The Glucocorticoid Low-dose Outcome in RheumatoId Arthritis Study Comparing the Cost-effectiveness and Safety of Additional Low-dose Glucocorticoid in Treatment Strategies for Elderly Patients With Rheumatoid Arthritis
Phase: PHASE4
Conditions: RheumatoId Arthritis
Sponsor: Amsterdam UMC, location VUmc

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RESEARCH PROTOCOL 
 
 
 
GLORIA 
The Glucocorticoid Low-dose Outcome in RheumatoId Arthritis Study 
Comparing the cost-effectiveness and safety of additional low-dose glucocorticoid in 
treatment strategies for elderly patients with rheumatoid arthritis 
 
 
 
 
 
 
 
 

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PROTOCOL TITLE  
Comparing the cost-effectiveness and safety of additional low-dose glucocorticoid in 
treatment strategies for elderly patients with rheumatoid arthritis:  
The Glucocorticoid Low-dose Outcome in RheumatoId Arthritis Study (GLORIA) 
 
 
Protocol ID 
VUMC-ARC-GLORIA 
Short title 
GLORIA 
EudraCT number  
2015-002729-21 
Version 
4.0 
Date 
12-Feb-2019 
Coordinating investigator / 
project leader 
 
Prof. Dr. M. Boers 
Amsterdam Rheumatology and immunology Center, 
location VU University Medical Center 
and  
Department of Epidemiology and Biostatistics 
VU University Medical Center 
Amsterdam, Netherlands 
E-mail: m.boers@vumc.nl 
Participating Centers 
29 centers in in 7 EU countries: Netherlands, 
Germany, Portugal, Italy, Rumania, Hungary, 
Slovakia 
Sponsor  
VU University Medical Center, Amsterdam 
Subsidising party 
Horizon 2020 
Independent expert 
Dr. E.M.W. Eekhoff 
Department of Internal Medicine 
VU University Medical Center 
Amsterdam, Netherlands 
E-mail: emw.eekhoff@vumc.nl 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Sponsor or legal representative: 
 
Drs. E. Janssen 
Director Division 6  
VU University Medical Center 
 
 
 
Coordinating Investigator /  
Project leader: 
 
Prof. Dr. M. Boers  
 
 
 
 
12-Apr-2019

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PROTOCOL SIGNATURE PAGE 
 
The Glucocorticoid Low-dose Outcome in RheumatoId Arthritis Study (GLORIA) 
Comparing the cost-effectiveness and safety of additional low-dose glucocorticoid in treatment 
strategies for elderly patients with rheumatoid arthritis 
 
 
I have read and understand the protocol and agree that it contains the ethical, legal and 
scientific information necessary to participate in this study. My signature confirms the 
agreement of both parties that the study will be conducted in accordance with this version of 
the protocol and all applicable local laws and regulations, Good Clinical Practice and to all 
stipulations, clinically and administratively, as stated in the protocol, including all statements 
as to confidentiality.  
I will provide copies of the protocol as needed to all physicians, nurses and other professional 
personnel responsible to me who will participate in the study. I will discuss the protocol with 
them to assure myself that they are sufficiently informed regarding the conduct of the study. I 
am aware that this protocol will need to be approved by an appropriate institutional Review 
Board (IRB) or Independent Ethics Committee (IEC) prior to any patients being enrolled and 
that I am responsible for verifying whether that requirement is met.  
I agree to conduct the clinical study in accordance with the design outlined in this protocol and 
to abide by all provisions of this protocol (including other manuals and documents referenced 
from this protocol). 
 
 
 
Investigator name: 
_____________________________ 
 
 
 
Institution name: 
_____________________________ 
 
 
 
Institution location: 
_____________________________ 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 

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TABLE OF CONTENTS 
 
1. SUMMARY ....................................................................................................................... 8 
2. LIST OF ABBREVIATIONS ............................................................................................ 11 
3. INTRODUCTION AND RATIONALE ............................................................................... 12 
4. OBJECTIVES ................................................................................................................. 15 
 
Primary objectives .................................................................................................. 15 
 
Other GLORIA project objectives ............................................................................ 15 
5. STUDY DESIGN............................................................................................................. 16 
6. STUDY POPULATION ................................................................................................... 17 
 
Population (base) ................................................................................................... 17 
 
Inclusion criteria...................................................................................................... 17 
 
Exclusion criteria .................................................................................................... 17 
 
Sample size calculation .......................................................................................... 18 
7. INTERVENTION/TREATMENT OF SUBJECTS ............................................................. 20 
 
Investigational product ............................................................................................ 20 
 
Use of co-interventions for the treatment of RA ...................................................... 21 
 
Escape medication ................................................................................................. 21 
 
Treatment for other medical conditions ................................................................... 22 
8. INVESTIGATIONAL PRODUCT ..................................................................................... 23 
 
Name and description of investigational product ..................................................... 23 
 
Summary of findings from non-clinical studies ........................................................ 23 
 
Summary of findings from clinical studies ............................................................... 23 
 
Summary of known and potential risks and benefits ............................................... 23 
 
Description and justification of route of administration and dosage ......................... 23 
 
Dosages, dosage modifications and method of administration ................................ 23 
 
Preparation and labelling of Investigational Medicinal Product................................ 24 
 
Drug accountability ................................................................................................. 24 
9. METHODS ..................................................................................................................... 25 
 
Study outcomes ...................................................................................................... 25 
 
Main study outcomes ...................................................................................... 25 
 
Secondary study outcomes/endpoints ............................................................. 27 
 
Randomization, blinding and treatment allocation ................................................... 27 
 
Study procedures ................................................................................................... 28 

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Demographic measurements, education, medical conditions; baseline 
assessment of prognostic factors .................................................................. 28 
 
Vital signs and physical examination ............................................................... 28 
 
Hand, wrist and feet X-ray ............................................................................... 28 
 
Laboratory measurements .............................................................................. 28 
 
Efficacy assessments...................................................................................... 28 
 
Withdrawal of individual subjects ............................................................................ 30 
 
Replacement of individual subjects after withdrawal ............................................... 30 
 
Follow-up of subjects withdrawn from treatment ..................................................... 30 
 
Premature termination of the study ......................................................................... 30 
 
Procedure for unblinding of study medication ......................................................... 30 
10. SAFETY REPORTING ................................................................................................... 32 
 Disadvantageous event .......................................................................................... 32 
 AEs, SAEs and SUSARs ........................................................................................ 32 
 
Adverse events (AEs) ..................................................................................... 32 
 
Adverse (Drug) reactions ................................................................................ 33 
 
Serious adverse events (SAEs) ...................................................................... 34 
 
Suspected unexpected serious adverse reactions (SUSARs) ......................... 34 
 Annual safety update report .................................................................................... 35 
 Follow-up of adverse events ................................................................................... 35 
 Monitoring............................................................................................................... 35 
11. STATISTICAL ANALYSIS .............................................................................................. 37 
 Primary study outcome(s) ....................................................................................... 37 
 Secondary study outcome(s) .................................................................................. 40 
12. ETHICAL CONSIDERATIONS ....................................................................................... 42 
 Regulation statement .............................................................................................. 42 
 Recruitment and consent ........................................................................................ 42 
 Benefits and risks assessment, group relatedness ................................................. 42 
 Compensation for injury .......................................................................................... 43 
 Incentives ............................................................................................................... 43 
13. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .............................. 44 
 Handling and storage of data and documents ......................................................... 44 
 
Data Handling ................................................................................................. 44 
 
Data Coding .................................................................................................... 44 
 
Data Confidentiality ......................................................................................... 45 
 
Data Storage ................................................................................................... 45 
 Monitoring and Quality Assurance .......................................................................... 45 
 Amendments .......................................................................................................... 45 

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 Annual progress report ........................................................................................... 45 
 End of study report ................................................................................................. 46 
 Public disclosure and publication policy .................................................................. 46 
14. REFERENCES ............................................................................................................... 47 
15. APPENDICES ................................................................................................................ 49 
 Appendix A: Schedule of assessments ................................................................... 50 
 Appendix B:  Joint counts ....................................................................................... 51 
 Appendix C:  Calculation of DAS28 and DAS44; EULAR response; ACR 
improvement ..................................................................................................................... 53 
 Appendix D:  Sharp/van der Heijde damage score ................................................. 54 
 Appendix E: Patient global assessment and stiffness ............................................. 55 
 Appendix F: Physician global assessment .............................................................. 56 
 Appendix G:  (M)HAQ – (Modified) Health Assessment Questionnaire ................... 57 
 Appendix H: RAID – RA Impact of Disease ............................................................ 60 
 Appendix I: Cost Questionnaire .............................................................................. 62 
 Appendix J: EQ-5D – EuroQoL in 5 dimensions ..................................................... 64 
 Appendix K: SF36 – Short Form 36-item Health Survey ......................................... 66 
 Appendix L: Patient symptom list ............................................................................ 72 
 Appendix M: Education level and Baseline prognostic factors ................................ 73 
 
 

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1. SUMMARY 
 
Rationale: Rheumatoid arthritis (RA) is a condition with high impact both on the individual and society. In the 
context of comparing the effectiveness of existing healthcare interventions in the elderly, RA is a condition 
highly relevant to the community since it has a strongly negative impact on the quality of life of the individual, 
is particularly frequent in the elderly, and is associated with significant costs. RA management remains 
challenging: there is an urgent unmet medical and societal need for improved treatment strategies that are 
effective, safe and affordable. Evidence based information on the glucocorticoid (GC) harm/benefit balance 
will have a high impact on RA treatment strategies and on treatment strategies for the many other inflammatory 
disorders for which GCs are considered. The Glucocorticoid Low-dose Outcome in RheumatoId Arthritis Study 
(GLORIA) is a 5-year project funded by the European Commission under the Horizon 2020 Program, designed 
to address these needs. 
 
Objective: The primary objectives of the GLORIA project are twofold: a) To assess the effectiveness, safety 
and cost-effectiveness of low-dose GC therapy (5 mg/day) compared to placebo given for two years as co-
treatment for elderly RA patients (≥ 65 years) in a pragmatic randomized trial; b) To assess study medication 
adherence through a medication packaging solution, and test the effectiveness of smart device technology to 
improve adherence. Other objectives of the GLORIA project are: to deliver an outcome prediction model for 
individual patient outcome, to tailor treatment strategies for elderly RA patients with comorbidities; and deliver 
data to support: 1) better guidelines on RA treatment in the elderly; 2) more accurate information for elderly 
RA patients, their physicians and researchers; 3) improved strategies for trial design and conduct in the elderly. 
 
Study design: The GLORIA study is a randomized, double-blind, placebo-controlled pragmatic multicenter 
clinical trial to assess the effectiveness and safety of a daily dose of 5 mg prednisolone or matching placebo 
in elderly RA patients. Patients will be randomized into two arms: the experimental arm (receiving prednisolone 
5 mg/day) or the control arm (receiving placebo). Our design emulates the routine care setting: eligibility criteria 
are very liberal, assessments and procedures are tailored to represent standard of care, and concurrent 
antirheumatic treatment is allowed next to the trial medication with minimal limitations. Furthermore, all patients 
will have an adherence monitoring device loaded into the cap of the drug bottle; adherence data will be 
monitored throughout the trial. In addition, to test the effect of adherence reminders, a substudy (another trial) 
will be nested in the main GLORIA trial. 
 
Substudy design: The substudy is limited to patients with a smartphone who have completed at least 3 
months of the main study on treatment. The experimental arm of the substudy will receive an application loaded 
onto their smartphone that communicates with an adherence monitoring device loaded into the cap of the drug 
bottle and delivers reminders to improve adherence. The control arm of the substudy will not have this 
application and reminders. The substudy has a duration of three months. 
 
Study population: Patients of 65 years of age and older with RA according to the 1987 or the 2010 
classification criteria of the American College of Rheumatology (ACR) and the European League Against 
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by a 28-joint disease activity score (DAS28) of ≥ 2.60. For eligibility, the DAS28 can be calculated with ESR 
or CRP, and also recalculated from the DAS of 44 joints.  
 
Substudy population: Patients in the main study who have completed at least 3 months on treatment, in 
possession of and familiar with a smartphone. 
 
Intervention: In this two-armed clinical trial, patients will be randomized to either the experimental arm or the 
control arm. The experimental arm will receive prednisolone 5 mg/day added to existing antirheumatic 
treatment. The control arm will receive matching placebo added to existing antirheumatic treatment. Treatment 
duration is two years per patient. Subsequently, study drug is tapered in linear fashion to zero in  approximately 
3 months  by inserting increasing numbers of non-treatment days. Patients experiencing a flare at that time 
can restart open label prednisolone at the discretion of the treating rheumatologist.  
 
Co-interventions: As part of standard of care all patients will receive Calcium 500 mg/Vitamin D3 800 IU. 
Besides the study medication, almost all treatment is allowed; both treatment for comorbidities, as well as 
antirheumatic treatment. This includes biologic and nonbiologic disease-modifying antirheumatic drugs 
(DMARDs), non-steroidal anti-inflammatory drugs (NSAIDs), short term oral and parenteral GC for flares or 
comorbidities (e.g. chronic obstructive pulmonary disease) and acetaminophen. However, it is advised not to 
start other antirheumatic therapy (DMARD, biologic) or give intra-articular or intramuscular GC injections, 
especially not in the first 3 months, but it is allowed if clinically judged as unavoidable. In such cases, preferred 
administration is at baseline.  
 
Substudy intervention: All patients will have an adherence monitoring device loaded into the cap of the drug 
bottle that will be equipped with a wireless transmitter, which not only tracks adherence but can also 
communicate real time with the smartphone of the patient, through special software to remind patients of the 
time of medication. In the substudy, patients with a smartphone will receive an application loaded on their 
smartphone that communicates with the adherence monitoring device loaded into the cap of the drug bottle. 
The app sends an alert message to inform the patient he or she has forgotten to take the medication. Eligible 
patients will be randomized to either the experimental arm that receive reminders on their smartphone, or to 
the control arm that will not receive reminders, for a period of 3 months.  
 
Main study endpoints:  
• 
To measure benefit, primary endpoints are a) signs and symptoms: the time-averaged mean value 
(estimated from linear mixed models) of the DAS28; b) damage progression: change from baseline after 
2-years in total Sharp/van der Heijde damage score of hands and forefeet radiographs.  
• 
To measure safety, the primary endpoint is the total number of patients experiencing at least one serious 
adverse event, or one clinical event related to the disease or its therapy.  
• 
Other major outcomes are cost-effectiveness, cost-utility, and medication adherence.  
Assessment takes place at varying intervals, and includes seven clinic visits and 3 assessments by telephone.   
 

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Nature and extent of the burden and risks associated with participation, benefit and group relatedness: 
GLORIA is a pragmatic trial, with measurements that are almost all part of standard of care, and therefore 
there are no additional risks associated with these measurements. However, the intervention in this trial is that 
patients are randomized to either standard of care with low-dose GCs or standard of care without low-dose 
GCs for a duration of two years. It is known that GCs have strong favourable effects on disease activity, of 
which patients randomised to the control arm (placebo) cannot benefit. However, side effects of GCs are 
known as well, and patients in the experimental arm (prednisone 5 mg/day) might suffer from them. Although 
side effects predominantly occur when GC are used in high doses for long periods of time, elderly are more 
likely to suffer from adverse effects of the disease and its therapy than younger patients. However, elderly are 
underrepresented or even excluded from many clinical trials, so it is difficult to estimate their risk: this forms 
the rationale for the trial. To reduce risks, participants are monitored and patients with a low probability of 
benefit or with a high probability of harm will be excluded from participation to this trial. For the substudy to 
measure adherence through an innovative application, no additional risks are expected: if the application 
appears to be successful, patients randomised to the intervention can only benefit from it since it improves 
their medication adherence; in case the application is not successful, for patients not randomised to the 
application or for patients without a smartphone, no difference is expected with the ‘normal’ situation, in which 
patients do not have access to an adherence application. 
 
