The Glucocorticoid Low-dose Outcome in RheumatoId Arthritis Study (Gloria)

• ClinicalTrials.gov Identifier: NCT02585258
• Recruitment Status: Completed
• First Posted: October 23, 2015
• Last Update Posted: August 25, 2021
• Sponsor: Amsterdam UMC, location VUmc
• Collaborator: European Commission
• Information provided by (Responsible Party): Prof. dr. M. Boers, Amsterdam UMC, location VUmc

Study Description

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)

Condition or disease	Intervention/treatment	Phase
RheumatoId Arthritis	Drug: Prednisolone; Other: Placebo	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 451 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: June 30, 2016
• Actual Primary Completion Date: December 31, 2020
• Actual Study Completion Date: December 31, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: arm A; prednisolone 5 mg per day	Drug: Prednisolone; capsules 5 mg / day
Placebo Comparator: arm B; placebo capsules once per day	Other: Placebo; capsules 1 / day

Outcome Measures

Primary Outcome Measures :

1. Signs and symptoms: the time-averaged mean value of the DAS28; [ Time Frame: 24 months ]
   DAS28
2. The total number of patients experiencing at least one AE of Special Interest (an SAE, or an AE on a prespecified list of clinically relevant AEs commonly associated with the disease and glucocorticoid use [ Time Frame: 24 months ]
   AEs

Secondary Outcome Measures :

1. Damage progression: 2-year change in total Sharp/van der Heijde damage score of hands and forefeet radiographs. [ Time Frame: 24 months ]
2. WHO-ILAR core set of RA outcome measures [ Time Frame: 24 months ]
3. Severity and duration of morning stiffness [ Time Frame: 24 months ]
4. Severity and duration of fatigue due to RA [ Time Frame: 24 months ]
5. SF36 - The Short Form 36-item Health Survey, a questionnaire about QoL [ Time Frame: 24 months ]
6. 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 [ Time Frame: 24 months ]
7. Health Assessment Questionnaire (HAQ) [ Time Frame: 24 months ]
8. cost questionnaire, including o Activity limitation (part of cost questionnaire) o Work disability (for those holding a paid job, part of cost questionnaire) [ Time Frame: 24 months ]
9. Utility/Quality-adjusted life years (QALY): Euro-QoL in 5 dimensions (EQ-5D) [ Time Frame: 24 months ]
10. Vital signs (heart rate and blood pressure) [ Time Frame: 24 months ]
11. Cost-effectiveness and cost-utility Estimate of costs of treatment and monitoring [ Time Frame: 24 months ]
12. 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. [ Time Frame: 24 months ]
13. Bone mass assessed by Dual-energy X-ray Absorptiometry (DXA) [ Time Frame: 24 months ]
14. Vertebral Fracture Analysis (by DXA OR lateral radiograph of thoracic and lumbar spine) [ Time Frame: 24 months ]

Eligibility Criteria

• Ages Eligible for Study: 65 Years and older (Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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 the 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 disease activity score of 28 joints calculated with erythrocyte sedimentation rate (DAS28) ≥2.60;
• 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;
• 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 7.1).

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);
• 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 smart device on adherence:

Inability/difficulty to measure benefit:

• Not in the possession of a smart device;
• Premature discontinuation of study medication within or at 3 months of the main trial.

Contacts and Locations

Locations

Germany

Charite

Berlin, Germany

Facharztpraxis

Magdeburg, Germany

Knappschaftsklinikum Saar

Püttlingen, Germany

Hungary

University of Debrecen

Debrecen, Hungary

Italy

University of Genova

Genova, Italy

Netherlands

Noordwest Ziekenhuis

Alkmaar, Netherlands

Meander

Amersfoort, Netherlands

VUmc

Amsterdam, Netherlands

Gelre

Apeldoorn, Netherlands

HAGA

Den Haag, Netherlands

Groene Hart Ziekenhuis

Gouda, Netherlands

UMCG

Groningen, Netherlands

Westfries Gasthuis

Hoorn, Netherlands

MCL

Leeuwarden, Netherlands

LUMC

Leiden, Netherlands

MC Zuiderzee

Lelystad, Netherlands

MUMC

Maastricht, Netherlands

Maasstad

Rotterdam, Netherlands

Antonius Ziekenhuis

Sneek, Netherlands

UMC Utrecht

Utrecht, Netherlands

VieCurie MC

Venlo, Netherlands

Portugal

CHU Coimbra

Coimbra, Portugal

Hospital de Egas Moniz

Lisboa, Portugal

Hospital de Santa Maria

Lisboa, Portugal

Instituto Portugues de Reumatologia

Lisboa, Portugal

Hospital de Ponte Lima

Ponte de Lima, Portugal

Romania

Carol Davila University of Medicine and Pharmacy

Bucarest, Romania

Carol Davila

Bucuresti, Romania

Slovakia

NURCH

Bratislava, Slovakia

Sponsors and Collaborators

Amsterdam UMC, location VUmc

European Commission

Investigators

• Principal Investigator: Maarten Boers, Prof. dr.; Amsterdam UMC, location VUmc

More Information

Publications:

