Conditions: RheumatoId Arthritis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 451
Healthy volunteers: no

Brief summary:
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)

Detailed description:
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:

1. 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;
2. 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). The 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 smart device (smartphone, tablet, etc) 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 smart device 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 Rheumatism (EULAR), requiring antirheumatic therapy because of inadequate disease control, as evidenced by a disease activity score of 28 joints calculated with erythrocyte sedimentation rate (DAS28) ≥2.60.

Substudy population: Patients in the main study who have completed at least 3 months on treatment, in possession of and familiar with a smart device.

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 6 weeks 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 or parental GCs for comorbidities 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 a smart device of the patient (smartphone, tablet, etc.), through special software to remind patients of the time of medication. In the substudy, patients with a smart device will receive an application loaded on their smart device 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. Eligible patients will be randomized to either the experimental arm that receive reminders on their smart device, 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.

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 favorable 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 and patients 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 smart device, no difference is expected with the 'normal' situation, in which patients do not have access to an adherence application.

Arms:
arm 1: prednisolone 5 mg per day arm 2: placebo capsules once per day

Interventions: intervention 1: Prednisolone intervention 2: Placebo
Intervention descriptions: intervention 1: 1 capsule containing a tablet of 5 mg prednisolone/ day intervention 2: 1 capsule containing a placebo tablet / day

Protocol document:
Prot_000.pdf: 
VUMC-ARC-GLORIA 
 
GLORIA 
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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 
Rheumatism (EULAR), requiring antirheumatic therapy because of inadequate disease control, as evidenced 


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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 
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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 
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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, 
assessment of 28 joints at 3, 6, 12 and 18 months. Joint swelling will be assessed as absent or present; joint 


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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 
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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 
reaction to the medicinal product under investigation, regardless of the administered dose; 


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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 
specific trainings; 
• 
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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 
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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 
treatment and placebo groups. Therefore, we can distinguish benefit confounding, which can be defined as 


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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 
keep costs comparable between countries. The unit prices of 2017 are used because most patients were 


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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 
number 101001. 


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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 


VUMC-ARC-GLORIA 
 
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Page 66 of 76 
 
 
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 


VUMC-ARC-GLORIA 
 
GLORIA 
Page 75 of 76 
 
 
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. 
 
 
 


VUMC-ARC-GLORIA 
 
GLORIA 
Page 76 of 76 
 
 
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. 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
 
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 
 
Sponsor: 
VU University Medical Center 
 
 
De Boelelaan 1117 
1081 HV Amsterdam 
The Netherlands 
 
Author:  
VU University Medical Center 
 
 
Department of Epidemiology and Biostatistics & 
 
Amsterdam Rheumatology and immunology Center, location VU University Medical      
 
Center 
 
Amsterdam, Netherlands 
 
Date:   
March 2, 2021 
 
Version:  
1.0  
 


GLORIA Statistical analysis plan Ͷ 2 
 
Sign-off signatures 
 
 
Author:  
Linda Hartman 
 
 
PhD student 
 
 
----------------------------------------------------- Signature 
-------------------------- Date 
Peer review:  
Leonie Middelink 
 
 
Project Operational Lead 
 
----------------------------------------------------- Signature 
-------------------------- Date 
 
Approved by: Maarten Boers 
 
 
Project leader and Principal Investigator 
 
 
 
----------------------------------------------------- Signature 
-------------------------- Date 
 
Approved by: Johannes Berkhof 
 
 
Statistician 
 
 
 
 
 
----------------------------------------------------- Signature 
-------------------------- Date  
02-Mar-2021


GLORIA Statistical analysis plan Ͷ 3 
 
Table of contents 
 
 List of abbreviations and definitions………………………………......................................................................5 
1 
Introduction ...................................................................................................................................... 6 
1.1 
Study population ...................................................................................................................... 6 
1.2 
Study design ............................................................................................................................. 6 
1.3 
Primary and secondary study objectives ................................................................................. 8 
1.3.1 
Primary objectives ........................................................................................................... 8 
1.3.2 
Secondary objectives ....................................................................................................... 8 
1.4 
Primary and secondary endpoints ........................................................................................... 8 
1.4.1 
Primary endpoints ........................................................................................................... 8 
1.4.2 
Secondary endpoints ..................................................................................................... 10 
2 
Analysis populations ....................................................................................................................... 12 
2.1 
Intent-to-treat population ..................................................................................................... 12 
2.2 
Per-protocol population, also excluding initial changes  in antirheumatic medication ........ 12 
2.3 
Safety population ................................................................................................................... 12 
3 
Blinded review of the data .............................................................................................................. 12 
4 
Statistical and analytical methods .................................................................................................. 13 
4.1 
General statistical considerations .......................................................................................... 13 
4.2 
Missing data handling ............................................................................................................ 13 
4.3 
Baseline definition ................................................................................................................. 14 
4.4 
Definition of study visit and visit window .............................................................................. 15 
4.4.1 
Study visit ...................................................................................................................... 15 
4.4.2 
Visit window .................................................................................................................. 15 
4.5 
Patient disposition ................................................................................................................. 15 
4.6 
Demographics and baseline characteristics ........................................................................... 15 
4.7 
Medical history ...................................................................................................................... 15 
4.8 
Benefit analyses ..................................................................................................................... 16 
4.8.1 
Primary analyses ............................................................................................................ 16 
4.8.2 
Secondary analyses ....................................................................................................... 17 
4.9 
Safety analyses ....................................................................................................................... 17 
4.9.1 
Primary analyses ............................................................................................................ 17 
4.10 
Modeling and estimating ....................................................................................................... 18 
4.10.1 
Model and statistical test for the effect of treatment on DAS28 (Hypotheses 1) ........ 18 


GLORIA Statistical analysis plan Ͷ 4 
 
4.10.2 
Model and statistical test for the effect of treatment on damage score (hypothesis 2)
 ..................................................................................................................................... 21 
4.10.3 
Model and statistical test for the effect of treatment on harm: SAEs or other AESIs 
(Hypotheses 3) ............................................................................................................. 22 
4.11 
Evaluation of possible confounded results due to differential co-intervention .................... 22 
4.11.1 
Testing and correcting for differential treatment changes ........................................... 23 
4.12 
Interpretation rules ................................................................................................................ 25 
4.13 
Analysis of secondary outcome variables .............................................................................. 26 
5 
Interim analyses .............................................................................................................................. 27 
6 
Sample size and power calculations ............................................................................................... 27 
7 
Tables, listings and figures .............................................................................................................. 29 
8 
Statistical software .......................................................................................................................... 76 
9 
References ...................................................................................................................................... 76 
10 Appendix A: secondary outcome measures that need further specification ................................. 78 
11 Appendix B – Modifications from the protocol .............................................................................. 80 
12 Appendix C. Report of blinded data review meetings .................................................................... 82 
13 Appendix D. Gloria final PP population,  also excluding initial changes in antirheumatic 
medication ............................................................................................................................................. 85 
 
 
 
 


GLORIA Statistical analysis plan Ͷ 5 
 
List of abbreviations and definitions 
 
aCCP 
Anti-CCP 
ACR 
American College of Rheumatology 
AE 
Adverse event 
AESI 
Adverse event of special interest 
CI 
Confidence Interval 
CRP 
C-reactive protein 
DAS 
Disease activity score 
DEXA 
Dual-energy X-ray absorptiometry 
DMARD 
Disease-modifying antirheumatic drugs 
ESR 
Erythrocyte sedimentation rate 
EULAR 
European League Against Rheumatism 
EQ-5D 
Euro-QoL in 5 dimensions 
GC 
Glucocorticoid 
GCP 
Good Clinical Practice 
GLORIA 
The Glucocorticoid Low-dose Outcome in RheumatoId Arthritis Study 
GRADE 
Grades of Recommendations, Assessment, Development, and Evaluation 
GTI 
Glucocorticoid Toxicity Index 
HAQ 
Health Assessment Questionnaire 
ITT 
Intent-to-treat  
LRT 
Log-likelihood-ratio test 
MAR 
Missing at random 
MCAR 
Missing completely at random 
MDA 
Minimal disease activity  
MICE 
Multiple imputation by chained equations 
NMAR 
Not missing at random 
NSAID 
Non-steroidal anti-inflammatory drug 
PP 
Per protocol 
QALY 
Quality-adjusted life years 
QoL 
Quality of life 
RA 
Rheumatoid arthritis 
RAID 
RA Impact of Disease 
RF 
Rheumatoid factor 
SAE 
Serious adverse event 
SAF 
Safety 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDAI 
Simple Disease Activity Index 
SF-36 
Short Form 36-item Health Survey 
WHO-ILAR 
World Health Organisation/International League of Associations for 
Rheumatology 
 
 
 


GLORIA Statistical analysis plan Ͷ 6 
 
1 Introduction 
We present the analysis plan executed on the data collected according to the GLORIA protocol. The 
analysis plan summarizes the study protocol, describes the statistical methods, data listings and 
summary tables for the analysis of the data from the GLORIA trial. Any differences with the original 
protocol will be documented.  
 
The details of the economic evaluation and analysis of the adherence substudy will be described in a 
separate analysis plan.  
 
1.1 Study population 
The study population consists of patients of 65 years or older with rheumatoid arthritis (RA) 
according to the 1987 or 2010 classification criteria of the American College of Rheumatology (ACR) 
and the European League Against Rheumatism (EULAR) (Aletaha, 2010), requiring antirheumatic 
therapy because of inadequate disease control, as evidenced by a 28-joint disease activity score 
(DAS2ϴ) of ш2.ϲ0. Patients were selected from 28 hospitals in Germany, Hungary, Italy, The 
Netherlands, Portugal, Romania and Slovakia. 
 
1.2 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). The trial period is 24 months with 3 
additional months during which study medication treatment is tapered. In the first 3 months, co-
medication is limited: co-medication can be changed only at baseline or after 3 months, creating a 
brief period in which the effects of prednisolone can be studied with minimum interference.  
 
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, and by a count of returned 
capsules at every clinic visit.  
 
Assessment takes place at varying intervals and includes 7 clinic visits and 3 assessments by 
telephone. The sequence and duration of all study periods is represented in Figure 1. 
 
 
 


GLORIA Statistical analysis plan Ͷ 7 
 
Figure 1: 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 
remot
e 
clinic 
remot
e 
clinic 
remot
e 
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) (safety) 
 
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) (effectiveness) 
X 
 
 
 
 
 
 
 
X 
 
Joint counts (28) (effectiveness) 
 
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 (safety) 
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.  
 


GLORIA Statistical analysis plan Ͷ 8 
 
1.3 Primary and secondary study objectives 
 
1.3.1 Primary objectives 
The primary objectives of the GLORIA project are to compare the effect of low-dose GC 
therapy (5 mg/day), relative to placebo, on time-averaged mean value of the disease 
activity AND the number of patients experiencing at least one AE of Special Interest for 
two years as co-treatment in elderly RA patients (шϲ5 years).  
 
1.3.2 Secondary objectives 
x 
To assess study medication adherence through a medication packaging solution; 
and, in a substudy, test the effectiveness of smart device technology to improve 
adherence (separate statistical analysis plan, not described here).  
x 
To assess the secondary outcome measures which are described in section 1.4.2.  
x 
Deliver an outcome prediction model for individual patient outcome, to tailor 
treatment strategies for elderly RA patients with comorbidities 
x 
Deliver data to support: 
o Better guidelines on RA treatment in elderly 
o More accurate information for elderly RA patients, their physicians and 
researchers 
o Improved strategies for trial design and conduct in the elderly 
 
1.4 Primary and secondary endpoints 
 
1.4.1 Primary endpoints 
• To measure benefit, the primary endpoints are: 
a) signs and symptoms: the time-averaged mean value (estimated from linear mixed models) 
of the DAS28;  
b) damage score: 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 adverse event of Special Interest (AESI). An AESI is defined as either a serious 
adverse event (SAE) according to the GCP definition, or the occurrence of one of the 
following AEs (‘other AESI’): 
o Any AE (except loss of efficacy, worsening of disease) that leads to the definite 
cessation of the trial medication; 
o A cardiovascular event (myocardial infarction, cerebrovascular event, peripheral 
arterial vascular event); 
 
Anything falling outside this definition is not an AESI.  
So  venous hemorrhoids, venous ulcus cruris, thrombosis, pulmonary 
embolism, subdural hematoma, and traumatic hemorrhagic brain lesions are 
not coded as AESI. Also cardiac rhythm disturbances, valve lesions, cardiac 
insufficiency, cardiomyopathy, and encephalopathy, are not coded as AESI 
unless part of an acute ischemic episode. 
o Newly occurring hypertension requiring drug treatment; 


GLORIA Statistical analysis plan Ͷ 9 
 
o Newly occurring diabetes mellitus requiring drug treatment; 
o Symptomatic bone fracture requiring treatment; 
 
AESI is coded as ‘no’ if the vertebral fracture was asymptomatic, and ‘yes’ for 
all nonvertebral fractures, unless expressly indicated that the fracture was 
asymptomatic. 
Note that vertebral fracture is also captured as secondary outcome through 
DEXA or spine radiographs. 
o Infection requiring antibiotic treatment; 
 
Any specific treatment aimed at microorganisms to treat an infection is 
included: includes topical, antiviral, antifungal, antiparasitic treatment. 
 
(Surgical) procedures with concomitant antibiotics: not (initially) an infection, 
so not AESI; AESI only when the procedure was done for a primary infection 
(e.g. abscess). Surgical complications treated with antibiotics are also not 
coded as AESI, because it is usually impossible to determine whether the 
antibiotic was given as prophylaxis or as treatment. 
Note: almost any surgery is of necessity (hospital admission) already an SAE. 
o Newly occurring cataract or glaucoma.  
 
Cataract and glaucoma are assumed to be bilateral. 
A medical history of the disease in one eye counts for both, so no AESI during 
the trial for procedures on the contralateral eye. We count bilateral 
procedures for new disease as one (not two) AESI. 
 
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.  
 
