@article {zhang_beta-interferon_2015, title = {Beta-interferon exposure and onset of secondary progressive multiple sclerosis}, journal = {European Journal of Neurology}, volume = {22}, number = {6}, year = {2015}, pages = {990{\textendash}1000}, abstract = {

Background and purpose Beta-interferons (IFNβ) are the most widely prescribed drugs for patients with multiple sclerosis (MS). However, whether or not treatment with IFNβ can delay secondary progressive MS (SPMS) onset remains unknown. Our aim was to examine the association between IFNβ exposure and SPMS onset in patients with relapsing-remitting MS (RRMS). Methods A retrospective cohort study using British Columbia (Canada) population-based clinical and health administrative data (1985{\textendash}2008) was conducted. RRMS patients treated with IFNβ (n\ =\ 794) were compared with untreated contemporary (n\ =\ 933) and historical (n\ =\ 837) controls. Cohort entry was the first clinic visit during which patients became eligible for IFNβ treatment (baseline). The outcome was time from baseline to SPMS onset. Cox regression models with IFNβ as a time-dependent exposure were adjusted for sex, and baseline age, disease duration, disability, *socioeconomic status and *comorbidities (*available for the contemporary cohorts only). Additional analyses included propensity score adjustment. Results The median follow-up for the IFNβ-treated, untreated contemporary and historical controls were 5.7, 3.7 and 7.3\ years, and the proportions of patients reaching SPMS were 9.2\%, 11.8\% and 32.9\%, respectively. After adjustment for confounders, IFNβ exposure was not associated with the risk of reaching SPMS when either the contemporary or the historical untreated cohorts were considered (hazard ratio 1.07; 95\% confidence interval 0.93{\textendash}1.48, and hazard ratio 1.04; 95\% confidence interval 0.74{\textendash}1.46, respectively). Further adjustments and the propensity score yielded results consistent with the main analysis. Conclusions Amongst patients with RRMS, use of IFNβ was not associated with a delayed onset of SPMS.

}, keywords = {beta-interferon, cohort study, multiple sclerosis, progression}, doi = {10.1111/ene.12698}, url = {http://onlinelibrary.wiley.com/doi/10.1111/ene.12698/abstract}, author = {Zhang, T and Shirani, A and Zhao, Y and Karim, ME and Gustafson, P and Petkau, J and Evans, C and Kingwell, E and van der Kop, M and Zhu, F and Oger, J and Tremlett, H and BC MS Clinic Neurologists} } @article {dong_further_2014, title = {Further investigation of safety monitoring guidelines based on magnetic resonance imaging lesion activity in multiple sclerosis clinical trials}, journal = {Multiple Sclerosis Journal}, volume = {21}, year = {2015}, pages = {101-104}, abstract = {

We assess two modified guidelines for monitoring patient safety in multiple sclerosis (MS) trials. These guidelines flag patients with an increase in contrast enhancing lesion (CEL) count above a threshold over the CEL level 1{\textendash}2 months earlier. We compare the new guidelines to the original guideline where the threshold is set according to the baseline by applying the guidelines to two previous studies. The odds ratios of a subsequent clinical relapse associated with meeting the CEL threshold based on the modified guidelines are similar to those based on the original guideline. There is a need for patient and cohort specific monitoring procedures.

}, keywords = {Clinical trials methodology, contrast-enhancing lesions, magnetic resonance imaging, multiple sclerosis, patient safety}, doi = {10.1177/1352458514533846}, url = {http://msj.sagepub.com/content/early/2014/05/20/1352458514533846}, author = {Dong, J and Zhao, Y and Petkau, A.John and Li, DKB and Riddehough, A and Traboulsee, A} } @article {zhao_personalized_2015, title = {Personalized activity index, a new safety monitoring tool for multiple sclerosis clinical trials}, journal = {Multiple Sclerosis Journal {\textendash} Experimental, Translational and Clinical}, volume = {1}, year = {2015}, pages = {1-15}, abstract = {

Background An abnormal increase of contrast-enhancing lesion (CEL) counts on frequent MRIs is interpreted as a signal of potential worsening in multiple sclerosis (MS) clinical trials. We demonstrate the utility of the MR personalized activity index (MR-pax) to identify such increases. Methods We analyzed a previous Phase II study in relapsing patients (n = 167) with MRIs at screening, baseline and months 1{\textendash}6. We performed five consecutive reviews at 90-day intervals. At each review, we evaluate the MR-pax for each patient and also identify those who meet the rule-of-five (an ad-hoc guideline currently in use). To evaluate its clinical relevance, we assess the relation between having a small MR-pax (<=0.05; indicating an unexpected CEL increase) and relapse status in the 12 weeks post-review. Results Of the 399 patient reviews, 35 cases met the rule-of-five; 35 had an MR-pax <= 0.05; 18 met both criteria. The proportions experiencing clinical relapse are 63\% among those meeting the rule-of-five, 61\% among those with MR-pax <=0.05, and 83\% for those meeting both criteria, more than double the rate of those meeting neither criterion (40\%). Conclusion A guideline combining this new personalized index and the existing threshold-based criterion is able to better identify patients with a higher risk of experiencing relapses.

}, keywords = {contrast-enhancing lesions, MRI, multiple sclerosis, safety monitoring in clinical trials}, doi = {10.1177/2055217315577829}, url = {http://mso.sagepub.com/content/1/2055217315577829}, author = {Zhao, Y and Kondo, Y and Traboulsee, A and Li, DKB and Riddehough, A and Petkau, A.John} } @article { ISI:000364916600010, title = {Predictors of disease activity in 857 patients with MS treated with interferon beta-1b}, journal = {Journal of Neurology}, volume = {262}, number = {11}, year = {2015}, pages = {2466-2471}, publisher = {SPRINGER HEIDELBERG}, address = {TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY}, abstract = {

Multiple sclerosis (MS) is a chronic demyelinating neurodegenerative disease of the CNS that requires long-term treatment. The identification of patient characteristics that can help predict disease outcomes could improve care for patients with MS. The objective of this study is to identify predictors of disease activity in patients from the BEYOND trial. This regression analysis of patients with relapsing-remitting MS from BEYOND examined the predictive value of patient characteristics at baseline and after 1 year of treatment with interferon beta-1b 250 mu g every other day for clinical and MRI outcomes after year 1 of the study. 857 and 765 patients were included in the analyses of clinical and MRI outcomes, respectively. In multivariate analyses of age, a higher number of relapses in the past 2 years, a parts per thousand yen3 new MRI lesions in the first year, and, especially, a higher number of relapses in year 1 predicted the future occurrence of relapses. By contrast, age, MRI activity, and the presence of neutralizing antibodies in the first year were principally predictive of future MRI activity. In patients with continued clinical disease activity or substantial MRI activity on therapy, an alternative therapeutic approach should be strongly considered.

}, keywords = {Interferon beta-1b, MRI lesion, multiple sclerosis, Predictor, Relapse}, doi = {10.1007/s00415-015-7862-9}, author = {Hartung, HP and Kappos, L and Goodin, DS and O{\textquoteright}Connor, P and Filippi, M and Arnason, B and Comi, G and Cook, S and Jeffery, D and Petkau, J and White, R and Bogumil, T and Beckmann, K and Stemper, B and Suarez, G and Sandbrink, R and Pohl, C} } @article { ISI:000345076200013, title = {Association between beta-interferon exposure and hospital events in multiple sclerosis}, journal = {Pharmacoepidemiology and Drug Safety}, volume = {23}, number = {11}, year = {2014}, pages = {1213-1222}, publisher = {WILEY-BLACKWELL}, address = {111 RIVER ST, HOBOKEN 07030-5774, NJ USA}, abstract = {

Purpose A systematic evaluation of hospital events can be an important surrogate measure for drug effectiveness or adverse effects. The purpose of this study was to examine the association between beta-interferon use and hospital events in a large cohort of patients with multiple sclerosis (MS). MethodsRetrospective cohort study comparing beta-interferon exposed and unexposed patients using clinical data from the British Columbia MS (BCMS) database linked with health administrative databases, 1996-2008. For each patient, the primary outcome was the number of hospital events in each month, analyzed by quasi Poisson regression. Beta-interferon exposure was examined two ways: current and cumulative exposure. Secondary outcomes included whether a hospital event occurred in each month for each specific primary diagnoses, grouped by International Classification of Diseases categories. ResultsCurrent exposure to beta-interferon was not associated with an altered rate of hospital events (adjusted incident rate ratio 1.018; 95\% CI 0.803-1.290). Similarly, there was no association with cumulative exposure. Cumulative beta-interferon exposure was associated with a lower odds of respiratory disease-related hospital events compared to those never exposed to beta-interferon. ConclusionsExposure to beta-interferon for MS was not associated with a change in overall hospital event rates. Preliminary evidence suggests that the beta-interferons may have a protective effect against respiratory diseases requiring hospitalization in MS patients. Copyright (c) 2014 John Wiley \& Sons, Ltd.

