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Vollmer T.L.,Aurora University | Sorensen P.S.,Copenhagen University | Sorensen P.S.,Rigshospitalet | Selmaj K.,Medical University of Lódz | And 7 more authors.
Journal of Neurology | Year: 2014

The phase III placebo-controlled BRAVO study assessed laquinimod effects in patients with relapsing-remitting MS (RRMS), and descriptively compared laquinimod with interferon beta (IFNβ)-1a (Avonex® reference arm). RRMS patients age 18-55 years with Expanded Disability Status Scale (EDSS) scores of 0-5.5 and documented pre-study relapse (≥ 1 in previous year, 2 in previous 2 years, or 1 in previous 1-2 years and≥ 1 GdE lesion in the previous year) were randomized (1:1:1) to laquinimod 0.6 mg once-daily, matching oral placebo, or IFNβ-1a IM 30 μg once-weekly (rater-blinded design), for 24 months. The primary endpoint was annualized relapse rate (ARR); secondary endpoints included percent brain volume change (PBVC) and 3-month confirmed disability worsening. In all, 1,331 patients were randomized: laquinimod (n = 434), placebo (n = 450), and IFNβ-1a (n = 447). ARR was not significantly reduced with laquinimod [-18 %, risk ratio (RR) = 0.82, 95 % CI 0.66-1.02; p = 0.075] vs. placebo. Laquinimod significantly reduced PBVC (28 %, p < 0.001). Confirmed disability worsening was infrequent (10 % laquinimod, 13 % placebo). The change in confirmed disability worsening with laquinimod measured using EDSS was -31 % [hazard ratio (HR) 0.69, p = 0.063], and using Multiple Sclerosis Functional Composite (MSFC) z-score was -77 % (p = 0.150), vs. placebo. IFNβ-1a reduced ARR 26 % (RR = 0.74, 95 % CI 0.60-0.92, p = 0.007), showed no effect on PBVC loss (+11 %, p = 0.14), and changes in disability worsening were -26 and -66 % as measured using the EDSS (HR 0.742, p = 0.13) and MSFC (p = 0.208), respectively. Adverse events occurred in 75, 82, and 70 % of laquinimod, IFNβ-1a, and placebo patients, respectively. Once-daily oral laquinimod 0.6 mg resulted in statistically nonsignificant reductions in ARR and disability progression, but significant reductions in brain atrophy vs. placebo. Laquinimod was well-tolerated. © 2014 Springer-Verlag Berlin Heidelberg.


Calabresi P.A.,Johns Hopkins University | Kieseier B.C.,Heinrich Heine University Düsseldorf | Arnold D.L.,Montreal Neurological Institute | Arnold D.L.,NeuroRx Research | And 8 more authors.
The Lancet Neurology | Year: 2014

Background: Subcutaneous pegylated interferon (peginterferon) beta-1a is being developed for treatment of relapsing multiple sclerosis, with less frequent dosing than currently available first-line injectable treatments. We assessed the safety and efficacy of peginterferon beta-1a after 48 weeks of treatment in the placebo-controlled phase of the ADVANCE trial, a study of patients with relapsing-remitting multiple sclerosis. Methods: We did this 2-year, double-blind, parallel group, phase 3 study, with a placebo-controlled design for the first 48 weeks, at 183 sites in 26 countries. Patients with relapsing-remitting multiple sclerosis (age 18-65 years, with Expanded Disability Status Scale score ≤5) were randomly assigned (1:1:1) via an interactive voice response or web system, and stratified by site, to placebo or subcutaneous peginterferon beta-1a 125 μg once every 2 weeks or every 4 weeks. The primary endpoint was annualised relapse rate at 48 weeks. This trial is registered with ClinicalTrials.gov, number NCT00906399. Findings: We screened 1936 patients and enrolled 1516, of whom 1512 were randomly assigned (500 to placebo, 512 to peginterferon every 2 weeks, 500 to peginterferon every 4 weeks); 1332 (88%) patients completed 48 weeks of treatment. Adjusted annualised relapse rates were 0·397 (95% CI 0·328-0·481) in the placebo group versus 0·256 (0·206-0·318) in the every 2 weeks group and 0·288 (0·234-0·355) in the every 4 weeks group (rate ratio for every 2 weeks group 0·644, 95% CI 0·500-0·831, p=0·0007; rate ratio for the every 4 weeks group 0·725, 95% CI 0·565-0·930, p=0·0114). 417 (83%) patients taking placebo, 481 (94%) patients taking peginterferon every 2 weeks, and 472 (94%) patients taking peginterferon every 4 weeks reported adverse events including relapses. The most common adverse events associated with peginterferon beta-1a were injection site reactions, influenza-like symptoms, pyrexia, and headache. 76 (15%) patients taking placebo, 55 (11%) patients taking study drug every 2 weeks, and 71 (14%) patients taking study drug every 4 weeks reported serious adverse events; relapse, pneumonia, and urinary tract infection were the most common. Interpretation: After 48 weeks, peginterferon beta-1a significantly reduced relapse rate compared with placebo. The drug might be an effective treatment for relapsing-remitting multiple sclerosis with less frequent administration than available treatments. Funding: Biogen Idec. © 2014 Elsevier Ltd.