The safety database uses the regular term and definition to describe SAE. The electronic Case 
Record Form and study database uses AESI to describe events that match one of the other 
bullets, regardless of whether the event is an SAE. So there an event can be labeled SAE (y/n) 
and separately AESI (y/n). In the primary analysis patients will be counted who have at least 
one SAE or AESI as scored in the safety database (‘other AESI’), to match with the definition 
of primary endpoint specified above. 
From here, the primary endpoint for safety is defined as ‘SAE or other AESI’ because one AE 
can be labeled as a SAE as well as an AESI.   
 
x 
Cost-effectiveness and cost-utility: more details are described in the separate analysis plan 
for the cost analyses 
 
x 
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 during the study visits at 
3, 6, 12, 18, 24 and 27 months. Each cap is sent back to the provider and the data are read 
out centrally.  
 
 


GLORIA Statistical analysis plan Ͷ 10 
 
1.4.2 Secondary endpoints 
 
Benefit  
x 
WHO-ILAR core set of RA outcome measures, including patient and physician global 
assessment of disease activity, joint counts (swollen joints and tender joints), acute phase 
reactants (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) at 0, 3, 6, 12, 
18, 24 and 27 months, and radiographs of hands and forefeet at 0 and 2 years.  
Remaining core set measures: pain and fatigue are part of the RAID questionnaire (see 
below), and physical function is assessed by the (m)HAQ. 
x 
DAS44 – at 0 and 24 months 
x 
DAS28 – at 3, 6, 12, 18, and 27 months 
x 
Severity and duration of morning stiffness - at every study visit 
x 
SF36 – The Short Form 36-item Health Survey, a questionnaire about quality of life (QoL) - at 
0 and 24 months 
x 
57-symptom list – at 0 and 24 months 
x 
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: pain, functional disability 
assessment, fatigue, sleep, physical well-being, emotional well-being, coping.  – at every 
study visit 
x 
(Modified) Health Assessment Questionnaire ((m)HAQ) at every study visit 
x 
RAPID3, calculated with the patient global assessment of disease activity, (m)HAQ and the 
question about pain from the RAID questionnaire, at every study visit 
x 
Cost questionnaire at 0, 3, 6, 12, 18, 24, 27 months, including  
o Activity limitation  
o Work disability (for those holding a paid job)   
x 
Utility/Quality-adjusted life years (QALY): Euro-QoL in 5 dimensions (EQ-5D) - at every study 
visit 
 
Harm  
x 
Vital signs (heart rate and blood pressure), height, weight – at 0, 3, 6, 12, 18, 24, 27 months 
x 
Bone mass assessed by Dual-energy X-ray Absorptiometry (DEXA) - at 0 and 24 months 
x 
Vertebral Fracture Analysis (by DEXA OR lateral radiograph of thoracic and lumbar spine) - at 
0 and 24 months 
x 
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 
x 
Change of antirheumatic treatment, with reason 
x 
Intensification of treatment for existing comorbidity, e.g. hypertension or diabetes 
x 
Joint replacement surgery 
x 
AEs, SAEs, other AESI at every study visit 
x 
Concomitant medication at every study visit 
Data collection is in agreement with industry standard (i.e. Meddra terminology etc.). 
 
GC harm/benefit balance 
x 
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 0,  3, 6, 12, 18, 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.  
 
 
 


GLORIA Statistical analysis plan Ͷ 11 
 
Medication adherence 
x 
Adherence to the 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 (pill count), as 
measured by the adherence tool at 3, 6, 12, 18, 24 and 27 months 
 
 
Other 
x 
Demographics, education and medical history – at baseline 
x 
Baseline prognostic factors: Morisky medication adherence scale (MMAS-8), health literacy, 
arthritis helplessness index questionnaires – at baseline 
x 
Cost-effectiveness and cost-utility: estimate of costs of treatment and monitoring   
x 
Patients retained on study drug over time: survival analysis 
 
 
 
 


GLORIA Statistical analysis plan Ͷ 12 
 
2  Analysis populations 
For the full trial period, we will perform analyses of the primary and secondary outcome variables on 
the intent-to-treat (ITT) population, with ad-hoc sensitivity analyses excluding selected patients 
based on blinded data review. The ITT principle asserts the effect of a treatment policy (that is, the 
planned treatment regimen), rather than the actual treatment given (i.e., it is independent of 
treatment adherence etc.). Accordingly, participants allocated to a treatment group (GC and placebo, 
respectively) should be followed up, assessed and analysed as members of that group, irrespective of 
their adherence to the planned course of treatment (i.e., independent of withdrawals and cross-over 
phenomena). Primary safety analyses will be repeated in the safety (SAF) population.  
 
2.1 Intent-to-treat population 
The intent-to-treat population is defined for efficacy as all patients randomized into the study who 
took the study medication (prednisolone or placebo) for at least one day and who have at least one 
baseline and one follow-up assessment. Patients will be analyzed in the group they were randomized 
to.  
2.2 Per-protocol population, also excluding initial changes  
in antirheumatic medication 
For the 3-month efficacy assessment: this population consists of all patients who during the first 3 
months:  
x 
received the study drug; 
x 
had at least 80% adherence to treatment as determined by tablet count; 
x 
completed the baseline and 3-month visit; 
x 
have a DAS28ESR value available on both visits; or a DAS28CRP value on both visits;  
x 
did not start, stop or change the dose of concurrent antirheumatic drugs,  
or receive glucocorticoid (oral or injection) at baseline or in the period up to the 3-month 
visit;  
x 
did not have any serious protocol violations as determined in section 3.  
The report from the blinded data review and the list of patients excluded from this population have 
finalized before the database is locked and are attached to this plan (appendix C). 
 
2.3 Safety population 
All patients who took at least one capsule of study medication belong to the safety population.  
3 Blinded review of the data 
Multiple blinded data review meetings with the principal investigator, medical monitor, study lead, 
trial statistician, a representative of data management and a member of the scientific advisory 
committee will be held before breaking the blind. During the blinded data review the protocol 
violations and their impact on the study outcomes will be discussed. The decisions taken during the 
blinded data review will be finalized and signed by the participants of this meeting before breaking 
the blind. The final report of these meetings are attached as appendix C. 
 


GLORIA Statistical analysis plan Ͷ 13 
 
 
4 Statistical and analytical methods 
4.1 General statistical considerations 
All continuous variables will be summarized with the following descriptive statistics: number of 
patients (n), mean, standard deviation (SD). If the data are non-normally distributed, median, 
minimum (min.) and maximum (max.) will be reported. For categorical variables, the absolute (N) 
and relative frequency (%) will be reported.  
4.2 Missing data handling 
Handling of missing DAS28 (disease activity) outcomes (applies to DAS28-ESR and DAS28-CRP) 
SƚeƉ ϭ͘ ImƉƵƚaƚiŽŶ Žf miƐƐiŶg DASϮϴ if ŽŶlǇ ƚhe cŽmƉŽŶeŶƚ ͚ƉaƚieŶƚ glŽbal aƐƐeƐƐmeŶƚ Žf diƐeaƐe 
acƚiǀiƚǇ͛ iƐ miƐƐiŶg 
If the missing DAS28 score is from an intermediate (i.e. not baseline or end) visit and only the patient 
global assessment of disease activity is missing, it will be replaced by the mean of the patient global 
score immediately before and after this visit, and the DAS28 score will be calculated with this result. 
If one or both of these are also missing the value will remain missing because we have no 
information to impute a value.  
Step 2. All remaining missing DAS28 
In principle, DAS28 outcomes may be incomplete for two reasons: 
1. Non-monotone missingness, for example because a patient skips a clinic visit/measurement 
occasion but is observed again at later points in time 
2. Monotone missingness in case of premature discontinuation of study medication  
 
For the primary analysis, we use single imputation by chained equations using the MICE package (van 
Buuren 2012) to impute missing values according to the following rules. At each study time point we 
observe or do not observe patient’s DAS2ϴ, DAS2ϴ-CRP, and RAPID-3 score. We impute missing 
values on these variables per measurement occasion, if at least one measurement is present. If all 
three measurements are missing, we do not impute any value. These cases usually occur due to 
discontinuation of the study. The main analysis model (section 4.10) is a mixed effects longitudinal 
model which gives consistent estimates under the assumption that the remaining missing DAS28 
outcomes are missing at random (Little and Rubin 2002). 
 
Sensitivity analysis: Nonresponder imputation 
Finally, in case of monotone missingness we investigate the possibility that the missingness occurs 
not at random (NMAR) with robustness analyses (nonresponder imputation). This imputation 
method recodes the outcomes of all complete units observed at the end of the study period (j=m), 
𝑌௠, as follows: 
𝑌෨௠ൌ൜1    𝑖𝑓𝑓 𝑌௠െ𝑌ଵ൏0.6 
0    𝑖𝑓𝑓 𝑌௠െ𝑌ଵ൒0.6   
where 0.6 denotes a minimum effect. Incomplete units receive 𝑌෨௠ൌ0 representing the conservative 
hypothesis that all incomplete cases would not have achieved a minimum treatment effect. 
-
-


GLORIA Statistical analysis plan Ͷ 14 
 
Subsequently, we test whether the proportions of responders (𝑌෨௠ൌ1ሻ differs significantly between 
treatment and placebo with a model for difference in proportions akin to model 3 in section 3.3. 
 
Handling of missing damage scores  
Step 1. Handling of assessments with partially missing data 
Joints with signs of surgery (e.g. prosthesis, arthrodesis) are not scored. Also, when assessments at 
both time points have been done, but groups of joints are missing from one time point, the scores 
from that group are also set to missing at the other time point. For example if the end assessment 
includes only hand films (feet films missing), the initial assessment of the feet will be set to missing. 
Likewise, if surgery is done on a joint during the trial, the initial assessment of that joint will also be 
set to missing. 
 
Step 2. All remaining missing damage assessments 
We may distinguish three missing data patterns in the damage scores at study onset and study end-
point: 
1. Damage score is not observed at study onset but the endpoint is observed, 
2. Damage score is observed at study onset but the endpoint is unobserved, 
3. Damage score is neither observed at study onset nor endpoint. 
 
The three missing data patterns are addressed as follows.  
 
For the primary analysis, we use the algorithm ‘MICE’ (multiple imputation by chained equations) to 
impute missing measurements (van Buuren, 2012). This procedure assumes missing at random 
(MAR) data. The imputation models use data available at baseline (damage score at baseline, disease 
duration, rheumatoid factor positivity, ACPA positivity, DAS28-ESR) and the endpoint measurement 
of damage. Study center is not taken into account in this imputation model in view of the large 
number of cases with missing endpoints. 
 
As a sensitivity analysis, we conduct a complete case analysis deleting all cases with (remaining) 
missing onset outcomes or missing endpoint outcomes list-wise. This analysis thus excludes cases 
with patterns 1, 2 and 3. This analysis assumes these outcomes are missing completely at random, 
MCAR (Little & Rubin, 2002). 
 
 
Handling of missing harm outcomes 
Harm is verified throughout the trial via remote and onsite checks against the source data. So harm 
assessment is assumed to be complete. 
 
4.3 Baseline definition 
Baseline is defined as the last value immediately before the start of the treatment.  
 
 


GLORIA Statistical analysis plan Ͷ 15 
 
4.4 Definition of study visit and visit window 
 
4.4.1 Study visit 
The baseline visit (visit 1, in the clinic) is defined as study month 0. The next visits are at 3 months 
(visit 2, in clinic), 6 months (visit 3, in clinic), 9 months (visit 4, remote), 12 months (visit 5, in clinic), 
15 months (visit 6, remote), 18 months (visit 7, in clinic), 21 months (visit 8, remote), 24 months (visit 
9, in clinic), 27 months (10, in clinic). The end of the study is defined as the date of the last study visit.  
 
4.4.2 Visit window 
The protocol allowed to minimize or maximize the visit window with two months. For the radiology 
data (x-rays hand and forefeet and DEXA), the time window for the baseline measurement was 6 
months before or 3 months after the baseline visit, and for the 24-months measurement 3 months 
before or after visit 9. If these are exceeded we will accept images up to 1 year before and 6 months 
after baseline, and up to 1 years after year 2. Data will be analyzed based on the visit number/month 
that is reported in the database. The calendar visit dates will not be used.  
 
4.5 Patient disposition 
The number and percentages of patients allocated to the prednisolone and placebo group will be 
summarized for all enrolled patients. The number and percentage of patients completing and 
withdrawing the study, the reasons of withdrawal, and study duration will be reported in a table 
overall and by treatment. 
 
4.6 Demographics and baseline characteristics 
Demographics and baseline characteristics, including birth month and year, sex, smoking , alcohol 
use, the possession of a smartphone, education level, rheumatoid factor (RF) status, anti-CCP (aCCP) 
status, duration of RA, evidence of structural joint damage, previous related surgical procedures, 
previous glucocorticoid use, previous NSAID use, previous DMARD use, previous biological use, 
number of comorbidities will be reported in a table by treatment group and overall.  
 
4.7 Medical history 
Number and percentages of patients with a history of diseases, abnormalities or surgery will be 
summarized by treatment group and overall. The reported term, preferred term, system organ class, 
and year of resolution or ongoing will be listed. The MedDRA coding dictionary, version 21.0, will be 
used to code the medical history.  
 
 


GLORIA Statistical analysis plan Ͷ 16 
 
4.8 Benefit analyses 
4.8.1 Primary analyses 
4.8.1.1 
DAS28 
 
 
The following primary benefit hypotheses will be tested for the DAS28 score: 
1a. Primary benefit hypotheses: 
H଴,ଵୟ: (Null) Prednisolone intake over a period of 24 months leads on average to no difference or a 
higher score in DAS28 than placebo intake. 
 
Hଵ,ଵୟ: (Alternate) Prednisolone intake over a period of 24 months leads on average to a lower score 
in DAS28 than placebo intake. 
 
𝐻଴,ଵ௔: μ୘ሺ𝑡ൌ24ሻെμେሺ𝑡ൌ24ሻ ൒0 
 
𝐻ଵ,ଵ௔: μ୘ሺ𝑡ൌ24ሻെμେሺ𝑡ൌ24ሻ൏0 
 
μ୘ሺ𝑡ൌ24ሻ is the mean of DAS28 over 24 months in the treatment group. μେሺ𝑡ൌ24ሻ is the mean of 
DAS28 over 24 months in the control group. 
 