}, keywords = {beta-interferon, hospitalization, multiple sclerosis, pharmacoepidemiology}, doi = {10.1002/pds.3667}, author = {Evans, C and Zhu, F and Kingwell, E and Shirani, A and van der Kop, ML and Petkau, J and Gustafson, P and Zhao, Y and Traboulsee, A and Oger, Joel and Tremlett, Helen} } @article {shirani_investigation_2014, title = {Investigation of heterogeneity in the association between interferon beta and disability progression in multiple sclerosis: an observational study}, journal = {European Journal of Neurology}, volume = {21}, number = {6}, year = {2014}, pages = {835{\textendash}844}, abstract = {

Background and purpose It was recently reported that there was no significant overall association between interferon beta exposure and disability progression in relapsing-remitting multiple sclerosis (RRMS) patients in an observational study from Canada. In the current study, the potential for heterogeneity in the association between exposure to interferon beta and disability progression across patients{\textquoteright} baseline characteristics was investigated. Methods RRMS patients treated with interferon beta (n\ =\ 868) and two cohorts of untreated patients (829 contemporary and 959 historical controls) were included. The main outcome was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained Expanded Disability Status Scale (EDSS) score 6 using a multivariable Cox model, with treatment as a time-varying predictor, testing interaction effects for five pre-specified baseline characteristics: sex, age, disease duration, EDSS and annualized relapse rate (ARR) based on the previous 2\ years. Results Significant heterogeneity was found in the association of interferon beta exposure and disability progression only across ARR, and only when treated patients were compared with historical controls (P\ =\ 0.005 at a Bonferroni-adjusted alpha of 0.01). For patients with ARR\>1, treatment-exposed time was associated with a hazard ratio of 0.38 (95\%CI 0.20{\textendash}0.75) for disability progression compared with the unexposed time. Conclusions RRMS patients with more frequent relapses at baseline may be more likely to benefit from interferon beta treatment with respect to long-term disability progression.

}, keywords = {British Columbia, disability progression, interferon beta, multiple sclerosis, observational studies}, doi = {10.1111/ene.12324}, url = {http://onlinelibrary.wiley.com/doi/10.1111/ene.12324/abstract}, author = {Shirani, A and Zhao, Y and Karim, ME and Petkau, J and Gustafson, P and Evans, C and Kingwell, E and van der Kop, ML and Oger, J and Tremlett, H} } @article { ISI:000339808700005, title = {Marginal structural Cox models for estimating the association between beta-interferon exposure and disease progression in a multiple sclerosis cohort}, journal = {American Journal of Epidemiology}, volume = {180}, number = {2}, year = {2014}, pages = {160-171}, publisher = {OXFORD UNIV PRESS INC}, address = {JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA}, abstract = {

Longitudinal observational data are required to assess the association between exposure to beta-interferon medications and disease progression among relapsing-remitting multiple sclerosis (MS) patients in the {\textquoteleft}{\textquoteleft}real-world{\textquoteright}{\textquoteright} clinical practice setting. Marginal structural Cox models (MSCMs) can provide distinct advantages over traditional approaches by allowing adjustment for time-varying confounders such as MS relapses, as well as baseline characteristics, through the use of inverse probability weighting. We assessed the suitability of MSCMs to analyze data from a large cohort of 1,697 relapsing-remitting MS patients in British Columbia, Canada (1995-2008). In the context of this observational study, which spanned more than a decade and involved patients with a chronic yet fluctuating disease, the recently proposed {\textquoteleft}{\textquoteleft}normalized stabilized{\textquoteright}{\textquoteright} weights were found to be the most appropriate choice of weights. Using this model, no association between beta-interferon exposure and the hazard of disability progression was found (hazard ratio = 1.36, 95\% confidence interval: 0.95, 1.94). For sensitivity analyses, truncated normalized unstabilized weights were used in additional MSCMs and to construct inverse probability weight-adjusted survival curves; the findings did not change. Additionally, qualitatively similar conclusions from approximation approaches to the weighted Cox model (i.e., MSCM) extend confidence in the findings.

