported a dose-dependent increased short-term (up to 12 months) risk of CVD events with 
prednisolone ≥5 mg daily, while the dose <5 mg daily was found to be CVD safe (20). In the 
Glucocorticoid LOw-dose in RheumatoId Arthritis (GLORIA) trial, patients with RA aged 
above 65 on standard of care with DAS28≥2.6 were randomized to receiving add-on 
prednisolone 5 mg daily for 2 years vs placebo (21). Among 224 patients receiving add-on 
prednisolone, 10 (4.5%) developed MACE; while 6 (2.7%) out of 225 patients in the placebo 
arm developed events. There was no statistically significant difference between the two groups. 
However, the follow-up duration of 2 years might not be adequate to reveal the long-term 
detrimental effects of GC. As prednisolone dose below 5 mg daily appeared to be 
cardiovascular risk neutral, it would be important to know whether this very low dose is in fact 
clinically effective in RA. 
 
In the GLORIA trial mentioned above, add-on prednisolone 5 mg daily led to significantly 
lower RA disease activity and less radiographic progression, compared with placebo (21). The 
Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-2) study, another 
randomized controlled trial, also showed that add-on modified-release prednisolone 5 mg daily 
resulted in doubling of treatment response (22). The Steroid EliMination In Rheumatoid 
Arthritis (SEMIRA) trial compared stable patients with RA on ‘tocilizumab with prednisolone 
5 mg/day’ versus ‘tocilizumab with prednisolone tapering 1 mg every 4 weeks to 0 mg’ (23). 
Although it was concluded that continuing prednisolone 5 mg/day was better for disease control 
(relative risk 0.83; 95% CI 0·71 to 0·97) at the end of the study (24 weeks), the flare-free 
proportion at 8 weeks was 0.96 and 0.97 in the tapered prednisolone and continued 
prednisolone groups respectively. This provided indirect evidence that prednisolone at 3 or 4 
mg daily could still be clinically effective. In a double-blind GC withdrawal trial, patients with 
RA originally on prednisolone 5 mg daily were randomized to gradual tapering with 1–4 mg 
prednisolone daily or placebo (i.e., direct discontinuation of GC) (24). It was found that patients 
in the tapering group were more likely to withdraw GC without flare, again indicating that very 
low dose GC could help RA disease control. However, the efficacy of prednisolone <5 mg 
daily in RA has not been formally evaluated in clinical trials. 
 
We have conducted a pilot open-label study evaluating the efficacy of add-on prednisolone 
4mg daily in patients with recently diagnosed RA [unpublished]. We recruited 7 consecutive 
patients not on any DMARDs with at least moderate disease activity from 11/23 to 1/24. Their 
baseline clinical characteristics are shown in table 1. Prednisolone 4mg daily was started 
together with methotrexate. The participants were reassessed in 4 weeks. Improvement in RA 
disease activity was noted in most of the patients post-treatment. The mean Disease Activity 
Score 28–C-Reactive Protein (DAS28-CRP) decreased from 5.1 ± 0.7 to 3.7 ± 1.6 (p=0.042). 
There was no significant adverse event reported. However, as there was no control group, the 
results were confounder by the therapeutic effect of methotrexate. It is of note that from our 
large local real-world RA database, about a quarter of the exposure to GC (in terms of person-
year interval) was below prednisolone 5mg daily, indirectly reflecting the clinical effectiveness 
and possibly safety of very low dose GC (19). 
 
Despite the advent of biologic and targeted synthetic DMARDs, there is a trend in the RA 
research field to revisit the effect and safety of low dose GC (25). Back in 2016, the EULAR 
task force re-evaluated the harm and safety of low dose GC use, and proposed that the risk of 
long-term prednisolone ≤5 mg daily was acceptably low (26). Evidence in favor of the safety 