 

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2. LIST OF ABBREVIATIONS 
 
ACR 
American College of Rheumatology  
AE 
Adverse event  
ANCOVA 
Analysis of Covariance  
CI  
Confidence intervals  
CRP 
C-reactive protein  
DAS28 
Disease activity score of 28 joints  
DAS44 
Disease activity score of 44 joints 
DMARDs 
Disease-modifying antirheumatic drugs 
DEXA 
Dual-energy X-ray Absorptiometry  
eCRF 
Electronic Case Report Form  
EDC 
Electronic data collection system  
EMA 
European Medicines Agency 
ESR 
Erythrocyte sedimentation rate  
EQ-5D 
EuroQoL in 5 dimensions 
EULAR 
European League Against Rheumatism  
GC 
Glucocorticoid  
GCP 
Good Clinical Practice  
GLORIA 
Glucocorticoid Low-dose Outcome in RheumatoId Arthritis 
GMP 
Good Manufacturing Practice  
HAQ 
Health Assessment Questionnaire  
ICER 
incremental Cost Effectiveness Ratio  
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonisation   
IEC 
Ethics committee  
IRB 
Institutional review board  
IWRS 
Interactive Web Response System  
NSAIDs 
Non-steroidal anti-inflammatory drugs  
PV 
Accelovance Pharmacovigilance  
QALY 
Quality-adjusted life year 
QoL 
Quality of life  
RA 
Rheumatoid arthritis  
RAI 
Ritchie Articular Index 
RAID 
RA Impact of Disease  
SAE 
Serious adverse event  
SF36 
Short Form 36-item Health Survey 
SOP 
Standard operating procedure 
SPC 
Summary of Product Characteristics  
SUSAR 
Suspected unexpected serious adverse drug reaction  
VFA 
Vertebral Fracture Assessment 
WMO 
Medical Research Involving Human Subjects Act  
 

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3. INTRODUCTION AND RATIONALE 
 
Rheumatoid arthritis treatment 
Rheumatoid arthritis (RA) is a systemic, inflammatory disease characterized by chronic pain, progressive 
disability, decreasing quality of life (QoL) and premature death. Pathological changes include periarticular 
cartilage and bone loss, but are not only restricted to joints. Inflammatory lesions can develop in many tissues, 
including the heart and pericardium, lungs, blood vessels, skin and subcutaneous tissues, eyes, and salivary 
and lacrimal glands. Both the disease and its treatment gives rise to multiple comorbidities such as an 
increased incidence of cardiovascular disease, diabetes, osteoporosis, declining organ function (especially 
hepatic, renal and pulmonary function) as well as osteoarthritis (Scott DL 2010). Current treatment strategies 
have considerably improved the prognosis, but recent treatment innovations (especially biologic drugs) have 
important safety issues and come at high societal cost. In addition, many patients still have a smoldering 
progressive disease despite treatment (Scott DL 2010).  
 
Benefits and harm of glucocorticoid treatment 
The introduction of glucocorticoids (GC) in the 1950s was a revolution in the treatment of inflammatory 
diseases, including RA. Enthusiasm generated by the initial results of unequalled efficacy in previously 
untreatable diseases led to the unrestricted use of high doses of GCs. Unfortunately, such use disclosed a 
spectrum of safety issues, which resulted in a still ongoing debate regarding the balance between benefit and 
harm of GC treatment. Whereas some clinicians are very restrictive in their application of GC treatment, most 
feel that GCs still have an important role in the management of inflammatory diseases such as RA. Particularly 
in the early phase of the disease the rapid effects of initially high dose prednisone are very useful in the “window 
of opportunity”. In the chronic phase of RA, many patients are treated with low-dose GC. A recent meta-
analysis has proven beyond doubt that GCs at low doses slow the progression of joint damage in RA (so-
called ‘disease modification’), which has renewed the debate on the benefit-risk balance of this treatment 
(Kirwan JR 2007). Low-dose GCs (defined as a daily dose of 7.5 mg prednisone equivalent or less) could 
prove an important co-treatment of RA in combination with standard of care. Apart from their clinical effects, 
low-dose GCs have the potential to reduce the need for expensive treatment with biologic agents: in view of 
an increasing RA prevalence in the elderly population such treatment may not be societally sustainable. 
Unfortunately, clinical studies large enough to adequately document the balance of benefit and harm of low-
dose GCs in combination with standard of care are lacking.  
 
Existing guidelines and opinions on safety and efficacy of GCs are mostly based on observational studies with 
high potential for bias, with a scarcity of information from controlled trials. Patients and health professionals, 
in rheumatology and other fields, tend to select one of two opposing strategies in GC use: either strong 
avoidance or strong acceptance. As the efficacy of this class of drugs in chronic use is no longer strongly 
questioned (Kirwan JR 2007), the opposing opinions are primarily based on safety concerns, especially in the 
elderly. Unfortunately, this stand-off is a reflection of the absence of definitive evidence: the limited high quality 
data from trials does not support strong claims of harm (as opposed to a wealth of observational studies with 
high potential for bias), but the generalizability of trial data is questioned. The result is a divergent landscape 
of RA treatment across Europe (Figure 1) (Sokka T 2007) and inappropriate treatment strategies associated 
with both under- and over-usage of GC, and consequently suboptimal treatment of RA. Furthermore, RA and 

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its associated comorbidities often lead to poly-pharmacy and high risk of negative drug interactions, especially 
in the elderly. According to current insights, the increased mortality is mostly due to increased incidence and 
lethality of cardiovascular disease caused by chronic inflammation (Kitas GD 2011). 
 
 
 
 
 
 
 
 
 
Elderly patients 
RA is one of the most common chronic inflammatory autoimmune diseases affecting over 3 million people in 
Europe. RA is known to increase in incidence and prevalence with age, with a peak prevalence around age 
85 (Figure 2). Approximately 1% of the world population is affected by RA with a prevalence of 2% in elderly 
of age 60 and older (Rasch EK 2003). In Europe the prevalence of RA is expected to increase along with the 
increase in the number of elderly in the population. However, although elderly patients are overrepresented in 
terms of patient numbers in RA, this group exemplifies the challenge of being underrepresented or even 
excluded from many clinical trials that generate the evidence-base for treatment of RA.  
 
Cost-effectiveness 
RA places a heavy burden on society through its social and economic cost (Kobelt G 2009). The costs of 
modern RA treatment are very high. Mean costs of RA treatment are currently estimated at nearly €3.000,-
/patient/year, but patients starting with new biologic treatment incur costs of €15.000,-/year for the drug alone. 
Significant savings can be realized by improving the RA treatment strategy.  It is very likely that the optimized 
use of GCs in RA would allow for important savings, specifically by delaying or avoiding the need for expensive 
biologics.  
 
Adherence 
The current treatment strategy for RA is far from ideal. A well-known phenomenon amongst all RA patients is 
multiple drug failure resulting in progressive disease. In addition, adherence (compliance; generally defined as 
the extent to which patients take medications as prescribed by their health care providers) is low, often below 
50% in patients with chronic diseases such as RA (Brown MT 2011). In RA, non-adherence increases the risk 
of a disease flare (Muller R 2012). These problems are dramatically increased in the elderly population. The 
measurement of medication adherence in clinical trials is challenging (Gellad WF 2011). Self-report and patient 
interviews may not provide accurate and reliable assessments, and prescription refill records and pill counts 
Figure 1. RA patients (%) treated with biologics 
and prednisolone (GC) across Europe (graph 
drawn with data from Sokka et al.  (Sokka T 2007). 

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often overestimate true adherence. Computerised devices or electronic monitoring devices may assess 
adherence more accurately.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. Prevalence of RA by age group, sex and region. A regions = developed countries in North America, Western 
Europe, Japan, Australia, and New Zealand. AF = countries in sub-Saharan Africa. AM BD = developing countries in the 
Americas. EM = countries in the Eastern Mediterranean and North Africa regions. EU BC = developing countries in Europe. 
SEA = countries in South-east Asia. WP B = countries in the Western Pacific region (Woolf AD 2003) 
 
 
In brief, RA is a condition with high impact both on the individual and society. In the context of comparing the 
effectiveness of existing healthcare interventions in the elderly, RA is a condition highly relevant to the 
community since it has a strongly negative impact on the QoL of the individual, is particularly frequent in the 
elderly, and is associated with significant costs (Kobelt G 2009). RA management remains challenging: there 
is an urgent unmet medical and societal need for improved treatment strategies that are effective, safe and 
affordable. Evidence based information on the GC harm/benefit balance will have a high impact on RA 
treatment strategies and on treatment strategies for the many other inflammatory disorders for which GCs are 
considered. 
 
 

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4. OBJECTIVES 
 
 Primary objectives 
 
Overall 
The primary objectives of the GLORIA study are twofold: 
a) To assess the effectiveness, safety and cost-effectiveness of 2 years of low-dose GC therapy (5 
mg/day) compared to placebo as co-treatment for elderly RA patients in a pragmatic randomized trial 
b) Study medication adherence through a medication packaging solution, and test the effectiveness of 
smart device technology to improve adherence 
 
Note: the trial is part of a larger EU-Horizon 2020 project that includes the following objectives: 
 
 Other GLORIA project objectives 
 
Overall 
• 
Deliver an outcome prediction model for individual patient outcome, to tailor treatment strategies for 
elderly RA patients with comorbidities 
• 
Deliver data to support:  
1) better guidelines on RA treatment in the elderly 
2) more accurate information for elderly RA patients, their physicians and researchers;  
3) improved strategies for trial design and conduct in the elderly. 
 
 
 
 
 

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5. STUDY DESIGN 
 
The GLORIA study is a randomized, double-blind, placebo-controlled pragmatic multicenter clinical trial to 
assess the effectiveness and safety of a daily dose of 5 mg prednisolone or matching placebo in elderly RA 
patients. 
 
Patients will be randomized into two arms: the experimental arm (receiving prednisolone 5 mg/day) or the 
control arm (receiving placebo). See chapter 7.1 for more details about the study medication. Treatment 
duration is two years. 
 
Pragmatic trials are designed to evaluate the effectiveness of interventions in real-life routine practice 
conditions (Schwartz D 1967). Our design emulates the routine care setting: eligibility criteria are minimal, 
assessments and procedures are tailored to represent standard of care, and concurrent antirheumatic 
treatment is allowed next to the trial medication with minimal limitations. Thus we expect that almost all elderly 
RA patients (specifically those with comorbidities) are eligible.  
 
The adherence of all patients in the main GLORIA trial is monitored throughout the study period by an 
adherence monitoring device loaded into the cap of the drug bottle. To measure the effect of smart reminders 
on medication adherence, a substudy (a randomized trial nested within the main study) will be performed. In 
this substudy, limited to patients with a smartphone, completing at least the first 3 months of the trial on 
treatment, the experimental arm will receive an application loaded onto their smartphone that communicates 
with the adherence monitoring device loaded into the cap of the drug bottle and delivers reminders to improve 
adherence. The control arm will not have this application and reminders. Intervention duration of the substudy 
is three months. 
 
 

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6. STUDY POPULATION 
 
 Population (base)  
RA patients of 65 years of age and older requiring antirheumatic therapy. 
 
 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following criteria: 
• RA according to the 1987 or 2010 classification criteria of the American College of Rheumatology (ACR) 
and the European League Against Rheumatism (EULAR) (Aletaha D 2010);  
• inadequate disease control, as evidenced by a 28-joint disease activity score (DAS28) of ≥ 2.60.  
For eligibility, the DAS28 can be calculated with ESR or CRP, and also recalculated from the DAS of 44 
joints. A DAS28 may be calculated with clinical and lab assessments obtained no more than 4 weeks before 
the baseline visit. 
• age ≥ 65 years. 
 
 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation in this study: 
 
Lower probability of benefit:  
• 
Change, stop or start of antirheumatic treatment in the last month prior to eligibility assessment, 
including methotrexate, sulfasalazine, hydroxychloroquine, leflunomide, azathioprine, intramuscular 
and oral gold, cyclosporine, biologic agents including anti-TNF, anakinra, abatacept, rituximab, 
tocilizumab (temporary exclusion);  
• 
Treatment with systemic GC: oral or parenteral GC with a cumulative prednisolone equivalent dose of 
200 mg or higher in the last 3 months (temporary exclusion); 
• 
Treatment with any GC (oral, intra-articular, intravenous or intramuscular) in the last 30 days 
(temporary exclusion); 
• 
Note: as this is a pragmatic trial, patients who require start of (other) antirheumatic treatment at 
baseline or during the trial can still be eligible (see 7.2). 
 
Higher probability of harm:  
• 
Exposure to investigational therapy in the last three months; 
• 
Current participation in another clinical trial; 
• 
Major surgery, donation or loss of approximately 500 ml blood within 4 weeks prior to the screening 
visit (temporary exclusion) 
• 
Absolute contraindication to low-dose prednisolone, as determined by the treating physician, such as: 
uncontrolled chronic infections, diabetes mellitus, hypertension, osteoporosis. When these conditions 
are under control (e.g. with antiosteoporosis drugs, antihypertensive drugs) these patients can enter;  
• 
Absolute contraindication to Calcium and/or Vitamin D supplement as determined by the treating 
physician, such as: hyperparathyroidism (when insufficiently treated); 
 
 

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• 
Uncontrolled comorbid conditions, short life span, etc. as determined by the treating physician. 
 
Difficulty to measure harm/benefit:  
• 
Absolute indication to start with oral or intravenous GC, according to the treating physician;  
• 
Inability to comply with medical instructions or inability to assess major outcomes at 6-monthly visits, 
in the assessment of the treating physician. 
 
Subjects/patients not capable or willing to provide informed consent.  
 
Substudy 
Additional exclusion criteria for subjects participating in the substudy to measure the effect of a reminder via 
smartphone on adherence: 
 
Inability/difficulty to measure benefit:  
• 
Not in the possession of a smartphone; 
• 
Premature discontinuation of study medication within or at 3 months of the main trial.  
 
 Sample size calculation 
In the main GLORIA trial, 225 patients per treatment group will be entered (total 450 patients). 
 
In the chosen analysis strategy (see chapter 10), to detect differences in benefit (disease activity, radiographs) 
extensive RA trial experience (both for GC and other agents) has shown a sample size of 200 patients per 
group is amply sufficient. For example, in the CAPRA-2 study that compared modified release prednisone 
5mg/d against placebo, the prednisone group had 231 patients, the placebo group 119 patients. The change 
in DAS28 after 3 months of treatment was –1.15 in the prednisone group, –0.63 in the placebo group; 
difference –0.52 (SE 0.13, p<0.001) (Buttgereit F 2013). However, the true incidence of adverse events (AEs) 
for GCs is currently unknown. Most relevant data to assess sample size adequacy for this study come from 
the reported CAMERA-2 trial (Bakker MF 2012). This trial randomized 236 early RA patients to tight-control 
high-dose methotrexate plus 10 mg prednisolone or placebo for two years. Interestingly, 22% of placebo 
patients compared to only 14% of prednisolone patients reported at least one serious AE or clinical event as 
defined in our protocol.  
 