4.8.1.2 
Damage score/progression 
Damage progression is analyzed as damage at end, with baseline damage as covariate 
 (see model, section 4.10). 
The following primary benefit hypothesis will be tested for damage: 
 
2a. Primary benefit hypothesis: 
H0,2a: (Null) Prednisolone intake over a period of 24 months leads on average to no difference or a 
higher damage progression compared to placebo intake. 
 
H1,2a: (Alternate) Prednisolone intake over a period of 24 months leads on average to a lower damage 
progression compared to placebo intake. 
 
𝐻଴,ଶ: δ୘ሺ𝑡ൌ24ሻെδେሺ𝑡ൌ24ሻ ൒0 
 
𝐻ଵ,ଶ: δ୘ሺ𝑡ൌ24ሻെδେሺ𝑡ൌ24ሻ൏0 
 
δ୘ሺ𝑡ൌ24ሻ is the mean damage score at 24 months in the treatment group. δେሺ𝑡ൌ24ሻ is the mean 
damage score at 24 months in the control group. 
 
 


GLORIA Statistical analysis plan Ͷ 17 
 
4.8.2 Secondary analyses 
The following secondary benefit hypothesis will be tested for the DAS28 in the per-protocol 
population (see 2.2): 
 
1b. Secondary benefit hypotheses: 
H଴,ଵୠ: (Null) Prednisolone intake over a period of 3 months leads on average to no difference or a 
larger score in DAS28 than placebo intake. 
 
Hଵ,ଵୠ: (Alternate) Prednisolone intake over a period of 3 months leads on average to a smaller score 
in DAS28 than placebo intake. 
 
𝐻଴,ଵ௕: μ୘ሺ𝑡ൌ3ሻെμେሺ𝑡ൌ3ሻ ൒0 
 
𝐻ଵ,ଵ௕: μ୘ሺ𝑡ൌ3ሻെμେሺ𝑡ൌ3ሻ൏0 
 
 
4.9 Safety analyses 
4.9.1 Primary analyses 
The following primary harm hypothesis will be tested: 
 
3a. Primary harm null hypothesis: 
𝐻଴,ଷ௔: (Null) The probability of patients receiving prednisolone to encounter at least one SAE or other 
AESI (as defined in the protocol) in a period of 24 months is equal to or less than the 
probability of patients receiving placebo. 
 
Hଵ,ଷୟ: (Alternate) The probability of patients receiving prednisolone to encounter at least one SAE or 
other AESI in a period of 24 months is greater than the probability of patients receiving 
placebo. 
 
𝐻଴,ଷ௔: π୘ሺ𝑡ൌ24ሻ/πେሺ𝑡ൌ24ሻ ൑1 
 
𝐻ଵ,ଷ௔: π୘ሺ𝑡ൌ24ሻ/πେሺ𝑡ൌ24ሻ൐1 
 
π୘ሺ𝑡ൌ24ሻ is the probability to encounter an SAE or other AESI over a 24 months period in the 
treatment group. πେሺ𝑡ൌ24ሻ is the probability to encounter an SAE or other AESI over a 24 months 
period in the control group.  
 
 
 


GLORIA Statistical analysis plan Ͷ 18 
 
4.10 Modeling and estimating 
The testing of the hypothesis sets requires estimating the average effect of treatment on benefit 
(operationalized as DAS28 and progression of joint damage) and harm (operationalized as 
encountering at least one SAE or other AESI). An observed effect with a probability of occurrence 
under the (one-sided) null hypothesis (p-value) of 5% or less will be considered significant causing us 
to reject the null and to accept the alternative hypothesis. The hypotheses and their tests are one-
sided in view of pre-existing knowledge for benefit and the likelihood that true benefit will be 
underestimated in the context of the pragmatic design and potential differential co-intervention (see 
section 4.11); and for harm because of limited power. This results in a higher chance of declaring 
benefit, but also a higher chance of declaring harm.  
 
The average effect of treatment on DAS28 (hypotheses 1) and damage progression (hypothesis 2) will 
be estimated in a mixed effects regression model. The exact form and empirical fit of the model are 
important determinants of the power of the statistical test of the treatment effect parameter, as 
described below. Hypotheses 3 require estimation of the difference in probability to encounter a SAE 
or other AESI between treatment and placebo over 24 months, which will be implemented by 
estimating the odds ratio of a SAE or other AESI in treatment versus placebo. All analyses will also 
take into account that the GLORIA study uses a stratified sampling design, where within each of 28 
participating centers randomization is executed stratified by earlier exposure to glucocorticoids 
(yes/no) and start or switch of other anti-rheumatic drugs at the beginning of the trial. 
 
We first describe how hypothesis testing for the GLORIA study will be executed. In this exposition, we 
assume that the observed data matrix is complete and that the estimated effects are not confounded 
with treatment changes. We describe methods to address incomplete data (section 4.2) and to 
assess confounding with treatment changes (section 4.11).  
Our general analysis strategy can be summarized as follows: 
 
1. Test hypotheses 1 to 3 with models described in this section and missing-at-random data 
correction (section 4.2). 
2. Execute robustness checks for monotonous not-missing-at-random data pattern with non-
responder imputation (NRI; section 4.2). 
3. Assess confounding with treatment changes (section 4.11) 
4. Formulate rules to interpret the overall trial results (section 4.12) 
 
4.10.1 Model and statistical test for the effect of treatment on DAS28 (Hypotheses 1) 
We first consider the analysis of the DAS28 outcome (benefit). The measurement level of DAS28 may 
be considered continuous so that we can model outcomes by continuous variable models. In the 
analysis, we need to solve two problems: first, how to estimate an average effect across the study 
period of two years, and second, how to take the longitudinal data structure into account. The 
second aspect poses two sub-problems; first, whether to treat time as continuous or discrete and, 
second, how to take into account that repeated measurements on the same individual are correlated 
(standard regression techniques assume uncorrelated observations).  
 


GLORIA Statistical analysis plan Ͷ 19 
 
The problem of intra-individual correlated observations will be addressed by mixed-effect regression 
models. The primary distinction in mixed-effect models for longitudinal data is the treatment of time 
in the model. In so-called fixed-occasion designs, time takes on a discrete form, whereas in so-called 
variable-occasion designs time takes on a continuous form (Hox, 2010; Snijders & Bosker, 2011). 
Fixed occasion designs are characterized by the fact that at given occasions outcomes of all (or most) 
of subjects are observed. Variable occasion designs are not limited by this restriction and there may 
be a large number of occasions at which only few subjects need to be observed.  
 
Although the design of the GLORIA study in principle lends itself to both types of model classes we 
will test hypotheses 1 with a fixed occasion model, because the number of time points at which 
individuals are observed is limited (up to six) and the model can accommodate non-linear trends in 
the data well by including occasion specific effects and occasion-treatment interactions (see 
expectations in figure 2). Continuous time models may also accommodate non-linear trends, but 
then the specification of the functional form becomes crucial and we do not have strong prior 
expectations of any particular functional model. We note continuous time models may be considered 
for secondary analyses. 
 
 


GLORIA Statistical analysis plan Ͷ 20 
 
4.10.1.1 Full model 
We model the treatment outcome by a mixed effect model with fixed effects measurement occasion 
after baseline (d), baseline measurement (𝑍), treatment condition (T), and random effects across 
individuals (level 2; random intercept U) and study centers (level 3; random intercept V). 
Furthermore, we include the strata of the GLORIA trial (S) as fixed effects. Centers could also be 
modeled as fixed effects, but we have chosen random effects because several centers have included 
only a very low number of patients. A compound symmetry correlation structure is assumed. 
 
We write down mixed effect model 1 as: 
𝑌௜௝௞ൌ𝛽଴௝௞൅ ∑
𝛽ଵ௝௞௦𝑑௜௝௞௦
ସ
௦ୀଵ
൅߳௜௝௞   
 
 
 
(level-1 model) 
𝛽଴௝௞ൌ𝛿଴଴௞൅𝛿଴ଵ௞𝑆௝௞ଵ൅𝛿଴ଶ௞𝑆௝௞ଶ൅𝛿଴ଷ௞𝑇௝௞൅𝛿଴ସ௞𝑍௝௞൅𝑈଴௝௞  
(level-2 model for intercept) 
𝛽ଵ௝௞௦ൌ𝛿ଵ଴௞௦     
 
 
 
 
 
 
(level-2 model for slope) 
𝛿଴଴௞ൌ𝛾଴଴଴൅𝑉଴଴௞  
 
 
 
 
 
 
(level-3 model for intercept) 
𝛿଴ଵ௞ൌ𝛾଴ଵ଴  
 
 
 
 
 
 
 
(level-3 model for slope) 
𝛿଴ଶ௞ൌ𝛾଴ଶ଴  
 
 
 
 
 
 
 
(level-3 model for slope) 
𝛿଴ଷ௞ൌ𝛾଴ଷ଴  
 
 
 
 
 
 
 
(level-3 model for slope) 
𝛿଴ସ௞ൌ𝛾଴ସ଴   
 
 
 
 
 
 
 
(level-3 model for slope) 
𝛿ଵ଴௞௦ൌ𝛾ଵ଴଴௦   
 
 
 
 
 
 
(level-3 model for slope) 
 
with 𝑈଴௝௞ the individual-level random effect, 𝑉଴଴௞ the center-level random effect,  
and ߳௜௝௞ the residual.  
 
The indices: 
iс 1,…, m : fixed measurement occasion after baseline (in GLORIA, m=5) 
jс 1,…,n : individuals 
kс1,…,K : study centers (currently, Kс2ϴ in GLORIA) 
 
The variables: 
𝑌௜௝௞  : DAS28 outcome  
𝑑௜௝௞௦ : dummy variables encoding the five measurement occasions after baseline, sс1,…, 4 
𝑇௝௞    : treatment indicator, 0 if placebo, 1 if active (prednisolone) treatment 
𝑍௝௞:  Baseline measurement of DAS28 
𝑆௝௞ଵ, 𝑆௝௞ଶ: Stratification factors 
 
The parameters: 
𝛾଴଴଴: the model intercept 
𝛾଴ଵ଴: fixed effect of stratification factor 1 
𝛾଴ଶ଴: fixed effect of stratification factor 2 
𝛾଴ଷ଴: fixed effect of treatment 
𝛾଴ସ଴: fixed effect of baseline measurement of DAS28 
𝛾ଵ଴଴௦: effect of time dummy s  
 
And the random effects : 
𝑈଴௝௞ : random intercept of individual i  
𝑉଴଴௞: random intercept of study center 
߳௜௝௞: residual  
 


GLORIA Statistical analysis plan Ͷ 21 
 
In hypotheses 1, we test for a difference in mean DAS score across a time of 24 months between 
treatment and placebo. In model (1), this difference in means is estimated by parameter 𝛾଴ଷ଴. For 
the PP analysis at 3 months, the model becomes two-level (no time) as there is only one assessment 
post baseline. 
 
4.10.1.2 Testing and exploration of treatment-time interactions 
The significance of all parameters in model 1 is evaluated using t-tests with Satterthwaite's method 
for approximating degrees of freedom (Kuznetsova, Brockhoff, and Christensen, 2017). In particular, 
hypothesis H1a is tested by evaluating the one-sided p-value of  𝛾଴ଷ଴ rejecting the one-sided null 
hypotheses if 𝛾଴ଷ଴൏0 significantly and not rejecting else. The main effect of measurement 
occasions across all dummy variable d is evaluated jointly by a likelihood ratio test (LRT).  
 
After this assessment, we will explore in a secondary analysis if the interaction between treatment 
and measurement occasions (time) interaction is significant using a LRT. If this test is significant we 
will test at which measurement occasions there is a significant difference using t-tests with 
Bonferroni correction of the p-values.  
 
4.10.2 Model and statistical test for the effect of treatment on damage score (hypothesis 2) 
The treatment effect on the damage score at 24 months (hypothesis 2) will be evaluated by the total 
Sharp/van der Heijde damage score of hands and forefeet. We will use a linear mixed-effects 
regression model defined similarly to model 1. Contrary to model 1 there are no repeated 
measurements. Therefore, we model outcomes of individuals nested in centers and include as main 
effects treatment, design strata, and the baseline measurement of the damage score. A random 
effect for study center is included. Model 2 is formalized as follows: 
 
𝑌௝௞ൌ𝛿଴௞൅𝛿ଵ௞𝑆௝௞ଵ൅𝛿ଶ௞𝑆௝௞ଶ൅𝛿ଷ௞𝑇௝௞൅𝛿ସ௞𝑍௝௞൅𝑈௝௞  
 
(level-1 model) 
𝛿଴௞ൌ𝛾଴଴൅𝑉଴௞  
 
 
 
 
 
 
(level-2 model for intercept) 
𝛿ଵ௞ൌ𝛾ଵ଴  
 
 
 
 
 
 
 
(level-2 model for slope) 
𝛿ଶ௞ൌ𝛾ଶ଴  
 
 
 
 
 
 
 
(level-2 model for slope) 
𝛿ଷ௞ൌ𝛾ଷ଴  
 
 
 
 
 
 
 
(level-2 model for slope) 
𝛿ସ௞ൌ𝛾ସ଴   
 
 
 
 
 
 
 
(level-2 model for slope) 
 
 
where now 𝑌௝௞ is the damage score at 24 months and 𝑍௝௞ is the damage score at baseline. Equivalent 
to section 3.1.1, it can be see that if a one-sided t-test of 𝛾ଷ଴൏0 is significant,  𝐻଴,ଶ is rejected. 
 
We note that the damage progression measurement can be positively skewed, threatening the 
accuracy (type 1 error rate) of the statistical tests in small samples (and other tests of regression 
coefficients including t- and F-tests). If we observe a strongly skewed distribution we will apply a 
bootstrapped test procedure instead of the t-test.  
 
 


GLORIA Statistical analysis plan Ͷ 22 
 
4.10.3 Model and statistical test for the effect of treatment on harm: SAEs or other AESIs 
(Hypotheses 3) 
Contrary to the hypothesis set 1 on the benefit of prednisolone treatment, hypotheses 3 require 
testing the difference in probabilities of encountering at least one SAE or other AESI over 24 months. 
On marginal level it would be sufficient to estimate these probabilities after t=24 months and 
evaluate the significance of their difference. However, to additionally account for the stratification of 
the GLORIA design, we apply a logistic mixed-effects regression (model 3): 
 
𝑃௝௞ൌ𝑔ିଵሺ𝛿଴௞൅𝛿ଵ௞𝑆௝௞ଵ൅𝛿ଶ௞𝑆௝௞ଶ൅𝛿ଷ௞𝑇௝௞൅𝑈௝௞ሻ 
 
𝛿଴௞ൌ𝛾଴଴൅𝑉଴௞  
 
 
 
 
 
 
(level-2 model for intercept) 
𝛿ଵ௞ൌ𝛾ଵ଴  
 
 
 
 
 
 
 
(level-2 model for slope) 
𝛿ଶ௞ൌ𝛾ଶ଴  
 
 
 
 
 
 
 
(level-2 model for slope) 
𝛿ଷ௞ൌ𝛾ଷ଴  
 
 
 
 
 
 
 
(level-2 model for slope) 
𝛿ସ௞ൌ𝛾ସ଴   
 
 
 
 
 
 
 
(level-2 model for slope) 
 
 
where now 𝑃௝௞ the probability of patient j in center k to encounter at least one SAE or other AESI 
over 24 months. The function  𝑔ିଵ denotes the inverse of the log link. Significance of 𝛿ଷ௞ will be 
evaluated with a t-test. Note that model 3 uses the log link as opposed to, for example, the logit link 
to estimate and test relative risk. 
 
4.11 Evaluation of possible confounded results due to differential co-intervention  
The data collected according to the GLORIA protocol are intended to allow a comparison of the effect 
of prednisolone treatment over placebo in terms of benefit and harm. Given that GLORIA is a 
pragmatic trial where changes in concomitant treatment (co-interventions for RA, i.e. antirheumatic 
co-medication) are allowed, an estimation of “pure effects” (i.e. without changes in concomitant 
treatment) is not possible. When changes in antirheumatic treatment differ between the groups this 
can result in a confounded estimate of the “pure” effects. Most changes in co-medication can be 
expected to lower the chance of finding a difference in efficacy between the treatment groups, 
because negative consequences of being in the placebo group can be countered by changing 
antirheumatic therapy. For this reason, we also analyze the short-term efficacy of prednisolone in the 
first three months in a per-protocol population where the chance of confounding is minimized. 
Note: adverse events leading to stop of study medication are part of the primary harm outcome, and 
are not covered here. 
 
We will test for potential confounding of the efficacy results. We will not test for confounding of the 
harm results, because straightforward interpretation is difficult: harm and changes in medication are 
probably related to each other in a complicated way. 
 
 


GLORIA Statistical analysis plan Ͷ 23 
 
4.11.1 Testing and correcting for differential treatment changes 
We plan to check for substantial confounding by comparing the incidence of lasting and substantial 
changes in co-medication categorized by the reason for change. For practical reasons, we will only 
consider the first instance of such a change in co-medication. Lasting means we do not consider brief 
starts or interruptions (i.e., lasting no more than 6 weeks); we also disregard changes in patients 
stopping the study medication within 3 months following the change.  
We will only consider changes that occur in the period starting at 3 months (V2) and 15 months (V6), 
because the potential for confounding is greatest in this period. Changes before V2 are too early to 
create confounding, and changes beyond V6 have relatively little effect on the outcome (effect on 
measurement at V7 and V9). Co-medication includes all disease-modifying antirheumatic drugs 
(conventional, biologic and targeted), and GC treatment classified as protocol violation and 
adjudicated in case of oral use. 
Oral GC treatment is adjudicated to select occurrences with potential for confounding similar to that 
of other antirheumatic drugs. Periods of oral treatment up to 3 weeks for RA are equated to one im 
injection for RA. More than two of either in the period assessed will count as intensification.  
Oral GC treatment for comorbidity creates less potential for confounding. More than 4 periods of 
oral treatment for comorbidity lasting no more than 3 weeks will count as intensification. 
Any period of oral therapy longer than 3 weeks for any indication (RA or otherwise) will also count as 
intensification.  
 
 
We distinguish 3 reasons for co-medication changes: 
1. Lack of efficacy: this includes instances of  
a. co-medication intensification: increase dose of current antirheumatic drug(s), or 
adding a new drug (co-medication) to the current treatment, including adjudicated 
GC treatment classified as protocol violation; 
b. co-medication switch (replacing one antirheumatic drug with another); 
2.  Adverse event: co-medication switch, or stop of an antirheumatic drug and start of another 
later; sole dose reduction for adverse event is not considered a substantial change; 
3. Good efficacy: co-medication taper: decrease dose or stop of current medication(s) without 
addition of or replacement by another medication.   
The remaining patients will be categorized as having no change in co-medication. 
 
For every patient we record and categorize the reason (lack of efficacy, adverse event, good efficacy) 
for the first change in co-medication in the specified time period. If an adverse event was reported at 
the moment of change(s) in medication, we will assume that the medication is changed due to 
adverse events.  
Otherwise, if a patient has no reported adverse event(s) at the moment of: 
x 
intensifying or switching the medication: we will assume that the treatment is changed due 
to lack of efficacy;   
x 
lowering or stopping co-medication: we will assume that the change is due to good efficacy. 
Situations that are unclear will be adjudicated by the medical monitor before the blind is broken. 
 
The effect of the co-medication change on the expected DAS28 depends on the reason: in case of 
lack of efficacy or adverse event, the change is expected to lead to a better outcome: a new drug or 


GLORIA Statistical analysis plan Ͷ 24 
 
an increased dose of the same drug is expected to work better. In case of good efficacy the change is 
expected to lead to the same or worse outcome: tapering a drug will most likely increase the DAS28 
somewhat and may cause a flare. 
Therefore, for both treatment groups we will calculate: 
1. the sum of patients experiencing a co-medication change for lack of efficacy, and for adverse 
events; and  
2. the number of patients experiencing a co-medication change for good efficacy.   
 
We will express 1) and 2) as proportion of the total number of patients in each treatment group and 
compare these between the groups with two Z-tests (each one-sided at p<0.025).  
The null hypotheses are: 
H0,4a : The probability of experiencing a co-medication change for lack of efficacy or for adverse 
events in the placebo group is lower than or equal to the probability in the  prednisolone group. 
H1,4a : The probability of experiencing a co-medication change for lack of efficacy or for adverse 
events in the placebo group is higher than the probability in the prednisolone group. 
 
H0,4b : The probability of experiencing a co-medication change for good efficacy in the placebo group 
is higher than or equal to the probability in the prednisolone group. 
 
H1,4b : The probability of experiencing a co-medication change for good efficacy in the placebo group 
is lower than the probability in the prednisolone group. 
 
We will assume confounding to the detriment of active treatment if: 
1. H0,4a  is rejected significantly at p < 0. 025 OR 
2. H0,4a  is rejected significantly at p < 0.025 
 
Assessing potential for confounding by co-medication changes in the analyses regarding harm of 
prednisolone is more difficult. Harm and changes in medication are probably related to each other in 
a complicated way. Therefore, we will not examine this. 
 
 


GLORIA Statistical analysis plan Ͷ 25 
 
4.12 Interpretation rules 
The outcomes of benefit (disease activity and damage progression) and harm (number of patients 
with at least one SAE or other AESI) will be interpreted simultaneously.  
The outcomes of benefit will be interpreted as follows (prednisolone group compared to placebo; 
reference to the specific rejected null hypotheses in parentheses): 
1. success:  
a. lower disease activity (H0,1a) 
AND lower damage score (H0,2a)  
b. lower disease activity OR lower damage score; AND confounding (H0,4a  or H0,4b) 
2. partial success/tradeoff:  
a. lower disease activity OR lower damage score AND NO confounding  
b. NO lower disease AND NO lower damage progression AND confounding  
3. failure: NO lower disease activity AND NO lower damage score AND NO confounding.         
 
The outcomes of harm will be interpreted as follows: 
1. success: NO significant increase in AEs  
2. failure: significant increase in AEs (H0,3a) 
 
Combined assessment of benefit and harm 
a. Success: success in benefit and harm 
b. Failure: failure in benefit and harm 
c. Partial success/tradeoff: all other scenarios 
 
For further interpretation of increases in the occurrence of SAE or other AESI in the active treatment 
group 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 interval (CI): 
1. > 1.3: GC associated with a trend towards greater occurrence;  
2. ч 1.2: GC appears to have little effect on the occurrence; 
3. > 1.2 and ч 1.3: results failed to demonstrate or exclude a greater occurrence. 
 
In the case of a numerical DECREASE in the occurrence of SAE or other AESI in the active treatment 
group, a more stringent test for significance will be performed (p<0.025).  
For the interpretation of decreases that did not reach significance: 
lower limit of one-sided 95% CI: 
1. < 0.7: GC associated with a trend towards reduced occurrence; 
2. ш 0.ϴ: appears to have little effect on the occurrence; 
3. ф 0.ϴ and ш 0.ϳ: results failed to demonstrate or exclude a reduced occurrence. 
 
 
 
 


GLORIA Statistical analysis plan Ͷ 26 
 
4.13 Analysis of secondary outcome variables  
We will estimate and test for the detrimental effects of prednisolone on bone mass and incident 
fracture rate. 
1. 
Continuous outcomes: bone mass lumbar spine, bone mass hip:  
analyzed according to model 1   
2. 
Discrete outcome: presence of at least one incident compression fracture  
(by VFA or lateral spine films): analyzed according to model 2 
Tests will be one-sided at p<0.05, with Benjamini-Hochberg adjustment for multiple testing. 
 
 
We will report the results of the other secondary outcome variables descriptively with 
means/proportions and 95%CI per treatment group per time point. 
 
3. 
Variables measured at every clinic visit  
a. Continuous outcomes: patient and physician global assessment of disease activity, 
joint counts (swollen joints and tender joints), acute phase reactants (C-reactive 
protein (CRP) and erythrocyte sedimentation rate (ESR)); vital signs, lab (blood) 
variables; adherence by pill count and by electronic adherence cap. 
b. Discrete outcomes: patients with at least one instance of remission; of minimal 
disease activity; patients with at least one long-term period (2 consecutive instances 
6 months apart) of remission; of minimal disease activity  
4. 
Variables measured at every visit (clinic and remote): 
a.  Continuous outcomes: severity and duration of morning stiffness, RA Impact of 
disease (total score, and components pain and fatigue analyzed separately), RAPID3 
index, EuroQoL, m(HAQ) 
b.  Discrete outcomes: discontinuations of study drug, of with reason; all changes of 
antirheumatic treatment, with reason; joint replacement surgery  
c. Expressed as survival curve: discontinuation of study drug over time 
5. 
Variables measured at baseline and end of study: 
a. Continuous outcomes: DAS44, SF36 (domains and summary mental and physical 
component scores), 57-symptom list;  
b. Discrete outcome: number of incident compression fractures (by VFA or lateral spine 
films) 
 
6. 
Variables measured only at baseline: 
a. Continuous/discrete: 
Demographics, education and medical history; Morisky medication adherence scale 
(MMAS-8), health literacy, arthritis helplessness index questionnaires; number of 
prevalent vertebral fractures (by VFA or lateral spine films), distribution of % height 
loss in vertebrae with fractures. 
7. 
Response indices calculated at 3 months in the PP analysis (discrete): ACR20, 50, 70; EULAR 
response. 
 
 
 


GLORIA Statistical analysis plan Ͷ 27 
 
5 Interim analyses 
No interim analyses were planned. However, we performed a new sample size calculation based on 
blinded AE incidence rates halfway through the trial (see below). 
6 Sample size and power calculations 
In the main GLORIA trial, 225 patients per treatment group will be entered (total 450 patients). 
 
In the chosen analysis strategy (see section 4), 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, 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, 
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 December 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 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 December 31, 2018 at a total of 452 patients. 
 


GLORIA Statistical analysis plan Ͷ 28 
 
Table 1. Sample size scenarios (one-sided alpha 5%). 
 
 
 
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 


GLORIA Statistical analysis plan Ͷ 29 
 
7 Tables, listings and figures 
 
Below are the titles for the planned study tables, figures, and listings. 
 