Palmowski Y, Buttgereit T, Dejaco C, Bijlsma JW, Matteson EL, Voshaar M, Boers M, Buttgereit F. "Official View" on Glucocorticoids in Rheumatoid Arthritis: A Systematic Review of International Guidelines and Consensus Statements. Arthritis Care Res (Hoboken). 2017 Aug;69(8):1134-1141. doi: 10.1002/acr.23185. Epub 2017 Jul 10. Erratum In: Arthritis Care Res (Hoboken). 2018 Jan;70(1):144.

Palmowski Y, Buttgereit F, Boers M. Reply. Arthritis Care Res (Hoboken). 2019 Apr;71(4):577-578. doi: 10.1002/acr.23452. No abstract available.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hartman L, da Silva JAP, Buttgereit F, Cutolo M, Opris-Belinski D, Szekanecz Z, Masaryk P, Voshaar MJH, Heymans MW, Lems WF, van der Heijde DMFM, Boers M. Development of prediction models to select older RA patients with comorbidities for treatment with chronic low-dose glucocorticoids. Rheumatology (Oxford). 2022 Sep 27:keac547. doi: 10.1093/rheumatology/keac547. Online ahead of print.

Boers M, Hartman L, Opris-Belinski D, Bos R, Kok MR, Da Silva JA, Griep EN, Klaasen R, Allaart CF, Baudoin P, Raterman HG, Szekanecz Z, Buttgereit F, Masaryk P, Klausch LT, Paolino S, Schilder AM, Lems WF, Cutolo M; GLORIA Trial consortium. Low dose, add-on prednisolone in patients with rheumatoid arthritis aged 65+: the pragmatic randomised, double-blind placebo-controlled GLORIA trial. Ann Rheum Dis. 2022 Jul;81(7):925-936. doi: 10.1136/annrheumdis-2021-221957. Epub 2022 May 31.

Buttgereit T, Palmowski A, Forsat N, Boers M, Witham MD, Rodondi N, Moutzouri E, Navidad AJQ, Van't Hof AWJ, van der Worp B, Coll-Planas L, Voshaar M, de Wit M, da Silva J, Stegemann S, Bijlsma JW, Koeller M, Mooijaart S, Kearney PM, Buttgereit F. Barriers and potential solutions in the recruitment and retention of older patients in clinical trials-lessons learned from six large multicentre randomized controlled trials. Age Ageing. 2021 Nov 10;50(6):1988-1996. doi: 10.1093/ageing/afab147.

Hartman L, Cutolo M, Bos R, Opris-Belinski D, Kok MR, Griep-Wentink HJRM, Klaasen R, Allaart CF, Bruyn GAW, Raterman HG, Voshaar MJH, Gomes N, Pinto RMA, Klausch LT, Lems WF, Boers M. Medication adherence in older people with rheumatoid arthritis is lower according to electronic monitoring than according to pill count. Rheumatology (Oxford). 2021 Nov 3;60(11):5239-5246. doi: 10.1093/rheumatology/keab207.

Forsat ND, Palmowski A, Palmowski Y, Boers M, Buttgereit F. Recruitment and Retention of Older People in Clinical Research: A Systematic Literature Review. J Am Geriatr Soc. 2020 Dec;68(12):2955-2963. doi: 10.1111/jgs.16875. Epub 2020 Oct 19.

Hartman L, Rasch LA, Klausch T, Bijlsma HWJ, Christensen R, Smulders YM, Ralston SH, Buttgereit F, Cutolo M, Da Silva JAP, Opris D, Rovensky J, Szamosi S, Middelink LM, Lems WF, Boers M. Harm, benefit and costs associated with low-dose glucocorticoids added to the treatment strategies for rheumatoid arthritis in elderly patients (GLORIA trial): study protocol for a randomised controlled trial. Trials. 2018 Jan 25;19(1):67. doi: 10.1186/s13063-017-2396-3.

• Responsible Party: Prof. dr. M. Boers, Professor, Amsterdam UMC, location VUmc
• ClinicalTrials.gov Identifier: NCT02585258
• Other Study ID Numbers: VUMC-ARC-GLORIA
• First Posted: October 23, 2015
• Last Update Posted: August 25, 2021
• Last Verified: August 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: (meta) data will be shared after signing a data sharing agreement, at reasonable cost
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: expected active from 2022
• Access Criteria: scientific use

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Arthritis; Arthritis, Rheumatoid; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Prednisolone; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents