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

Linda Hartman, Linda A Rasch, Thomas Klausch, Hans W J Bijlsma, Robin Christensen, Yvo M Smulders, Stuart H Ralston, Frank Buttgereit, Maurizio Cutolo, Jose A P Da Silva, Daniela Opris, Jozef Rovenský, Szilvia Szamosi, Leonie M Middelink, Willem F Lems, Maarten Boers

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Abstract

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints affecting 1% of the world population. It has major impact on patients through disability and associated comorbidities. Current treatment strategies have considerably improved the prognosis, but recent innovations (especially biologic drugs and the new class of so-called "JAK/STAT inhibitors") have important safety issues and are very costly. Glucocorticoids (GCs) are highly effective in RA, and could reduce the need for expensive treatment with biologic agents. However, despite more than 65 years of clinical experience, there is a lack of studies large enough to adequately document the benefit/harm balance. The result is inappropriate treatment strategies, i.e. both under-use and over-use of GCs, and consequently suboptimal treatment of RA.

METHODS: The GLORIA study is a pragmatic multicentre, 2-year, randomised, double-blind, clinical trial to assess the safety and effectiveness of a daily dose of 5 mg prednisolone or matching placebo added to standard of care in elderly patients with RA. Eligible participants are diagnosed with RA, have inadequate disease control (disease activity score, DAS28 ≥ 2.6), and are ≥ 65 years. The primary outcome measures are the time-averaged mean value of the DAS28 and the occurrence of serious adverse events or adverse events of special interest. During the trial, change in antirheumatic therapy is permitted as clinically indicated, except for GCs. Cost-effectiveness and cost-utility are secondary outcomes. The main challenge is the interpretation of the trial result with two primary endpoints and the pragmatic trial design that allows co-interventions. Another challenge is the definition of safety and the relative lack of power to detect differences between treatment groups. We have chosen to define safety as the number of patients experiencing at least one serious adverse event. We also specify a decision tree to guide our conclusion on the balance of benefit and harm, and our methodology to combat potential confounding caused by co-interventions.

DISCUSSION: Pragmatic trials minimise impact on daily practice and maximise clinical relevance of the results, but analysis and interpretation of the results is challenging. We expect that the results of this trial are of importance for all rheumatologists who treat elderly patients with RA.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02585258 . Registered on 20 October 2015.

Original languageEnglish
Article number67
JournalTrials
Volume19
Number of pages12
ISSN1745-6215
DOIs
Publication statusPublished - 25. Jan 2018
Externally publishedYes

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Glucocorticoids
Cost-Benefit Analysis
Randomized Controlled Trials
Safety
Decision Trees
Comorbidity
Joints
Placebos
Outcome Assessment (Health Care)
Clinical Trials
Pharmaceutical Preparations
Population

Keywords

  • Age Factors
  • Aged
  • Antirheumatic Agents/administration & dosage
  • Arthritis, Rheumatoid/diagnosis
  • Clinical Trials, Phase IV as Topic
  • Cost-Benefit Analysis
  • Double-Blind Method
  • Drug Costs
  • Drug Therapy, Combination
  • Europe
  • Female
  • Glucocorticoids/administration & dosage
  • Humans
  • Male
  • Medication Adherence
  • Multicenter Studies as Topic
  • Pragmatic Clinical Trials as Topic
  • Prednisolone/administration & dosage
  • Risk Factors
  • Time Factors
  • Treatment Outcome
  • Glucocorticoids
  • Benefit
  • Safety
  • Prednisolone
  • Harm
  • Rheumatoid arthritis
  • Cost-effectiveness
  • Elderly