Bar-Or A.,Montreal Neurological Institute | Gold R.,Ruhr University Bochum | Kappos L.,University of Basel | Arnold D.L.,Montreal Neurological Institute | And 6 more authors.
Journal of Neurology | Year: 2013

In the double-blind, placebo-controlled, Phase 3 DEFINE study in patients with relapsing-remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) significantly reduced the proportion of patients relapsed (primary endpoint), the annualized relapse rate (ARR), and confirmed disability progression (secondary endpoints) at two years compared with placebo. We investigated the efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, expanded disability status scale score, T2 lesion volume, and gadolinium-enhancing lesions. The clinical efficacy of BG-12 was generally consistent across patient subgroups and reflected positive findings in the overall DEFINE study population. Treatment with BG-12 BID and TID reduced the proportion of patients relapsed and the ARR at two years compared with placebo in all patient subgroups. Reductions in the risk of relapse with BG-12 BID vs. placebo ranged from 68 % [hazard ratio 0.32 (95 % confidence interval (CI) 0.16-0.62)] to 26 % [0.74 (0.51-1.09)] and from 66 % [0.34 (0.23-0.50)] to 25 % [0.75 (0.42-1.36)] with BG-12 TID vs. placebo. BG-12 also reduced the risk of disability progression at two years compared with placebo in most subgroups of patients treated with the BID dosing regimen and in all subgroups treated with the TID regimen. These analyses indicate that treatment with BG-12 is consistently effective across a wide spectrum of patients with relapsing-remitting multiple sclerosis with varied demographic and disease characteristics. © 2013 Springer-Verlag Berlin Heidelberg.


Gold R.,Ruhr University Bochum | Kappos L.,University of Basel | Arnold D.L.,NeuroRx Research | Arnold D.L.,Montreal Neurological Institute | And 8 more authors.
New England Journal of Medicine | Year: 2012

Background: BG-12 (dimethyl fumarate) was shown to have antiinflammatory and cytoprotective properties in preclinical experiments and to result in significant reductions in disease activity on magnetic resonance imaging (MRI) in a phase 2, placebo-controlled study involving patients with relapsing-remitting multiple sclerosis. Methods: We conducted a randomized, double-blind, placebo-controlled phase 3 study involving patients with relapsing-remitting multiple sclerosis. Patients were randomly assigned to receive oral BG-12 at a dose of 240 mg twice daily, BG-12 at a dose of 240 mg three times daily, or placebo. The primary end point was the proportion of patients who had a relapse by 2 years. Other end points included the annualized relapse rate, the time to confirmed progression of disability, and findings on MRI. Results The estimated proportion of patients who had a relapse was significantly lower in the two BG-12 groups than in the placebo group (27% with BG-12 twice daily and 26% with BG-12 thrice daily vs. 46% with placebo, P<0.001 for both comparisons). The annualized relapse rate at 2 years was 0.17 in the twice-daily BG-12 group and 0.19 in the thrice-daily BG-12 group, as compared with 0.36 in the placebo group, representing relative reductions of 53% and 48% with the two BG-12 regimens, respectively (P<0.001 for the comparison of each BG-12 regimen with placebo). The estimated proportion of patients with confirmed progression of disability was 16% in the twicedaily BG-12 group, 18% in the thrice-daily BG-12 group, and 27% in the placebo group, with significant relative risk reductions of 38% with BG-12 twice daily (P = 0.005) and 34% with BG-12 thrice daily (P = 0.01). BG-12 also significantly reduced the number of gadolinium-enhancing lesions and of new or enlarging T 2-weighted hyperintense lesions (P<0.001 for the comparison of each BG-12 regimen with placebo). Adverse events associated with BG-12 included flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain, as well as decreased lymphocyte counts and elevated liver aminotransferase levels. Conclusions: In patients with relapsing-remitting multiple sclerosis, both BG-12 regimens, as compared with placebo, significantly reduced the proportion of patients who had a relapse, the annualized relapse rate, the rate of disability progression, and the number of lesions on MRI. Copyright © 2012 Massachusetts Medical Society.