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of low dose GC in terms of bone health has been emerging, where prednisolone ≤5 mg daily 
did not seem to be associated with reduced bone-mineral density in the recent Glucocorticoid-
induced Osteoporosis in Patients With Chronic Inflammatory Rheumatic Diseases or Psoriasis 
(Rh-GIOP) study (27). The GLORIA trial also provide partial reassurance with regard to 
infection risk which is another most recognized adverse event of GC therapy. After 2 years of 
5mg/day prednisolone, the proportion of patients (all aged ≥65) with at least one adverse event 
of special interest (serious or glucocorticoids-related) was increased by 24%, mostly due to 
non-severe infections. The result sets a benchmark for the upper limit of harm, and the risk in 
a less vulnerable population with lower dose and shorter duration of GC use is expected to be 
lower. All in all, “does the concomitant use of GCs at very low doses increase therapeutic 
success without producing unacceptable side effects?” is explicitly listed as one of the top 
research agenda in the latest EULAR RA management recommendations published in 2023 (6). 
 
We believe the half-a-century long controversy regarding GC use in RA boils down to one 
final clinical question that whether very low dose GC is an effective and safe bridging therapy, 
as 1) chronic GC use is unanimously not advisable, 2) very low dose GC (prednisolone < 
5mg/day) appears to have no or minimal toxicity concern (28), and 3) prednisolone 4mg daily 
shows promising therapeutic effect in our preliminary study. Very low dose GC could be the 
universal add-on treatment for all RA patients initiating csDMARDs with an optimal benefit-
risk ratio. To formally address this important clinical question, we plan to perform the first 
randomized controlled trial assessing the efficacy and safety of prednisolone 4 mg/day added 
to standard of care in patients with newly diagnosed RA. The results of our study are anticipated 
to be immediately implemental and can guide daily clinical practice. 
 
c. Aims and Hypotheses to be Tested: 
The aim of this study is to evaluate the efficacy of prednisolone 4mg/day added to standard of 
care in newly diagnosed RA patients with active disease. We hypothesise add-on prednisolone 
4mg/day is efficacious compared to placebo in newly diagnosed RA patients with active 
disease. 
 
d. Plan of Investigation: 
(i) Study design 
This is an investigator-initiated, single-center, randomized, placebo-controlled, double-blind 
study. The intervention duration is 10 weeks. The follow-up period is 24 weeks. The 
recruitment period is 30 months. The total study duration will be 3 years. 
 
(ii) Methods 
Primary outcome 
The primary outcome is the change of DAS28-CRP at 4 weeks comparing prednisolone group 
and placebo group. 
 
Secondary outcomes 
1) Changes of RA disease activity at week-8, week-12 and week 24 comparing the 2 
groups. 
2) Changes of RA disease activity at different time points within the 2 groups. 
3) Disability at different time points comparing the 2 groups. 
4) Proportion of patients with adverse events comparing the 2 groups. 
5) Independent predictors of RA disease control in all participants. 
 
Treatment and clinical evaluations 

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All the participants (n=112) will be randomized in a 1:1 ratio to prednisolone (n=56) or placebo 
(n=56) group. Randomization will be performed using a computer-generated randomization 
list provided by the research pharmacist, adopting a permuted blocks design with block sizes 
of 4. Allocation concealment will be ensured by the use of sequentially numbered, opaque, 
sealed envelopes. Treatment will be masked to patients and investigators. The participants will 
be instructed to take one study capsule (prednisolone or placebo) daily for 10 weeks. For the 
prednisolone group, the dose of the active drug will be 4mg once daily for 4 weeks then tapering 
at 1mg/week every 2-week till off at week 10. All participants will also be given csDMARDs 
and treated to a target of DAS28 low disease activity (<3.2) at Prince of Wales Hospital (PWH) 
throughout the study period according to a standard protocol modified to our study based on 
the EULAR recommendation and the Hong Kong guideline on the use of DMARDs. Disease 
activity and adverse events will be monitored at 4 weeks, 8 weeks, 12 weeks and 24 weeks. 
Patients will be advised to reach out to the rheumatologists earlier if the condition changes 
unexpectedly. Changes in the dosage or addition of nonsteroidal anti-inflammatory drugs are 
allowed. Switching to a new csDMARD is possible in case of toxicity or intolerance. The use 
of b/tsDMARDs or additional systemic GC will be prohibited throughout the study. All 
medication changes will be documented in detail. Participants who required rescue 
b/tsDMARDs or systemic GC will be withdrawn from the study. They will be treated according 
to the standard of care with regular assessment till the end of the study. All patients will be 
given calcium and vitamin D supplements throughout the study period. 
 