Table 1  
Patient distribution 
Table 2.A  
Patient distribution by center (ITT) 
Table 2.B  
Patient distribution by center (PP) 
Table 3.A  
Demographics and baseline characteristics (ITT) 
Table 3.B  
Demographics and baseline characteristics (PP) 
Table 4  
Health literacy 
Table 5  
Morisky medication adherence scale (MMAS-8) 
Table 6  
Arthritis helplessness index Table 7 .A Medical history (ITT) 
Table 7.B 
Medical history (PP) 
Table 8.A  
DAS28 scores (ITT) 
Table 8.B  
DAS28 scores (PP) 
Table 9   
Mixed effects model of time-averaged DAS28 (ITT) 
Table 10 
  
DAS44 scores (ITT)Table 11.A  Swollen joints 28 joint count (ITT) 
Table 11.B  
Swollen joints 28 joint count (PP) 
Table 12.A 
Tender joints 28 joint count (ITT) 
Table 12.B 
Tender joints 28 joint count (PP) 
Table 13.A  
Patient global assessment of disease activity (ITT) 
Table 13.B  
Patient global assessment of disease activity (PP) 
Table 14.A  
Physician global assessment of disease activity (ITT) 
Table 14.B  
Physician global assessment of disease activity (PP) 
Table 15.A 
CRP (ITT) 
Table 15.B 
CRP (PP) 
Table 16.A 
ESR (ITT) 
Table 16.B 
ESR (PP)Table 17  
EULAR response (PP) 
Table 18  
ACR response (PP) 
Table 19.A  
Minimal disease activity (ITT) 
Table 19.B  
Minimal disease activity (PP) 
Table 20 
Total Sharp/van der Heijde damage score of hands and forefeet radiographs (ITT) 
Table 21  
Morning stiffness (ITT) 
Table 22  
SF-36 questionnaire (ITT) 
Table 23  
RAID questionnaire (ITT) 
Table 24  
(Modified) Health Assessment Questionnaire ((m)HAQ) (ITT) 
Table 25 
RAPID3 (ITT) 
Table 26 
EuroQoL questionnaire (ITT) 
Table 27  
57-symptom list (ITT) 
Table 28.A  
Laboratory results in SI and original units (ITT) 
Table 28.B 
Laboratory results in SI and original units (SAF) 
Table 29.A  
Vital signs (ITT) 
Table 29.B 
Vital signs (SAF) 
Table 30.A  
Adherence (ITT) 
Table 30.B  
Adherence (PP) 


GLORIA Statistical analysis plan Ͷ 30 
 
Table 30.C 
Adherence (SAF) 
Table 31  
Concomitant medications summary (ITT) 
Table 32  
Bone mass (ITT) 
Table 33  
Number of prevalent vertebral fractures (by VFA or lateral spine films) (ITT) 
Table 34 
Distribution of % height loss in vertebrae with fractures 
Table 35  
Joint replacement surgery (ITT) 
Table 36.A  
AEs, SAEs and other AEs of special interest summary (ITT) 
Table 36.B 
AEs, SAEs and other AEs of special interest summary (SAF) 
Table 36.C  
AEs, SAEs and other AEs of special interest (ITT) 
Table 36.D 
AEs, SAEs and other AEs of special interest (SAF) 
Table 37 
Presence of SAE or other AE of special interest (ITT) 
 
 
 
 


GLORIA Statistical analysis plan Ͷ 31 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
Patient 
distribution 
1 
Intent-to-treat 
population 
Distribution 
Baseline 
- 
Dichotomous 
% (n) 
Patient 
distribution by 
center 
2A 
Intent-to-treat 
population 
Distribution 
Baseline 
Treatment group 
Dichotomous 
% (n) 
Patient 
distribution by 
center 
2B 
Per-protocol 
population 
Distribution 
Baseline 
Treatment group 
Dichotomous 
% (n) 
Demographics 
and baseline 
characteristics 
3A + 3B 
3A. Intent-to-
treat 
population 
3B. Per-
protocol 
population 
Age 
Baseline 
Treatment group 
Continuous 
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
Sex 
Baseline 
Treatment group 
Dichotomous 
% (n) female 
 
 
 
Smoking status 
Baseline 
Treatment group 
Categorical 
Current: % (n) 
Previous: % (n) 
Never: % (n) 


GLORIA Statistical analysis plan Ͷ 32 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Alcohol intake (units 
per week) 
Baseline 
Treatment group 
Categorical 
Every day: % 
(n) 
5-6 days per 
week: % (n) 
3-4 days per 
week: % (n) 
1-2 days per 
week: % (n) 
1-3 days per 
month: % (n) 
<1 day per 
month: % (n) 
Never: % (n) 
 
 
 
Possession of 
smartphone 
Baseline 
Treatment group 
Dichotomous 
% (n) 
 
 
 
Education level  
Baseline 
Treatment group 
Categorical 
% (n) higher 
education 
 
 
 
Duration of 
rheumatoid arthritis 
(months) 
Baseline 
Treatment group 
Continuous 
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
Rheumatoid factor 
status 
Baseline 
Treatment group 
Dichotomous 
% (n), positive 
 
 
 
Anti-CCP status 
Baseline 
Treatment group 
Dichotomous 
% (n), positive 


GLORIA Statistical analysis plan Ͷ 33 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Evidence of structural 
joint damage 
Baseline 
Treatment group 
Categorical 
% (n), yes 
 
 
 
Previous related 
surgical procedures 
Baseline 
Treatment group 
Categorical 
% (n), yes 
 
 
 
Previous 
glucocorticoid 
treatment 
Baseline 
Treatment group 
Dichotomous 
% (n), yes 
 
 
 
Previous NSAID 
treatment 
Baseline 
Treatment group 
Dichotomous 
% (n), yes 
 
 
 
Previous DMARD 
treatment 
Baseline 
Treatment group 
Dichotomous 
% (n), yes 
 
 
  
Previous biological 
treatment 
Baseline 
Treatment group 
Dichotomous 
% (n), yes 
 
 
 
Number of 
comorbidities 
Baseline 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
DAS28 
Baseline  
Treatment group 
Continuous  
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 34 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Tender joint count 
Baseline  
Treatment group 
Continuous  
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
Swollen joint count 
Baseline  
Treatment group 
Continuous  
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
ESR 
Baseline  
Treatment group 
Continuous  
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
CRP 
Baseline  
Treatment group 
Continuous  
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
Morning stiffness, 
duration in minutes 
Baseline  
Treatment group 
Continuous  
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed) 
 
 
 
Morning stiffness 
severity 
Baseline 
Treatment group 
Continuous 
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 35 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Patient global 
assessment of disease 
activity (scale 0-10) 
Baseline  
Treatment group 
Continuous  
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
Physician global 
assessment of disease 
activity (scale 0-10) 
Baseline  
Treatment group 
Continuous  
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
Pain (scale 0-10) 
Baseline  
Treatment group 
Continuous  
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
HAQ (scale 0-3) 
Baseline  
Treatment group 
Continuous  
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
RAID 
Baseline  
Treatment group 
Continuous  
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
EQ-5D 
Baseline  
Treatment group 
Continuous  
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 36 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
SF36 
Baseline  
Treatment group 
Continuous  
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
Health literacy 
4 
Intent-to-treat 
population 
Health literacy  
Baseline  
Treatment group 
Continuous  
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
Morisky 
medication 
adherence scale 
(MMAS-8) 
5 
Intent-to-treat 
population 
Morisky medication 
adherence scale 
Baseline  
Treatment group 
Continuous  
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
Arthritis 
helplessness 
index  
 
6 
Intent-to-treat 
population 
Arthritis helplessness 
index 
Baseline  
Treatment group 
Categorical 
-Low: % (n) 
-Normal: % (n) 
-High: % (n) 
Medical history 
7A 
Intent-to-treat 
population 
Number of 
comorbidities per 
organ system class 
Baseline  
Treatment group 
Continuous 
% (n) 
 
 
 
Top 3 of most 
common comorbidity 
categories 
Baseline  
 
 
1. % (n) 
2. % (n) 
3. % (n) 
 
7B 
Per-protocol 
population 
Number of 
comorbidities per 
organ system class 
Baseline  
Treatment group 
Continuous 
% (n) 


GLORIA Statistical analysis plan Ͷ 37 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Top 3 of most 
common comorbidity 
categories 
Baseline 
Treatment group 
Continuous 
1. % (n) 
2. % (n) 
3. % (n) 
DAS28 scores 
8A 
Intent-to-treat 
population 
DAS28 score 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
Change in DAS28 score 0-3 months 
Treatment group 
Continuous 
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
Change in DAS28 score 0-24 months 
Treatment group 
Continuous 
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
8B 
Per-protocol 
population 
DAS28 score 
0, 3 months 
Treatment group 
Continuous 
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
Change in DAS28 score 0-3 months 
Treatment group 
Continuous 
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 38 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
Mixed effects 
model of time-
averaged DAS28 
9 
Intent-to-treat 
population 
DAS28 score 
0, 3, 6, 9, 12, 
18, 24 months 
Treatment group 
Continuous 
Value, 
Standard 
Error, Df, p-
value  
DAS44 scores 
10 
Intent-to-treat 
population 
DAS44 score 
0 months 
Treatment group 
Continuous 
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
Change in DAS44 score 0-24 months 
Treatment group 
Continuous 
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
Swollen joints 28 
joint count 
11A 
Intent-to-treat 
population 
Number of swollen 
joints  
0, 3, 6, 9, 12, 
18, 24 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
11B 
Per-protocol 
population 
Number of swollen 
joints 
0, 3 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 39 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
Tender joints 28 
joint count 
12A 
Intent-to-treat 
population 
Number of tender 
joints 
0, 3, 6, 9, 12, 
18, 24 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
12B 
Per-protocol 
population 
Number of tender 
joints 
0, 3 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
Patient global 
assessment of 
disease activity 
13A 
Intent-to-treat 
population 
Patient global 
assessment of disease 
activity 
0, 3, 6, 9, 12, 
18, 24 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
13B 
Per-protocol 
population 
Patient global 
assessment of disease 
activity 
0, 3 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
Physician global 
assessment of 
disease activity 
14A 
Intent-to-treat 
population 
Physician global 
assessment of disease 
activity 
0, 3, 6, 9, 12, 
18, 24 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 40 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
14B 
Per-protocol 
population 
Physician global 
assessment of disease 
activity 
0, 3 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
CRP 
15A 
Intent-to-treat 
population 
CRP 
0, 3, 6, 9, 12, 
18, 24 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
 
15B 
Per-protocol 
population 
CRP 
0, 3 months 
Treatment group 
Continuous 
(median, min, 
max if data are 
non-normal 
distributed), n 
ESR 
16A 
Intent-to-treat 
population 
ESR 
0, 3, 6, 9, 12, 
18, 24 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
 
16B 
Per-protocol 
population 
ESR 
0, 3 months 
Treatment group 
Continuous 
(median, min, 
max if data are 
non-normal 
distributed), n 
EULAR response 
17 
 
Per-protocol 
population 
EULAR response 
3 months 
Treatment group 
Categorical 
Good: % (n) 
Moderate: % 
(n) 
None: % (n)  
American College 
of Rheumatology 
(ACR) response  
18 
 
Per-protocol 
population 
ACR20 response 
3 months 
Treatment group 
Dichotomous 
% (n), yes 
 
 
 
ACR50 response 
3 months 
Treatment group 
Dichotomous 
% (n), yes 
 
 
 
ACR70 response 
3 months 
Treatment group 
Dichotomous 
% (n), yes 
Minimal disease 
activity 
19A 
Intent-to-treat 
population 
Minimal disease 
activity 
3, 6, 12, 18, 
24months 
Treatment group 
Dichotomous 
% (n), yes 


GLORIA Statistical analysis plan Ͷ 41 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Boolean remission 
episode 
3, 6, 12, 18, 24 
months 
Treatment group 
Dichotomous 
% (n), yes 
 
 
 
Long-term Boolean 
remission 
12, 18, 24 
months 
Treatment group 
Dichotomous 
% (n), yes 
 
 
 
Simple Disease Activity 
Index (SDAI) 
3, 6, 12, 18, 
24months 
Treatment group 
Dichotomous 
% (n), yes 
 
19B 
Per-protocol 
population 
Minimal disease 
activity 
3 months 
Treatment group 
Dichotomous 
% (n), yes 
 
 
 
Boolean remission 
episode 
3 months 
Treatment group 
Dichotomous 
% (n), yes 
 
 
 
Simple Disease Activity 
Index (SDAI) 
3 months 
Treatment group 
Dichotomous 
% (n), yes 
Total Sharp/van 
der Heijde 
damage score of 
hands and 
forefeet 
radiographs 
20 
Intent-to-treat 
population 
Sharp/van der Heijde 
damage score 
0, 24 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
Change in Sharp/van 
der Heijde damage 
score 
0-24 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
Morning stiffness 21 
Intent-to-treat 
population 
Duration (minutes) of 
morning stiffness  
0, 3, 6, 9, 12, 
15, 18, 21, 24 
months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 42 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
Intent-to-treat 
population 
Severity of morning 
stiffness 
0, 3, 6, 9, 12, 
15, 18, 21, 24 
months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
SF-36 
22 
Intent-to-treat 
population 
SF-36 physical 
functioning score 
0 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
Change in SF-36 
physical functioning  
score 
0-24 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
SF-36 role-physical 
score 
0 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
Change in SF-36 role-
physical score 
0-24 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 43 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
Intent-to-treat 
population 
SF-36 bodily pain 
score 
0 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
Change in SF-36 bodily 
pain score 
0-24 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
SF-36 general health 
score 
0 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
Change in SF-36 
general health score 
0-24 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
SF-36 vitality score 
0 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
Change in SF-36 
vitality score 
0-24 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 44 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
Intent-to-treat 
population 
SF-36 social 
functioning score 
0 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
Change in SF-36 social 
functioning score 
0-24 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
SF-36 role-emotional 
score 
0 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
Change in SF-36 role-
emotional score 
0-24 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
SF-36 mental health 
score 
0 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
Change in SF-36 
mental health score 
0-24 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 45 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
Intent-to-treat 
population 
SF-36 physical 
component summary 
score 
0 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
Change in SF-36 
physical component 
summary score 
0-24 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
SF-36 mental 
component summary 
score 
0 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
Change in SF-36 
mental component 
summary score 
0-24 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
RAID 
23 
Intent-to-treat 
population 
RAID total score 
0, 3, 6, 9, 12, 
15, 18, 21, 
24months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 46 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
RAID pain score 
0, 3, 6, 9, 12, 
15, 18, 21, 
24months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
RAID fatigue score 
0, 3, 6, 9, 12, 
15, 18, 21, 
24months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
(m)HAQ 
24 
Intent-to-treat 
population 
(m)HAQ score 
0, 3, 6, 9, 12, 
15, 18, 21, 24 
months 
Treatment group 
Continuous  
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
RAPID3 
25 
Intent-to-treat 
population 
RAPID3 index score 
0, 3, 6, 9, 12, 
15, 18, 21, 24 
months 
Treatment group 
Continuous  
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
EuroQoL 
26 
Intent-to-treat 
population 
EQ-5D score 
0, 3, 6, 9, 12, 
15, 18, 21, 
24months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 47 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
57-symptom list 
27 
Intent-to-treat 
population 
Number of symptoms 
0 months 
Treatment group 
Continuous 
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
Change in number of 
symptoms 
0-24 months 
Treatment group 
Continuous 
Mean (SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
Laboratory 
results 
28A+28B 
 