Cite this

Hartman, Linda ; Rasch, Linda A ; Klausch, Thomas ; Bijlsma, Hans W J ; Christensen, Robin ; Smulders, Yvo M ; Ralston, Stuart H ; Buttgereit, Frank ; Cutolo, Maurizio ; Da Silva, Jose A P ; Opris, Daniela ; Rovenský, Jozef ; Szamosi, Szilvia ; Middelink, Leonie M ; Lems, Willem F ; Boers, Maarten. / 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. In: Trials. 2018 ; Vol. 19.
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abstract = "BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints affecting 1{\%} of the world population. It has major impact on patients through disability and associated comorbidities. Current treatment strategies have considerably improved the prognosis, but recent innovations (especially biologic drugs and the new class of so-called {"}JAK/STAT inhibitors{"}) have important safety issues and are very costly. Glucocorticoids (GCs) are highly effective in RA, and could reduce the need for expensive treatment with biologic agents. However, despite more than 65 years of clinical experience, there is a lack of studies large enough to adequately document the benefit/harm balance. The result is inappropriate treatment strategies, i.e. both under-use and over-use of GCs, and consequently suboptimal treatment of RA.METHODS: The GLORIA study is a pragmatic multicentre, 2-year, randomised, double-blind, clinical trial to assess the safety and effectiveness of a daily dose of 5 mg prednisolone or matching placebo added to standard of care in elderly patients with RA. Eligible participants are diagnosed with RA, have inadequate disease control (disease activity score, DAS28 ≥ 2.6), and are ≥ 65 years. The primary outcome measures are the time-averaged mean value of the DAS28 and the occurrence of serious adverse events or adverse events of special interest. During the trial, change in antirheumatic therapy is permitted as clinically indicated, except for GCs. Cost-effectiveness and cost-utility are secondary outcomes. The main challenge is the interpretation of the trial result with two primary endpoints and the pragmatic trial design that allows co-interventions. Another challenge is the definition of safety and the relative lack of power to detect differences between treatment groups. We have chosen to define safety as the number of patients experiencing at least one serious adverse event. We also specify a decision tree to guide our conclusion on the balance of benefit and harm, and our methodology to combat potential confounding caused by co-interventions.DISCUSSION: Pragmatic trials minimise impact on daily practice and maximise clinical relevance of the results, but analysis and interpretation of the results is challenging. We expect that the results of this trial are of importance for all rheumatologists who treat elderly patients with RA.TRIAL REGISTRATION: ClinicalTrials.gov, NCT02585258 . Registered on 20 October 2015.",
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author = "Linda Hartman and Rasch, {Linda A} and Thomas Klausch and Bijlsma, {Hans W J} and Robin Christensen and Smulders, {Yvo M} and Ralston, {Stuart H} and Frank Buttgereit and Maurizio Cutolo and {Da Silva}, {Jose A P} and Daniela Opris and Jozef Rovensk{\'y} and Szilvia Szamosi and Middelink, {Leonie M} and Lems, {Willem F} and Maarten Boers",
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doi = "10.1186/s13063-017-2396-3",
language = "English",
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Hartman, L, Rasch, LA, Klausch, T, Bijlsma, HWJ, Christensen, R, Smulders, YM, Ralston, SH, Buttgereit, F, Cutolo, M, Da Silva, JAP, Opris, D, Rovenský, J, Szamosi, S, Middelink, LM, Lems, WF & Boers, M 2018, '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, vol. 19, 67. https://doi.org/10.1186/s13063-017-2396-3

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. / Hartman, Linda; Rasch, Linda A; Klausch, Thomas; Bijlsma, Hans W J; Christensen, Robin; Smulders, Yvo M; Ralston, Stuart H; Buttgereit, Frank; Cutolo, Maurizio; Da Silva, Jose A P; Opris, Daniela; Rovenský, Jozef; Szamosi, Szilvia; Middelink, Leonie M; Lems, Willem F; Boers, Maarten.

In: Trials, Vol. 19, 67, 25.01.2018.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Harm, benefit and costs associated with low-dose glucocorticoids added to the treatment strategies for rheumatoid arthritis in elderly patients (GLORIA trial)

