Periodic Reporting for period 5 - GLORIA (Comparing the effectiveness and safety of additional low-dose glucocorticoid in treatment strategies for elderly patients with rheumatoid arthritis)
Periodo di rendicontazione: 2020-09-01 al 2021-08-31
GLORIA aims to prove that the add-on, low dose prednisolone to current antirheumatic therapy is cost-effective and safe in elderly patients with rheumatoid arthritis (RA). The main component of GLORIA is a large pragmatic trial: 450 elderly (>65y) RA patients receiving standard of care will be randomized to additionally receive 5 mg prednisolone daily or placebo for 2 years. A novel tool will monitor compliance; it can send personalized reminders to a patient’s smart device. The efficacy of this technology will be tested in a nested trial. Compliance and other characteristics will be entered into a model that may allow personalized risk and benefit assessment in the future. Qualitative research in patients and physicians of member states will explore expectations and challenges in guideline implementation. This information and the study results will enable an update to existing guidelines and patient information, in collaboration with guideline committees and regulatory agencies. Networking conferences will improve health technology assessment in the elderly in general.
In the final year of the project data collection was successful despite considerable challenges due to the covid crisis. Data cleaning and analysis was performed in record time (3 months for the primary analyses) and followed by scientific and technical reporting. Results were discussed in an interactive meeting with partners, principal investigators and outside stakeholders. All milestones were reached, and deliverables met.
Overview of results
Trial
451 patients with established, impactful RA were randomized: mean age 72 years, mean 2.1 comorbidities; 62% completed the trial. Most discontinuations were for reasons unrelated to study treatment, including the covid crisis; mean time in study 19 months.
Prednisolone resulted in substantial long-term effects on disease activity and damage progression in established RA, with a tradeoff of 24% increase in patients with mostly non-severe adverse events. Secondary analyses suggest a larger contrast in the early phase, and a decrease in contrast after 1 year, most likely caused by changes in antirheumatic treatment favoring placebo.
Interpretation
Add-on low dose prednisolone has a favorable balance of benefit and harm in routine clinical care of elderly RA patients.
Cost-effectiveness analysis
Total costs (including direct medical costs, (un)paid help, absenteeism) after two years were similar: both groups about €9000.
QALYs were slightly (but non-significantly) lower in the prednisolone group.
Interpretation
Add-on low dose prednisolone is cost-effective in the treatment of elderly RA patients.
Adherence
Adherence data was collected by capsule counts and by smartcap technology that recorded the opening of the study medication bottle. Based on capsule counts 90% of the patients had good adherence; based on cap data, only 20%. Cap data classified 30% of patients as non-user and 40% as irregular user.
Interpretation
The majority of trial patients was adherent. Results from caps conflicted with those of pill counts, with patterns suggesting patients did not use the bottle for daily dispensing, despite specific advice to do so.
Adherence substudy
In the substudy an advanced cap was tested that communicates with a smart device via Bluetooth. Patients with a smart device were randomized to receive or not to receive adherence reminders on their device for three months. Multiple problems emerged that precluded an answer to the research question: sample size (overly optimistic estimates of older patients with a smart device), logistic issues (availability of smartcaps, data extraction), randomization and treatment allocation errors (despite training of personnel), and low quality of the data in the intervention group (hardware failure, discovered too late because data was read in batches).
Interpretation
For future trials testing new technology we recommend keeping it simple, starting with a field test before the actual study starts, and monitoring performance from the beginning of the study.
Prediction model
A total of 8 models were examined: the first set of 4 models disregarded treatment allocation, the second set included treatment allocation. For each set of 4 models, there were 2 for harm (adverse event of special interest: occurrence of at least one event; and total number); and 2 for benefit (early response of disease activity; lack of joint damage progression). Among total of 37 possible predictors, including treatment adherence., several were found to be predictive in each model. Model explained variance (R-square) ranged between 0.06 and 0.16.
Interpretation
Overall, only treatment (the study intervention) strongly predicts benefit and harm. There are no factors at baseline to suggest the possibility of personalized treatment.
Guidelines and regulatory guidance
A systematic review concluded that current recommendations for use of glucocorticoid (GC) in the management of RA are suboptimal, more rigorous evaluation of dosages, timing and duration of their use is needed, and existing nomenclature on glucocorticoid therapy should be used uniformly.
Updating recommendations for safer use of GC (especially in the elderly)
Ongoing, see exploitation and dissemination
Current status and points to consider for trials in the elderly
Systematic reviews concluded that elderly are under-represented in rheumatology trials, their retention is similar to younger patients; however, the generalizability of GC trials in rheumatology is good.
Another review explored the reported barriers and solutions concerning recruitment and retention of elderly patients in trials, straddled by two networking meetings and a survey among beneficiaries of the H2020 call that conducted trials in the elderly.
The resulting points to consider are fully published.
Education
A website is active since 2016, scientific publications supported the awareness of the GLOIRA trial, and a large survey on perceptions of benefit and harm was conducted among patients and health professionals.
The survey demonstrated that most participants supported efficacy but overestimated harm.
Overview of results
Trial
451 patients with established, impactful RA were randomized: mean age 72 years, mean 2.1 comorbidities; 62% completed the trial. Most discontinuations were for reasons unrelated to study treatment, including the covid crisis; mean time in study 19 months.