28A. Intent-to-
treat 
population 
28B. Safety 
population 
Hemoglobin SI unit 
(unit: mmol/L) 
 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
Hemoglobin original 
unit (unit: mmol/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 48 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Hemoglobin original 
unit (unit: g/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
Hemoglobin original 
unit (unit: g/dl) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
Mean cell volume SI 
unit 
(unit: fl) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
White blood cells SI 
unit 
(unit: x10^9/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 49 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
White blood cells 
original unit 
(unit: x10^9/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
White blood cells 
original unit 
(unit: /nl) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
White blood cells 
original unit 
(unit: /ul) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
White blood cells 
original unit 
(unit: c/nl) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 50 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
White blood cells 
original unit 
(unit: G/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
White blood cells 
original unit 
(unit: Gpt/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
White blood cells 
original unit 
(unit: n/nl) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
White blood cells 
original unit 
(unit: 
x10^3mm/mm^3) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 51 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Neutrophils SI unit   
(unit: x10^9/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Neutrophils relatively 
(unit: %) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Neutrophils original 
unit (unit: x10^9/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Neutrophils original 
unit (unit: 
x10^3mm/mm^3) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 52 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Neutrophils original 
unit (unit: /nl) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Neutrophils original 
unit (unit: G/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Neutrophils original 
unit (unit: c/nl) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Neutrophils original 
unit (unit: /uL) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 53 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Basophils SI unit (unit: 
x10^9/L)  
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Basophils relatively 
(unit: %) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Basophils original unit 
(unit: x10^9/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Basophils original unit 
(unit: /nl) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 54 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Basophils original unit 
(unit: /uL) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Basophils original unit 
(unit: G/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Basophils original unit 
(unit: 
x10^3mm/mm^3) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Eosinophils SI unit 
(unit: x10^9/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 55 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Eosinophils relatively 
(unit: %) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Eosinophils original 
unit (unit: /nl) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Eosinophils original 
unit (unit: /uL) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Eosinophils original 
unit (unit: G/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 56 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Eosinophils original 
unit (unit: 
x10^3mm/mm^3) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD)  (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Lymphocytes SI unit 
(unit: x10^9/L)   
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Lymphocytes relatively 
(unit: %) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Lymphocytes original 
unit (unit: x10^9/L)   
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 57 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Lymphocytes original 
unit (unit: /nl)   
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Lymphocytes original 
unit (unit: /uL)   
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Lymphocytes original 
unit (unit: c/nl)   
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Lymphocytes original 
unit (unit: G/L)   
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 58 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Lymphocytes 
(unit: 
x10^3mm/mm^3)  
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Monocytes SI unit  
(unit: x10^9/L)   
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Monocytes relatively 
(unit: %) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Monocytes original 
unit (unit: x10^9/L)   
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 59 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Monocytes original 
unit (unit: /nl)   
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Monocytes original 
unit (unit: /uL)   
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Monocytes original 
unit (unit: G/L)   
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Monocytes original 
unit (unit: 
x10^3mm/mm^3)   
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 60 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Platelets SI unit 
(unit: x10^9/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD)  (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Platelets original unit 
(unit: x10^9/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Platelets original unit 
(unit: /nl) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Platelets original unit 
(unit: /uL) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 61 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Platelets original unit 
(unit: c/nl) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Platelets original unit 
(unit: G/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Platelets original unit 
(unit: Gpt/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Platelets original unit 
(unit: 10^3mm/mm^3) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 62 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Glucose SI unit 
(unit: mmol/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Glucose original unit 
(unit: mmol/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Glucose original unit 
(unit: mg/dl) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Creatinine SI unit 
(unit: mcmol/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 63 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Creatinine original unit 
(unit: mcmol/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
Creatinine original unit 
(unit: mg/dl) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD)  
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
 
Creatinine original unit 
(unit: mmol/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
ALAT SI unit 
(unit: U/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 64 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
ALAT original unit 
(unit: U/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
ALAT original unit 
(unit: ukat/L) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
ALAT original unit 
(unit: umol/s*l) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Cholesterol SI unit 
(unit: mmol/L) 
0, 3, 12, 24 
months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 65 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Cholesterol original 
unit (unit: mmol/L) 
0, 3, 12, 24 
months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Cholesterol original 
unit (unit: mg/dl) 
0, 3, 12, 24 
months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
- 
HDL cholesterol SI unit 
(unit: mmol/L) 
0, 3, 12, 24 
months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
HDL cholesterol 
original unit 
(unit: mmol/L) 
0, 3, 12, 24 
months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 66 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
HDL cholesterol 
original unit 
(unit: mg/dl) 
0, 3, 12, 24 
months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
CRP SI unit 
(unit: mg/L) 
0, 3, 6, 12, 18, 
24, 27 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
ESR SI unit 
(unit: mm/h) 
0, 3, 6, 12, 18, 
24, 27 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
Vital signs  
29A + 29B  
29A. Intent-to-
treat 
population 
29B. Safety 
population 
Weight (kg) 
0, 3, 6, 12, 18, 
24months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 67 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
 
Height (cm) 
0, 24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Systolic blood 
pressure (mmHg) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Diastolic blood 
pressure (mmHg) 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 
 
 
 
Heart rate per minute 
0, 3, 6, 12, 18, 
24 months 
Treatment group 
Continuous 
Mean change 
from baseline 
(SD) (median, 
min, max if 
data are non-
normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 68 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
Adherence 
30A 
Intent-to-treat 
population 
% adherence 
according to pill count 
3, 6, 12, 18, 24 
months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
% adherence 
according to electronic 
caps 
3, 6, 12, 18, 24 
months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
30B 
Per-protocol 
population 
% adherence 
according to pill count 
3 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Per-protocol 
population 
% adherence 
according to electronic 
caps 
3 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
30C 
Safety 
population 
% adherence 
according to pill count 
3, 6, 12, 18, 24 
months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Safety 
population 
% adherence 
according to electronic 
caps 
3, 6, 12, 18, 24 
months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 


GLORIA Statistical analysis plan Ͷ 69 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
Concomitant 
medications 
summary 
31 
Intent-to-treat 
population 
Concomitant 
medication summary 
Baseline  
Treatment group 
Dichotomous/continuous -DMARDs: % 
(n) 
-NSAIDs: % (n) 
-Biologicals: % 
(n) 
-Other anti-
rheumatic 
medication: % 
(n) 
-Other 
medication: 
Mean number 
(SD) (median, 
min, max if 
data are non-
normal 
distributed) 
-Top 3 of most 
common 
concomitant 
medication 
class:  
1. % (n) 
2. % (n) 
3. % (n) 


GLORIA Statistical analysis plan Ͷ 70 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
Bone mass  
32 
Intent-to-treat 
population 
Bone mass lumber 
spine 
0, 24 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
Change in bone mass 
lumbar spine 
0-24 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
Bone mass hip 
0, 24 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
Change in bone mass 
hip 
0-24 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
 
 
Intent-to-treat 
population 
Number of patients 
with at least one 
incident compression 
fracture (by VFA or 
lateral spine films) 
24 months 
Treatment group 
Dichotomous 
% (n), yes 


GLORIA Statistical analysis plan Ͷ 71 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
 
Intent-to-treat 
population 
Number of incident 
compression fractures 
(by VFA or lateral 
spine films) 
24 months 
Treatment group 
Continuous 
Mean (SD) + 
95% CI 
(median, min, 
max if data are 
non-normal 
distributed), n 
Number of 
prevalent 
vertebral 
fractures (by VFA 
or lateral spine 
films) 
33 
Intent-to-treat 
population 
Number of prevalent 
vertebral fractures  
0 months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n 
Distribution of % 
height loss in 
vertebrae with 
fractures 
34 
Intent-to-treat 
population 
Distribution of % 
height loss in 
vertebrae with 
fractures 
0- months 
Treatment group 
Continuous 
Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed), n  
Joint 
replacement 
surgery 
 
35 
Intent-to-treat 
population 
Number of joint 
replacement surgeries 
0, 3, 6, 9, 12, 
15, 18, 21, 24 
months 
Treatment group 
Continuous 
n (%) 


GLORIA Statistical analysis plan Ͷ 72 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
AE, SAE, other AE 
of special 
interest 
summary 
36A 
Intent-to-treat 
population  
Number of AEs, SAEs, 
other AEs of special 
interest 
3, 24 months 
Treatment group 
Continuous  
-Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed)  
-Top 3 of most 
common AE 
categories: 
1. % (n) 
2. % (n) 
3. % (n) 
 
36B 
Safety 
population 
Number of AEs, SAEs, 
other AEs of special 
interest 
3, 24 months 
Treatment group 
Continuous  
-Mean (SD) 
(median, min, 
max if data are 
non-normal 
distributed)  
-Top 3 of most 
common AE 
categories: 
1. % (n) 
2. % (n) 
3. % (n) 
AEs, SAEs, other 
AEs of special 
interest 
36C 
Intent-to-treat 
population 
Number of AE, SAE, 
other AE of special 
interest per organ 
system 
3, 24 months 
Treatment group 
Categorical 
-Category 1: n 
(%) 
-Category 2: 
(n%) 
-Category 3: n 
(%) 
Etc.   


GLORIA Statistical analysis plan Ͷ 73 
 
Table title 
Number  
Population 
Endpoint  
Time points or 
how to 
conglomerate 
Covariates or 
subgroups 
Type of variable 
Summary 
statistics 
 
36D 
Safety 
population 
Number of AE, SAE, 
other AE of special 
interest per organ 
system 
3, 24 months 
Treatment group 
Categorical 
-Category 1: n 
(%) 
-Category 2: 
(n%) 
-Category 3: n 
(%) 
Etc.   
Presence of SAE 
or other AE of 
special interest 
37 
Intent-to-treat 
population 
Presence of SAE or 
other AE of special 
interest 
24 months 
Treatment group 
Dichotomous 
-Yes: n(%) 
-No: n(%) 
 
 


GLORIA Statistical analysis plan Ͷ 74 
 
Figure 1 
Patient disposition: consort flow chart 
Figure 2 
Premature discontinuation per treatment group: Kaplan-Meier survival curve 
Figure 2 
DAS28 score per treatment group over time 
Figure 3 
Number of SAEs and other AEs of special interest per treatment group : Kaplan-Meier 
survival curve 
Figure 4 
Probability density plot of x-rays at 0 and 24 months 
 
 


GLORIA Statistical analysis plan Ͷ 75 
 
Listing 1  
Patient disposition 
Listing 2  
Patients excluded from the analysis populations  
Listing 3  
Protocol violations 
Listing 4  
Visit windows 
Listing 5 
Study completion including reason early withdrawal 
Listing 6  
Demographics and baseline characteristics  
Listing 7 
History of glaucoma and cataract 
Listing 8 
RA history 
Listing 9.A  
Medical history  
Listing 9.B  
Medical history with MedDRA Coding  
Listing 10.A  
Treatment not given according to protocol - interrupted 
Listing 10.B  
Treatment not given according to protocol – discontinued 
Listing 11  
Change of antirheumatic treatment, with reason 
Listing 12  
Intensification of treatment for existing comorbidity, e.g. hypertension or diabetes 
Listing 13  
DAS28 scores, DAS44 scores and EULAR response 
Listing 14  
Swollen and tender joints 
Listing 15.A  
Patient global assessment of disease 
Listing 15.B  
Physician global assessment of disease 
Listing 16  
ACR 20 response 
Listing 17  
Minimal disease activity 
Listing 18  
Total Sharp/van der Heijde damage score of hands and forefeet radiographs 
Listing 19  
Morning stiffness 
Listing 20.A  
SF-36 questionnaire 
Listing 20.B  
SF-36 scores 
Listing 21.A  
(m)HAQ questionnaire 
Listing 21.B  
(m)HAQ scores 
Listing 22.A  
RAID questionnaire 
Listing 22.B  
RAID scores 
Listing 23.A  
EQ-5D questionnaire 
Listing 23.B  
EQ-5D scores 
Listing 24  
Patient symptom list questionnaire 
Listing 25.A  
Laboratory – Hematology and chemistry 
Listing 25.B  
Laboratory – Lipids 
Listing 25.C  
Laboratory – CRP and ESR 
Listing 26  
Vital signs 
Listing 27  
Physical examination 
Listing 28 
Previous medication 
Listing 29  
Concomitant medications 
Listing 30.A  
Adverse events 
Listing 30.B  
Serious adverse events 
Listing 30.C  
Other adverse events of special interest 
Listing 31 
Death 
 
 
 


GLORIA Statistical analysis plan Ͷ 76 
 
8 Statistical software 
The statistical programming and analysis platform R will be used for the analysis (R Core Team, 
2020).  
SPSS version 26 or higher will be used for the descriptive statistics. Graphpad Prism version 9.0.2 or 
higher will be used for the figures. 
9 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. 
 
Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to 
Multiple Testing. Journal of the Royal Statistical Society Series B (Methodological) 1995;57:289-300. 
 
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. 
 
Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, et al. American College of 
Rheumatology/European League against Rheumatism provisional definition of remission in 
rheumatoid arthritis for clinical trials. Ann Rheum Dis 2011;70:404-13. 
 
Genant HK, Jergas M, Palermo L, Nevitt M, Valentin RS, Black D, et al. Comparison of 
semiquantitative visual and quantitative morphometric assessment of prevalent and incident 
vertebral fractures in osteoporosis The Study of Osteoporotic Fractures Research Group. J Bone 
Miner Res 1996;11:984-96. 
 
Guyatt GH, Norris SL, Schulman S, Hirsh J, Eckman MH, Akl EA, et al. 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. 
 
Hox JJ. Multilevel analysis. Techniques and applications. New York: Routledge; 2010. 


GLORIA Statistical analysis plan Ͷ 77 
 
 
Kuznetsova A, Brockhoff PB, Christensen RHB. lmerTest Package: Tests in Linear Mixed Effects 
Models.J Stat Softw 2017;82:1-26. https://doi.org/10.18637/jss.v082.i13 
 
Little RJA, Rubin DB. Statistical analysis with missing data (2nd ed.). Hoboken: Wiley; 2002.  
 
R Core Team. R: A language and environment for statistical computing. Vienna; R Foundation for 
Statistical Computing; 2020. https://www.R-project.org/ 
 
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. 
 
Rubin DB. Causal Inference Using Potential Outcomes. J Am Stat Assoc 2005;100:322-31. 
http://doi.org/10.1198/016214504000001880 
 
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. 
 
Snijders TAB, Bosker RJ.  Multilevel Analysis: An Introduction to Basic and Advanced Multilevel 
Modeling. New York: SAGE; 2011. 
 