The original protocol used a base case expectation for a total of 20% of patients experiencing at least one 
event over two years in the placebo group and calculated a need for 400 patients in each treatment group, 
to have about 80% power to detect an increase of 7% (from 20% to 27% events; 90% power for an increase 
of 9%). However, based on our current experience the sample can be decreased to about 450 instead of 800.  
Elaboration: 
In Dec 2018 we had >400 patients in the trial with a mean follow up of 9 months, and we had 84 cases with 
at least one serious adverse event or an event of special interest (the primary harm outcome). A simple 
extrapolation leads to an estimated rate of about 49% over 2 years (pooled over the whole blinded trial 

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population, i.e. both treatment groups taken together). We have also performed life table analysis, which 
accounts for patients stopping prematurely; this analysis leads to an estimated rate of 40% (95% confidence 
interval: 30%-50%). 
Given the above we can now assume with confidence that the base rate of patients with events in the placebo 
group will be substantially higher than originally predicted. 
This adds power to the trial: we need only between 400 and 450 patients to detect the originally targeted 
contrast of 27,5%/20%= relative risk of 1,38 (Table 1).  
At the expected pooled event rate of 40%, with 400 patients we have 80% power to detect a difference of 
12% between placebo and prednisolone: i.e. placebo 34% and prednisolone 46%, a relative risk of 1,35. The 
results are better with 450 patients, and when the event rate is higher (Table 1).   
At the moment of submission of the amendment trial recruitment has been closed on Dec 31, 2018 at a total 
of 452 patients.  
Table 1. Sample size scenarios (one-sided alpha 5%). 
 
 
 
 
For the substudy to measure adherence, no formal sample size calculation has been done. In feasibility 
assessments in the centres, the proportion of elderly patients with a smartphone was about 20%. However, in 
our current experience this is true only in the Netherlands. All other countries have indicated none of their 
currently included patients has a smartphone. Assuming that patients with a smartphone are technically 
interested, we can expect about 80% of them  to be willing to participate. This gives a total sample size of 50 
patients (25 per group). No data is available on actual adherence or its variability between patients. 
expected event rate over 2 years  
 
 
(% unique patients 
with power 80%, 
with at least one event) 
detectable rate in predn group 
        Relative Risk 
pooled 
placebo 
n=400 
n=450 
n=400 
n=450 
30% 
26% 
38% 
37% 
1,47 
1,43 
35% 
30% 
42% 
41% 
1,40 
1,37 
40% 
34% 
46% 
45% 
1,35 
1,32 
45% 
39% 
52% 
52% 
1,31 
1,31 
50% 
43% 
55% 
55% 
1,28 
1,28 

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7. INTERVENTION/TREATMENT OF SUBJECTS 
 
 Investigational product 
In this two-armed clinical trial, patients will be randomized to either the experimental arm or the control arm. 
The experimental arm will receive prednisolone 5 mg/day added to existing antirheumatic treatment. The 
control arm will receive matching placebo added to existing antirheumatic treatment. Both treatments will be 
given for the duration of two years. 
 
Subsequently, study drug is slowly tapered in linear fashion to zero in 3 months by inserting increasing 
numbers of non-treatment days. For this purpose and to prevent unblinding, 3 months of extra study treatment 
will be made available. Patients experiencing a flare at that time can restart open label prednisolone at the 
discretion of the treating rheumatologist. 
 
Co-medication 
As part of standard of care all patients with receive Calcium 500 mg/Vitamin D3 800 IU. The supplement is 
beneficial in all RA patients, given the almost universally low levels of vitamin D and low intake of calcium in 
the diet of the target population.  
 
Adherence 
To measure adherence, an adherence medication packaging solution that combines Objective therapy 
Compliance Monitoring technology (OtCM) and special software is delivered. All patients will have an 
adherence monitoring device loaded into the cap of the drug bottle. Adherence data will be registered in the 
study database for all patients, and analysed at the end of the study. Furthermore, the use of RA-friendly pill 
bottles will avoid the difficulties many RA patients experience with blister packs (small size combined with the 
force required to push pills out).  
 
For the substudy, the electronic pill bottles will be equipped with a wireless transmitter, which not only tracks 
adherence but can also communicate real time with a smartphone of the patient, through special software to 
remind patients of the time of medication. The effectiveness of this application will be tested in the substudy: 
patients with a smartphone will receive an application loaded on their smartphone that communicates with the 
adherence monitoring device loaded into the cap of the drug bottle. The app sends a reminder message to the 
patient when it’s time to take the medication and in case of non-adherence the app also sends an alert 
message to inform the patient he or she has forgotten to take the medication. Patients will be randomized to 
either the experimental arm that receive reminders on their smartphone, or to the control arm that will not 
receive reminders, for a period of 3 months. In patients without a smartphone, data on adherence will be read 
out from the OtCM when the patient returns for a control visit. 
 
 

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 Use of co-interventions for the treatment of RA 
Besides the study medication (prednisolone 5 mg/day or placebo), almost all treatment is allowed; both 
treatment for comorbidities, as well as antirheumatic treatment, at the discretion of the treating physician. This 
includes biologic and nonbiologic disease-modifying antirheumatic drugs (DMARDs), non-steroidal anti-
inflammatory drugs (NSAIDs), short-term GC for comorbidities (eg, chronic obstructive pulmonary disease; 
see below) and acetaminophen. Patients requiring such therapy will stay in the study, continue to use study 
medication and will follow the normal assessment schedule. Treatment changes for worsening of disease after 
study start should also be coded as AE. 
 
To further minimize intrusion in daily clinical practice, the following policy is instituted: It is advised not to start 
other antirheumatic therapy (DMARD, biologic, etc.) or give intra-articular or intramuscular GC injections, 
especially not in the first 3 months, but it is allowed if clinically judged as unavoidable. In such cases, preferred 
administration is at baseline. We strongly advise physicians to consider changing antirheumatic therapy if GC 
injections are required more than once a year. Patients receiving more than 2 intramuscular injections or more 
than 4 intra-articular injections after the start of the trial will also continue study drug, but be categorized as 
protocol violation and flagged for separate analysis, including non-responder imputation.  
 
Treatment with oral or intravenous GC, for RA constitutes a protocol violation. All such patients will continue 
to be followed up at the regular study visits. Short treatments for comorbidity are not considered a protocol 
violation. 
Regarding study medication, patients will be handled as follows: 
1. Regardless of dose, patients requiring GC for a consecutive period of no more than 3 weeks, and 
no more than 4 of such periods in the total trial period can continue study medication and stay in 
the study. The use is noted, and these patients will be flagged for separate analysis.  
2. Patients treated for a longer period, or more frequently will be regarded as having developed an 
absolute indication for chronic oral or intravenous GC therapy. Whether or not study medication is 
continued will be decided by the Scientific Lead in consultation with the center PI. As above, they 
will be retained in follow-up and handled separately in the analysis, including non-responder 
imputation. 
3. Patients undergoing emergency or routine surgery can be unblinded if parenteral GC are needed 
perioperatively. In case of elective surgery, study medication can be given as oral GC 
perioperatively as adrenal crisis prophylaxis if local guidelines permit, thus obviating the need for 
unblinding.  
 
 Escape medication 
There is no escape medication. See previous section. 
 

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 Treatment for other medical conditions 
Any medication, considered necessary for the subjects safety and well-being, may be given at the discretion 
of the investigator(s). The administration of all medication will be recorded in the appropriate sections of the 
electronic Case Report Form (eCRF). A description of the type of drug or procedure, the amount, duration, 
reason for administration of drug, and the outcome of any procedures will be documented. AEs related to the 
administration of a concomitant medication or the performance of a procedure must also be documented in 
the appropriate eCRF section. When related surgical intervention is needed (in exceptional cases) this will be 
registered as a serious adverse event (SAE) and as a safety endpoint. 
 
 

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8. INVESTIGATIONAL PRODUCT  
 
 Name and description of investigational product 
Prednisolone 5 mg capsules 
 
 Summary of findings from non-clinical studies 
The Investigational Medicinal Product that will be manufactured by Bluepharma consists in a modification of a 
medicinal product which is authorised and marketed in the EU. As the Summary of Product Characteristics 
(SPC) of the approved medicinal product is available, information regarding the findings from non-clinical 
studies is mentioned in the SPC (please refer to section “5 - Pharmacological properties” of the SPC). 
 
 Summary of findings from clinical studies 
The Investigational Medicinal Product that will be manufactured by Bluepharma consists in a modification of a 
medicinal product which is authorised and marketed in the EU. As the SPC of the approved medicinal product 
is available, information regarding the findings from clinical studies is mentioned in the SPC (please refer to 
section “5 - Pharmacological properties” of the SPC). 
 
 Summary of known and potential risks and benefits 
For known and potential risks please refer to the following sections of the SPC: 
• 4.3 - Contraindications 
• 4.4 - Special warnings and precautions for use 
• 4.5 - Interaction with other medicinal products and other forms of interaction. 
• 4.6 - Fertility, pregnancy and lactation 
• 4.8 - Undesirable effects 
 
For benefits of the Investigational Medicinal Product please refer to section “4.1 - Therapeutic indications” of 
the SPC. 
 
 Description and justification of route of administration and dosage 
The Investigational Medicinal Product has the pharmaceutical form of capsules to be taken orally. Regarding 
dosage, please refer to the information included in the section “4.2 - Posology and method of administration” 
of the SPC of the authorised product. 
 
 Dosages, dosage modifications and method of administration 
Please refer to the information included in the section “4.2 - Posology and method of administration” of the 
SPC. 
 

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 Preparation and labelling of Investigational Medicinal Product 
The Investigational Medicinal Product and the matching placebo will be manufactured according to the Good 
Manufacturing Practice (GMP). Quality control testing will be performed to confirm that the study medication 
complies with all the defined quality standards for human use. 
  
The study medication will be packed in bottles and labelled for the trial in accordance to the requirements 
described in EU GMP Annex 13: Investigational Medicinal Products. The label information will be in the official 
language(s) of the country in which the investigational medicinal product is to be used. 
 
 Drug accountability 
After all the necessary regulatory approvals and upon Sponsor’s request, defined quantities of study 
medication (investigational product and matching placebo) will be shipped to the clinical centers in appropriate 
conditions in order to guarantee the quality of the investigational medicinal products. Relative humidity and 
temperature will be controlled during shipment, if needed using a data logger. 
 
In accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) 
guidelines, after each study medication receipt, the research staff of each center will account for all study 
medication. Details of receipt, storage, dosing preparation, administration and return will be recorded. 
Investigational products will be provided to study subjects only. An adequate quantity of reserve samples for 
the investigational medicinal products and matching placebo will be retained. The packaging, storage 
conditions and retention period of the reserve samples shall comply with the current version of the applicable 
regulations. 
 
Upon completion or premature termination of the study, both the unused and partially unused investigational 
products and matching placebo (except for the retention samples) will be destroyed. 
 
 

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9. METHODS 
 
 Study outcomes 
Assessment takes place ten times during the two years of the trial. At seven timepoints the assessments are 
performed during a visit to the clinic, and at three timepoints the information with regard to the assessments is 
gathered by telephone. See Table 3 for more information. 
 
Main study outcomes  
 
a) GC benefit/harm balance 
Benefit 
Primary outcome measure 
• 
Signs and symptoms: the time-averaged mean value of the DAS28; 
 
Secondary outcome measures 
• 
Damage progression: 2-year change in total Sharp/van der Heijde damage score of hands and forefeet 
radiographs. 
• 
WHO-ILAR core set of RA outcome measures, including pain, patient and physician global 
assessment, physical disability, joint counts (swollen joints and tender joints), acute phase reactants 
(C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)), and radiographs of hands and 
forefeet at 0 and 2 years 
o 
DAS28 is calculated is calculated from 4 of these 
• 
Severity and duration of morning stiffness 
• 
Fatigue 
• 
SF36 - The Short Form 36-item Health Survey, a questionnaire about QoL 
• 
RA Impact of Disease (RAID) tool – The RAID is a validated questionnaire assessing the seven most 
important domains of impact of RA on the patients 
• 
Health Assessment Questionnaire (HAQ) 
• 
cost questionnaire, including 
o 
Activity limitation (part of cost questionnaire) 
o 
Work disability (for those holding a paid job, part of cost questionnaire) 
• 
Utility/Quality-adjusted life years (QALY): Euro-QoL in 5 dimensions (EQ-5D) 
 
Harm 
Primary outcome measure 
The total number of patients experiencing at least one AE of Special Interest. An ‘AE of Special Interest’ is 
defined as either a SAE according to the GCP definition (described in chapter 10.2.2), or the occurrence of 
one the following AEs:  
• 
any AE (except loss of efficacy, worsening of disease) that leads to the definite cessation of one of the 
antirheumatic drugs, including trial medication;  

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• 
a cardiovascular event (myocardial infarction, cerebrovascular event, peripheral arterial vascular 
event) 
• 
newly occurring hypertension requiring drug treatment; 
• 
newly occurring diabetes mellitus requiring drug treatment; 
• 
symptomatic bone fracture requiring treatment; 
• 
infection requiring antibiotic treatment; 
• 
newly occurring cataract or glaucoma. 
AEs can be reported spontaneously by patients, on prompting at clinic visits or by telephone interviews, 
and by the treating physician. The AEs specified above will be recorded with special care in a separate 
procedure. This procedure includes adjudication through the collection of evidence. This can be a 
declaration of the treating physician (in case of start of treatment), or a copy of a letter confirming the event, 
kept on file in the center. 
 
Secondary outcome measures 
• 
Vital signs, height, weight, and abdominal circumference 
• 
Bone mass assessed by Dual-energy X-ray Absorptiometry (DEXA).  
• 
Vertebral Fracture Analysis (by DEXA OR lateral radiograph of thoracic and lumbar spine)  
• 
Discontinuation of study drug with reason 
This includes patients in whom treatment with prednisolone becomes clinically indicated or 
those with unacceptable side effects attributable to study medication; 
• 
Change of antirheumatic treatment, with reason 
• 
Intensification of treatment for existing comorbidity, e.g. hypertension or diabetes 
• 
Joint replacement surgery 
Data collection is in agreement with industry standard (i.e. Meddra terminology etc.) 
 
b) Cost-effectiveness and cost-utility 
Estimate of costs of treatment and monitoring, including prevention and treatment of side effects; out of pocket 
costs. Estimate of indirect costs based on activity limitations valued at shadow price; and work disability for 
those still holding a paid job. Resource use data will be obtained by a cost questionnaire completed three/six-
monthly, medication use data will be collected with the eCRF, and the number of hospitalization days will be 
extracted from the narratives of the SAE forms. 
 
c) Medication adherence 
Adherence to trial drug is measured through the e-communicative packaging solution as the count of days in 
which the bottle is opened on the appropriate days, as measured by the adherence tool. The tool (cap) is 
collected at every study visit and replaced by a new specimen. Each cap (identified by study ID only) is sent 
back to the provider and the data are read out centrally. At the end of the study, the adherence data is added 
to the study database.  
 
 
 

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Secondary study outcomes/endpoints 
 
a) GC harm/benefit balance 
• 
Collection of biological samples 
• 
Blood samples will be collected during the study as part of the standard of care of RA patients, of 
which non fasting blood samples at baseline and after 3, 12, 24 and 27 months. No additional blood 
samples will be taken for this study. In specific cases, extra lipid analysis will be performed on the 
blood samples collected as part of the standard of care.  
Blood samples will not be stored for additional tests. 
b) Cost-effectiveness 
c) Medication adherence 
• 
Pill count at every study visit 
• 
For patients in the substudy:  
o 
Satisfaction with the application (21-point Likert scale) 
o 
Technical performance of the application-adherence tool dyad (to be determined) 
 
 Randomization, blinding and treatment allocation 
Four hundred and fifty elderly subjects with RA, will be randomized to either prednisolone 5 mg/day or matching 
placebo, both added to existing anti-rheumatic treatment in a 1:1 ratio. The two groups are double-blinded.  
 
Randomisation will be stratified for participating study site, for prior exposure to GC, and for concurrent start 
of other anti-rheumatic therapy. 
 
For randomisation, an Interactive Web Response System (IWRS) will be integrated in the data management 
system. The minimization randomisation method based on the principles of Pocock and Simon (Pocock SJ 
1975) will be used. Minimization is a method of randomization that allocates subjects to the treatment group 
that best maintains balance in stratifying factors. It is effective even at small sample sizes and with multiple 
stratification variables. Rules to calculate the amount of variation and the imbalance for each treatment, and 
rules to assign a probability to each treatment will be discussed with the sponsor before the implementation. 
 
