Author Of 2 Presentations
P0131 - Predicting long-term sustained disability progression in multiple sclerosis: application in the CLARITY trial (ID 1071)
Abstract
Background
Prevention of disability over the long-term is the main treatment goal in multiple sclerosis (MS), however, randomized clinical trials provide only short-term (3-6-month) treatment effect on disability.
Objectives
To externally validate the previously developed sustained progression score which established 6-month confirmed disability progression events as indicators of long-term disability worsening in randomized double-blind CLARITY (Cladribine Tablets Treating MS Orally) trials. A higher score indicates a greater probability of a progression event to be sustained over the long-term.
Methods
Data from the CLARITY and CLARITY 2-year Extension study were used. The 3-and 6-month confirmed disability progression events and the time over which progression remained sustained were identified. Patient characteristics at the time of progression previously associated with the likelihood of improvement after confirmed progression event (age, primary progressive MS, a relapse in previous month, expanded disability status scale score≥6 and its change from baseline, number of affected functional system domains, and worsening in pyramidal, brainstem and sensory domains) were used to calculate the sustained progression score for each progression event. A Cox proportional hazards model was used to validate the association of the score calculated for each 6-month confirmed disability progression event with time to improvement. To demonstrate application of the score in trial setting, the analysis of the CLARITY study were repeated estimating the effect of therapy on long-term disability outcomes. Effect of cladribine on 3-month confirmed progression events with any score and score˃1.5 was evaluated.
Results
A total of 667 6-month confirmed disability progression events were identified in the combined dataset, of which only 12 were followed by a 6-month confirmed disability improvement. The external validation of the score illustrated a trend towards a decrease in the likelihood of disability improvement in progression events with higher score (Hazard Ratio HR=0.72, 95% CI: 0.21-2.42). Results of the original trial were confirmed in addition to that oral cladribine reduced the risk of disability progression that was likely to be sustained over the long-term (only events with score˃1.5; HR: 0.64; 95% CI: 0.47-0.87).
Conclusions
The sustained progression score, estimated using the characteristics of confirmed progression events, provides important complementary information that will allow future trials to establish the effect of therapy not only on short-term but also on long-term disability accrual.
P0862 - Disability accrual in primary-progressive & secondary-progressive multiple sclerosis (ID 1232)
- S. Harding-Forrester
- I. Roos
- S. Sharmin
- I. Diouf
- C. Malpas
- A. Nguyen
- N. Moradi
- D. Horáková
- E. Kubala Havrdová
- F. Patti
- G. Izquierdo
- S. Eichau
- A. Prat
- M. Girard
- P. Duquette
- M. Onofrj
- A. Lugaresi
- F. Grand'Maison
- B. Weinstock-Guttman
- M. Amato
- P. Grammond
- O. Gerlach
- S. Ozakbas
- P. Sola
- D. Ferraro
- H. Butzkueven
- J. Lechner-Scott
- C. Boz
- R. Alroughani
- V. Van Pesch
- E. Cartechini
- M. Terzi
- D. Maimone
- C. Ramo-Tello
- D. Spitaleri
- L. Kappos
- B. Yamout
- M. Sá
- M. Slee
- Y. Blanco
- R. Bergamaschi
- E. Butler
- G. Iuliano
- F. Granella
- Y. Sidhom
- R. Gouider
- R. Ampapa
- B. Van Wijmeersch
- R. Karabudak
- J. Prevost
- J. Sánchez-Menoyo
- F. Verheul
- P. McCombe
- T. Castillo-Triviño
- R. Macdonell
- A. Altintas
- G. Laureys
- L. Van Hijfte
- A. Van Der Walt
- S. Vucic
- R. Turkoglu
- M. Barnett
- E. Cristiano
- M. Zakaria
- V. Shaygannejad
- S. Hodgkinson
- A. Soysal
- T. Kalincik
Abstract
Background
Some cohort studies have reported similar onset age and disability accrual in primary and secondary progressive MS (PPMS, SPMS); others have reported later onset and faster disability accrual in SPMS. Comparisons are complicated by differences in baseline disability and exposure to disease-modifying therapies (DMT), and by lack of a standardized definition of SPMS.
Objectives
We compared hazards of disability accrual in PPMS and SPMS patients from the MSBase cohort using multivariable Cox models, applying validated diagnostic criteria for SPMS (Lorscheider et al., Brain 2016).