}, keywords = {bias (epidemiology), causality, confounding factors (epidemiology), epidemiologic methods, inverse probability weighting, marginal structural Cox model, multiple sclerosis, survival analysis}, doi = {10.1093/aje/kwu125}, author = {Karim, ME and Gustafson, P and Petkau, J and Zhao, Y and Shirani, A and Kingwell, E and Evans, C and van der Kop, M and Oger, J and Tremlett, H} } @article {altman_mri-based_2012, title = {MRI-based clinical trials in relapsing-remitting multiple sclerosis: new sample size calculations based on a longitudinal model}, journal = {Multiple Sclerosis Journal}, volume = {18}, number = {11}, year = {2012}, pages = {1600{\textendash}1608}, abstract = {

BACKGROUND: Sample sizes for magnetic resonance imaging (MRI)-based clinical trials in multiple sclerosis (MS) generally assume that lesion counts are reasonably described by the negative binomial (NB) model. OBJECTIVE: This study aimed to assess the appropriateness of the NB model for lesion count data and to provide sample sizes for placebo-controlled, MRI-based clinical trials in relapsing-remitting MS using a more realistic model. METHODS: The fit of the NB model in each arm of five MS clinical trials was assessed using Pearson{\textquoteright}s chi-squared statistic. Required sample sizes associated with various tests of treatment effect were estimated by simulating data from a new, longitudinal model for repeated lesion count data on individual patients. RESULTS: Evidence (p \< 0.05) against the NB model was found in at least one arm of four of the five trials. If a trial is designed using this model but the resulting clinical data do not follow its assumptions then this trial can be seriously under-powered for assessing differences in mean lesion counts. CONCLUSION: Sample sizes based on the longitudinal model are more realistic and often smaller than those previously reported using the NB model.

}, keywords = {Brain, Chi-Square Distribution, Computer Simulation, Controlled Clinical Trials as Topic, Endpoint Determination, Humans, Longitudinal Studies, magnetic resonance imaging, Models, multiple sclerosis, Predictive Value of Tests, Relapsing-Remitting, Sample Size, Statistical, Time Factors, Treatment Outcome}, doi = {10.1177/1352458512444326}, author = {Altman, RM and Petkau, A.John and Vrecko, D and Smith, A} } @article { ISI:000309359000009, title = {Natural, innate improvements in multiple sclerosis disability}, journal = {Multiple Sclerosis Journal}, volume = {18}, number = {10}, year = {2012}, pages = {1412-1421}, publisher = {SAGE PUBLICATIONS LTD}, address = {1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND}, abstract = {

Background: Improvements in multiple sclerosis (MS) disability have recently been reported in immunomodulatory drug (IMD) clinical trials and observational studies. However, improvements have rarely been examined in natural history or IMD naive patients. We investigated annual and biennial improvements in Expanded Disability Status Scale (EDSS) scores in British Columbia, Canada. Methods: The British Columbian MS database was accessed for definite MS patients (1980-2009). Consecutive IMD-free EDSS scores one and two years apart (+/- 3 months) were examined; improvements (\>= 0.5,\>= 1,\>= 2 EDSS points) and sustained improvements (confirmed at one year) were described. The influence of patient characteristics on improvements was examined using logistic regression. Results: From 16,132 EDSS scores, 7653 yearly and 5845 biennial EDSS intervals were available for 2961 and 2382 patients respectively. Of the yearly intervals, 14.9\% showed an improvement (\>= 0.5 points), 8.3\% \>= 1 point and 2.2\% \>= 2 point improvement, with nearly half being sustained. Corresponding worsenings were observed in 32.9\%, 20.5\% and 7.9\% respectively, with stability in just over half (53\%). Biennial findings were similar. Characteristics generally associated with improvements included: female sex, younger age, shorter disease duration, relapsing-onset and presence of moderate disability (compared with mild or advanced) and a previous episode of worsening (disassociated from a relapse). However, improvements were also observed after periods of stability and in primary-progressive MS. Conclusion: Improvements in MS disability over one or two years are not unusual. We suggest the term {\textquoteleft}innate improvements{\textquoteright}. Our findings have implication for the design of clinical trials and observational studies in MS targeting improvements on the EDSS.