For the substudy to measure the effect of smart reminders to adherence, 50 subjects with a smartphone will 
be randomized, between an application loaded on their smartphone that communicates with an adherence 
monitoring device loaded into the cap of the drug bottle and no such application loaded on their smartphone. 
Randomisation will be stratified for participating country and treatment in order to have for each treatment a 
balance between an application and no application on the smartphone. The same method as mentioned before 
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 Study procedures 
The study procedures are described in detail below, and measurements that are included in this trial are stated 
in Table 2. Almost all measurements can be regarded as standard of care in the participating countries and 
sites.  
 
All clinical procedures can be repeated at any time and study procedures may be performed at unscheduled 
time points, if deemed necessary by the investigator. Any additional tests or assessments for safety reasons 
may be performed if deemed necessary by the sponsor or investigator. These unscheduled assessments 
should be recorded in the eCRF. 
 
 
Demographic measurements, education, medical conditions; baseline 
assessment of prognostic factors 
Demographic data to be recorded are date of birth, sex, body weight, height, smoking, alcohol use, and the 
possession of a smartphone. Body weight and height will be obtained with the subject’s shoes off, jacket or 
coat removed. Body weight will be assessed at baseline, and after 3, 6, 12, 18, 24 and 27 months, height will 
be measured at the baseline visit and at 24 months. 
 
Education level (Appendix M), relevant medical history, vaccination status and current medical conditions will 
be obtained by the investigator or qualified designee and recorded in the eCRF. At baseline the following 
prognostic factors will be assessed by brief questionnaires (Appendix M): risk factors glaucoma (4 items); 
adherence (8 items); health literacy (3 items); arthritis helplessness index (5 items).  
 
 
Vital signs and physical examination  
Vital signs will be performed at the baseline visit, 3, 6, 12, 18, 24 and 27 months. Vital signs include heart rate 
and blood pressure. Any abnormalities will be recorded in the eCRF. Physical examination will be performed 
at the discretion of the treating physician. 
 
Hand, wrist and feet X-ray 
Radiographs of both hands (including wrists) (one film anteroposterior) and forefeet (one film anteroposterior) 
will be obtained at baseline and 24 months. 
 
 Laboratory measurements 
Laboratory tests performed as in standard of care for hematology, biochemistry, and lipids are described in 
detail below (Table 2). 
 
Efficacy assessments  
 
Evaluation of joints and disease activity scores 
An assessment of 44 joints for swelling and tenderness will be performed at baseline and after 24 months, 
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tenderness will be graded semi-quantitatively from 0-3 for the 44 joint score (Ritchie Articular Index (RAI)) 
(Ritchie DM 1968) and as absent or present for the 28-joint score. Appendix B. 
 
The DAS28 is a composite index taking into account the tenderness and swelling score of 28 joints, laboratory 
ESR, and the global assessment of disease activity. The DAS28 has a range of 0 to 9.4, in which levels below 
3.2 represent low disease activity, and levels equal or greater than 3.2 represent high disease activity. The 
EULAR response and ACR response are rated according to appendix C. 
 
Damage progression of the joints in the hands and forefeet will be evaluated by the total Sharp/van der Heijde 
damage score (appendix D). 
 
Global disease activity 
The physician will answer a question on global assessment of disease activity on a 21-point Likert Scale (at 
the time points indicated in Table 2; appendix F). 
 
The patient will answer two questions in a similar way: 
1. global assessment of disease activity (appendix E). 
2. pain question: this question is part of the RA Impact of Disease (RAID) questionnaire, see appendix H. 
 
Stiffness 
Morning stiffness severity is assessed using a 21-point Likert Scale. In addition, morning stiffness duration in 
minutes is assessed. See appendix E. 
 
(Modified) Health Assessment Questionnaire ((M)HAQ) 
The (M)HAQ index is a patient completed questionnaire specific for RA to assess physical functioning. The full 
HAQ consists of 20 questions referring to 8 component sets: dressing/grooming, arising, eating, walking, 
hygiene, reach, grip, and activities. The MHAQ consists of 10 questions. Appendix GF. 
 
Rheumatoid Arthritis Impact of Disease Questionnaire (RAID) 
The RAID is a validated questionnaire assessing the seven most important domains of impact of RA on the 
patients, with a 21-point Likert Scale. See appendix H. 
 
Cost questionnaire 
Data about costs for health care and housekeeping, and sick leave in paid and unpaid work are collected with 
the cost questionnaire in appendix I. 
 
Quality of life 
The EQ-5D and the SF36 will be completed to assess QoL. They are added as appendix J and appendix K. 
 
 
 

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Patient symptom list 
Patients will be asked to fill out the patient symptom list, a list with a number of physical complaints, as depicted 
in appendix L. 
 
 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any consequences. The 
investigator and sponsor can decide to withdraw a subject from the study for urgent medical reasons. 
 
 Replacement of individual subjects after withdrawal 
For this study subjects will not be replaced after withdrawal. 
 
 Follow-up of subjects withdrawn from treatment 
All patients taking study medication will be followed up for a maximum of 2 years and 3 months, when 
tapering of study medication is complete. When a patient prematurely discontinues study medication a full 
end of study visit (V9) is performed. This visit includes radiographic assessment (X-ray and DEXA) if study 
medication is stopped at or after 9 months from study start and if local standards permits.   
Where this is not possible (because the stop of study medication lies in the past), the first visit after the event 
must be executed as a V9 visit.  
For completeness: regulations stipulate that all adverse events (serious or nonserious) MUST be followed 
until resolved or stable, this also applies to situations where study medication is prematurely stopped. For all 
adverse events the last possible follow up will be at V10. 
In addition, all patients stopping prematurely are invited to attend a follow up visit (V10) at or around 2 years 
after the inclusion date. Data collected at this visit is the same as those collected for a normal V10 (‘follow 
up/taper visit’). 
For patients who stop prematurely, AE evaluation will be limited to SAE and events of special interest. At visit 
10, completeness of follow up for events occurring in the first 3 months after stop of study medication will 
also be checked. 
Completion of the data for V10 is required to receive the full fee for a patient. 
 
  Premature termination of the study 
Not applicable: prednisolone at doses exceeding 5 mg/d is currently widely used as chronic therapy in the 
target population, so unexpected safety findings that would necessitate premature termination are extremely 
unlikely. One of the main objectives of the study is to provide an accurate estimate of the safety this licensed 
therapy. 
 
 
 Procedure for unblinding of study medication 
The treating physician or pharmacist can request unblinding of study medication for medical reasons. Please 
refer to the Gloria IMP manual for unblinding instructions via the ALEA e-CRF or via telephone. 
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The patient can stay in the study, but the data collected will be handled separately in the analysis (see section 
7.2). 
 
 
 
 
 
 

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10. SAFETY REPORTING 
 
 Disadvantageous event  
 
In accordance to applicable legislation and guidelines, the investigator will inform the subjects and the 
reviewing accredited ethical committee if anything occurs, on the basis of which it appears that the 
disadvantages of participation may be significantly greater than was foreseen in the research proposal. The 
study will be suspended pending further review by the accredited ethical committee, except insofar as 
suspension would jeopardise the subjects’ health. The investigator will take care that all subjects are kept 
informed. 
 
 AEs, SAEs and SUSARs 
 
Adverse events (AEs) 
An AE is any untoward medical occurrence in a subject who has received study drug, or any untoward or 
unintended response to an experimental intervention which does not necessarily have a causal relationship 
with the treatment.  
An undesirable medical condition can be symptoms (e.g. dizziness, flushing), signs (e.g. local progression of 
swelling or hematoma), disease or the abnormal results of an investigation (e.g. laboratory findings) 
temporarily associated with the use of a medicinal (investigational) product. Any worsening of pre-existing 
condition that is temporally associated with the use of the pharmaceutical product, is also an AE. 
 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for elective surgery, 
social and/or convenience admissions) do not represent AEs.  
 
Subjects will be carefully monitored throughout the study for AEs. At each study visit, subjects will be asked to 
report any AE. All AEs are followed until they are resolved or stabilized, or until all attempts to determine 
resolution of the event are exhausted. The investigator will use his/her discretion in ordering additional tests 
as necessary to monitor the resolution of such events.  
Each collected AE, regardless of the relationship to study drug, will be recorded in the AE eCRF. All entries 
should contain an event term, date of onset, date of resolution, severity, action taken, outcome, relationship 
to study drug, and a seriousness assessment. The investigator will document all AEs in the subject’s source 
document. Reported (change in) symptoms in the “Patient symptom list” do not need to be reported in the 
eCRF as an AE. 
 
Severity will be assessed by the investigator according to the following definitions: 
• 
Mild: The event is of little concern to the subject and/or of no clinical significance. The event is not expected 
to have any effect on the subject’s health or wellbeing. 

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• 
Moderate: The subject experienced discomfort enough to cause interference with usual activity, and/or the 
condition required specific treatment. The event is of some concern to the subject’s health or wellbeing. 
The event may require medical intervention. 
• 
Severe: The subject is incapacitated and unable to work or participate in many or all usual activities. The 
event is of definite concern to the subject and/or poses substantial risk to the subject’s health or wellbeing. 
The event is likely to require medical intervention and/or close follow-up. 
• 
Life-threatening: The subject is at risk of death due to the AE as it occurred. This does not refer to an event 
that hypothetically might have caused death if it were more severe. 
• 
Death: Death related to AE. 
 
Action taken is categorized as “none”, “study drug discontinued”, “dose modified”, “required concomitant 
medication”, “required procedure”, or “other”. 
 
Event outcome at resolution, or time last follow-up was recorded is categorized as: “event resolved”; “resolved 
with sequelae”; “ongoing”; “lost to follow-up”; or “death”.  
 
The investigator will determine the relationship of the event to the study drug according to the following criteria: 
• 
Not related: The event does not follow a plausible chronological sequence relative to trial medication 
administration and can be clearly assigned to other factors, such as subject’s clinical condition, therapeutic 
procedures or administration of concomitant medications. 
• 
Possibly related: There is sufficient information to accept the possibility of a causal relationship, although 
the connection is uncertain or doubtful, i.e. causal relationship is not impossible and not unlikely.  The 
event follows a plausible chronological sequence relative to trial medication administration and/or presents 
the usual response to the drug tested.  The event might also be caused by other factors, such as the 
subject’s clinical condition, therapeutic procedures or administration of concomitant medications. 
• 
Probably related: There are good reasons and sufficient documentation to assume a causal relationship 
in the sense of plausible, conceivable, likely, but not necessarily highly probable. The event follows a 
plausible chronological sequence relative to trial medication administration and/or presents an unexpected 
response to the trial drug and cannot reasonably be explained by other factors, such as the subject’s 
clinical condition, therapeutic procedures or administration of concomitant medications.  
• 
Definitely Related: When the event cannot be attributed to the subject’s underlying medical condition or 
other concomitant therapy and there is compelling temporal relationship between the onset of the event 
and the study investigational product administration that leads the PI to believe there is evidence of a 
reasonable causal relationship. 
 
Adverse (Drug) reactions 
 
According Directive 2001/20/EC adverse (drug) reactions (ADR) are all untoward and unintended responses 
to an investigational medicinal product related to any dose administered.  

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The definition implies a reasonable possibility of a causal relationship between the event and the 
investigational medicinal product (IMP). This means that there are facts (evidence) or arguments to suggest a 
causal relationship. The definition covers also medication errors, misuse and abuse of the product. 
 
Serious adverse events (SAEs) 
A SAE is any untoward medical occurrence or effect that at any dose:  
• results in death; 
• is life threatening (at the time of the event); 
• requires in-subject hospitalisation or prolongation of existing inpatients’ hospitalisation, unless it was a 
planned hospitalization, for instance for an elective surgery; 
• results in persistent or significant disability or incapacity; 
• is a congenital anomaly or birth defect; 
• Is an important medical event that may jeopardize the subject or may require medical intervention to prevent 
one of the outcomes listed above.. 
 
Medical and scientific judgment should be exercised in deciding whether an AE is serious in other instances, 
such as an important medical event that may not be immediately life-threatening or resulting in death, or a 
hospitalisation that may jeopardize the subject or require intervention to prevent one of the above outcomes. 
Elective surgery for pre-existing conditions as noted in the CRF will not be included as SAE, unless the surgery 
is triggered by unexpected worsening of the clinical condition. 
 
All SAEs will be reported by the investigator to the Accelovance Pharmacovigilance (PV) within 24 hours of 
first knowledge of the investigator or its team. All SAEs will be reported by submitting a completed SAE Report 
Form. Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology. It is critical that the information provided on the sponsor’s SAE Report Form matches the information 
recorded in AE eCRF for the same event. In addition, the same information is to be recorded in the source 
documents. 
 
PV will notify the sponsor of all SAE’s within 24 hours of its initial receipt. 
The CIOMS prepared by PV will be shared with sponsor for review and approval. 
 
Pregnancy screening and handling is not applicable in this study as all subjects are 65 years or older.  
 
Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational product related to any dose 
administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 10.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an undesirable 
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3. the adverse reaction must be unexpected, that is to say, the nature and severity of the adverse 
reaction are not in agreement with the product information as recorded in the SPC for an 
authorised medicinal product; 
 
All serious and unexpected adverse reactions that are possibly, probably or definitely related to IMP are subject 
to expedited reporting to Regulatory Authorities and Ethic Committees, in accordance with ICH guidelines for 
GCP and the EU Directive 2001/20/EC and applicable local regulations. 
 
SUSARs that are fatal or life-threatening must be reported as soon as possible and in any case no later than 
7 calendar days after knowledge by PV/sponsor of such a case, and that relevant follow-up information is 
subsequently communicated within an additional eight days. 
All other suspected serious unexpected adverse reactions shall be reported to the competent 
authorities  concerned and to the IRB/IEC concerned as soon as possible but within a maximum of 
15 calendar days of first knowledge by PV/sponsor. 
PV will report any SUSARs on behalf of the sponsor to the IEC/CA according to local requirements. The 
IRB/IEC should receive the following SUSARs expeditedly: 
• SUSARs that have arisen in the clinical trial that was assessed by the accredited ethical committee; 
 
 Annual safety update report 
In addition to the expedited reporting of SUSARs,  once a year throughout the clinical trial, a safety report will 
be submitted to the accredited ethical committee, competent authority and ethical committees & competent 
authorities of the concerned Member States. 
This safety report will comprise a line listing of all SAEs, along with an aggregated summary table of all reported 
SAEs and other events of special interest (see 9.1.1.a), ordered by organ system. 
 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached; last potential follow 
up is at V10. Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist.  
 
 Monitoring  
Clinical trial management and monitoring will be performed by Curve Clinical. In order to ensure the clinical 
trial is managed and conducted properly Curve Clinical will: 
• 
Set up workflows, timelines, project specific procedures and tracking tools; 
• 
Monitor timelines and milestones on an ongoing basis and communicating the project status to the project 
team throughout the duration of the entire project; 
• 
Conduct regular team meetings to discuss project status, activities, address issues, coordination of project 
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• 
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• 
Provide status reports to principal investigator, regular site contacts, back-up according to agreed project 
structures; 
• 
Provide weekly internal status reports to senior Curve Clinical staff; 
• 
Maintain files according to the Standard operating procedures (SOPs); 
• 
Supporting the site with protocol and study related questions; 
• 
Supporting the study sites with patient visit coordination and patient follow up; 
• 
Initiate actions to address project issues. 
 