Van Buuren S. Flexible Imputation of Missing Data. Boca Raton: CRC Press; 2012.  
 
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 ofthe 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. 
 
Wells, G.A., Boers, M., Shea, B., Brooks, P.M., Simon, L.S., Strand, C.V., et al. (2005). Minimal disease 
activity for rheumatoid arthritis: a preliminary definition. J Rheumatol, 32, 2016-24. 
 
 
  
 


GLORIA Statistical analysis plan Ͷ 78 
 
 
10 Appendix A: secondary outcome measures that need further specification 
 
Remission and minimal disease activity (MDA), according to ACR/EULAR criteria 
Remission is defined according to the Boolean Based definition of remission in clinical trials. A patient 
must satisfy a tender joint count ч1, a swollen joint count ч1, CRP ч1 mg/dL, and a patient global 
assessment ч1 (on a 0-10 scale). MDA is defined as a DAS28 <2.6 (Felson et al., 2011; Wells et al., 2005).  
 
ACR response 
This index is described in the protocol. To calculate ACR50 and ϳ0, the ‘20й’ criterion is replaced by 
50 resp 70%.  
 
 
Vital signs 
Systolic and diastolic blood pressure, pulse rate, weight and height.  
 
Physical examinations 
Physical examinations were performed at the discretion of the treating physician. The results will be 
summarized in a table per treatment group. All abnormalities will be reported. 
 
Bone mass assessment  
Bone mass of lumbar spine and total hip is assessed by Dual-energy X-ray Absorptiometry (DEXA), 
and expressed as g/cm2 for analysis.  
In addition, description of bone mass at femoral neck, and bone mass of all sites as T-score. 
 
Vertebral fracture analysis (by DEXA, or alternatively, by assessment of lateral spine X-rays)  
Vertebrae are viewed on transversal image and height loss (%) is scored according to Genant: 
Grade 0: <20%; Grade 1: 20-25й; Grade 2 ш25-40%; Grade 3 >40%. 
baseline: prevalent fracture: number of vertebrae with at least Grade 1;  
description of distribution of % height loss in vertebrae of patients with a prevalent fracture. 
follow up: incident fracture: sum of: 
a. number of vertebrae with baseline Grade 0 increasing to Grade 1-3 
 (% height loss <20% increasing to >20%) 
b. number of vertebrae with baseline Grade >0 increasing in Grade   
(Grade 1 increasing to 2 or 3; Grade 2 increasing to 3)  
 
 
 
 


GLORIA Statistical analysis plan Ͷ 79 
 
Medication adherence 
Medication adherence according to pill count is calculated as follows: if the number of capsules 
dispensed is D, the treatment period in number of days is P, and the number of capsules returned is 
R, medication adherence (expressed as %) is calculated as: 100*(D-R)/P. In alignment with the 
literature, good medication adherence is defined as an intake of at least 80% of the prescribed doses. 
 
For medication adherence according to electronic caps the assumption is made that a bottle opening 
is equal to the intake of one capsule. If the number of days that the cap wis not opened is O and the 
treatment period in number of days is P, adherence according to electronic caps (expressed as %) is 
calculated as: 100*(P-O)/P.  
 
 


GLORIA Statistical analysis plan Ͷ 80 
 
11 Appendix B – Modifications from the protocol 
 
Definition of AESI 
We refined the definitions of AESI in the protocol because it was not always completely clear when 
we were adjudicating the blinded events. The protocol text has been updated in order to make 
binding decisions on whether an event is AESI or not. The following changes and clarifications to the 
definition of an AESI were made:  
 
x 
‘Stop of antirheumatic treatment for AE’ was one of the options to define an event as an 
adverse event of special interest. However, the event ‘stop of antirheumatic treatment for 
AE’ is also taken into account as potential harm confounder in the analyses. We deleted this 
event from the definition of AE of special interest because we don’t want to double count 
this event. So, the event ‘’any AE (except loss of efficacy, worsening of disease) that leads to 
the definite cessation of one of the antirheumatic drugs, including trial medication’’ was 
changed to ‘’any AE (except loss of efficacy, worsening of disease) that leads to the definite 
cessation of trial medication’’. 
x 
‘Infection requiring antibiotic treatment’ was discussed because the definition is not clear 
about topical treatments, and treatments for fungi and viruses. Therefore, we decided that: 
o For the purpose of classification, ‘antibiotic’ includes any specific treatment aimed at 
microorganisms to treat an infection: so this includes topical, antiviral, antifungal, 
antiparasitic treatment. 
o (Surgical) procedures with concomitant antibiotics: not (initially) an infection, so not 
AESI; AESI only when the procedure was done for a primary infection (e.g. abscess). 
Surgical complications treated with antibiotics are also not coded as AESI, because it 
is usually impossible to determine whether the antibiotic was given as prophylaxis or 
as treatment. 
Note: any surgery is of necessity (hospital admission) already an SAE. 
x 
A cardiovascular event (myocardial infarction, cerebrovascular event, peripheral arterial 
vascular event); 
o Anything falling outside this definition is not an AESI.  
So venous hemorrhoids, venous ulcus cruris, thrombosis, pulmonary embolism, 
subdural hematoma, and traumatic hemorrhagic brain lesions are not coded as AESI. 
Also cardiac rhythm disturbances, valve lesions, cardiac insufficiency, 
cardiomyopathy, and encephalopathy, are not coded as AESI unless part of an acute 
ischemic episode. 
x 
Newly occurring hypertension requiring drug treatment; 
x 
Newly occurring diabetes mellitus requiring drug treatment; 
x 
Symptomatic bone fracture requiring treatment; 
o AESI is coded as ‘no’ if the vertebral fracture was asymptomatic, and ‘yes’ for all 
nonvertebral fractures, unless expressly indicated that the fracture was 
asymptomatic. 
Note that vertebral fracture is also captured as secondary outcome through DEXA or 
spine radiographs. 
 


GLORIA Statistical analysis plan Ͷ 81 
 
x 
Newly occurring cataract or glaucoma.  
o Cataract and glaucoma are assumed to be bilateral. 
A medical history of the disease in one eye counts for both, so no AESI during the 
trial for procedures on the contralateral eye. We count bilateral procedures for new 
disease as one (not two) AESI.  
x 
‘’Newly occurring diabetes or hypertension’’: no problems in adjudication. 
 
10.2 Secondary endpoints 
The measurements severity and duration of fatigue due to RA are included in the initial protocol, but 
not in the assessment. Severity of fatigue is part of the RA Impact of Disease (RAID) questionnaire 
and will be reported as described in section 1.4.2. Duration of fatigue was not included in the 
assessment and will not be reported. 
 
The number of patients retained on study drug over time was not described as secondary endpoint in 
the protocol. However, this proportion is measured and will be presented with survival analysis.  
 
 


GLORIA Statistical analysis plan Ͷ 82 
 
12 Appendix C. Report of blinded data review meetings 
 
Blinded Review of deviations leading to exclusion  
from the Per-Protocol Analysis 
 
Report of Review Meetings 9 June, 14 July, 17 November 2020 and 8 February 2021. 
Final version dd 2 March 2021. 
 
Attendees: Maarten Boers (PI/MM), Linda Hartman (PhD candidate), Hans Bijlsma (SAC member), 
Nick van der Bulk (CR2O, Head Clin Ops), Liza Bakker (sr. CRA), Linda Doerwald (Linical, Program Data 
manager), Leonie Middelink (Ops lead Gloria) 
 
Documents used 
– Clinical study protocol version 4.0 12 February 2019 
– Medical monitor plan dd. 05 April 2018 
– PD tacker dd. 18 February 2021 
– Manual listings 11 February 2021 
 
1. Investigational Medicinal Product (IMP) deviations 
The list of patients missing >20% of capsules per period (up to 3 months and up to 24 months) was 
reviewed. It was agreed that for the Per Protocol (PP) population adherence of at least 80% up to 3 
months is required. 
Review list : 
1. Adherence should be at least 80% first 3 months done (between baseline and V2), if 
adherence is < 80%, the patients are excluded from the PP group. For the complete 
overview, see attachment PP vs ITT overview.   
2. The periods of non-compliance after 3 months up to 24 months are left out of scope as they 
do not influence the PP population that applies only to the first 3 months.  
 
2. Protocol Deviations 
The PD tracker (dd 04 Feb 2021, later updated with version 18 February 2021) was reviewed, and 
following deviations were discussed: 
 
Possible unblinding 
Patients 107005 and -021 opened the capsules themselves.  
As the unblinding took place in the first 3 months, they are out of the PP group. 
Patient 107005 ICF signed on 31 Jan 2017, unblinding 24 Mar 2017; 107021 ICF signed on 22 aug 
2018 and unblinding 6 Nov 2018 
 
Prednisone open label use 
The PD tracker was reconciled with the Conmeds page in the manual listings. This has been done 
after final coding. This list has been crossed checked with the PD tracker, and for all prohibited 
prednisolone open label use an PD form has been created. If this prohibited open label use took 
place in the 30 days before baseline, or between ICF signature date and V2, the patient is excluded 


GLORIA Statistical analysis plan Ͷ 83 
 
from the PP population (see prohibited meds sections). Other prednisolone open label use (after V2) 
will be flagged for analysis, but does not affect the PP selection. 
   
In the coded conmeds file, the H02 ATC codes were selected. And the following rules were applied: 
x 
IV GCs are always a Protocol Deviation (if before stop of IMP). 
x 
Oral GCs are allowed for a maximum period of 3 weeks, for max 4 times, during IMP use.  
x 
Intra-Articular and Intra Bursal are allowed a maximum of 4 times during IMP use 
x 
Intra Muscular GCs are allowed to a maximum of 2 times during IMP use. 
 
IMP deviations 
If a patient misses a substantial percentage of the doses in a certain period (e.g. patient 116004 and 
501009) after month 3, this does not affect the PP population, see above.  
 
Time window deviations 
As the time window deviations all have taken place after V2, this does not affect the PP evaluation.  
 
Missed assessments 
Only missing DAS-scores during the first 3 months of the trial will lead to exclusion from PP. 
A DAS28-CRP can be used instead of the DAS28ESR. It was decided not to impute the DAS-ESR with a 
RAPID3. For the following visits the DASESR will be imputed with a DASCRP.  
 
 
PatiëntID 
Imputation 
Visite 
104016 
DAS28ESR imputed with DAS28CRP 
2 
106004 
DAS28ESR imputed with DAS28CRP 
2 
110002 
DAS28ESR imputed with DAS28CRP 
2 
110004 
DAS28ESR imputed with DAS28CRP 
2 
113007 
DAS28ESR imputed with DAS28CRP 
2 
113010 
DAS28ESR imputed with DAS28CRP 
2 
114013 
DAS28ESR imputed with DAS28CRP 
2 
117006 
DAS28ESR imputed with DAS28CRP 
2 
 
 
Process deviations  
Deviations such as SAE timelines, ICF signatures etc. do not lead to exclusion. 
 
Eligibility criteria 
All the deviations regarding eligibility criteria have been reviewed. Patients with actual deviations 
regarding violation of selection criteria are excluded from the PP. Process deviations relating to e.g. 
the Informed Consent process will not. 
 
 
 
1
1


GLORIA Statistical analysis plan Ͷ 84 
 
3. Other RA medication 
The type of medication, timing and exposure to the RA medication next to the IMP has been 
reviewed based on the manual listings.    
The objective of the PP analysis in the first three months is to study the effects of low-dose 
prednisolone in a population without co-interventions. As the impact of concurrent RA med use is so 
substantial, patients who start or change prohibited meds (biologicals, DMARDs, GCs) between ICF 
and V2 of the trial are excluded from the PP population as well. As per protocol, start with other RA 
meds was not absolutely prohibited, we changed the term “per protocol population”, “per protocol 
population, also excluding initial changes in antirheumatic medication”. This terminology has also 
been updated in the final SAP. 
 
4. Other reviews to consider 
x 
Safety reporting: cases of increase in disease activity (DA) were reported as AEs. No increase 
in DA reported as AE (based in coding file 5feb2021). Discussion pat 104008, AE# 9, swollen 
ancle left and right (NB site 114 3x painful joints / knee). All these AEs have been queried and 
the site confirmed it was an actual separate AE. 
 
x 
The check of efficacy data for patients with an early end of treatment has been incorporated 
in the SAP.  
 
The wording of the definitions of AEs of SI has been finetuned. Although this does not affect the PP 
evaluation, this has been discussed (as well as with the SAC), and the new rules for stop of RA meds 
and “anti-biotics” are to be applied after data export and before analysis. This has also been added to 
the SAP in the section “deviations from protocol”. 
 
The final list of patients included in the PP population is shown in Appendix D, below.