The following clinical variables will be assessed at each visit: erythrocyte sedimentation rate 
(ESR), CRP, number of swollen joints (0–28), number of tender joints (0–28), visual analogue 
scale (VAS) for pain (0–100 mm=most pain), VAS for patient’s global assessment (0–100 
mm=worst score), VAS for physician’s global assessment (0–100 mm=worst score), and 
DAS28 score. The presence of rheumatoid factor (RF) and cyclic citrullinated peptide (CCP) 
antibody with their respective serum levels will be documented at baseline. The number of 
damaged joints will be assessed at baseline and the end of the study. Rheumatoid factor status 
and anti-cyclic citrullinated peptide antibodies status will be determined at baseline. Functional 
disability is assessed by the disability index of HAQ (0-3=most functional disability). 
ACR20/50/70 responses are defined as at least 20%, 50%, and 70% improvement in swollen 
joint and tender joint counts, and three of five other variables (i.e., ESR or CRP, HAQ score, 
pain score, and physicians’ and patients’ global assessments). All assessments and 
consultations will be done by rheumatologists (investigators) with more than 10 years 
experience. 
 
Preparation of study medications 
Both the active drug (prednisolone) and placebo will be repackaged into capsules with identical 
appearance according to the standard operating procedure of the Clinical Research Pharmacy, 
School of Pharmacy, The Chinese University of Hong Kong. On entering the trial, each 
participant will be given a filled and labeled bottle, coded with a unique study number, which 
will be used for all future supplies of study drugs for that patient. Study treatment will remain 
masked for the patients, investigators, and study personnel throughout the trial. Code breaking 
is allowed in special circumstances by informing the Clinical Research Pharmacy or at end of 
the study. 
 
 

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Toxicity monitoring 
To monitor the possible side effect of prednisolone and other medications, complete blood 
count, liver function test and renal function test will be performed at screening, week 4, week 
8 and week 12 and week 24. Body mass index, blood pressure, blood sugar and lipid profile 
will be checked at baseline, week 4, week 8, week 12 and week 24. Chest x-rays will be 
obtained at screening and when clinically indicated. Hepatitis status and electrocardiogram will 
be done at screening. The treating physicians will record all adverse events (AEs) and, if 
necessary, make treatment adjustments in accordance with the protocol. Serious AEs (SAEs) 
are defined as the occurrence of life-threatening condition or death, a significant or permanent 
disability, a malignancy, hospitalization or prolongation of hospitalization, a congenital 
abnormality, or a birth defect. AEs of special interest (AESI) will also be collected which 
include any AE leading to drug discontinuation, MACE (myocardial infarction, 
cerebrovascular 
or 
peripheral 
arterial 
vascular 
event), 
newly 
occurring 
hypertension/diabetes/infection/cataract/glaucoma and fragility fracture. 
 
iii) Subjects (with justification on the sample size) 
Consecutive RA patients attending the rheumatology clinics of PWH will be screened for 
eligibility. The inclusion criteria are: 1) ≥18 year-old, 2) fulfilment of the 2010 ACR/EULAR 
classification criteria of RA, 3) never use of any DMARDs for RA, 4) disease activity score 
28-C-reactive protein (DAS28-CRP) >3.2, and 5) Chinese subjects only. The exclusion criteria 
are: 1) pregnancy or premenopausal women planning pregnancy, 2) functional status class IV 
(limited in ability to perform usual self-care, vocational, and avocational activities), 3) use of 
systemic GC in recent one month, and 4) contraindications to prednisolone. A total of 112 
patients who meet the criteria will be included. 
 