During the study, the monitor/clinical research associate will visit the investigational site regularly to check the 
completeness of patient records, the accuracy of entries in the eCRF, the adherence to the protocol and to 
GCP, the progress of enrollment, and to ensure that study drug is being stored, dispensed, and accounted for 
according to specifications. The monitor/clinical research associate is capable of reading the local language 
as well as being fluent in English. Key trial personnel must be available to assist the monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of case and visit 
notes (hospital or clinic medical records) containing demographic and medical information, laboratory data and 
the results of any other tests or assessments. All information on eCRFs must be traceable to these source 
documents in the patient’s file. Data not requiring a written or electronic record will be defined before study 
start and will be recorded directly in the eCRFs, which will be documented as being the source data. The 
investigator must also keep the original of the signed informed consent form. The investigator must give the 
monitor access to all relevant source documents to confirm their consistency with the CRF entries. Curve 
Clinical monitoring standards require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs, and the recording of data that will be used for all primary 
and safety variables.  

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11. STATISTICAL ANALYSIS 
 
 Primary study outcome(s) 
 
Benefit 
The two primary outcomes for benefit are RA disease activity and progression of joint damage. Disease activity 
is operationalized as DAS28. This index comprises a formula that includes 28 tender and swollen joint counts, 
general health (GH; patient assessment of disease activity; Likert scale from 0-10 recoded to 0-100, with 
0=best, 100=worst), plus levels of ESR (mm/h)). For calculation of DAS28, please see appendix C. Damage 
progression will be evaluated by the total Sharp/van der Heijde damage score of hands and forefeet (appendix 
D). 
 
Primary analysis: DAS28 
The DAS28 is a continuous variable. We will compute the “time averaged DAS28” based on the trajectories 
over time for each individual, as part of the repeated measures in the longitudinal design. Observations are 
included in the follow up time until end of trial or the occurrence of a protocol violation (i.e., GC co-interventions 
as outlined in section 7.2).  
 
The term ‘repeated measures' refers to data with multiple observations on the same sampling unit; in this case, 
the multiple observations are taken over time (10 visits) in 450 RA patients. To address the issue of covariation 
between measures on the same unit, linear mixed models will be fitted because they permit the covariance 
structure to be incorporated into the statistical model. After modelling the covariance structure, inference about 
fixed effects proceeds essentially as when using simple Analysis of Covariance (ANCOVA); i.e., enabling 
estimation of group effects “averaged over time” measured in DAS28-units. Using repeated-measures mixed 
models we will analyse mean trajectories in continuous end points. The model will include treatment (group), 
and the multiple stratification variables (participating study site, prior exposure to GC, and concurrent start of 
other anti-rheumatic therapy) as fixed effects, with the baseline value of the relevant variable as a covariate. 
 
Secondary analyses: DAS28 
Change in DAS28 over the first 3 months of the trial (when the chance of co-intervention is least) will be 
compared between the treatment groups by ANCOVA, adjusting for the level at baseline. In secondary 
analyses, observations in patients after the protocol violation will be included in the analysis described above. 
 
Damage progression will be evaluated by the change in total Sharp/van der Heijde damage score of hands 
and forefeet. It is known that this variable has a positively skewed distribution. Cumulative probability plot with 
the distribution of change in total Sharp/van der Heijde score from baseline to two-year follow-up will be applied 
as well as a non-parametric test (the Mann-Whitney test) to compare intervention and control groups. 
 
 
Harm 

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The primary outcome variable for harm is operationalized as a binary variable with two categories (0= no 
adverse event, 1= at least one adverse event of special interest (see 9.1.1.a). This variable will be presented 
as a proportion. A chi-square test will be used to test for differences between the proportion of adverse events 
in intervention and control groups. 
 
Secondary analyses:  
A logistic regression model with harm as dependent variable will be fitted in order to adjust for potential factors 
that may alter the probability of AEs (as explained above for benefit). In addition absolute incremental risk and 
relative risk will be calculated for all major events, with confidence intervals. 
 
Analysis strategy: 
• 
One-sided significance levels (alpha=0.05); asymmetric null hypotheses: this approach increases the 
chance of rejecting the null hypotheses compared to standard two-sided testing. This results in a 
higher chance of declaring benefit (justified in view of scientific knowledge and the pragmatic trial 
design), but also a higher chance of declaring harm (to guard against the limited power of the study to 
detect harm). 
o 
confirmation of benefit: on the basis of the trial data we expect to reject the null hypothesis of 
GC (added to standard of care) yielding similar effectiveness compared to placebo  (H0); the 
alternative (H1) hypothesis is that GC yields better effectiveness;  
o 
demonstration of absence of harm: we expect NOT to reject the null hypothesis that GC yields 
similar side effects; see 4.4 for considerations of the 95% non-inferiority confidence bound.  
- 
In case the trial detects a difference in AEs favoring the GC group, the superiority of 
GC will be tested in a secondary analysis. 
• 
Handling of premature discontinuations, dropouts and missing data: for primary analysis of signs and 
symptoms (efficacy), after the baseline screening and the first assessment visit, each patient with at 
least one follow up visit (this can be an extra premature discontinuation visit) will contribute until 
moment of discontinuation. For harm, patients experiencing an event at or before discontinuation will 
be counted; patients without such an event will be included in the group numerator (weighted by total 
time in trial).  
 
Different missing data pattern will be studied and Multiple Imputation will be used to handle for discontinuations 
and drop-out. In the imputation model all variables related with the presence of missing will be included. Then, 
at least 20 data-sets will be imputed and the pooled results will be reported. Sensitivity analyses will be used 
to assess the robustness of our results. 
 
Prespecified interpretation rules: 
The co-primary outcomes of benefit (average disease activity) and harm (occurrence of AE of special interest) 
will be assessed and analyzed together.  
Given that GLORIA is a pragmatic trial where co-interventions are allowed, the observed effects are likely a 
compound of the ‘’pure’’ treatment effects and the effects of (potentially differential) co-interventions in the 
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the event that placebo patients more frequently require co-interventions because their RA is not under control, 
leading to subsequent improvement in disease activity. 
The outcomes of benefit will be interpreted as follows (GC group compared to placebo): 
1. success:  
a. lower disease activity (one-sided p<0.05)  
AND lower damage progression (one sided p<0.05) 
b. lower disease activity (one-sided p<0.05) OR lower damage progression (one-sided p<0.05) 
AND benefit confounding 
2. partial success/tradeoff:  
a. lower disease activity (one-sided p<0.05) OR 
lower damage progression (one-sided p<0.05) 
b. Benefit confounding 
3. failure: NO lower disease activity (one-sided p≥0.05)  
AND NO lower damage progression (one sided p≥0.05) 
AND NO benefit confounding 
 
The outcomes of harm will be interpreted as follows: 
1. success: NO significant increase in AEs (one sided p≥0.05) 
2. failure: significant increase in AEs (one-sided p<0.05) 
 
For the interpretation of increases in the occurrence of AE of special interest that did not reach significance 
we will use the suggestions of the GRADE (Grades of Recommendations, Assessment, Development, and 
Evaluation) Working Group (Guyatt 2012), upper limit of one-sided 95% confidence limit (CL): 
1. > 1.3: GC associated with a trend towards greater occurrence;  
2. ≤ 1.2: GC appears to have little effect on the occurrence; 
3. > 1.2 and ≤ 1.3: results failed to demonstrate or exclude a greater occurrence. 
 
In the case of a numerical DECREASE in AE, a more stringent test for significance will be performed (p<0.025). 
For the interpretation of decreases in the occurrence of AE that did not reach significance: 
lower limit of one-sided 95% CL: 
1. < 0.7: GC associated with a trend towards reduced occurrence; 
2. ≥ 0.8: appears to have little effect on the occurrence; 
3. < 0.8 and ≥ 0.7: results failed to demonstrate or exclude a reduced occurrence. 
 
Economic evaluation 
The economic evaluation will comprise a cost-effectiveness and a cost-utility study. The evaluation will be 
performed according to the intention-to-treat principle and from a societal perspective. All direct medical and 
non-medical, and indirect costs were combined to calculate the costs per patient. Costs of hospitalization 
days, visits to medical specialists (direct costs), and help in the household (indirect costs) are valued with 
standard prices according to the Dutch manual for costing studies. Dutch prices will be used for all costs to 
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included in this year. The Dutch consumer price index will be used to account for inflation. Production losses 
will be valued using the friction cost method: only sick leave during a friction period (23 weeks) needed to 
replace a person is taken into account (indirect costs).  
Outcome measures are time-averaged disease activity (DAS28) for the cost-effectiveness analysis and 
Quality-Adjusted Life Year (QALY) for the cost-utility analysis.  
 
Confidence intervals (CI) for costs will be estimated with bias-corrected accelerated bootstrapping with 1000 
iterations.  
 
All patients will be included in the cost-utility and cost-effectiveness analyses according to the intention-to-
treat principle. Missing data will be imputed with multiple imputation by chained equations (with predictive 
mean matching). Stepwise linear and logistic regression analyses will be used to examine which variables 
are associated with missingness. and such variables will be included in the multiple imputation model. The 
data are imputed as total costs or utility score or DAS28 per time point per treatment arm (prednisolone or 
placebo). The imputed datasets will be bootstrapped with 5000 replications in order to estimate the 
uncertainty around the difference in costs and effects.   
 
The imputed datasets will be bootstrapped with 5000 replications in order to estimate the uncertainty around 
the difference in costs and effects. The incremental Cost-Effectiveness and Cost-Utility Ratios (ICER and 
ICUR) will be calculated by dividing the difference between the mean costs per treatment group by the 
difference between the time-averaged disease activity per group and by the difference in QALYs per patient. 
The results will be graphically presented on a cost-effectiveness and cost-utility plane, and a cost-
effectiveness acceptability curve will be constructed. This results in four different quadrants: two showing 
dominance of one treatment over the other, and two indicating a tradeoff between QALYs and costs. 
 
Medication adherence 
• 
Nonparametric and parametric comparisons between treatment groups where appropriate; one-sided 
significance levels (alpha=0.05) 
• 
Handling of premature discontinuations, dropouts and missing data: each patient will contribute until 
moment of discontinuation (weighted by total time in trial) 
 
 Secondary study outcome(s)  
For continuous variables, (e.g. RA core, SF36, RAID, QALY) first univariate analyses will be conducted to 
evaluate their distributions and the presence of outliers. If the variables are not normally distributed they will 
be transformed. Then mixed regression models will be used to study changes in their levels over the follow-
up.  
 
For categorical variables (e.g. ACR response, EULAR response) multiple exclusive groups will be defined and 
differences between the intervention and control groups will be tested by a chi-squared test for linear-by-linear 
association. In secondary analyses, generalized linear mixed models (GLMM) will be used to assess different 

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patterns of change during the follow-up. Finally, number needed to treat and number needed to harm analyses 
will be conducted on selected categorical variables based on the observed events in the placebo group. 
 
 

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12. ETHICAL CONSIDERATIONS 
 
 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (64th WMA 
General Assembly, Fortaleza, Brazil, October 2013, see for the most recent version: www.wma.net), GCP and 
in accordance with the Medical Research Involving Human Subjects Act (WMO) and other guidelines, 
regulations, and Acts. 
 
 Recruitment and consent 
Subjects will be recruited from the investigational sites based on the eligibility criteria provided in the protocol. 
They will be informed about the study by their treating rheumatologist, where after they receive the patient 
information letter and the researcher or research nurse will provide extra information on request. Subjects can 
think about participation as long as needed. 
 
Voluntary written Informed Consent Form (ICF) must be obtained from each subject prior to performing any 
study related procedures in compliance with the recommendations of the Declaration of Helsinki. Subjects 
should not be screened or study drug administered until the subject has signed an approved ICF written in a 
language that is understandable to the subject. 
 
Each subject should be given both verbal and written information describing the nature and duration of the 
clinical study. The ICF should be signed and personally dated in two originals by the subject and the person 
who conducted the informed consent discussion. The Investigator, or the attending health care professional 
will explain the nature, purpose and risks of the study. The subject will be informed that he/she has the right 
to withdraw at any time from the study, without giving reasons. In this condition, the subject will also be 
informed that he/she will not receive any indemnity. The informed consent process should take place under 
conditions where the subject has adequate time to consider the risks and benefits associated with his/her 
participation in the study.  
 
Each subject should receive one original of the signed and dated written ICF and any other information 
provided to the subject. The second original of the signed and dated ICF should be retained in the investigator’s 
file. The investigator should maintain a log of all subjects who sign the ICF. 
 
 Benefits and risks assessment, group relatedness 
Since GLORIA is a pragmatic trial, it is designed to evaluate the effectiveness of interventions in real-life routine 
practice conditions. This means almost all measurements are part of standard of care, and therefore there are 
no additional risks associated with these measurements.  
 
However, the intervention in this trial is that patients are randomised to either standard of care with low-dose 
GCs or standard of care with matching placebo for a duration of two years. It is known that GCs have strong 
favourable effects on disease activity, however, side effects are known as well, predominantly when used in 

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high-doses and for a long period of time. Unfortunately, clinical studies large enough to adequately document 
the balance between benefit and harm of low-dose GCs in combination with standard of care are lacking. And 
although elderly patients are overrepresented in terms of patient numbers in RA, this group exemplifies the 
challenge that they are underrepresented or even excluded from many clinical trials that generate the 
evidence-base for treatment of RA. However, the limited high-quality data from trials does not support strong 
claims of harm, but the generalizability of trial data is questioned. Therefore, the primary objective of the 
GLORIA trial is to deliver evidence-based information on the GC harm/benefit balance. 
 
For the substudy to measure adherence, no additional risks are expected. Non-adherence substantially 
increases the risk of a disease flare in RA. GLORIA measures adherence through a medication packaging 
device and tests an innovative application to improve medication adherence in elderly patients. If this 
application appears to be successful, patients randomised to this intervention can only benefit from it since it 
improves their medication adherence. In case the application is not successful, or patients are not randomised 
to the application, or for patients without a smartphone, no difference is expected with the ‘normal’ situation, 
in which patients do not have access to an adherence application. Furthermore, results of adherence 
monitoring and a positive result of the adherence intervention will have a large impact in the elderly population 
as a whole, and even more in the younger population where the penetration of smartphones is so much greater. 
 
 Compensation for injury 
The Sponsor and/or Investigator has a liability insurance which is in accordance with relevant legislation. In 
the event of any suffering, deterioration in health or well-being or any harmful susceptibility or toxicity caused 
to subjects’ participation in the trial, the subject will receive appropriate compensation irrespective of the 
question of legal liability.  
  
The Sponsor and/or Investigator has an insurance which is in accordance with the legal requirements in the 
participating countries. This insurance provides cover for damage to research subjects through injury or death 
caused by the study. The insurance applies to the damage that becomes apparent during the study or within 
4 years after the end of the study. Each partner will ensure proper insurance to cover their liability, and damage 
for subjects participating in their country. 
 
 Incentives 
Patients participating in this trial will receive compensation for travelling costs if extra visits to the treating 
centre (outside of regular care) are necessary. 
 
 

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13. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
 Handling and storage of data and documents 
 
Data Handling 
Subject medical information obtained by this study is confidential, and disclosure to third parties other than 
those noted below is prohibited. With the subject’s permission, medical information may be given to his 
personal physician or other appropriate medical personnel responsible for his/her welfare.  
 
The information required by the protocol into is entered into an electronic data collection system (EDC). The 
eCRF data are to be considered source data in addition to the automatic print outs as well as patient records. 
 
The eCRF will be developed by the data manager for the study. Detailed information on the eCRF completion 
will be provided during the site initiation visits. Each site will also be provided with an eCRF completion manual. 
In general, all users who have access to the EDC system will be trained. The access to the eCRF is password 
controlled. Plausibility checks will be performed according to a data validation plan. Inconsistencies in the data 
will be queried to the investigators via the electronic data collection system; answers to queries or changes of 
the data will directly be documented in the system. After all data are entered and all queries are solved, the 
database will be closed. 
 
Data generated by this study must be available for inspection by representatives of other national and local 
health authorities, the sponsor, and the IRB/IEC for each study site, if appropriate. 
 
Subjects will be identified on CRFs and other documents submitted to the Sponsor or organisations working 
on behalf of the Sponsor by their subject number, not by name or initials. Documents not to be submitted to 
the Sponsor or organisations working on behalf of the Sponsor that identify the subject (e.g., the signed 
informed consent) must be maintained in confidence by the Investigator.  
 
