Mark S Freedman

Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Are you Mark S Freedman?

Claim your profile

Publications (173)1169.38 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective Some previous studies suggest modest to strong effects of 25-hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D.Methods This study measured serum 25(OH)D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta-1b (IFNB-1b) after a clinically isolated syndrome. MS disease activity was assessed by the number of gadolinium-enhancing lesions present on repeated magnetic resonance imaging (MRIs).ResultsThe number of gadolinium-enhancing lesions was highly significantly associated with 25(OH)D levels. Conducting various systems-level analyses on the molecular level, multiple lines of evidence indicated that 25(OH)D regulates expression dynamics of a large gene–gene interaction system which primarily regulates immune modulatory processes modulating MS activity. The vitamin D response element was significantly enriched in this system, indicating a direct regulation of this gene interaction network through the vitamin D receptor. With increasing 25(OH)D levels, resulting regulation of this system was associated with a decrease in MS activity. Within the complex network of genes that are regulated by 25(OH)D, well-described targets of IFNB-1b and a regulator of sphingosine-1-phosphate bioavailability were found. The 25(OH)D effects on MS activity were additively enhanced by IFNB-1b.InterpretationHere, we provide mechanistic evidence that an unbalanced 25(OH)D gene expression system may affect MS activity. Our findings support a potential benefit of monitoring and managing vitamin D levels (e.g., through supplementation) in early MS patients treated with IFN-beta-1b.
    Annals of Clinical and Translational Neurology. 08/2014;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. This post hoc analysis of the Phase III TOWER study evaluated the effects of teriflunomide treatment on five severe relapse outcomes: relapses with sequelae defined by an increase in Expanded Disability Status Scale (EDSS)/functional system (FS) score (sequelae-EDSS/FS) 30 days post relapse; relapses with sequelae defined by the investigator (sequelae-investigator); relapses leading to hospitalization; relapses treated with intravenous corticosteroids; and intense relapses using the definition of Panitch et al. from the EVIDENCE study based on specified increases in EDSS for severe relapses. Adjusted annualized rates for the five severe relapse outcomes were derived using a Poisson model with robust error variance, with treatment, baseline EDSS strata and region as covariates. Compared with placebo, teriflunomide significantly reduced annualized rates of relapses with sequelae-EDSS/FS [14 mg, 36.6 % (p = 0.0021); 7 mg, 31.3 % (p = 0.0104)] and sequelae-investigator [14 mg only, 53.5 % (p = 0.0004)], relapses leading to hospitalization [14 mg only, 33.6 % (p = 0.0155)], relapses requiring intravenous corticosteroids [14 mg, 35.7 % (p = 0.0002); 7 mg, 21.5 % (p = 0.0337)], and intense relapses [14 mg only, 52.5 % (p = 0.0015)]. Patients treated with teriflunomide 14 mg spent significantly fewer nights in hospital for relapse (p = 0.009) and had lower annualized rates of all hospitalizations (p = 0.030). Taken together, the positive effects of teriflunomide on severe relapses indicate that teriflunomide may reduce relapse-related healthcare costs.
    Journal of neurology. 06/2014;
  • Source
    Mark S Freedman
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Evidence suggests that MS should be treated as early as possible in order to maximize the benefit of treatment. Areas covered: This review details current understanding about the treatment of relapsing-remitting MS (RRMS). The pharmacological and clinical data on the use of subcutaneous (s.c.) interferon β-1a (IFN-β-1a) as a therapeutic option for RRMS are covered, with a focus on the importance of treating patients with MS as early as possible in the course of the disease, in order to delay permanent axonal damage that is responsible for the signs and symptoms of disease progression. Expert opinion: There is a wealth of data on the treatment of RRMS with s.c. IFN-β-1a indicating that patients treated during the early inflammatory stages of the disease have significantly improved short-term outcomes compared with patients who commence treatment late. It remains to be determined whether the short-term effects of early treatment will translate into long-lasting benefits, although it is hoped that ongoing research will help to answer this question.
    Expert opinion on biological therapy. 06/2014;
  • Mark S Freedman
    Nature Reviews Neurology 06/2014; · 15.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined. Open access full paper at //www.neurology.org/content/83/3/278.abstract
    Neurology 05/2014; · 8.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This double-blind, placebo-controlled, dose-finding phase IIb study evaluated the efficacy and safety of ponesimod, an oral selective S1P1 receptor modulator, for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). 464 patients were randomised to receive once-daily oral ponesimod 10, 20 or 40 mg, or placebo for 24 weeks. The primary endpoint was the cumulative number of new T1 gadolinium-enhanced (T1 Gd+) lesions per patient recorded every 4 weeks from weeks 12 to 24 after study drug initiation. Secondary endpoints were the annualised confirmed relapse rate (ARR) and time to first confirmed relapse. Safety and tolerability were also evaluated. The mean cumulative number of new T1 Gd+ lesions at weeks 12-24 was significantly lower in the ponesimod 10 mg (3.5; rate ratio (RR) 0.57; p=0.0318), 20 mg (1.1; RR 0.17; p<0.0001) and 40 mg (1.4; RR 0.23; p<0.0001) groups compared with placebo (6.2). The mean ARR was lower with 40 mg ponesimod versus placebo, with a maximum reduction of 52% (0.25 vs 0.53; p=0.0363). The time to first confirmed relapse was increased with ponesimod compared with placebo. The proportion of patients with ≥1 treatment-emergent adverse events (AEs) was similar across ponesimod groups and the placebo group. Frequently reported AEs with higher incidence in the three ponesimod groups compared with placebo were anxiety, dizziness, dyspnoea, increased alanine aminotransferase, influenza, insomnia and peripheral oedema. Once-daily treatment with ponesimod 10, 20 or 40 mg significantly reduced the number of new T1 Gd+ lesions and showed a beneficial effect on clinical endpoints. Ponesimod was generally well tolerated, and further investigation of ponesimod for the treatment of RMMS is under consideration. NCT01006265.
    Journal of neurology, neurosurgery, and psychiatry 03/2014; · 4.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing or relapsing-remitting multiple sclerosis. We aimed to provide further evidence for the safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis. METHODS: This international, randomised, double-blind, placebo-controlled, phase 3 study enrolled adults aged 18-55 years with relapsing multiple sclerosis, one or more relapse in the previous 12 months or two or more in the previous 24 months but no relapse in the previous 30 days, and an Expanded Disability Status Scale (EDSS) score of 5.5 points or less. Patients were recruited from 189 sites in 26 countries and randomly assigned (1:1:1) to once-daily placebo, teriflunomide 7 mg, or teriflunomide 14 mg via an interactive voice recognition system. Treatment duration was variable, ending 48 weeks after the last patient was included. The primary endpoint was annualised relapse rate (number of relapses per patient-year) and the key secondary endpoint was time to sustained accumulation of disability (an EDSS score increase of at least 1 EDSS point sustained for a minimum of 12 weeks), both analysed in the modified intention-to-treat population (all patients who received at least one dose of assigned study medication). This study is registered with ClinicalTrials.gov, number NCT00751881. FINDINGS: Between Sept 17, 2008, and Feb 17, 2011, 1169 patients were randomly assigned to a treatment group, of whom 388, 407, and 370 patients received at least one dose of placebo, teriflunomide 7 mg, or teriflunomide 14 mg, respectively. By the end of the study, the annualised relapse rate was higher in patients assigned to placebo (0.50 [95% CI 0.43-0.58]) than in those assigned to teriflunomide 14 mg (0.32 [0.27-0.38]; p=0.0001) or teriflunomide 7 mg (0.39 [0.33-0.46]; p=0.0183). Compared with placebo, teriflunomide 14 mg reduced the risk of sustained accumulation of disability (hazard ratio [HR] 0.68 [95% CI 0.47-1.00]; log-rank p=0.0442); however, teriflunomide 7 mg had no effect on sustained accumulation of disability (HR 0.95 [0.68-1.35]; log-rank p=0.7620). The most common adverse events were alanine aminotransferase increases (32 [8%] of 385 patients in the placebo group vs 46 [11%] of 409 patients in the teriflunomide 7 mg group vs 52 [14%] of 371 patients in the teriflunomide 14 mg group), hair thinning (17 [4%] vs 42 [10%] vs 50 [13%]), and headache (42 [11%] vs 60 [15%] vs 46 [12%]). Incidence of serious adverse events was similar in all treatment groups (47 [12%] vs 52 [13%] vs 44 [12%]). Four deaths occurred, none of which was considered to be related to study drug (respiratory infection in the placebo group, traffic accident in the teriflunomide 7 mg group, and suicide and septicaemia due to Gram-negative infection complicated by disseminated intravascular coagulopathy in the teriflunomide 14 mg group). INTERPRETATION: Teriflunomide 14 mg was associated with a lower relapse rate and less disability accumulation compared with placebo, with a similar safety and tolerability profile to that reported in previous studies. These results confirm the dose effect reported in previous trials and support the use of teriflunomide 14 mg in patients with relapsing multiple sclerosis.
    The Lancet Neurology 03/2014; 13(3):247-256. · 23.92 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: IMPORTANCE It remains unclear whether vitamin D insufficiency, which is common in individuals with multiple sclerosis (MS), has an adverse effect on MS outcomes. OBJECTIVES To determine whether serum concentrations of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, predict disease activity and prognosis in patients with a first event suggestive of MS (clinically isolated syndrome). DESIGN, SETTING, AND PARTICIPANTS The Betaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment study was a randomized trial originally designed to evaluate the impact of early vs delayed interferon beta-1b treatment in patients with clinically isolated syndrome. Serum 25(OH)D concentrations were measured at baseline and 6, 12, and 24 months. A total of 465 of the 468 patients randomized had at least 1 25(OH)D measurement, and 334 patients had them at both the 6- and 12-month (seasonally asynchronous) measurements. Patients were followed up for 5 years clinically and by magnetic resonance imaging. MAIN OUTCOMES AND MEASURES New active lesions, increased T2 lesion volume, and brain volume on magnetic resonance imaging, as well as MS relapses and disability (Expanded Disability Status Scale score). RESULTS Higher 25(OH)D levels predicted reduced MS activity and a slower rate of progression. A 50-nmol/L (20-ng/mL) increment in average serum 25(OH)D levels within the first 12 months predicted a 57% lower rate of new active lesions (P < .001), 57% lower relapse rate (P = .03), 25% lower yearly increase in T2 lesion volume (P < .001), and 0.41% lower yearly loss in brain volume (P = .07) from months 12 to 60. Similar associations were found between 25(OH)D measured up to 12 months and MS activity or progression from months 24 to 60. In analyses using dichotomous 25(OH)D levels, values greater than or equal to 50 nmol/L (20 ng/mL) at up to 12 months predicted lower disability (Expanded Disability Status Scale score, -0.17; P = .004) during the subsequent 4 years. CONCLUSIONS AND RELEVANCE Among patients with MS mainly treated with interferon beta-1b, low 25(OH)D levels early in the disease course are a strong risk factor for long-term MS activity and progression.
    JAMA neurology. 01/2014;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The oral Symbol Digit Modalities Test (SDMT) has been recommended to assess cognition for multiple sclerosis (MS) patients. However, the lack of adequate normative data has limited its clinical utility. Recently published regression-based norms may resolve this limitation but, because these norms were derived from a relatively small sample, their stability is unclear. We aimed to evaluate the stability of regression-based SDMT norms by comparing existing norms to a cross-validation dataset. First, regression-based normative data were created from a similarly-sized, independent, control sample (n = 94). Next the original and cross-validation norms were compared for equivalency, management of demographic influences, construct validity, and impairment classification rates in a mildly affected MS sample (n = 70). Lastly, similar comparisons were made for a large, representative MS clinic sample (n = 354). We found construct validity and management of demographic influences were equivalent for the two sets of regression-based norms but lower T-scores were obtained using the original dataset, resulting in discrepancies in impairment classification. In conclusion, regression-based norms for the oral SDMT attenuate demographic influences and possess adequate construct validity. However, norms generated using small samples may yield unreliable classification of cognitive impairment. Larger, representative databases will be necessary to improve the clinical utility of regression-based norms.
    The Clinical Neuropsychologist 01/2014; · 1.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The REFLEX study (NCT00404352) established that subcutaneous (sc) interferon (IFN) β-1a reduced the risks of McDonald MS (2005 criteria) and clinically definite multiple sclerosis (CDMS) in patients with a first clinical demyelinating event suggestive of MS. The aim of this subgroup analysis was to assess the treatment effect of sc IFN β-1a in patient subgroups defined by baseline disease and demographic characteristics (age, sex, use of steroids at the first event, classification of first event as mono- or multifocal, presence/absence of gadolinium-enhancing lesions, count of <9 or ≥9 T2 lesions), and by diagnosis of MS using the revised McDonald 2010 MS criteria. Patients were randomized to the serum-free formulation of IFN β-1a, 44 μg sc three times weekly or once weekly, or placebo, for 24 months or until diagnosis of CDMS. Treatment effects of sc IFN β-1a on McDonald 2005 MS and CDMS in the predefined subgroups were similar to effects found in the intent-to-treat population. McDonald 2010 MS was retrospectively diagnosed in 37.7 % of patients at baseline. Both regimens of sc IFN β-1a significantly reduced the risk versus placebo of McDonald 2005 MS and CDMS, irrespective of McDonald 2010 status at baseline (risk reductions between 29 and 51 %). The effect of sc IFN β-1a was not substantially influenced by baseline patient demographic and disease characteristics, or baseline presence/absence of McDonald 2010 MS.
    Journal of Neurology 01/2014; · 3.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Individuals with MS undergoing immunoablative therapy and hematopoietic stem cell transplantation (HSCT) show substantial decrease in brain volume over 2.4 months, presumably from chemotoxic effects, although other mechanisms have also been postulated. Objective We examined whether volume loss was accompanied by a concomitant decrease in cognition. White and gray matter volumes, and the effect of stem cell dosage were considered. Methods Seven individuals with rapidly progressing MS and poor prognosis underwent high dose immunosuppression and autologous HSCT. Neuropsychological testing and MRI scans were performed at baseline, 2 and 24 months post-procedure. Results Cognitive impairment was noted at all times in most participants. Median decline of 1.39% in total brain volume was noted 2 months post-HSCT. By 24 months a further decline of 1.65% was noted. At 2 months significant decline was observed for areas of executive functioning. At 24 months almost no significant declines were noted. No significant correlations were found between cognitive decline and change in imaging variables or stem cell dosage. Conclusions Cognition changed in the early period following treatment but with little apparent relationship to volume changes. With temporal distance from the HSCT procedure, cognition returned to baseline levels. With the caution of a very small sample, preliminary results suggest that immunoablation and HSCT may have no lasting deleterious effects on cognition.
    Multiple Sclerosis and Related Disorders. 01/2014; 3(1):129–135.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. We aimed to assess the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of multiple sclerosis. Methods In this randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 18–55 years with clinically isolated syndrome (defined as a neurological event consistent with demyelination, starting within 90 days of randomisation, and two or more T2-weighted MRI lesions ≥3 mm in diameter) from 112 centres (mostly hospitals) in 20 countries. Participants were randomly assigned (1:1:1) in a double-blind manner (by an interactive voice response system) to once-daily oral teriflunomide 14 mg, teriflunomide 7 mg, or placebo, for up to 108 weeks. Patients, staff administering the interventions, and outcome assessors were masked to treatment assignment. The primary endpoint was time to relapse (a new neurological abnormality separated by ≥30 days from a preceding clinical event, present for ≥24 h in the absence of fever or known infection), which defined conversion to clinically definite multiple sclerosis. The key secondary endpoint was time to relapse or new gadolinium-enhancing or T2 lesions on MRI, whichever occurred first. The primary outcome was analysed for the modified intention-to-treat population; safety analyses included all randomised patients who were exposed to the study drug, as treated. This trial is registered with ClinicalTrials.gov, number NCT00622700. Findings Between Feb 13, 2008, and Aug 22, 2012, 618 patients were enrolled and randomly assigned to teriflunomide 14 mg (n=216), teriflunomide 7 mg (n=205), or placebo (n=197). Two patients in each of the teriflunomide groups did not receive the study drug, so the modified intention-to-treat population comprised 214 patients in the teriflunomide 14 mg group, 203 in the teriflunomide 7 mg group, and 197 in the placebo group. Compared with placebo, teriflunomide significantly reduced the risk of relapse defining clinically definite multiple sclerosis at the 14 mg dose (hazard ratio [HR] 0·574 [95% CI 0·379–0·869]; p=0·0087) and at the 7 mg dose (0·628 [0·416–0·949]; p=0·0271). Teriflunomide reduced the risk of relapse or a new MRI lesion compared with placebo at the 14 mg dose (HR 0·651 [95% CI 0·515–0·822]; p=0·0003) and at the 7 mg dose (0·686 [0·540–0·871]; p=0·0020). During the study, six patients who were randomly assigned to placebo accidently also received teriflunomide at some point: four received 7 mg and two received 14 mg. Therefore, the safety population comprised 216 patients on teriflunomide 14 mg, 207 on teriflunomide 7 mg, and 191 on placebo. Adverse events that occurred in at least 10% of patients in either teriflunomide group and with an incidence that was at least 2% higher than that with placebo were increased alanine aminotransferase (40 [19%] of 216 patients in the 14 mg group, 36 [17%] of 207 in the 7 mg group vs 27 [14%] of 191 in the placebo group), hair thinning (25 [12%] and 12 [6%] vs 15 [8%]), diarrhoea (23 [11%] and 28 [14%] vs 12 [6%]), paraesthesia (22 [10%] and 11 [5%] vs 10 [5%]), and upper respiratory tract infection (20 [9%] and 23 [11%] vs 14 [7%]). The most common serious adverse event was an increase in alanine aminotransferase (four [2%] and five [2%] vs three [2%]). Interpretation TOPIC is to our knowledge the first study to report benefits of an available oral disease-modifying therapy in patients with early multiple sclerosis. These results extend the stages of multiple sclerosis in which teriflunomide shows a beneficial effect. Funding Genzyme, a Sanofi company.
    The Lancet. Neurology. 01/2014;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The first clinical presentation of multiple sclerosis (MS) is usually a single episode of typical symptoms and signs and is designated a “first clinical demyelinating event” (FCDE) or a “clinically isolated syndrome”. Patients with an FCDE who show ‘silent’ magnetic resonance imaging lesions are at high risk of further clinical events and therefore of meeting the criteria for the diagnosis of clinically definite MS (CDMS). Here we review five Phase III trials, in which treatment with the following disease-modifying drugs (DMDs) was initiated at this early stage: interferon beta (ETOMS, CHAMPS, BENEFIT, and REFLEX) and glatiramer acetate (PreCISe). Differences in the design of the trials and their patient inclusion criteria limit comparisons. However, the proportion of placebo-treated patients who developed CDMS within 2 years was 38–45% across studies, and this rate was significantly reduced by DMD treatment. Conversion to McDonald MS was reported by only two of the trials: BENEFIT (2001 criteria) and REFLEX (2005 criteria). Around 85% of placebo-treated patients developed McDonald MS by 2 years in each, and again a beneficial effect of DMD treatment was seen. Overall, these studies support early use of DMDs to treat patients with an FCDE who are at high risk of conversion to CDMS.
    Multiple Sclerosis and Related Disorders. 01/2014; 3(2):147–155.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing or relapsing–remitting multiple sclerosis. We aimed to provide further evidence for the safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis. Methods This international, randomised, double-blind, placebo-controlled, phase 3 study enrolled adults aged 18–55 years with relapsing multiple sclerosis, one or more relapse in the previous 12 months or two or more in the previous 24 months but no relapse in the previous 30 days, and an Expanded Disability Status Scale (EDSS) score of 5·5 points or less. Patients were recruited from 189 sites in 26 countries and randomly assigned (1:1:1) to once-daily placebo, teriflunomide 7 mg, or teriflunomide 14 mg via an interactive voice recognition system. Treatment duration was variable, ending 48 weeks after the last patient was included. The primary endpoint was annualised relapse rate (number of relapses per patient-year) and the key secondary endpoint was time to sustained accumulation of disability (an EDSS score increase of at least 1 EDSS point sustained for a minimum of 12 weeks), both analysed in the modified intention-to-treat population (all patients who received at least one dose of assigned study medication). This study is registered with ClinicalTrials.gov, number NCT00751881. Findings Between Sept 17, 2008, and Feb 17, 2011, 1169 patients were randomly assigned to a treatment group, of whom 388, 407, and 370 patients received at least one dose of placebo, teriflunomide 7 mg, or teriflunomide 14 mg, respectively. By