A sample size determination was conducted for the primary outcome measurement, the 
difference in the change of DAS28-CRP at 4 weeks comparing the 2 groups, using Power 
Analysis and Sample Size Software (PASS version 11). From the published results of the 
GLORIA trial, the short-term (3 months) improvement in DAS28 in the prednisolone group 
and placebo group was 1.36±1.14 (baseline 4.40±1.04) and 0.73±1.21 (baseline 4.46±0.99) 
respectively (21). In our pilot study mentioned above, the improvement in mean DAS28 was - 
1.4 ± 1.3 post-treatment. Therefore, more conservatively, we expect the difference of the 
change of DAS28-CRP at 4 weeks to be 0.6 comparing the prednisolone and placebo group. 
At least 49 patients will be required in each group to achieve a statistical power of 0.8 with a 
two-sided α of 0.05. With an estimated dropout rate of 15%, a total sample size of 112 would 
be required. 
 
The study will be submitted to The Joint Chinese University of Hong Kong – New Territories 
East Cluster Clinical Research Ethics Committee and the Central Institutional Research Board 
of the Hospital Authority for approval. It will also be submitted to the clinicaltrials.gov for 
registration. Written informed consent will be obtained from all participants prior to any of the 
trial procedure. The study will be conducted according to the Declaration of Helsinki and ICH-
GCP guidelines. 
 
(iv) Data processing and analysis 
Patients who discontinue treatment or violate treatment protocol will be excluded from the 
analysis (per-protocol analysis). Missing data are assumed missing at random and will be 
treated using a multiple imputation method. Descriptive statistics will be used to present the 
baseline demographic and clinical variables included frequencies, means with standard 

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deviations and median with interquartile range. T-test or Mann-Whitney U test and Chi-square 
test or fisher exact test will be used to evaluate the differences in clinical variables between the 
prednisolone and the placebo group at baseline, depending on the data distribution. The primary 
outcome measurement, the difference in the change of DAS28-CRP at 4 weeks comparing the 
2 groups, will be analyzed by T-test. Clinical variables which are significantly different 
between the 2 groups in the univariate analyses and are biologically plausible (eg. age, sex, 
disease duration, disease activity or treatment) will be adjusted in the multivariate logistic 
regression model to confirm the prednisolone treatment effect. The secondary outcomes on 
disease activity at week 8, week 12 and week 24 or disability in terms of HAQ at different time 
points will be compared likewise. The within group changes of these measurements before and 
after treatment will be examined using paired t-test or Wilcoxon signed-rank test. To look for 
the changes across study period across 2 groups, the repeated ANOVA test will be performed. 
To address the secondary outcome of comparison of proportion of patients with AE in the 2 
groups, Chi-square test will be performed and cross-checked by generalized estimating 
equation (GEE) analysis. Sensitivity analysis using an intention-to-treat approach including all 
randomized patients will be done. A 2-tailed probability value of p<0.05 is considered 
statistically significant. Calculation will be performed using IBM SPSS Statistics Version 24 
(IBM, Armonk, NY, USA). 
 
(v) Potential pitfalls and contingency plans 
There are several limitations in this study. First, consumption of NSAID and titration of 
csDMARDs are allowed in both groups within the 24-week study period for ethical reason and 
to minimize dropouts. Their usage will be recorded and adjusted in multivariable models if 
needed. Second, a compulsory tapering dose of prednisolone is adopted which might appear to 
be too early. However, it could provide important strategic data that help inform clinical 
practice and possibly support the therapeutic effect of very low dose prednisolone. Lastly, due 
to the limited duration of follow-up, the long-term efficacy and safety of short-course very low 
dose prednisolone could not be examined, which could be another research agenda. 
Additionally, conducting a randomized placebo-controlled clinical trial might meet with 
difficult recruitment and high drop-out, despite the relatively short study period. We intend to 
have a long recruitment period, screen patients in multiple centers and conservatively plan the 
sample size accommodating a potential higher dropout rate. Logistic issues with investigator-
initiated placebo trial (e.g. production of placebo or regulatory approvals) are anticipated. The 
study team has secure source of placebo tablet production and experienced personnel to ensure 
the smooth implementation of the trial. We will also advise all the participants to have 
appropriate vaccinations, especially seasonal flu and COVID-19 vaccines, before entering the 
trial. In case of significant worsening of outbreak transmission rate or tightening of community 
mitigation measures, participants can be followed up at designated sites with the use of personal 
protective equipment, away from high risk individuals, to reduce the risk of infection. A healthy 
life-style with balanced diet, adequate rest and regular exercise will be recommended to every 
patients entering the trial. 
 