T2 - study protocol for a randomised controlled trial

AU - Hartman, Linda

AU - Rasch, Linda A

AU - Klausch, Thomas

AU - Bijlsma, Hans W J

AU - Christensen, Robin

AU - Smulders, Yvo M

AU - Ralston, Stuart H

AU - Buttgereit, Frank

AU - Cutolo, Maurizio

AU - Da Silva, Jose A P

AU - Opris, Daniela

AU - Rovenský, Jozef

AU - Szamosi, Szilvia

AU - Middelink, Leonie M

AU - Lems, Willem F

AU - Boers, Maarten

PY - 2018/1/25

Y1 - 2018/1/25

N2 - BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints affecting 1% of the world population. It has major impact on patients through disability and associated comorbidities. Current treatment strategies have considerably improved the prognosis, but recent innovations (especially biologic drugs and the new class of so-called "JAK/STAT inhibitors") have important safety issues and are very costly. Glucocorticoids (GCs) are highly effective in RA, and could reduce the need for expensive treatment with biologic agents. However, despite more than 65 years of clinical experience, there is a lack of studies large enough to adequately document the benefit/harm balance. The result is inappropriate treatment strategies, i.e. both under-use and over-use of GCs, and consequently suboptimal treatment of RA.METHODS: The GLORIA study is a pragmatic multicentre, 2-year, randomised, double-blind, clinical trial to assess the safety and effectiveness of a daily dose of 5 mg prednisolone or matching placebo added to standard of care in elderly patients with RA. Eligible participants are diagnosed with RA, have inadequate disease control (disease activity score, DAS28 ≥ 2.6), and are ≥ 65 years. The primary outcome measures are the time-averaged mean value of the DAS28 and the occurrence of serious adverse events or adverse events of special interest. During the trial, change in antirheumatic therapy is permitted as clinically indicated, except for GCs. Cost-effectiveness and cost-utility are secondary outcomes. The main challenge is the interpretation of the trial result with two primary endpoints and the pragmatic trial design that allows co-interventions. Another challenge is the definition of safety and the relative lack of power to detect differences between treatment groups. We have chosen to define safety as the number of patients experiencing at least one serious adverse event. We also specify a decision tree to guide our conclusion on the balance of benefit and harm, and our methodology to combat potential confounding caused by co-interventions.DISCUSSION: Pragmatic trials minimise impact on daily practice and maximise clinical relevance of the results, but analysis and interpretation of the results is challenging. We expect that the results of this trial are of importance for all rheumatologists who treat elderly patients with RA.TRIAL REGISTRATION: ClinicalTrials.gov, NCT02585258 . Registered on 20 October 2015.

AB - BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints affecting 1% of the world population. It has major impact on patients through disability and associated comorbidities. Current treatment strategies have considerably improved the prognosis, but recent innovations (especially biologic drugs and the new class of so-called "JAK/STAT inhibitors") have important safety issues and are very costly. Glucocorticoids (GCs) are highly effective in RA, and could reduce the need for expensive treatment with biologic agents. However, despite more than 65 years of clinical experience, there is a lack of studies large enough to adequately document the benefit/harm balance. The result is inappropriate treatment strategies, i.e. both under-use and over-use of GCs, and consequently suboptimal treatment of RA.METHODS: The GLORIA study is a pragmatic multicentre, 2-year, randomised, double-blind, clinical trial to assess the safety and effectiveness of a daily dose of 5 mg prednisolone or matching placebo added to standard of care in elderly patients with RA. Eligible participants are diagnosed with RA, have inadequate disease control (disease activity score, DAS28 ≥ 2.6), and are ≥ 65 years. The primary outcome measures are the time-averaged mean value of the DAS28 and the occurrence of serious adverse events or adverse events of special interest. During the trial, change in antirheumatic therapy is permitted as clinically indicated, except for GCs. Cost-effectiveness and cost-utility are secondary outcomes. The main challenge is the interpretation of the trial result with two primary endpoints and the pragmatic trial design that allows co-interventions. Another challenge is the definition of safety and the relative lack of power to detect differences between treatment groups. We have chosen to define safety as the number of patients experiencing at least one serious adverse event. We also specify a decision tree to guide our conclusion on the balance of benefit and harm, and our methodology to combat potential confounding caused by co-interventions.DISCUSSION: Pragmatic trials minimise impact on daily practice and maximise clinical relevance of the results, but analysis and interpretation of the results is challenging. We expect that the results of this trial are of importance for all rheumatologists who treat elderly patients with RA.TRIAL REGISTRATION: ClinicalTrials.gov, NCT02585258 . Registered on 20 October 2015.

KW - Age Factors

KW - Aged

KW - Antirheumatic Agents/administration & dosage

KW - Arthritis, Rheumatoid/diagnosis

KW - Clinical Trials, Phase IV as Topic

KW - Cost-Benefit Analysis

KW - Double-Blind Method

KW - Drug Costs

KW - Drug Therapy, Combination

KW - Europe

KW - Female

KW - Glucocorticoids/administration & dosage

KW - Humans

KW - Male

KW - Medication Adherence

KW - Multicenter Studies as Topic

KW - Pragmatic Clinical Trials as Topic

KW - Prednisolone/administration & dosage

KW - Risk Factors

KW - Time Factors

KW - Treatment Outcome

KW - Glucocorticoids

KW - Benefit

KW - Safety

KW - Prednisolone

KW - Harm

KW - Rheumatoid arthritis

KW - Cost-effectiveness

KW - Elderly

U2 - 10.1186/s13063-017-2396-3

DO - 10.1186/s13063-017-2396-3

M3 - Journal article

C2 - 29370811

VL - 19

JO - Trials

JF - Trials

SN - 1745-6215

M1 - 67

ER -