Kappos L.,University of Basel | Gold R.,Ruhr University Bochum | Arnold D.L.,NeuroRx Research | Bar-Or A.,Montreal Neurological Institute | And 8 more authors.
Multiple Sclerosis | Year: 2014

Background: Oral BG-12 (dimethyl fumarate), approved for the treatment of the relapsing forms of MS, has demonstrated clinical efficacy with an acceptable safety profile in the Phase III "Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (RRMS)" (DEFINE) and "Comparator and an Oral Fumarate in RRMS" (CONFIRM) studies. Objectives: To evaluate the health-related quality of life (HRQoL) impairment that is associated with RRMS and to assess the effects of BG-12 on HRQoL in the DEFINE study. Methods: Patients with RRMS were randomized to BG-12 240 mg twice (BID) or three times (TID) daily, or placebo, for 2 years. HRQoL was assessed by the Short Form-36 (SF-36), global assessment of well-being visual analog scale and the EuroQol-5D. Results: In the 1237 patients from DEFINE, HRQoL impairment was greatest in patients who had higher disability scores and in those who had experienced relapse. Change in SF-36 physical component summary scores during 2 years' treatment significantly favored BG-12 over placebo (both doses: p < 0.001). We saw similar benefits in other measures of functioning and general well-being as early as Week 24. These benefits were maintained during the study. Conclusions: Our results add to evidence for a negative impact of RRMS on HRQoL and they demonstrate the benefits of BG-12 on HRQoL measures, which coupled with significant clinical efficacy, further support its use as a new treatment for RRMS. © 2013 The Author(s).


Elliott C.,McGill University | Arnold D.L.,NeuroRx Research | Collins D.L.,Montreal Neurological Institute | Arbel T.,McGill University
IEEE Transactions on Medical Imaging | Year: 2013

Detection of new Multiple Sclerosis (MS) lesions on magnetic resonance imaging (MRI) is important as a marker of disease activity and as a potential surrogate for relapses. We propose an approach where sequential scans are jointly segmented, to provide a temporally consistent tissue segmentation while remaining sensitive to newly appearing lesions. The method uses a two-stage classification process: 1) a Bayesian classifier provides a probabilistic brain tissue classification at each voxel of reference and follow-up scans, and 2) a random-forest based lesion-level classification provides a final identification of new lesions. Generative models are learned based on 364 scans from 95 subjects from a multi-center clinical trial. The method is evaluated on sequential brain MRI of 160 subjects from a separate multi-center clinical trial, and is compared to 1) semi-automatically generated ground truth segmentations and 2) fully manual identification of new lesions generated independently by nine expert raters on a subset of 60 subjects. For new lesions greater than 0.15 cc in size, the classifier has near perfect performance (99% sensitivity, 2% false detection rate), as compared to ground truth. The proposed method was also shown to exceed the performance of any one of the nine expert manual identifications. © 1982-2012 IEEE.


Nakamura K.,Montreal Neurological Institute | Nakamura K.,Cleveland Clinic | Brown R.A.,Montreal Neurological Institute | Narayanan S.,Montreal Neurological Institute | And 4 more authors.
NeuroImage | Year: 2015

We investigated fluctuations in brain volume throughout the day using statistical modeling of magnetic resonance imaging (MRI) from large populations. We applied fully automated image analysis software to measure the brain parenchymal fraction (BPF), defined as the ratio of the brain parenchymal volume and intracranial volume, thus accounting for variations in head size. The MRI data came from serial scans of multiple sclerosis (MS) patients in clinical trials (n. =. 755, 3269 scans) and from subjects participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI, n. =. 834, 6114 scans). The percent change in BPF was modeled with a linear mixed effect (LME) model, and the model was applied separately to the MS and ADNI datasets. The LME model for the MS datasets included random subject effects (intercept and slope over time) and fixed effects for the time-of-day, time from the baseline scan, and trial, which accounted for trial-related effects (for example, different inclusion criteria and imaging protocol). The model for ADNI additionally included the demographics (baseline age, sex, subject type [normal, mild cognitive impairment, or Alzheimer's disease], and interaction between subject type and time from baseline). There was a statistically significant effect of time-of-day on the BPF change in MS clinical trial datasets (-. 0.180 per day, that is, 0.180% of intracranial volume, p=. 0.019) as well as the ADNI dataset (-. 0.438 per day, that is, 0.438% of intracranial volume, p<. 0.0001), showing that the brain volume is greater in the morning. Linearly correcting the BPF values with the time-of-day reduced the required sample size to detect a 25% treatment effect (80% power and 0.05 significance level) on change in brain volume from 2 time-points over a period of 1. year by 2.6%.Our results have significant implications for future brain volumetric studies, suggesting that there is a potential acquisition time bias that should be randomized or statistically controlled to account for the day-to-day brain volume fluctuations. © 2015 Elsevier Inc.