 

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patients with rheumatic disease. Ann Rheum Dis. 2022;81(9):1313-22. 
28. Bijlsma JWJ. <em>Annals of the Rheumatic Diseases</em> collection on 
glucocorticoids (2020–2023): novel insights and advances in therapy. Annals of the 
Rheumatic Diseases. 2024;83(1):4-8. 
29. So H, Cheng IT, Lau SL, Chow E, Lam T, Hung VW, et al. Effects of RANKL 
inhibition on promoting healing of bone erosion in rheumatoid arthritis using HRpQCT: 
a 2-year, randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 
2021;80(8):981-8. 
30. Tam LH, Shang Q, Li EK, Wong PC, Kwok KY, Kun EW, et al. Effect of Treat-
totarget Strategies Aiming at Remission of Arterial Stiffness in Early Rheumatoid 
Arthritis: A Randomized Controlled Study. J Rheumatol. 2018;45(9):1229-39. 
 
 

Page 10 of 12 
Very low dose GC protocol v1.2 date 10 Feb 2025 
Table 1 – Clinical features and disease activity at baseline and week 4 of the patients treated 
with prednisolone 4mg daily (n=6) 
 
 
Baseline 
Week 4 
Age 
55 ± 14 
 
Sex, female 
4 (67%) 
 
Disease duration, months 
4.4 ± 8.0 
 
RF titre, IU 
68.0 ± 85.6 
 
Anti-CCP titre, IU 
143.2 ± 90 
 
Tender joint count 
10.5 ± 8.9 
5.8 ± 11 
Swollen joint count 
2.5 ± 0.5 
0.7 ± 1.0 
ESR 
63 ± 43 
45 ± 37 
CRP 
12.0 ± 7.4 
8.1 ± 9.4 
DAS28-CRP 
5.0 ± 0.7 
3.4 ± 1.6 
Anti-CCP – anti-cyclic citrullinated peptide antibody; ESR - erythrocyte sedimentation rate; 
CRP – C-reactive protein  
 
 
 
 Figure 1 Change of DAS28-CRP from baseline to week-4 after prednisolone 4mg 
daily in patients with early RA (n=7) 
 
 

Page 11 of 12 
Very low dose GC protocol v1.2 date 10 Feb 2025 
 
 
Figure 2 Subject flow diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Key inclusion criteria 
≥18 year-old 
Fulfilment of the 2010 ACR/EULAR 
classification criteria of RA 
Never use of any DMARDs for RA 
DAS28-CRP>3.2. 
Key exclusion criteria 
Pregnancy 
or 
premenopausal 
women 
planning pregnancy 
Functional status class IV (limited in ability 
to perform usual self-care, vocational, and 
avocational activities) 
Use of systemic GC in recent one month 
Contraindications to prednisolone 
Week 24 
End-of-study follow up 
Week 24 
End-of-study follow up 
Follow up  
at week 4,8,12 and 
24* 
for disease activity and 
safety assessment 
Follow up  
at week 4,8,12 and 
24* 
for disease activity and 
safety assessment 
Receive one capsule daily^ 
 for 10 weeks 
 
^4mg once daily for 4  
weeks, then tapering at 
 1mg/2-week in week 5-10 
 
Receive one capsule daily^ 
 for 10 weeks 
*Patients will be advised to reach out to the rheumatologists earlier if the condition changes 
unexpectedly. 
Prednisolone group 
(n=56) 
Placebo group 
 (n=56) 
Randomization  
(n=112) 
Subject recruitment 
from 4 regional 
hospitals 

Page 12 of 12 
Very low dose GC protocol v1.2 date 10 Feb 2025