Prednisolone resulted in substantial long-term effects on disease activity and damage progression in established RA, with a tradeoff of 24% increase in patients with mostly non-severe adverse events. Secondary analyses suggest a larger contrast in the early phase, and a decrease in contrast after 1 year, most likely caused by changes in antirheumatic treatment favoring placebo.
Interpretation
Add-on low dose prednisolone has a favorable balance of benefit and harm in routine clinical care of elderly RA patients.
Cost-effectiveness analysis
Total costs (including direct medical costs, (un)paid help, absenteeism) after two years were similar: both groups about €9000.
QALYs were slightly (but non-significantly) lower in the prednisolone group.
Interpretation
Add-on low dose prednisolone is cost-effective in the treatment of elderly RA patients.
Adherence
Adherence data was collected by capsule counts and by smartcap technology that recorded the opening of the study medication bottle. Based on capsule counts 90% of the patients had good adherence; based on cap data, only 20%. Cap data classified 30% of patients as non-user and 40% as irregular user.
Interpretation
The majority of trial patients was adherent. Results from caps conflicted with those of pill counts, with patterns suggesting patients did not use the bottle for daily dispensing, despite specific advice to do so.
Adherence substudy
In the substudy an advanced cap was tested that communicates with a smart device via Bluetooth. Patients with a smart device were randomized to receive or not to receive adherence reminders on their device for three months. Multiple problems emerged that precluded an answer to the research question: sample size (overly optimistic estimates of older patients with a smart device), logistic issues (availability of smartcaps, data extraction), randomization and treatment allocation errors (despite training of personnel), and low quality of the data in the intervention group (hardware failure, discovered too late because data was read in batches).
Interpretation
For future trials testing new technology we recommend keeping it simple, starting with a field test before the actual study starts, and monitoring performance from the beginning of the study.
Prediction model
A total of 8 models were examined: the first set of 4 models disregarded treatment allocation, the second set included treatment allocation. For each set of 4 models, there were 2 for harm (adverse event of special interest: occurrence of at least one event; and total number); and 2 for benefit (early response of disease activity; lack of joint damage progression). Among total of 37 possible predictors, including treatment adherence., several were found to be predictive in each model. Model explained variance (R-square) ranged between 0.06 and 0.16.
Interpretation
Overall, only treatment (the study intervention) strongly predicts benefit and harm. There are no factors at baseline to suggest the possibility of personalized treatment.
Guidelines and regulatory guidance
A systematic review concluded that current recommendations for use of glucocorticoid (GC) in the management of RA are suboptimal, more rigorous evaluation of dosages, timing and duration of their use is needed, and existing nomenclature on glucocorticoid therapy should be used uniformly.
Updating recommendations for safer use of GC (especially in the elderly)
Ongoing, see exploitation and dissemination
Current status and points to consider for trials in the elderly
Systematic reviews concluded that elderly are under-represented in rheumatology trials, their retention is similar to younger patients; however, the generalizability of GC trials in rheumatology is good.
Another review explored the reported barriers and solutions concerning recruitment and retention of elderly patients in trials, straddled by two networking meetings and a survey among beneficiaries of the H2020 call that conducted trials in the elderly.
The resulting points to consider are fully published.
Education
A website is active since 2016, scientific publications supported the awareness of the GLOIRA trial, and a large survey on perceptions of benefit and harm was conducted among patients and health professionals.
The survey demonstrated that most participants supported efficacy but overestimated harm.
Exploitation and dissemination
The results of the trial will be presented at the American Rheumatology Annual meeting in November, and submitted to the European meeting in 2022. The main manuscript has been submitted to a peer reviewed journal and is currently under review. The reports of the cost-effectiveness analysis and the prediction model have been completed and will be submitted in the coming months. Linda Hartman will defend her PhD thesis on the GLORIA project in 2022.
The adherence studies are published. The partner BeyondDevices will profit from the lessons learned in their next implementation of the adherence cap and associated technology. The results of guidelines, trials in the elderly, and education surveys have all been published. Updating recommendations for safer use, and correcting misperceptions on harm will await the publication of the main trial results, and will be actively pursued in the coming two years.
Outside of the project, several satellite studies are currently completing, and will result in publications in 2022.
11 publications are listed in the portal. Several abstracts were presented at international meetings.
The results of the trial will be presented at the American Rheumatology Annual meeting in November, and submitted to the European meeting in 2022. The main manuscript has been submitted to a peer reviewed journal and is currently under review. The reports of the cost-effectiveness analysis and the prediction model have been completed and will be submitted in the coming months. Linda Hartman will defend her PhD thesis on the GLORIA project in 2022.
The adherence studies are published. The partner BeyondDevices will profit from the lessons learned in their next implementation of the adherence cap and associated technology. The results of guidelines, trials in the elderly, and education surveys have all been published. Updating recommendations for safer use, and correcting misperceptions on harm will await the publication of the main trial results, and will be actively pursued in the coming two years.
Outside of the project, several satellite studies are currently completing, and will result in publications in 2022.
11 publications are listed in the portal. Several abstracts were presented at international meetings.