GLORIA Statistical analysis plan Ͷ 85 
 
13 Appendix D. Gloria final PP population,  
also excluding initial changes in antirheumatic medication  
 
Patient 
IMP <3 m 
Possible 
unblinding 
Prohib pred 
use 
Missed 
Ass 
Eligibility 
Vio 
Other RA 
meds ICF-V2 
Final 
101001 
In 
Out 
Out  
Out 
101002 
In 
101003 
In 
Out 
Out  
Out 
101004 
In 
101005 
Out 
DAS28 v2 
Out  
Out 
101006 
In 
DAS28 v2 
Out 
Out 
101007 
In 
101008 
In 
DAS28 V2 
Out 
101009 
In 
101010 
In 
101011 
Out 
Out 
101012 
Out 
DAS28 v2 
Out  
Out 
101013 
In 
Out  
Out 
101014 
In 
101015 
In 
 
 
 
 
 
 
101016 
In 
101017 
In 
DAS28 v1 
Out  
Out 
101018 
Out 
 
 
DAS28 v2 
Out 
Out  
Out 
101019 
In 
Out  
Out 
101020 
In 
Out  
Out 
101021 
In 
101022 
In 
101023 
In 
101024 
In 
101025 
In 
Out  
Out 
101026 
In 
101027 
In 
101028 
Out 
Out 
101029 
In 
101030 
In 
Out  
Out 
101031 
In 
101032 
In 
101033 
In 
101034 
In 
101035 
In 
101036 
In 
101037 
In 
101038 
In 
Out  
Out 
101039 
In 
 
 
 
 
 
 
102001 
In 
 
 
 
 
Out  
Out 
102002 
In 


GLORIA Statistical analysis plan Ͷ 86 
 
Patient 
IMP <3 m 
Possible 
unblinding 
Prohib pred 
use 
Missed 
Ass 
Eligibility 
Vio 
Other RA 
meds ICF-V2 
Final 
102003 
In 
 
 
 
 
 
 
102004 
In 
Out 
Out  
Out 
102005 
Out 
Out 
102006 
In 
102007 
In 
102008 
In 
102009 
In 
104001 
In 
Out  
Out 
104004 
In 
 
 
 
 
Out  
Out 
104005 
In 
 
 
 
 
 
 
104006 
In 
104007 
In 
Out  
Out 
104008 
In 
104009 
In 
104010 
In 
104011 
In 
Out  
Out 
104012 
In 
104013 
In 
104014 
In 
 
 
 
 
Out  
Out 
104015 
In 
Out  
Out 
104016 
In 
Out  
Out 
104017 
In 
104018 
In 
 
 
 
 
 
 
104019 
In 
106001 
In 
Out  
Out 
106002 
In 
106003 
In 
 
 
 
 
 
 
106004 
In 
106005 
In 
106006 
In 
106007 
In 
Out  
Out 
106008 
In 
107001 
In 
107002 
In 
GC use first 3 
months 
Out  
Out 
107003 
In 
107004 
In 
107005 
In 
Unblinding 
< m3 
DAS28 v2 
Out 
107006 
In 
 
 
 
 
 
 
107007 
Out 
 
 
DAS28 v2 
 
 
Out 
107008 
In 
107009 
In 
DAS28 v2 
Out  
Out 
107010 
In 
107011 
In 
Out  
Out 
107012 
In 
 
 
 
 
 
 
107013 
In 
Out  
Out 


GLORIA Statistical analysis plan Ͷ 87 
 
Patient 
IMP <3 m 
Possible 
unblinding 
Prohib pred 
use 
Missed 
Ass 
Eligibility 
Vio 
Other RA 
meds ICF-V2 
Final 
107014 
In 
 
 
 
 
Out  
Out 
107015 
In 
Out  
Out 
107016 
In 
107018 
In 
107019 
In 
Out  
Out 
107020 
In 
Out  
Out 
107021 
In 
Unblinding 
< m3 
Out 
107022 
In 
107023 
In 
 
 
 
 
Out  
Out 
107024 
In 
Out  
Out 
108001 
In 
108002 
In 
108003 
In 
Out  
Out 
108004 
In 
108005 
In 
108006 
Out 
DAS28 v2 
Out  
Out 
108007 
In 
108008 
In 
108009 
In 
108010 
In 
108011 
In 
108012 
Out 
 
 
 
 
 
Out 
108013 
In 
108014 
In 
 
 
 
 
 
 
108015 
Out 
DAS28 v2 
Out 
108016 
In 
 
 
 
 
 
 
108017 
In 
108018 
In 
108019 
Out 
DAS28 v2 
Out  
Out 
108020 
Out 
Out  
Out 
108021 
In 
Out  
Out 
108022 
In 
108023 
In 
Out  
Out 
108024 
In 
108025 
Out 
Out 
108026 
In 
Out  
Out 
108027 
Out 
DAS28 v2 
Out  
Out 
108028 
In 
108029 
In 
108030 
In 
 
 
 
 
 
 
108031 
In 
 
 
 
 
Out  
Out 
108032 
In 
 
 
 
 
 
 
108033 
In 
DAS28 v2 
Out  
Out 
108034 
In 
Out  
Out 
108035 
Out 
 
 
 
 
Out  
Out 
108036 
In 


GLORIA Statistical analysis plan Ͷ 88 
 
Patient 
IMP <3 m 
Possible 
unblinding 
Prohib pred 
use 
Missed 
Ass 
Eligibility 
Vio 
Other RA 
meds ICF-V2 
Final 
108037 
In 
 
 
 
 
 
 
108038 
In 
Out  
Out 
108039 
Out 
DAS28 v2 
Out  
Out 
108040 
In 
Out  
Out 
108041 
In 
108042 
Out 
Out 
108043 
In 
Out  
Out 
109001 
In 
109002 
In 
Out  
Out 
109003 
In 
109004 
In 
 
 
 
 
 
 
109005 
In 
109007 
In 
Out  
Out 
109008 
In 
109009 
In 
109010 
In 
109011 
In 
109012 
In 
Out  
Out 
109013 
In 
Out  
Out 
109014 
In 
109015 
In 
Out  
Out 
109016 
Out 
Out 
109017 
In 
 
 
 
 
 
 
109018 
In 
109019 
In 
Out  
Out 
110001 
In 
110002 
In 
110003 
In 
110004 
In 
110005 
In 
110006 
Out 
DAS28 v2 
Out 
110007 
Out 
Out 
110008 
In 
Out  
Out 
110009 
In 
110010 
Out 
Out 
111001 
In 
111002 
In 
111003 
In 
111004 
In 
111005 
In 
111006 
In 
111007 
In 
111008 
In 
111009 
In 
112001 
In 
 
 
 
 
 
 
112002 
In 
112003 
In 


GLORIA Statistical analysis plan Ͷ 89 
 
Patient 
IMP <3 m 
Possible 
unblinding 
Prohib pred 
use 
Missed 
Ass 
Eligibility 
Vio 
Other RA 
meds ICF-V2 
Final 
112004 
In 
 
 
 
 
 
 
112005 
In 
Out  
Out 
112006 
In 
DAS28 V2 
Out 
112007 
In 
112008 
Out 
Out 
112009 
In 
112010 
In 
112011 
In 
112012 
In 
 
 
 
 
 
 
112013 
In 
 
 
 
 
 
 
112014 
In 
112015 
In 
Out  
Out 
112016 
In 
Out  
Out 
112017 
In 
112018 
In 
112019 
In 
Out  
Out 
112020 
In 
112021 
In 
Out  
Out 
112022 
In 
 
 
 
 
 
 
112023 
In 
112024 
In 
112025 
In 
112026 
In 
 
 
 
 
 
 
112027 
In 
112028 
In 
112029 
In 
112030 
In 
Out  
Out 
112031 
In 
112032 
In 
112033 
In 
Pred < 30d 
baseline 
Out 
112034 
In 
112035 
In 
112036 
In 
112037 
Out 
Out 
112038 
Out 
Out 
112039 
In 
Pred < 30d 
baseline 
Out  
Out 
112040 
In 
112041 
In 
112042 
In 
Out  
Out 
112043 
Out 
DAS28 v2 
Out 
112044 
In 
112045 
In 
DAS28V2 
Out 
112046 
In 
112047 
In 
 
 
 
 
 
 
112048 
Out 
Out 
112049 
In 


GLORIA Statistical analysis plan Ͷ 90 
 
Patient 
IMP <3 m 
Possible 
unblinding 
Prohib pred 
use 
Missed 
Ass 
Eligibility 
Vio 
Other RA 
meds ICF-V2 
Final 
112050 
In 
 
 
 
 
Out  
Out 
112051 
In 
112052 
In 
112053 
In 
112054 
In 
Out  
Out 
113001 
In 
113002 
Out 
DAS28 v2 
Out 
113003 
In 
113004 
In 
 
 
 
 
 
 
113005 
In 
 
 
 
 
Out  
Out 
113006 
In 
Out  
Out 
113007 
In 
113008 
In 
113009 
In 
113010 
In 
Out  
Out 
113011 
In 
113012 
In 
DAS28 v2 
Out  
Out 
114001 
In 
DAS28 v1 
Out  
Out 
114002 
In 
 
 
 
 
 
 
114003 
In 
114004 
In 
Out  
Out 
114005 
Out 
Out 
114006 
Out 
 
 
 
 
 
Out 
114007 
In 
114008 
In 
114009 
In 
114010 
In 
Out  
Out 
114011 
In 
114012 
In 
Out  
Out 
114013 
In 
114015 
In 
DAS28V2 
Out 
Out 
114016 
In 
115001 
In 
115002 
In 
115003 
In 
116001 
In 
116002 
In 
116003 
In 
116004 
In 
Out 
Out 
116005 
In 
116006 
In 
116007 
In 
116008 
In 
116009 
In 
116010 
In 
116011 
Out 
 
 
DAS28 v2 
 
 
Out 
116012 
In 


GLORIA Statistical analysis plan Ͷ 91 
 
Patient 
IMP <3 m 
Possible 
unblinding 
Prohib pred 
use 
Missed 
Ass 
Eligibility 
Vio 
Other RA 
meds ICF-V2 
Final 
116013 
In 
 
 
DAS28 v2 
 
 
Out 
116014 
In 
116015 
In 
117001 
In 
117002 
In 
117003 
In 
Out  
Out 
117004 
In 
117005 
In 
117006 
In 
 
 
 
 
 
 
117007 
In 
 
 
 
 
 
 
117008 
In 
117009 
In 
117010 
In 
201001 
In 
201002 
In 
204001 
Out 
DAS28 v2 
Out 
204002 
In 
204003 
In 
204004 
In 
 
 
 
 
 
 
204005 
In 
204006 
In 
204007 
In 
205001 
Out 
 
 
 
 
Out  
Out 
301001 
In 
301002 
In 
301003 
In 
301004 
In 
301005 
In 
301006 
Out 
DAS28 v2 
Out 
301007 
In 
301008 
In 
301009 
In 
DAS28 V2 
Out 
302001 
In 
303001 
In 
304001 
In 
304002 
Out 
Out 
304003 
In 
304004 
In 
304005 
In 
304006 
In 
304007 
Out 
Out 
304008 
In 
305001 
In 
305002 
In 
305003 
In 
305004 
In 
 
 
 
 
 
 
305005 
In 


GLORIA Statistical analysis plan Ͷ 92 
 
Patient 
IMP <3 m 
Possible 
unblinding 
Prohib pred 
use 
Missed 
Ass 
Eligibility 
Vio 
Other RA 
meds ICF-V2 
Final 
305006 
In 
 
 
 
 
Out  
Out 
305007 
In 
401001 
In 
401002 
In 
501001 
In 
501002 
In 
501003 
In 
501004 
In 
501005 
In 
 
 
 
 
 
 
501006 
In 
 
 
 
 
 
 
501007 
In 
501008 
In 
501009 
In 
501010 
In 
501011 
In 
501012 
In 
501013 
In 
501014 
In 
501015 
In 
 
 
 
 
 
 
501016 
In 
501017 
In 
501018 
In 
501019 
In 
 
 
 
 
 
 
501020 
In 
501021 
In 
501022 
In 
501023 
In 
501024 
In 
Out  
Out 
501025 
In 
501026 
In 
501027 
In 
501028 
In 
Out  
Out 
501029 
In 
501030 
In 
Out  
Out 
501031 
In 
501032 
In 
501033 
In 
501034 
In 
501035 
In 
Out  
Out 
501036 
In 
501037 
In 
501038 
In 
501039 
In 
501040 
In 
501041 
In 
501042 
In 
 
 
 
 
 
 
501043 
In 
Out  
Out 


GLORIA Statistical analysis plan Ͷ 93 
 
Patient 
IMP <3 m 
Possible 
unblinding 
Prohib pred 
use 
Missed 
Ass 
Eligibility 
Vio 
Other RA 
meds ICF-V2 
Final 
501044 
In 
 
 
 
 
 
 
501045 
In 
501046 
In 
501047 
In 
501048 
Out 
DAS28 v2 
Out 
501049 
In 
501050 
In 
501051 
Out 
Out  
Out 
501052 
Out 
 
 
DAS28 v2 
 
 
Out 
501053 
In 
 
 
 
 
 
 
501054 
In 
501055 
Out 
Out 
501056 
In 
501057 
In 
501058 
In 
501059 
In 
501060 
In 
601001 
Out 
DAS28 v2 
Out 
601002 
Out 
 
 
DAS28 v2 
 
 
Out 
601003 
In 
601004 
In 
601005 
Out 
DAS28 v2 
Out  
Out 
601006 
In 
 
 
 
 
 
 
601007 
In 
601008 
In 
601009 
Out 
DAS28 v2 
Out 
601010 
In 
601011 
Out 
DAS28 v2 
Out 
601012 
In 
701001 
In 
701002 
In 
701003 
In 
701004 
In 
701005 
In 
701006 
Out 
DAS28 v2 
Out 
701007 
In 
701008 
In 
701009 
In 
701010 
Out 
Out 
701011 
In 
701012 
In 
Out  
Out 
701013 
In 
701014 
In 
701015 
In 
701016 
In 
701017 
In 
 
 
 
 
 
 
701018 
In 


GLORIA Statistical analysis plan Ͷ 94 
 
Patient 
IMP <3 m 
Possible 
unblinding 
Prohib pred 
use 
Missed 
Ass 
Eligibility 
Vio 
Other RA 
meds ICF-V2 
Final 
701019 
Out 
 
 
DAS28 v2 
 
 
Out 
701020 
In 
701021 
Out 
Out 
701022 
In 
701023 
Out 
Out 
701024 
Out 
DAS28 v2 
Out  
Out 
701025 
In 
701026 
In 
Out  
Out 
701027 
In 
 
 
 
 
 
 
701028 
In 
 
 
 
 
 
 
701029 
In 
701030 
Out 
DAS28 v2 
Out 
701031 
In 
701032 
In 
701033 
Out 
DAS28 v2 
Out 
701034 
In 
701035 
In 
Out  
Out 
701036 
In 
701037 
In 
 
 
 
 
 
 
701038 
In 
701039 
Out 
DAS28 v2 
Out 
701040 
In 
701041 
In 
 
 
 
 
 
 
701042 
In 
701043 
In 
701044 
Out 
Out  
Out 
701045 
In 
Out  
Out 
702001 
Out 
Out 
702002 
In 
702003 
Out 
DAS28 v2 
Out 
702004 
Out 
Out 
702005 
In 
702006 
In 
702007 
Out 
Out 
702008 
In 
702009 
In 
702010 
Out 
Out 
702011 
Out 
Out 
total 
60 
2 
3 
42 
7 
90 
147