}, keywords = {disability, disease progression, improvement, innate improvement, multiple sclerosis, natural history}, doi = {10.1177/1352458512439119}, author = {Tremlett, H and Zhu, F and Petkau, J and Oger, J and Zhao, Y} } @article { ISI:000299903700010, title = {Neutralizing antibodies to interferon beta-1b in multiple sclerosis: a clinico-radiographic paradox in the BEYOND trial}, journal = {Multiple Sclerosis Journal}, volume = {18}, number = {2}, year = {2012}, pages = {181-195}, publisher = {SAGE PUBLICATIONS LTD}, address = {1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND}, abstract = {

Background: The frequency and impact of neutralizing antibodies (NAbs) to interferon beta-1b (IFN beta-1b) on clinical and radiographic outcomes is controversial. Objective: To assess NAb impact in the BEYOND study. Methods: 2244 patients were randomized (2:2:1) to receive IFN beta-1b, either 250 or 500 mu g, or glatiramer acetate, 20 mg, and observed for 2-3.5 years. NAb titers were determined every 6 months. A titer \>= 20 NU/ml was considered NAb positive. Efficacy was compared between NAb-positive and NAb-negative patients, using comprehensive statistical analyses, taking into account the delayed appearance of NAbs, the time-dependent changes in the relapse rate, spontaneous reversions to NAb-negative status, NAb-titer level, and also adjusting for baseline factors. Results: In the IFN beta-1b 250 mu g group, NAb-positive titers were detected (\>= once) in 319 patients (37.0\%); of these, 112 (35.1\%) reverted to NAb-negative status. In the IFN beta-1b 500 mu g group, 340 patients (40.7\%) became NAb-positive and 119 (35.0\%) reverted to NAb-negative status. In both IFN beta groups, especially the 250 mu g arm, NAb-positive status was not associated with a convincing impact on any clinical outcome measure by any statistical analysis. By contrast, in both IFN beta groups, NAbs were associated with a very consistent deleterious impact on most MRI outcomes. Conclusion: There was a notable dissociation between the impact of NAbs on MRI and clinical outcomes. On MRI measures, the impact was consistent and convincing, whereas on clinical measures a negative impact of NAbs was not found. The basis for this clinico-radiographic paradox is unknown but it suggests that the relationship between NAbs and the therapeutic effects of IFN beta-1b is complex.

}, keywords = {BEYOND study, Interferon beta-1b, multiple sclerosis, neutralizing antibodies}, doi = {10.1177/1352458511418629}, author = {Goodin, DS and Hartung, HP and O{\textquoteright}Connor, P and Filippi, M and Arnason, B and Comi, G and Cook, S and Jeffery, D and Kappos, L and Bogumil, T and Knappertz, V and Sandbrink, R and Beckmann, K and White, R and Petkau, J and Pohl, C} } @article {petkau_magnetic_2008, title = {Magnetic resonance imaging as a surrogate outcome for multiple sclerosis relapses}, journal = {Multiple Sclerosis}, volume = {14}, year = {2008}, pages = {770-778}, abstract = {

Background Magnetic resonance imaging (MRI) of lesions in the brain may be the best current candidate for a surrogate biological marker of clinical outcomes in relapsing remitting multiple sclerosis (MS), based on its role as an objective indicator of disease pathology. No biological surrogate marker has yet been validated for MS clinical outcomes. Objective The objective of this study was to use a multi-phased study to determine if a valid surrogate relationship could be demonstrated between counts of contrast enhancing lesions (CELs) and occurrence of relapses in MS. Methods We examined correlations for the concurrent and predictive relationship between CELs over 6 months and MS relapses over the same 6 months and an additional 6 months (total: 12 months), using available data on untreated patients from a large clinical trial and natural history database. Results Concurrent and predictive correlations were inadequate to justify continuation of this study to the planned additional phases required to demonstrate a surrogate relationship between CELs and MS relapses. Conclusions Confidence intervals for correlations between CELs and MS relapses exclude the possibility that CELs can be a good surrogate for relapses over the time scales we investigated. Further exploration of surrogacy between MRI measures and MS clinical outcomes may require improved datasets, the development of MRI techniques that couple better to clinical disease, and the ability to test a wide range of imaging- and clinically-based hypotheses for surrogacy.

}, keywords = {correlations, gadolinium enhanced lesions, magnetic resonance imaging, multiple sclerosis, prognosis, surrogacy}, doi = {10.1177/1352458507088104}, url = {http://msj.sagepub.com/content/early/2008/06/05/1352458507088104}, author = {Petkau, J. and Reingold, S. C. and Held, U. and Cutter, G. R. and Fleming, T. R. and Hughes, M. D. and Miller, D. H. and McFarland, H. F. and Wolinsky, J. S.} }