Data Coding 
All subjects who sign a study informed consent will be assigned a unique subject identification number at the 
time of their Screening visit (after consent). Subjects will be identified by this unique subject identification 
number for the duration of their participation in the study.  
 
All subjects enrolled must be identifiable throughout the study. The Investigator will maintain a list of subject 
numbers and subject names to enable records to be found at a later date. Subjects will be assigned 
identification numbers automatically via the eCRF. 
 
The unique subject identification number consists of a combination of numbers: the first number is the land 
code, followed by the site number and the patient number. For example: in the Netherlands (land code 1) in 
the first site (site number 01), the first patient (patient number 001) will have the unique subject identification 
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Data Confidentiality 
The Investigator is required to ensure that any documents or data given to the Sponsor or its representatives 
do not contain information that would affect the anonymity of the subjects. The Investigator will obtain 
permission for direct access to subject data from the subject as part of the written informed consent procedure. 
This gives permission to examine, analyse, verify, and reproduce any records and reports that are important 
to the evaluation of the trial. Any party (e.g., domestic and foreign regulatory authorities, Sponsor personnel 
or its representatives, and auditors) with direct access must take all reasonable precautions, within the 
constraints of the applicable regulatory requirement(s), to maintain the confidentiality of the subject’s identity 
and Sponsor’s proprietary information. 
 
 
Data Storage 
Each research site will retain copies/originals of the approved trial or study protocol, subjects' participation 
agreements, relevant source documents and all other supporting documentation related to the trial or study 
for a period of fifteen (15) years. These documents should be retained for a longer (or shorter) period however 
if required by the applicable regulatory requirements or by an agreement with the Sponsor. 
 
The Sponsor will provide each Investigator with information concerning the current status of the investigational 
drug as this may relate to the above stated obligation for the retention of study records. The Sponsor will inform 
each study site as to when these documents no longer need to be retained. Study sites should contact the 
Sponsor prior to disposing of or archiving any such records. 
 
 Monitoring and Quality Assurance  
More information about monitoring can be found in chapter 10.5. 
 
 Amendments  
A ‘substantial amendment’ is defined as an amendment to the terms of the IEC application, or to the protocol 
or any other supporting documentation, that is likely to affect to a significant degree: 
• the safety or physical or mental integrity of the subjects of the trial; 
• the scientific value of the trial; 
• the conduct or management of the trial; or 
• the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the IEC and to the competent authority. Non-substantial 
amendments will not be notified to the accredited IEC and the competent authority, but will be recorded and 
filed by the sponsor. 
 
 Annual progress report 
The sponsor/investigator or CRO representative will submit a summary of the progress of the trial to the 
accredited IEC once a year. Information will be provided on the date of inclusion of the first subject, numbers 

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of subjects included and numbers of subjects that have completed the trial, SAEs/serious adverse reactions, 
other problems, and amendments.  
 
 End of study report 
The sponsor will notify the accredited IEC and the competent authority of the end of the study within a period 
of 90 days. The end of the study is defined as the last patient’s last visit.  
 
In case the study is ended prematurely, the sponsor will notify the accredited IEC and the competent authority 
within 15 days, including the reasons for the premature termination. 
 
Within one year after the end of the study, the investigator/sponsor will submit a final study report with the 
results of the study, including any publications/abstracts of the study, to the accredited IEC and the Competent 
Authority. 
  
 Public disclosure and publication policy 
The final report will be written in English in a Word format and its structure will follow a template based upon 
the ICH E3, guidelines unless otherwise specified by the sponsor during financial agreement. 
Suggested inclusions in the report are: study objectives, materials and methods (including any deviations from 
the study protocol), evaluation of the study results, observations by the investigator as to the value of the study 
drug per se, and a discussion of all adverse experiences with interpretation by the investigator as to the study 
drug involvement. 
All information concerning the tested drug and the sponsor's operation, such as patent applications, formulae, 
manufacturing processes, basic scientific data and formulation information supplied by the sponsor and not 
previously published are considered confidential and shall remain the sole property of the sponsor. The 
investigator agrees to use this information only in accomplishing this study and will not use it for other purposes 
without written consent from the sponsor.  
It is understood by the investigator that the information from the clinical study will be used by the sponsor in 
connection with the development of the tested drug and, therefore, may be disclosed as required to other 
clinical Investigators or to government agencies. In order to allow for the use of the information derived from 
the clinical studies, it is understood that there is an obligation to provide the sponsor with complete test results 
and all data developed in the study. 
The trial drug and the information in this document and in any future information supplied contain trade secrets 
and commercial information that are privileged or confidential and may not be disclosed unless such disclosure 
is required by law or regulations.  
In any event, persons to whom the information is disclosed must be informed that the information is privileged 
or confidential and may not be further disclosed by them. 
Publication rules will be consistent with local regulation and will be addressed in the study contract and should 
not be in contradiction with the text in the protocol. 
Furthermore, a trial publication policy will be formulated by the GLORIA Study Consortium by the end of 2015. 
 

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14. REFERENCES 
 
Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of 
Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010 
Sep;62(9):2569-81. 
 
Bakker MF, Jacobs JW, Welsing PM, et al. Low-dose prednisone inclusion in a methotrexate-based, tight 
control strategy for early rheumatoid arthritis: a randomized trial. Annals of Internal Medicine 2012;156:329-
39. 
 
Brown MT, Bussell JK. "Medication Adherence: WHO Cares?" Mayo Clin Proc, 2011: 86(4):304-314. 
 
Buttgereit F, Mehta D, Kirwan J, Szechinski J, Boers M, Alten RE, et al. Low-dose prednisone chronotherapy 
for rheumatoid arthritis: a randomised clinical trial (CAPRA-2). Ann Rheum Dis 2013;72:204-10. 
 
Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of 
Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995 
Jun;38(6):727-35. 
 
Gellad WF, Grenard JL, Marcum ZA. "A systematic review of barriers to medication adherence in the elderly: 
looking beyond cost and regimen complexity." Am J Geriatr Pharmacother. 2011 Feb;9(1):11-23. 
 
Guyatt GH, Norris SL, Schulman S, Hirsh J, Eckman MH, Akl EA, Crowther M, Vandvik PO, Eikelboom 
JW, McDonagh MS, Lewis SZ, Gutterman DD, Cook DJ,Schünemann HJ; American College of Chest 
Physicians. Methodology for the development of antithrombotic therapy and prevention of thrombosis 
guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest 
Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):53S-70S. 
 
Kirwan JR, Bijlsma JW, Boers M et al. "Effects of glucocorticoids on radiological progression in rheumatoid 
arthritis." Cochrane Database Syst Rev, 2007: CD006356. 
 
Kitas GD, Gabriel SE. "Cardiovascular disease in rheumatoid arthritis: styate of the art and future 
perspectives." Ann Rheum Dis, 2011: 70: 8-14. 
 
Kobelt, G. "The social and economic impact of rheumatoid arthritis." In Rheumatoid Arthritis, by Silman AJ, 
Smolen JS, Weinblatt ME, Weisman MH, eds. Hochberg MC, 83-89. Philadelphia, Penn: Mosby Elsevier, 
2009. 
 
Muller R, Kallikorm R, Polluste K, Lember M. "Compliance with treatment of rheumatoid arthritis." Rheumatol 
Int, 2012: 32:3131–3135. 
 

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Pocock, SJ, Simon R. "Sequential Treatment Assignment with Balancing for Prognostic Factors in the 
Controlled Clinical Trial". Biometrics (International Biometric Society), 1975. 31 (1): 103–115. 
 
Rasch EK, Hirsch R, Paulose-Ram R, Hochberg MC. "Prevalence of rheumatoid arthritis in persones 60 years 
of age and older in the United Staes: effect of different methods of case classification." Arthritis Rheum, 2003: 
48(4):917-926. 
 
Ritchie DM, Boyle JA, McInnes JM et al. Clinical studies with an articular index for the assessment of joint 
tenderness in patients with rheumatoid arthritis. Q J Med 1968; 37: 393-406. 
 
Schwartz D, Lellouch J. "Explanatory and pragmatic attitudes in therapeutical trials." J Chronic Dis. 1967; 20: 
637–648. 
 
Scott DL, Wolfe F, Huizinga TW. "Rheumatoid arthritis." Lancet, 2010: 376: 1094-1108. 
 
Sharp JT, Young DY, Bluhm GB et al. How many joints in the hands and wrists should be included in a score 
of radiologic abnormalities used to assess rheumatoid arthritis? Arthritis Rheum 1985; 28: 1326-35. 
 
Sokka T, Kautiainen H, Toloza S, Makinen H, Verstappen SM, Lund Hetland M, et al. "QUEST-RA: quantitative 
clinical assessment of patients with rheumatoid arthritis seen in standard rheumatology care in 15 countries." 
Ann Rheum Dis, 2007: (66) 1491-6. 
 
Van der Heijde DM, Van Riel P, Nuver-Zwart IH, Gribnau FW, Van der Putte LB. Effects of hydroxychloroquine 
and sulphasalazine on progression of joint damage in rheumatoid arthritis. Lancet 1989; 1: 1036-8. 
 
Van Gestel AM, Prevoo ML, Van 't Hof MA, Van Rijswijk MH, Van de Putte LB, Van Riel PL. 
Development and validation of the European League Against Rheumatism response criteria for rheumatoid 
arthritis. Comparison with the preliminary American College of Rheumatology and the World Health 
Organization/International League Against Rheumatism Criteria. Arthritis Rheum. 1996 Jan;39(1):34-40. 
 
Van Gestel AM, Anderson JJ, Van Riel PL, Boers M, Haagsma CJ, Rich B, Wells G, Lange ML, Felson DT. 
ACR and EULAR improvement criteria have comparable validity in rheumatoid arthritis trials. 
American 
College of Rheumatology European League of Associations for Rheumatology. J Rheumatol. 1999 
Mar;26(3):705-11. 
 
Woolf AD, Pfleger B. "Burden of major musculoskeletal conditions." Bulletin of the World Health Organization, 
2003: 81 (9). 
 
 
 

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15. APPENDICES 
 
Appendix A:  Schedule of assessments 
Appendix B: Joint counts 
Appendix C: Calculation of DAS28 and DAS44; EULAR response; ACR improvement 
Appendix D: Sharp/van der Heijde damage score 
Appendix E: Patient global assessment and stiffness 
Appendix F: 
Physician global assessment 
Appendix G: (M)HAQ – (Modified) Health Assessment Questionnaire 
Appendix H: RAID – RA Impact of Disease  
Appendix I: 
Cost Questionnaire 
Appendix J: 
EQ-5D – EuroQoL in 5 dimensions 
Appendix K: SF36 – Short Form 36-item Health Survey 
Appendix L: 
Patient symptom list 
Appendix M: Education level and Baseline prognostic factors 
 
 
 

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 Appendix A:  
Schedule of assessments 
 
 
Base-
line 
2 year treatment period 
Follow
up / 
taper
Visit No 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Month (visit window +/- 2 months) 
0 
3 
6 
9 
12 
15 
18 
21 
24LV 
27 
Location 
clinic 
clinic 
clinic 
remote 
clinic 
remote 
clinic 
remote 
clinic 
clinic
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
In- / exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics, education & medical 
history  
X 
 
 
 
 
 
 
 
 
 
Baseline prognostic factors: 
adherence, health literacy, arthritis 
helplessness index 
X* 
 
 
 
 
 
 
 
 
 
Randomization 
X* 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
X 
 
Vital signs /  weight  
X 
X 
X 
 
X 
 
X 
 
X 
X 
AE evaluation (inc. surgery, 
comorbidity) 
 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lab (hematology1, chemistry2) 
X 
X 
X 
 
X 
 
X 
 
X 
 
Lab lipids3 
X 
X 
 
 
X3 
 
 
 
X 
 
Lab CRP, ESR 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Joint counts (44) 
X 
 
 
 
 
 
 
 
X 
 
Joint counts (28) 
 
X 
X 
 
X 
 
X 
 
 
X 
DEXA either with VFA,  
or without VFA plus  
X-lat spine (thor, lumb)4,5 
X 
 
 
 
 
 
 
 
X 
 
X-rays hand and forefeet4 
X 
 
 
 
 
 
 
 
X 
 
Patient global assessment, stiffness 
duration, stiffness severity 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physician global assessment 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Questionnaires: 
- RAID 
- full HAQ-DI (24 items) 
- MHAQ-DI (10 items)  
- Cost questionnaire 
- EQ-5D 
 
X* 
X* 
 
X* 
X* 
 
X* 
X* 
 
X* 
X* 
 
X* 
X* 
 
X* 
X* 
 
X* 
 
X 
 
X* 
 
X* 
X* 
 
X* 
X* 
 
X* 
 
X 
 
X* 
 
X* 
X* 
 
X* 
X* 
 
X* 
 
X 
 
X* 
 
X* 
X* 
 
X* 
X* 
 
X* 
X* 
 
X* 
X* 
- SF36 
- Patient symptom list 
X* 
X* 
 
 
 
 
 
 
 
X* 
X* 
 
X* 
GC or placebo, dispense adherence 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
 
*  procedures not belonging to standard of care 
lv End of study visit. This visit also needs to be completed by subjects who early terminated the trial. 
Apart from CRP and ESR, the following standard of care lab tests will be done on peripheral blood samples.  
Lab results of CRP and ESR no more than 4 weeks old may be used for the baseline visit. 
Results of the below tests 1, 2,3  no more than  2 months old may be used for the baseline visit: 
1) Hemoglobin, Mean Cell Volume, White blood cell count, White blood cell differential count, Platelet count. 
2) Glucose (non-fasting), Creatinine, Alanine Aminotransferase;  
3) Total cholesterol, HDL cholesterol. Optional for month 12. 
4) For the baseline visit: DEXA, DEXA VFA and X-ray images with a maximum of 6 months before or until 3 months after 
the baseline visit may be used. 
5) If possible a whole body DEXA may be performed.  
 

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 Appendix B:  
Joint counts 
 
 
  
RIGHT 
  
LEFT 
  
 
Pain 
Swelling 
Pain 
Swelling 
  
0= not tender 
0=no 
0= not tender 
0=no 
  
1= tender on 
palpation 
1=yes 
 
1= tender on 
palpation 
1=yes 
 
  
2= tender, patient 
winces 
  
2= tender, patient 
winces 
  
  
3= tender, patient 
winces, tries to 
withdraw 
  
3= tender, patient 
winces, tries to 
withdraw 
  
Cervical spine 
  
 --- 
 --- 
--- 
Jaw 
  
  
  
  
Sternoclavicular 
  
  
  
  
Acromioclavicular 
  
  
  
  
Shoulder 
  
  
  
  
Elbow 
  
  
  
  
Wrist 
  
  
  
  
MCP I 
  
  
  
  
MCP II 
  
  
  
  
MCP III 
  
  
  
  
MCP IV 
  
  
  
  
MCP V 
  
  
  
  
PIP I 
  
  
  
  
PIP II 
  
  
  
  
PIP III 
  
  
  
  
PIP IV 
  
  
  
  
PIP V 
  
  
  
  
Hip 
  
--- 
  
--- 
Knee 
  
  
  
  
Ankle 
  
  
  
  
Subtalar 
  
  
  
  
Midtarsal 
  
  
  
  
MTP I 
  
  
  
  
MTP II 
  
  
  
  
MTP III 
  
  
  
  
MTP IV 
  
  
  
  
MTP V 
  
  
  
  
MCP = Metacarpophalangeal; MTP = metatarsophalangeal; PIP = proximal interphalangeal. 
Joints in grey only have to be assessed for the DAS44 joint count. 
 
 
For tenderness, the examiner will exert pressure on each joint and grade the response as: not tender; tender 
on palpation; tender and patient winces; tender, patient winces, and patients tries to withdraw by pressure 
and joint manipulation on physical examination.  
 