Methods
Inclusion required adult-onset progressive MS; ≥ 3 recorded Expanded Disability Status Scale (EDSS) scores; and, for SPMS, initial records with EDSS ≤ 3 to allow objective identification of SPMS conversion. Phenotypes were subgrouped as active (PPMS-A, SPMS-A) if ≥ 1 progressive-phase relapse was recorded, and inactive (PPMS-N, SPMS-N) otherwise. Disability accrual was defined by sustained EDSS increases confirmed over ≥ 6 months. Hazard ratios (HR) for disability accrual were obtained using Andersen-Gill Cox models, adjusted for sex and time-varying age, disability, visit frequency, and proportion of time on DMT or immunosuppressive therapy. Sensitivity analyses were performed using (1) PPMS and SPMS diagnosed since 1995, and (2) physician-diagnosed SPMS. Cumulative probability of reaching EDSS ≥ 7 (wheelchair required) was assessed (Kaplan-Meier).
Results
5461 patients were included (1257 PPMS-N; 1308 PPMS-A; 1731 SPMS-N; 1165 SPMS-A). Age at progression onset was older in SPMS than PPMS (47.2 ± 10.2, vs. 41.5 ± 10.7 [mean ± SD]), and in the inactive subgroups of each phenotype. Hazard of disability accrual was decreased in SPMS relative to PPMS (HR 0.85; 95% CI 0.78–0.92); decreased by proportion of time on DMT (HR 0.99 per 10% increment; 0.98–0.99); and higher in males (1.18; 1.12–1.25). Relative to PPMS-N, hazard was decreased in SPMS-A (0.79; 0.71–0.87) but similar for PPMS-A (1.01; 0.93–1.10) and SPMS-N (0.94; 0.85–1.05). Sensitivity analyses corroborated these results. However, patients with SPMS-A reached EDSS ≥ 7 at younger ages (cumulative probability 30% by 57, vs. 64–66 for SPMS-N, PPMS-A, PPMS-N).
Conclusions
Progressive phase onset is later in SPMS than PPMS. Hazard of disability accrual during the progressive phase is lower in SPMS than PPMS. However, patients with SPMS-A reach wheelchair requirement younger than other progressive phenotypes, reflecting earlier progression onset versus SPMS-N, and greater disability at onset versus PPMS
Presenter Of 1 Presentation
P0131 - Predicting long-term sustained disability progression in multiple sclerosis: application in the CLARITY trial (ID 1071)
Abstract
Background
Prevention of disability over the long-term is the main treatment goal in multiple sclerosis (MS), however, randomized clinical trials provide only short-term (3-6-month) treatment effect on disability.
Objectives
To externally validate the previously developed sustained progression score which established 6-month confirmed disability progression events as indicators of long-term disability worsening in randomized double-blind CLARITY (Cladribine Tablets Treating MS Orally) trials. A higher score indicates a greater probability of a progression event to be sustained over the long-term.
Methods
Data from the CLARITY and CLARITY 2-year Extension study were used. The 3-and 6-month confirmed disability progression events and the time over which progression remained sustained were identified. Patient characteristics at the time of progression previously associated with the likelihood of improvement after confirmed progression event (age, primary progressive MS, a relapse in previous month, expanded disability status scale score≥6 and its change from baseline, number of affected functional system domains, and worsening in pyramidal, brainstem and sensory domains) were used to calculate the sustained progression score for each progression event. A Cox proportional hazards model was used to validate the association of the score calculated for each 6-month confirmed disability progression event with time to improvement. To demonstrate application of the score in trial setting, the analysis of the CLARITY study were repeated estimating the effect of therapy on long-term disability outcomes. Effect of cladribine on 3-month confirmed progression events with any score and score˃1.5 was evaluated.
Results
A total of 667 6-month confirmed disability progression events were identified in the combined dataset, of which only 12 were followed by a 6-month confirmed disability improvement. The external validation of the score illustrated a trend towards a decrease in the likelihood of disability improvement in progression events with higher score (Hazard Ratio HR=0.72, 95% CI: 0.21-2.42). Results of the original trial were confirmed in addition to that oral cladribine reduced the risk of disability progression that was likely to be sustained over the long-term (only events with score˃1.5; HR: 0.64; 95% CI: 0.47-0.87).
Conclusions
The sustained progression score, estimated using the characteristics of confirmed progression events, provides important complementary information that will allow future trials to establish the effect of therapy not only on short-term but also on long-term disability accrual.