Contributions
Abstract: 215
Type: Oral
Abstract Category: Therapy - disease modifying - Treatment of progressive MS
Background: Most of the clinical trials testing drugs effective in RRMS, have been negative when tested in progressive patients. The hypothesis that there may be a therapeutic lag of anti-inflammatory therapies in progressive MS has been formulated but never directly tested.
Objectives: To test the hypothesis that in people with MS who have substantial disability it may take several years for disease modifying therapies (DMT) to stabilise their disease progression, by re-analysing individual patient data of progressive MS clinical trials, assuming a delayed treatment effect.
Methods: .A post-hoc analysis was run on data of 2 clinical trials in progressive MS: the 6-year extension of the SPECTRIMS trial, including 618 SPMS patients randomized 1:1:1 to placebo and 2 doses of subcutaneous (sc) Interferon (IFN)beta-1a (pooled together in the analysis); and the PROMISE study, randomizing 943 PPMS patients 2:1 to GA or placebo, with a 3 year-follow up. A Cox model with a time-dependent treatment effect was applied to check a delayed effect on the risk of 3-months confirmed disability progression. The time-dependent treatment was defined by a variable set to 0 for treatment arms, becoming 1 after a delayed time, chosen by a stepwise procedure.
Results: The HR for the effect of scIFNbeta-1a vs placebo in SPMS patients was 0.88, p=0.18 and the HR of GA vs placebo in PPMS patients was 0.87, p=0.18. A stepwise selection run independently on the 2 trials indicated 2.5 years as the best cut-off to identify the start of the treatment effect in the SPECTRIMS trial and 2 years in the PROMISE trial. The HR (for a treatment starting its effect after 2.5 years) was 0.65, p=0.041 in the SPECTRIMS trial and (for a treatment starting its effect after 2 years) was 0.65, p=0.044 in the PROMISE trial. In the pooled cohort the delay of the treatment effect increased with baseline EDSS. These observations are supported by the visual inspection of the survival curves.
Conclusions: This post-hoc analysis run independently on data from two clinical trials testing the effect of two different drugs (IFN and GA) in two population of progressive MS patients (SP and PP) indicates that the effect of both drugs become evident after 2-2.5 years from treatment start. These observations support the hypothesis that in progressive MS it may take several years for DMTs to manifest their effect on disease progression and warrant further confirmation on independent long term clinical data.
Disclosure:
MP Sormani has received personal compensation for consulting services and for speaking activities from Genzyme, Merck Serono, Teva, Vertex, Roche, Novartis and Biogen
G Giovannoni is a steering committee member for AbbVie´s daclizumab trials, Biogen-Idec´s BG12 and daclizumab trials, Novartis" fingolimod and siponimoid trials, Teva´s laquinimod trials and Roche´s ocrelizumab trials. He has received consultancy fees from Biogen-Idec, Merck-Serono, Novartis and Genzyme-Sanofi advisory board meetings, GSK´s Phase 3 MS trial programme and Synthon BV DSMB activities. He has received honoraria for speaking at Genzyme-Sanofi and Biogen-Idec meetings.
Abstract: 215
Type: Oral
Abstract Category: Therapy - disease modifying - Treatment of progressive MS
Background: Most of the clinical trials testing drugs effective in RRMS, have been negative when tested in progressive patients. The hypothesis that there may be a therapeutic lag of anti-inflammatory therapies in progressive MS has been formulated but never directly tested.
Objectives: To test the hypothesis that in people with MS who have substantial disability it may take several years for disease modifying therapies (DMT) to stabilise their disease progression, by re-analysing individual patient data of progressive MS clinical trials, assuming a delayed treatment effect.
Methods: .A post-hoc analysis was run on data of 2 clinical trials in progressive MS: the 6-year extension of the SPECTRIMS trial, including 618 SPMS patients randomized 1:1:1 to placebo and 2 doses of subcutaneous (sc) Interferon (IFN)beta-1a (pooled together in the analysis); and the PROMISE study, randomizing 943 PPMS patients 2:1 to GA or placebo, with a 3 year-follow up. A Cox model with a time-dependent treatment effect was applied to check a delayed effect on the risk of 3-months confirmed disability progression. The time-dependent treatment was defined by a variable set to 0 for treatment arms, becoming 1 after a delayed time, chosen by a stepwise procedure.
Results: The HR for the effect of scIFNbeta-1a vs placebo in SPMS patients was 0.88, p=0.18 and the HR of GA vs placebo in PPMS patients was 0.87, p=0.18. A stepwise selection run independently on the 2 trials indicated 2.5 years as the best cut-off to identify the start of the treatment effect in the SPECTRIMS trial and 2 years in the PROMISE trial. The HR (for a treatment starting its effect after 2.5 years) was 0.65, p=0.041 in the SPECTRIMS trial and (for a treatment starting its effect after 2 years) was 0.65, p=0.044 in the PROMISE trial. In the pooled cohort the delay of the treatment effect increased with baseline EDSS. These observations are supported by the visual inspection of the survival curves.
Conclusions: This post-hoc analysis run independently on data from two clinical trials testing the effect of two different drugs (IFN and GA) in two population of progressive MS patients (SP and PP) indicates that the effect of both drugs become evident after 2-2.5 years from treatment start. These observations support the hypothesis that in progressive MS it may take several years for DMTs to manifest their effect on disease progression and warrant further confirmation on independent long term clinical data.
Disclosure:
MP Sormani has received personal compensation for consulting services and for speaking activities from Genzyme, Merck Serono, Teva, Vertex, Roche, Novartis and Biogen
G Giovannoni is a steering committee member for AbbVie´s daclizumab trials, Biogen-Idec´s BG12 and daclizumab trials, Novartis" fingolimod and siponimoid trials, Teva´s laquinimod trials and Roche´s ocrelizumab trials. He has received consultancy fees from Biogen-Idec, Merck-Serono, Novartis and Genzyme-Sanofi advisory board meetings, GSK´s Phase 3 MS trial programme and Synthon BV DSMB activities. He has received honoraria for speaking at Genzyme-Sanofi and Biogen-Idec meetings.