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For the DAS44, the number of painful joints is calculated with the Ritchie Articular Index (RAI). The RAI is 
calculated as follows: 
• 
For the jaw, sternoclavicular, and acromioclavicular: only the highest score of the right and left joint 
is counted  
- 
E.g. the right jaw is scored 1 and the left jaw is scored 2, then the pain score for the jaws is 
2; the right sternoclavicular is scored 3 and the left sternoclavicular is scored 0, then the pain 
score for the sternoclaviculars is 3 
• 
Complex joints are counted as one: of the MCP, PIP and MTP joints, only the highest score of the 
right joint and the highest score of left joint is counted 
- 
E.g. on the right hand the MCPI,II,IV are scored 1 and MCP III,V are scored 2, then the pain 
score for the MCPs on the right is 2 (pain score for the left hand is calculated separately); on 
the left foot the MTPI,II are scored 0, MTPIII is scored 3 and MTPIV,V are scored 1, then the 
pain score for the MTPs on the left is 3 (pain score for the right foot is calculated separately) 
• 
For all other joints, the pain score is as indicated during assessment. 
 
For the DAS28, no grades in tenderness will be used for the calculation of the tender joint count. All joints 
with a pain score of 1 or higher are counted as 1 painful joint. 
 
Joint prosthesis, arthrodesis, or fused joints will not be taken into consideration for tenderness or swelling. 

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 Appendix C:  
Calculation of DAS28 and DAS44; EULAR response; ACR improvement 
 
 
CALCULATION DAS28 
DAS28 is calculated as follows:  
DAS28 = 0.56 * sqrt(tender28) + 0.28 * sqrt(swollen28) + 0.70 * ln(ESR) + 0.014 * GH. 
 
CALCULATION DAS44 
DAS44 is calculated as follows: 
DAS44 = 0.54 * sqrt(RAI) + 0.065 * (swollen44) + 0.33 * (ln)ESR + 0.0072 * GH 
 
Note: for both DAS44 and DAS28, the joint factors are adjusted in case of unevaluable joints.  
E.g. left knee unevaluable due to knee prosthesis:  
DAS28 = (28/27)*0.56 * sqrt (tender27) + (28/27) * 0.28 * sqrt (swollen27) + etc. 
 
 
EULAR RESPONSE CRITERIA FOR THE DAS28 AND DAS44 
Current value of the 
DAS28 
Current value of the 
DAS44 
Improvement in DAS from baseline 
>1.2 
>0.6 - ≤1.2 
≤0.6 
≤3.2 
≤2.4 
good 
moderate 
none 
>3.2 and ≤5.1 
>2.4 and ≤3.7 
moderate 
moderate 
none 
>5.1 
>3.7 
moderate 
none 
none 
Abbreviations: DAS28 = Disease activity score of 28 joints calculated with erythrocyte sedimentation rate; DAS44 = 
Disease activity score of 44 joints. (Van Gestel 1996; Van Gestel 1999) 
 
 
ACR RESPONSE CRITERIA 
American College of Rheumatology response score 
≥20% improvement in tender joint count 
≥20% improvement in swollen joint count 
≥20% improvement in at least 3 of the following 5 measures: 
• Patient’s global assessment of disease activity 
• Physician’s global assessment of disease activity 
• Patient’s assessment of pain 
• Disability 
• Acute-phase reactant 
(Felson 1995) 
 
 

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 Appendix D:  
Sharp/van der Heijde damage score 
 
 
Hand radiographs are scored according to the method described by Sharp et al (Sharp JT 1985), as modified 
by Van der Heijde et al (Van der Heijde DM 1989). Foot radiographs are scored according to the method 
described by Van der Heijde et al (Van der Heijde DM 1989). 
 
On each side of the upper limb (right and left), erosions are counted in the five metacarpophalangeal joints, 
the four proximal interphalangeal joints, the interphalangeal joints of the thumb, the first metacarpal bone, 
the radius and ulnar bones, the trapezium and trapezoid (as one unit; multangular), the navicular bone, and 
the lunate bone. On each side of the lower limb, erosions are counted in the five metatarsophalangeal joints 
and the hallux proximal interphalangeal joint. 
 
Joint space narrowing is counted on each side of the upper limb, in the five metacarpophalangeal joints, the 
four proximal interphalangeal joints, the third, fourth, and fifth carpometacarpal joints, the multangulo-
navicular joint, the capitato-naviculolunate joint, the radiocarpal joint. Joint space narrowing is counted on 
each side of the lower limb, in the five metatarsophalangeal joints and the hallux proximal interphalangeal 
joint. 
 
Erosions are scored as 1 if there is a discrete interruption of the cortical surface; if there is a greater defect a 
score according to the surface of the joint involved is given (2-5). Consequently, for confluent erosions the 
score cannot become smaller. In the hands, the maximum score in a joint is 5; in the feet, it is 10. 
 
Five grades of joint space narrowing are recognized: 0 = absent; 1 = doubtful or focal; 2 = general, less than 
50% of the original joint space; 3 = general, more than 50% of the original joint space, or subluxation; 4 = 
ankylosis. 
 
The maximum erosion score is 160 in the hands and 120 in the feet. The maximum joint space score is 120 
and 48, respectively. The scores are added for the final radiologic score. 
 
 
 
 
 
 
 

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 Appendix E: 
Patient global assessment and stiffness 
 
 
PATIENT GLOBAL ASSESSMENT OF DISEASE ACTIVITY  
(Adapted from question 3 of the Routine Assessment of Patient Index Data (RAPID3)) 
 
Considering all the ways in which your rheumatoid arthritis has affected you, please indicate below how you 
have been doing the last week. 
 
 
 
 
STIFFNESS 
(Question 6 of the Multidimensional Health Assessment Questionnaire (MDHAQ); Pincus T. Bulletin of the NYU Hospital 
for Joint Diseases. 2007) 
 
When you are awakened in the morning over the last week, did you feel stiff? 
q No 
q Yes 
 
 
 
 
If yes,  
 
 
please indicate the number of minutes or hours until you are as limber as you will be for the 
 
 
day. 
 
 
 
 
If yes, please indicate how severe your morning stiffness was. 
 
 
 
 
 
 
Very  
well 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Very 
poorly  
m m m m m m m m m m m m m m m m m m m m m 
0 
0,5 
1 
1,5 
2 
2,5 
3 
3,5 
4 
4,5 
5 
5,5 
6 
6,5 
7 
7,5 
8 
8,5 
9 
9,5 
10 
q 
q 
q 
q 
q 
q 
q 
q 
q 
q 
q 
q 
q 
q 
<15m 
15m 
30m 
45m 
1 hour 
1hour 
15m 
1hour 
30m 
1hour 
45m 
2 hrs 
2hrs 
15m 
2hrs 
30m 
2hrs 
45m 
3 hrs 
>3hrs 
Not 
severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Very 
severe  
m m m m m m m m m m m m m m m m m m m m m 
0 
0,5 
1 
1,5 
2 
2,5 
3 
3,5 
4 
4,5 
5 
5,5 
6 
6,5 
7 
7,5 
8 
8,5 
9 
9,5 
10 

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 Appendix F: 
Physician global assessment 
 
 
PHYSICIAN GLOBAL ASSESSMENT OF DISEASE ACTIVITY  
(According to ACR/EULAR remission criteria; RA added) 
 
What is your assessment of the patient’s current RA disease activity? Please indicate below. 
 
 
 
 
 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Very 
active  
m m m m m m m m m m m m m m m m m m m m m 
0 
0,5 
1 
1,5 
2 
2,5 
3 
3,5 
4 
4,5 
5 
5,5 
6 
6,5 
7 
7,5 
8 
8,5 
9 
9,5 
10 

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 Appendix G:  
(M)HAQ – (Modified) Health Assessment Questionnaire 
 
 
G1. Full HAQ: 
 
 
  
 
Health Assessment Questionnaire  
Stanford University School of Medicine · Division of Immunology & Rheumatology
Name_____________________________________________   Date_____________
We are interested in learning how your illness affects your ability to function in daily life.
Please feel free to add any additional comments on the back of this page.
! Please check the response that best describes your usual abilities 
OVER THE PAST WEEK:
DRESSING & GROOMING
Are you able to: – Dress yourself, including tying shoelaces and doing buttons?
□
□
□
□
– Shampoo your hair?
□
□
□
□
ARISING
Are you able to: – Stand up from a straight chair?
□
□
□
□
– Get in and out of bed?
□
□
□
□
EATING
Are you able to: – Cut your meat?
□
□
□
□
– Lift a full cup or glass to your mouth?
□
□
□
□
– Open a new milk carton?
□
□
□
□
WALKING
Are you able to: – Walk outdoors on flat ground?
□
□
□
□
– Climb up five steps?
□
□
□
□
! Please check any AIDS OR DEVICES that you usually use for any of these activities:
! Please check any categories for which you usually need HELP FROM ANOTHER PERSON:
□ Dressing and grooming               □ Arising               □ Eating               □ Walking
□ Cane
□ Walker
□ Crutches
□ Wheelchair
□ Devices used for dressing
(button hook, zipper pull,
long shoe horn, etc.)
□ Built-up or special utensils
□ Special or built-up chair
□ Other (Specify:) 
___________________
Without ANY difficulty 0
Continued on other side
With SOME difficulty 1
With MUCH difficulty 2
UNABLE to do 3
© Stanford University   CL1002[5-1]C   6/02     IN02188

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! Please check the response that best describes your usual abilities
OVER THE PAST WEEK:
HYGIENE
Are you able to: – Wash and dry your body?
□
□
□
□
– Take a tub bath?
□
□
□
□
– Get on and off the toilet?
□
□
□
□
REACH
Are you able to: – Reach and get down a 5-pound object (such as a bag of sugar) 
from just above your head?
□
□
□
□
– Bend down to pick up clothing from the floor?
□
□
□
□
GRIP
Are you able to: – Open car doors?
□
□
□
□
– Open jars which have been previously opened?
□
□
□
□
– Turn faucets on and off?
□
□
□
□
ACTIVITIES
Are you able to: – Run errands and shop?
□
□
□
□
– Get in and out of a car?
□
□
□
□
– Do chores such as vacuuming or yardwork?
□
□
□
□
! Please check any AIDS OR DEVICES that you usually use for any of these activities:
□ Raised toilet seat
□ Bathtub bar 
□ Other (Specify):________________
□ Bathtub seat
□ Long-handled appliances for reach
□ Jar opener (for jars previously opened)
□ Long-handled appliances in bathroom
! Please check any categories for which you usually need HELP FROM ANOTHER PERSON:
□ Hygiene 
□ Reach 
□ Gripping and opening things 
□ Errands and chores
Without ANY difficulty 0
With SOME difficulty 1
With MUCH difficulty 2
UNABLE to do 3

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G2. Modified HAQ: 
 
 
In the modified HAQ, only 8 questions of the full HAQ are asked, and 2 additional questions (with the 
same response options): 
 
Are you able to: 
- Walk two miles or three kilometers, if you wish? 
- Participate in recreational activities and sports as you would like, if you wish? 
 
 
 

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 Appendix H: 
RAID – RA Impact of Disease 
 
 
1. PAIN 
Please indicate the number that best describes the pain you felt due to your rheumatoid arthritis during the 
last week: 
 
 
 
2. FUNCTIONAL DISABILITY ASSESSMENT 
Please indicate the number that best describes the difficulty you had in doing daily physical activities due to 
your rheumatoid arthritis during the last week. 
 
 
 
3. FATIGUE 
Please indicate the number that best describes how much fatigue you felt due to your rheumatoid arthritis 
during the last week. 
 
 
 
4. SLEEP 
Please indicate the number that best describes the sleep difficulties (i.e., resting at night) you felt due to your 
rheumatoid arthritis during the last week. 
 
 
 
 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Extreme  
m m m m m m m m m m m m m m m m m m m m m 
0 
0,5 
1 
1,5 
2 
2,5 
3 
3,5 
4 
4,5 
5 
5,5 
6 
6,5 
7 
7,5 
8 
8,5 
9 
9,5 
10 
No 
difficulty 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Extreme 
difficulty 
m m m m m m m m m m m m m m m m m m m m m 
0 
0,5 
1 
1,5 
2 
2,5 
3 
3,5 
4 
4,5 
5 
5,5 
6 
6,5 
7 
7,5 
8 
8,5 
9 
9,5 
10 
No  
fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Totally 
exhausted 
m m m m m m m m m m m m m m m m m m m m m 
0 
0,5 
1 
1,5 
2 
2,5 
3 
3,5 
4 
4,5 
5 
5,5 
6 
6,5 
7 
7,5 
8 
8,5 
9 
9,5 
10 
No 
difficulty 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Extreme 
difficulty 
m m m m m m m m m m m m m m m m m m m m m 
0 
0,5 
1 
1,5 
2 
2,5 
3 
3,5 
4 
4,5 
5 
5,5 
6 
6,5 
7 
7,5 
8 
8,5 
9 
9,5 
10 

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5. PHYSICAL WELL-BEING 
Considering your arthritis overall, how would you rate your level of physical well-being during the past 
week? Please indicate the number that best describes your level of physical well-being. 
 
 
 
6. EMOTIONAL WELL-BEING 
Considering your arthritis overall, how would you rate your level of emotional well-being during the past 
week? Please indicate the number that best describes your level of emotional well-being. 
 
 
 
7. COPING 
Considering your arthritis overall, how well did you cope (manage, deal, make do) with your disease during 
the last week? Please indicate below. 
 
 
 
 
 
 
 
 
 
 
 
 
RAID - United Kingdom/English - Mapi Institute. RAID_AU1.0_eng-GBori.doc 
Very  
good 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Very 
bad 
m m m m m m m m m m m m m m m m m m m m m 
0 
0,5 
1 
1,5 
2 
2,5 
3 
3,5 
4 
4,5 
5 
5,5 
6 
6,5 
7 
7,5 
8 
8,5 
9 
9,5 
10 
Very 
good 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Very 
bad 
m m m m m m m m m m m m m m m m m m m m m 
0 
0,5 
1 
1,5 
2 
2,5 
3 
3,5 
4 
4,5 
5 
5,5 
6 
6,5 
7 
7,5 
8 
8,5 
9 
9,5 
10 
Very 
well 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Very 
poorly 
m m m m m m m m m m m m m m m m m m m m m 
0 
0,5 
1 
1,5 
2 
2,5 
3 
3,5 
4 
4,5 
5 
5,5 
6 
6,5 
7 
7,5 
8 
8,5 
9 
9,5 
10 

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 Appendix I: 
Cost Questionnaire 
 
 
A. Health care 
The following questions are about the use of health care. We are interested in the number of times you used 
health care facilities in the past 4 weeks. 
 
 
In the past 4 weeks, did you visit a: 
No (0) 
Yes, 
how many 
times? 
A1. 
General practitioner 
¨ 
____  times 
A2. 
Physiotherapist 
¨ 
____  times 
A3. 
Occupational therapist 
¨ 
____  times 
A4. 
Dietician 
¨ 
____  times 
A5. 
Rheumatologist (unrelated to this trial) 
¨ 
____  times 
A6. 
Medical specialist (other than your rheumatologist) 
¨ 
____  times 
A7. 
Psychiatrist, psychologist or psychotherapist 
¨ 
____  times 
A8. 
Another health professional, namely: 
¨ 
____  times 
 
 
In the past 4 weeks, have you been admitted to: 
No (0) 
Yes, how 
many days? 
A9. 
Hospital 
¨ 
____  day(s) 
A10. 
Nursing home 
¨ 
____  day(s) 
A11. 
Rehabilitation center 
¨ 
____  day(s) 
A12. 
Another health facility, namely: 
¨ 
____  day(s) 
 
A13. 
In the past 4 weeks, have you had help from a nurse for 
personal care?  
If no, please continue with question B1. 
¨ No (0) 
¨ Yes (1) 
 
A13.1. How many hours have you had help from a nurse 
in the past 4 weeks? 
 