Karimaghaloo Z.,McGill University | Arnold D.L.,NeuroRx Research | Arbel T.,McGill University
Medical Image Analysis | Year: 2016

Detection and segmentation of large structures in an image or within a region of interest have received great attention in the medical image processing domains. However, the problem of small pathology detection and segmentation still remains an unresolved challenge due to the small size of these pathologies, their low contrast and variable position, shape and texture. In many contexts, early detection of these pathologies is critical in diagnosis and assessing the outcome of treatment. In this paper, we propose a probabilistic Adaptive Multi-level Conditional Random Fields (AMCRF) with the incorporation of higher order cliques for detecting and segmenting such pathologies. In the first level of our graphical model, a voxel-based CRF is used to identify candidate lesions. In the second level, in order to further remove falsely detected regions, a new CRF is developed that incorporates higher order textural features, which are invariant to rotation and local intensity distortions. At this level, higher order textures are considered together with the voxel-wise cliques to refine boundaries and is therefore adaptive. The proposed algorithm is tested in the context of detecting enhancing Multiple Sclerosis (MS) lesions in brain MRI, where the problem is further complicated as many of the enhancing voxels are associated with normal structures (i.e. blood vessels) or noise in the MRI. The algorithm is trained and tested on large multi-center clinical trials from Relapsing-Remitting MS patients. The effect of several different parameter learning and inference techniques is further investigated. When tested on 120 cases, the proposed method reaches a lesion detection rate of 90%, with very few false positive lesion counts on average, ranging from 0.17 for very small (3-5 voxels) to 0 for very large (50+ voxels) regions. The proposed model is further tested on a very large clinical trial containing 2770 scans where a high sensitivity of 91% with an average false positive count of 0.5 is achieved. Incorporation of contextual information at different scales is also explored. Finally, superior performance is shown upon comparing with Support Vector Machine (SVM), Random Forest and variant of an MRF. © 2015 Elsevier B.V.


Derakhshan M.,Montreal Neurological Institute | Caramanos Z.,Montreal Neurological Institute | Narayanan S.,Montreal Neurological Institute | Arnold D.L.,Montreal Neurological Institute | And 2 more authors.
Human Brain Mapping | Year: 2014

The in vivo detection of subpial cortical gray matter lesions in multiple sclerosis is challenging. We quantified the spatial extent of subpial decreases in the magnetization transfer ratio (MTR) of cortical gray matter in subjects with multiple sclerosis, as such reductions may indicate regions of cortical demyelination. We exploited the unique geometry of cortical lesions by using two-dimensional parametric surface models of the cortex instead of traditional three-dimensional voxel-wise analyses. MTR images were mapped onto intermediate surfaces between the pial and white matter surfaces and were used to compute differences between secondary-progressive MS (n = 12), relapsing-remitting MS (n = 12), and normal control (n = 12) groups as well as between each individual patient and the normal controls. We identified large regions of significantly reduced cortical MTR in secondary-progressive patients when compared with normal controls. We also identified large regions of reduced cortical MTR in 11 individual patients (8 secondary-progressive, 3 relapsing-remitting). The secondary-progressive patients showed larger areas of abnormally low MTR compared with relapsing-remitting patients both at the group level and on an individual basis. The spatial distributions of abnormal MTR preferentially involved cingulate cortex, insula, and the depths of sulci, in agreement with pathological descriptions of subpial gray matter lesion distribution. These findings suggest that our method is a plausible in vivo imaging technique for quantifying subpial cortical demyelinating lesions in patients with multiple sclerosis and, furthermore, can be applied at the typical clinical field strength of 1.5 T. © 2013 Wiley Periodicals, Inc.


Konziase B.,Osaka University | Konziase B.,NeuroRx Research
Analytical Biochemistry | Year: 2015

We studied the target proteins of artemisinin in Trypanosoma brucei brucei using the affinity-labeling method. We designed and synthesized four biotinylated probes of artemisinin for use as molecular tools. Their in vitro trypanocidal activities (data not shown) proved that they mimicked the biological action of artemisinin. We assessed the chemical stability for all of the probes in the parasite culture medium and lysate using reversed-phase high-performance liquid chromatography (HPLC). After 3-h incubations, the probes remained undecomposed in a range of 40 to 65% in the parasite culture medium, whereas approximately 80% of the probes remained stable in the parasite lysate. Using liquid chromatography mass spectrometry (LC-MS), we demonstrated that, with respect to all of the probes, uptakes into the parasite ranging from 81 to 96% occurred after 30-min incubations. In a competitive binding assay between artemisinin and the four biotinylated probes, we searched for the trypanosomal target protein of artemisinin. Consequently, we observed that only the diazirine-free probe 5 could provide the desired result with high affinity-labeling efficiency. Using the horseradish peroxidase-tagged streptavidin-biotin method, we showed that artemisinin could specifically bind to candidate target proteins of approximately 60, 40, and 39 kDa. © 2015 Elsevier Inc. All rights reserved.

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