Contributions
Abstract: P772
Type: Poster
Abstract Category: Therapy - disease modifying - 30 Tools for detecting therapeutic response
Background: Baseline (BL) magnetic resonance imaging (MRI) activity predicts subsequent brain volume loss (BVL), while normalised brain volume (NBV) at BL and BVL over time predict future disability in studies with patients with relapsing−remitting multiple sclerosis (RRMS). However, the predictive value for clinical outcomes of NBV categories, in the absence of MRI lesion activity and clinical symptoms, remains to be explored.
Objective: To study long-term (up to 8 years) MS outcomes of patients with low vs high NBV at BL and no disease activity during the first 24 months (M).
Methods: The Normative Brain Volumes: application in Multiple Sclerosis (NoViMS) dataset of 600 healthy subjects was used to generate an age-based NBV percentile chart. The BL NBV of patients with RRMS from the FREEDOMS and FREEDOMS II trials of fingolimod were plotted against this normative dataset and a quantile regression analysis was performed. Patients were categorised into four subgroups based on percentiles: ≤P10 (N=540), >P10 to ≤P25 (N=556), >P25 to ≤P50 (N=605), and >P50 (N=631). At M24, patients on placebo were switched to fingolimod and treatment effects by NBV percentiles were assessed. Outcomes of patients with no disease activity, defined as no relapse, no disability progression and no gadolinium-enhancing T1 lesions at M24, were assessed at M96 for each NBV category.
Results: At BL, patients in lower percentiles had higher MS disease burden (p< 0.0001 for most measures). Low BL NBV correlated with increased T2 lesion volume (T2LV) and annualised rate of brain volume loss (ARBVL) at 2 years (p≤0.0001 for both). Compared with placebo, fingolimod treatment improved outcomes in all NBV percentiles at 2 years. At 8 years, patients with no disease activity at M24 had consistently worse outcomes if they had low vs high NBV at BL: change in Expanded Disability Status Scale score (0.5 vs −0.2), 6M-confirmed disability progression (CDP) (27 [32.1%] vs 17 [13.8%]), change in T2LV (1565.8 vs 450.4 mm3) and ARBVL (−0.28% vs −0.22%). Overall, risk of 6M-CDP at 8 years was higher in patients with low NBV compared with high NBV at BL (hazard ratio [95% CI]: 1.64 [1.30; 2.07]: p< 0.0001).
Conclusions: Despite the initial absence of clinical and radiological disease activity, patients with low brain volume at baseline were at a higher risk of future disease progression. NoViMS, a healthy subject brain volume normative dataset, is a useful tool to identify such at-risk patients based on their NBV.
Disclosure:
Funding source: This study was funded by Novartis Pharma AG.
Michael H Barnett has received institutional support for research, speaking and/or participation in advisory boards for Biogen, Merck, Novartis, Roche and Sanofi Genzyme. Dr Barnett is a research consultant at Medical Safety Systems and research director for the Sydney Neuroimaging Analysis Centre.
Chenyu Wang declared no conflict of interest.
Nicola De Stefano has received personal compensation for activities with Schering, Biogen, Teva, Novartis, Genzyme and Merck Serono S.A. as a consultant and/or speaker.
Marco Battaglini declared no conflict of interest.
Maria Pia Sormani received consulting fees from Biogen Idec, Merck Serono, Teva, Genzyme, Roche and Novartis.
Rolf Meinert is an employee of DATAMAP GmbH, Freiburg, Germany, which provides services to Novartis Pharma AG.
Douglas Arnold has received personal compensation for activities with, Biogen, Celgene, Genentech, Genzyme, Medday, NeuroRx Research, Novartis, Roche, and Sanofi.
Diego Silva and Davorka Tomic are employees of Novartis.
Abstract: P772
Type: Poster
Abstract Category: Therapy - disease modifying - 30 Tools for detecting therapeutic response
Background: Baseline (BL) magnetic resonance imaging (MRI) activity predicts subsequent brain volume loss (BVL), while normalised brain volume (NBV) at BL and BVL over time predict future disability in studies with patients with relapsing−remitting multiple sclerosis (RRMS). However, the predictive value for clinical outcomes of NBV categories, in the absence of MRI lesion activity and clinical symptoms, remains to be explored.
Objective: To study long-term (up to 8 years) MS outcomes of patients with low vs high NBV at BL and no disease activity during the first 24 months (M).
Methods: The Normative Brain Volumes: application in Multiple Sclerosis (NoViMS) dataset of 600 healthy subjects was used to generate an age-based NBV percentile chart. The BL NBV of patients with RRMS from the FREEDOMS and FREEDOMS II trials of fingolimod were plotted against this normative dataset and a quantile regression analysis was performed. Patients were categorised into four subgroups based on percentiles: ≤P10 (N=540), >P10 to ≤P25 (N=556), >P25 to ≤P50 (N=605), and >P50 (N=631). At M24, patients on placebo were switched to fingolimod and treatment effects by NBV percentiles were assessed. Outcomes of patients with no disease activity, defined as no relapse, no disability progression and no gadolinium-enhancing T1 lesions at M24, were assessed at M96 for each NBV category.
Results: At BL, patients in lower percentiles had higher MS disease burden (p< 0.0001 for most measures). Low BL NBV correlated with increased T2 lesion volume (T2LV) and annualised rate of brain volume loss (ARBVL) at 2 years (p≤0.0001 for both). Compared with placebo, fingolimod treatment improved outcomes in all NBV percentiles at 2 years. At 8 years, patients with no disease activity at M24 had consistently worse outcomes if they had low vs high NBV at BL: change in Expanded Disability Status Scale score (0.5 vs −0.2), 6M-confirmed disability progression (CDP) (27 [32.1%] vs 17 [13.8%]), change in T2LV (1565.8 vs 450.4 mm3) and ARBVL (−0.28% vs −0.22%). Overall, risk of 6M-CDP at 8 years was higher in patients with low NBV compared with high NBV at BL (hazard ratio [95% CI]: 1.64 [1.30; 2.07]: p< 0.0001).
Conclusions: Despite the initial absence of clinical and radiological disease activity, patients with low brain volume at baseline were at a higher risk of future disease progression. NoViMS, a healthy subject brain volume normative dataset, is a useful tool to identify such at-risk patients based on their NBV.
Disclosure:
Funding source: This study was funded by Novartis Pharma AG.
Michael H Barnett has received institutional support for research, speaking and/or participation in advisory boards for Biogen, Merck, Novartis, Roche and Sanofi Genzyme. Dr Barnett is a research consultant at Medical Safety Systems and research director for the Sydney Neuroimaging Analysis Centre.
Chenyu Wang declared no conflict of interest.
Nicola De Stefano has received personal compensation for activities with Schering, Biogen, Teva, Novartis, Genzyme and Merck Serono S.A. as a consultant and/or speaker.
Marco Battaglini declared no conflict of interest.
Maria Pia Sormani received consulting fees from Biogen Idec, Merck Serono, Teva, Genzyme, Roche and Novartis.
Rolf Meinert is an employee of DATAMAP GmbH, Freiburg, Germany, which provides services to Novartis Pharma AG.
Douglas Arnold has received personal compensation for activities with, Biogen, Celgene, Genentech, Genzyme, Medday, NeuroRx Research, Novartis, Roche, and Sanofi.
Diego Silva and Davorka Tomic are employees of Novartis.