____  hour(s) 
 
A13.2. How many of those hours were paid help?  
____  hour(s) 
 

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B. Household 
The following questions are about help in housekeeping in the past 4 weeks. 
 
B1. 
In the past 4 weeks, have you had help with housekeeping? 
If no, please continue with question C1. 
¨ No (0) 
¨ Yes (1) 
 
B1.1. How many hours have you had help with housekeeping 
in the past 4 weeks? 
 
____  hour(s) 
 
B1.2. How many of those hours were paid help in 
housekeeping? 
____  hour(s) 
 
C. Occupation 
The following questions are about a paid job in the past 4 weeks. 
 
C1. 
Do you have a paid job?  
If no, please continue with question D1. 
¨ No (0) 
¨ Yes (1) 
 
C1.1. How many hours do you work? 
Count and sum (add up) the number of hours you 
performed paid work in the past 4 weeks. 
____  hour(s) 
 
C1.2. How many hours were you on sick leave in the past 4 
weeks? 
If you were not on sick leave, please enter ‘0’. 
 
 
____  hour(s) 
 
D. Voluntary work 
The following questions are about an unpaid job in the past 4 weeks. 
 
D1. 
Do you have an unpaid job?  
If no, this is the end of the questionnaire for you. 
¨ No (0) 
¨ Yes (1) 
 
D1.1. How many hours do you work for this unpaid job? 
Count and sum (add up) the number of hours you 
performed unpaid work  
in the past 4 weeks. 
____  hour(s) 
 
D1.2. How many hours were you on sick leave in the past 4 
weeks for this unpaid job? 
If you were not on sick leave, please enter ‘0’. 
 
 
____  hour(s) 
 
 
 

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Appendix J: 
EQ-5D – EuroQoL in 5 dimensions 
 
 
Under each heading, please indicate the ONE box that best describes your health today.  
 
MOBILITY  
I have no problems in walking about 
 
 
 
 
 
q0 
I have slight problems in walking about  
 
 
 
 
q1 
I have moderate problems in walking about 
 
 
 
 
q2 
I have severe problems in walking about 
 
 
 
 
q3 
I am unable to walk about 
 
 
 
 
 
 
q4 
 
SELF-CARE  
I have no problems washing or dressing myself  
 
 
 
q0 
I have slight problems washing or dressing myself 
 
 
 
q1 
I have moderate problems washing or dressing myself  
 
 
q2 
I have severe problems washing or dressing myself 
 
 
 
q3 
I am unable to wash or dress myself 
 
 
 
 
 
q4 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities)  
I have no problems doing my usual activities 
 
 
 
 
q0 
I have slight problems doing my usual activities  
 
 
 
q1 
I have moderate problems doing my usual activities 
 
 
 
q2 
I have severe problems doing my usual activities 
 
 
 
q3 
I am unable to do my usual activities 
 
 
 
 
 
q4 
 
PAIN / DISCOMFORT  
I have no pain or discomfort 
 
 
 
 
 
 
q0 
I have slight pain or discomfort  
 
 
 
 
 
q1 
I have moderate pain or discomfort 
 
 
 
 
 
q2 
I have severe pain or discomfort 
 
 
 
 
 
q3 
I have extreme pain or discomfort 
 
 
 
 
 
q4 
 
ANXIETY / DEPRESSION  
I am not anxious or depressed  
 
 
 
 
 
q0 
I am slightly anxious or depressed 
 
 
 
 
 
q1 
I am moderately anxious or depressed  
 
 
 
 
q2 
I am severely anxious or depressed 
 
 
 
 
 
q3 
I am extremely anxious or depressed 
 
 
 
 
 
q4 
 

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• 
We would like to know how good or bad your health is today.  
• 
This scale is numbered from 0 to 100.  
• 
100 means the best health you can imagine.  
0 means the worst health you can imagine.  
• 
Mark an X on the scale to indicate how your health is today.  
• 
Now, please write the number you marked on the scale in the box below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UK (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
 
10
0 
20
30
40
50
60
80
70
90
100 
5 
15
25
35
45
55
75
65
85
95
YOUR HEALTH TODAY = 
THE WORST 
HEALTH YOU 
CAN IMAGINE 

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Appendix K: 
SF36 – Short Form 36-item Health Survey 
 
 
Your Health and Well-Being 
 
HEALTH STATUS SURVEY SF-36 
 
 
 
 
This survey asks for your views about your health. This information will help 
keep track of how you feel and how well you are able to do your usual 
activities. Thank you for completing this survey! 
 
For each of the following questions, please mark an 
 in the one box that 
best describes your answer. 
 
 
1.  In general, would you say your health is: 
 
 
 
Excellent 
Very good 
Good 
Fair 
Poor
1 
2 
3 
4 
5
 
 
 
2. Compared to one year ago, how would you rate your health in general 
now?  
 
 
Much better 
Somewhat 
About the 
Somewhat 
Much worse 
now than one 
better now 
same as one 
worse now 
now than one 
year ago 
than one year 
year ago 
than one year 
year ago 
ago 
ago 
1 
2 
3 
4 
5 
 

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3. The following questions are about activities you might do during a typical 
day. Does your health now limit you in these activities? If so, how much?  
 
 
Yes, 
Yes, 
No, not 
limited 
limited 
limited 
a lot 
a little 
at all 
a Vigorous activities, such as running, lifting 
heavy objects, participating in strenuous 
sports .................................................................... 
1 ................... 
2 ..................
3 
b Moderate activities, such as moving a table, 
pushing a vacuum cleaner, bowling, or 
playing golf ........................................................... 
1 ................... 
2 ..................
3 
c Lifting or carrying groceries ................................. 
1 ................... 
2 ..................
3 
d Climbing several flights of stairs........................... 
1 ................... 
2 ..................
3 
e Climbing one flight of stairs ................................. 
1 ................... 
2 ..................
3 
f Bending, kneeling, or stooping .............................. 
1 ................... 
2 ..................
3 
g Walking more than a mile ..................................... 
1 ................... 
2 ..................
3 
h Walking several hundred yards ............................. 
1 ................... 
2 ..................
3 
i Walking one hundred yards.................................... 
1 ................... 
2 ..................
3 
j Bathing or dressing yourself.................................. 
1 ................... 
2 ..................
3 
 

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4. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health?  
 
 
 
All of 
Most of Some of A little 
None of 
the time the time the time of the 
the time 
time 
a  Cut down on the amount of time you spent 
on work or other activities....................................... 
1 ......... 
2 ........ 
3 ......... 
4 ......... 
5 
b Accomplished less than you would like ................. 
1 ......... 
2 ........ 
3 ......... 
4 ......... 
5 
c Were limited in the kind of work or other 
activities ................................................................. 
1 ......... 
2 ........ 
3 ......... 
4 ......... 
5 
d 
Had difficulty performing the work or other 
activities (for example, it took extra effort) ........... 
1 ......... 
2 ........ 
3 ......... 
4 ......... 
5 
 
 
 
 
5. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or anxious)?  
 
All of 
Most of Some of A little 
None of 
the time the time the time of the 
the time 
time 
a  Cut down on the amount of time you spent 
on work or other activities .................................... 
1 ......... 
2 ........ 
3 .......... 
4 ......... 
5 
b Accomplished less than you would like................ 
1 ......... 
2 ........ 
3 .......... 
4 ......... 
5 
c Did work or other activities less carefully 
than usual............................................................... 
1 ......... 
2 ........ 
3 .......... 
4 ......... 
5 
 

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6. During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities 
with family, friends, neighbors, or groups?  
 
 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely
1 
2 
3 
4 
5 
 
 
 
 
 
 
7.  How much bodily pain have you had during the past 4 weeks? 
 
 
None 
Very mild 
Mild 
Moderate 
Severe 
Very Severe
1 
2 
3 
4 
5 
6 
 
 
 
 
 
 
8. During the past 4 weeks, how much did pain interfere with your normal 
work (including both work outside the home and housework)?  
 
 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely
1 
2 
3 
4 
5 
 

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9. These questions are about how you feel and how things have been with you 
during the past 4 weeks. For each question, please give the one answer that 
comes closest to the way you have been feeling. How much of the time 
during the past 4 weeks...  
 
All of 
Most of Some of A little 
None of 
the time the time the time 
of the 
the time 
time 
a Did you feel full of life?.............................. 
1 .......... 
2 .......... 
3 .......... 
4 .......... 
5 
b Have you been very nervous? .............................. 
1 .......... 
2 .......... 
3 .......... 
4 .......... 
5 
c Have you felt so down in the dumps 
that nothing could cheer you up? ......................... 
1 .......... 
2 .......... 
3 .......... 
4 .......... 
5 
d Have you felt calm and peaceful?........................ 
1 .......... 
2 .......... 
3 .......... 
4 .......... 
5 
e Did you have a lot of energy? .............................. 
1 .......... 
2 .......... 
3 .......... 
4 .......... 
5 
f Have you felt downhearted and 
depressed? ............................................................ 
1 .......... 
2 .......... 
3 .......... 
4 .......... 
5 
g Did you feel worn out? ........................................ 
1 .......... 
2 .......... 
3 .......... 
4 .......... 
5 
h Have you been happy? ......................................... 
1 .......... 
2 .......... 
3 .......... 
4 .......... 
5 
i Did you feel tired?................................................ 
1 .......... 
2 .......... 
3 .......... 
4 .......... 
5 
 
 
 
 
10. During the past 4 weeks, how much of the time has your physical health 
or emotional problems interfered with your social activities (like visiting 
friends, relatives, etc.)?  
 
All of the 
Most of the 
Some of the 
A little of the 
None of the 
time 
time 
time 
time 
time 
1 
2 
3 
4 
5 
 

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11.  How TRUE or FALSE is each of the following statements for you? 
 
Definitely 
Mostly 
Don't 
Mostly 
Definitely 
true 
true 
know 
false 
false 
a I seem to get sick a little easier 
than other people.................................... 
1 ............ 
2 ........... 
3 ...........
4 ........... 
5 
b I am as healthy as anybody I know........ 
1 ............ 
2 ........... 
3 ...........
4 ........... 
5 
c I expect my health to get worse ............. 
1 ............ 
2 ........... 
3 ...........
4 ........... 
5 
d My health is excellent ............................ 
1 ............ 
2 ........... 
3 ...........
4 ........... 
5 
 
 
 
 
 
THANK YOU FOR COMPLETING THESE QUESTIONS! 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF-36v2™ Health Survey 1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust. All Rights Reserved. SF-36® is a registered 
trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 

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Appendix L: 
Patient symptom list 
 
 
Please indicate if you have experienced any of the following over the last 4 weeks: 
 
q Fever 
q Dry mouth 
q Dizziness 
q Weight gain (>5 kg) 
q Problems with smell or taste 
q Losing your balance 
q Weight loss (> 5 kg) 
q Lump in your throat 
q Muscle pain, aches, or cramps 
q Feeling sickly 
q Cough 
q Muscle weakness 
q Headaches 
q Shortness of breath 
q Paralysis of arms or legs 
q Unusual fatigue 
q Wheezing 
q Numbness or tingling of arms or 
q Swollen glands 
q Pain in the chest 
legs 
q Loss of appetite 
q Heart pounding (palpitations) 
q Fainting spells 
q Skin rash or hives 
q Trouble swallowing 
q Back pain 
q Unusual bruising or bleeding 
q Heartburn or stomach gas 
q Neck pain 
q Other skin problems 
q Stomach pain or cramps 
q Depression – feeling blue 
q Loss of hair 
q Nausea 
q Anxiety – feeling nervous 
q Dry eyes 
q Vomiting 
q Problems with thinking 
q Other eye problems 
q Constipation 
q Problems with memory 
q Problems with hearing 
q Diarrhoea 
q Problems with sleeping 
q Ringing in the ears 
q Dark or bloody stools 
q Sexual problems 
q Stuffy nose 
q Problems with urination 
q Burning in sex organs 
q Sores in the mouth 
q Gynaecological (female) 
problems 
q Problems with social activities      
 
 
 
 
 
 
 
 
 
 

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Appendix M: Education level and Baseline prognostic factors:  
risk factors glaucoma, adherence, health literacy, and arthritis helplessness 
index 
 
Education level:  
• 
How many years did you go to school?  
Please count from the moment you started to learn to read and write, and arithmetic. 
• 
What is the highest level of schooling you completed? 
a. primary school 
b. secondary school 
c. higher education (specify) 
 
 
Risk factors glaucoma: 
• 
Do you have a history of: 
- 
Increased eye pressure (glaucoma)? 
- 
Cataract? 
- 
Strong myopia (prescription glasses of -6D or more)? 
• 
Do you have blood relatives with any of these conditions?  
If so, which conditions(s)? (specify below) 
 
 

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Morisky Medication Adherence Scale (MMAS-8): 
Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self-reported measure of medication 
adherence. Med Care. 1986;24:67–74. 
 
 
 
 
MMAS‐8 
1) Do you sometimes forget to take your pills? 
2) People sometimes miss taking their medications 
for reasons other than forgetting. Thinking over the 
past two weeks, were there any days when you did 
not take your medicine? 
3) Have you ever cut back or stopped taking your 
medicine without telling your doctor because you felt 
worse when you took it? 
4) When you travel or leave home, do you sometimes 
forget to bring along your medicine? 
5) Did you take all your medicine yesterday? 
6) When you feel like your symptoms are under 
control, do you sometimes stop taking your 
medicine? 
7) Taking medicine every day is a real inconvenience 
for some people. Do you ever feel hassled about 
sticking to your treatment plan? 
8) How often do you have difficulty remembering to 
take all your medicine? 
___A. Never/rarely 
___B. Once in a while 
___C. Sometimes 
___D. Usually 
___E. All the time 

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Health literacy index:  
1. How often do you have someone help you read hospital materials? 
(for example labels on drugs) 
a. always 
b. often 
c. sometimes 
d. rarely 
e. never 
 
2. How often do you complete medical forms by yourself?  
(for example a health insurance form) 
a. always 
b. often 
c. sometimes 
d. rarely 
e. never 
 
3. How often do you have difficulty reading about your disease because you do not understand the 
written information (for example in brochures)? 
a. always 
b. often 
c. sometimes 
d. rarely 
e. never 
 
Adapted from : Chew LD, Bradley KA, Boyko EJ. Brief questions to identify patients with inadequate health literacy. 
Fam Med 2004; 36:588-94. 
 
 
 

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RAI/AHI Helplessness subscale: 
1. 
My arthritis is controlling my life. 
a. completely disagree 
b. disagree 
c. neither disagree nor agree 
d. agree 
e. completely agree 
 
2. 
I would feel helpless if I couldn’t rely on other people for help with my arthritis.  
a. completely disagree 
b. disagree 
c. neither disagree nor agree 
d. agree 
e. completely agree 
 
3. 
No matter what I do, or how hard I try, I just can’t seem to get relief from pain.  
a. completely disagree 
b. disagree 
c. neither disagree nor agree 
d. agree 
e. completely agree 
 
4. 
I am not coping effectively with my arthritis.  
a. completely disagree 
b. disagree 
c. neither disagree nor agree 
d. agree 
e. completely agree 
 
5. 
It seems as though fate and other factors beyond my control affect my arthritis completely.  
a. completely disagree 
b. disagree 
c. neither disagree nor agree 
d. agree 
e. completely agree 
 
DeVellis RF, Callahan LF. A brief measure of helplessness in rheumatic disease: the helplessness subscale of the 
Rheumatology Attitudes Index. J Rheumatol 1993;20:866-9. 
Callahan LF, Brooks RH, Pincus T. Further analysis of learned helplessness in rheumatoid arthritis using a 
"Rheumatology Attitudes Index". J Rheumatol 1988;15:418-26.