the end of the study, the annualised relapse rate was higher in patients assigned to placebo (0·50 [95% CI 0·43–0·58]) than in those assigned to teriflunomide 14 mg (0·32 [0·27–0·38]; p=0·0001) or teriflunomide 7 mg (0·39 [0·33–0·46]; p=0·0183). Compared with placebo, teriflunomide 14 mg reduced the risk of sustained accumulation of disability (hazard ratio [HR] 0·68 [95% CI 0·47–1·00]; log-rank p=0·0442); however, teriflunomide 7 mg had no effect on sustained accumulation of disability (HR 0·95 [0·68–1·35]; log-rank p=0·7620). The most common adverse events were alanine aminotransferase increases (32 [8%] of 385 patients in the placebo group vs 46 [11%] of 409 patients in the teriflunomide 7 mg group vs 52 [14%] of 371 patients in the teriflunomide 14 mg group), hair thinning (17 [4%] vs 42 [10%] vs 50 [13%]), and headache (42 [11%] vs 60 [15%] vs 46 [12%]). Incidence of serious adverse events was similar in all treatment groups (47 [12%] vs 52 [13%] vs 44 [12%]). Four deaths occurred, none of which was considered to be related to study drug (respiratory infection in the placebo group, traffic accident in the teriflunomide 7 mg group, and suicide and septicaemia due to Gram-negative infection complicated by disseminated intravascular coagulopathy in the teriflunomide 14 mg group). Interpretation Teriflunomide 14 mg was associated with a lower relapse rate and less disability accumulation compared with placebo, with a similar safety and tolerability profile to that reported in previous studies. These results confirm the dose effect reported in previous trials and support the use of teriflunomide 14 mg in patients with relapsing multiple sclerosis. Funding Genzyme, a Sanofi company.
    01/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Patients who develop relapsing-remitting multiple sclerosis (MS) present with a first clinical demyelinating event. In this double-blind, multicentre, randomised, phase 3 study we investigated the effect of oral cladribine on conversion to clinically definite MS in patients with a first clinical demyelinating event, when given at the same doses shown to be effective in relapsing-remitting MS. Methods Between Oct 21, 2008, and Oct 11, 2010, we recruited patients aged 18–55 years, inclusive, from 160 hospitals, private clinics, or treatment centres in 34 countries. Eligible patients had a first clinical demyelinating event within 75 days before screening, at least two clinically silent lesions of at least 3 mm on a T2-weighted brain MRI scan, and an Expanded Disability Status Scale score of 5·0 or lower. Patients with a first clinical demyelinating event ≤75 days before screening were randomly assigned (1:1:1) to receive cladribine tablets at cumulative doses of 5·25 mg/kg or 3·5 mg/kg or placebo. Randomisation was done with a central web-based randomisation system and was stratified by geographic region. Masking was maintained using a two-physician model. The primary endpoint of this 96-week study was time to conversion to clinically definite MS according to the Poser criteria. This study is registered with ClinicalTrials.gov, number NCT00725985. Findings Of 903 participants assessed for eligibility, 616 patients received cladribine 5·25 mg/kg (n=204), cladribine 3·5 mg/kg (n=206), or placebo (n=206). At trial termination on Oct 25, 2011, cladribine was associated with a risk reduction versus placebo for time to conversion to clinically definite MS (hazard ratio [HR] for 5·25 mg/kg=0·38, 95% CI 0·25–0·58, p<0·0001; HR for 3·5 mg/kg=0·33, 0·21–0·51, p<0·0001). Adverse events were reported in 165 (81%) patients in the cladribine 5·25 mg/kg group, 168 (82%) patients in the cladribine 3·5 mg/kg group, and 162 (79%) patients in the placebo group. We noted no increase in risk of adverse events with active treatment versus placebo apart from lymphopenia, which was a severe event in 10 (5%) patients in the 5·25 mg/kg group and four (2%) patients in the 3·5 mg/kg group. Interpretation Both doses of cladribine significantly delayed MS diagnosis compared with placebo. The safety profile of cladribine was similar to that noted in a trial in patients with relapsing-remitting MS. Further research could clarify the potential effects of oral cladribine treatment in the early stages of MS. Funding Merck Serono SA Geneva, a subsidiary of Merck KGaA, Darmstadt, Germany.
    01/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Depletion of B lymphocytes is associated with suppression of inflammatory activity in multiple sclerosis. We aimed to assess the safety and efficacy of atacicept, a recombinant fusion protein that suppresses B-cell function and antibody production. Methods In this placebo-controlled, double-blind, 36-week, phase 2 trial (ATAMS) in Australia, Canada, Europe, and the USA, patients aged 18–60 years with relapsing multiple sclerosis were randomly assigned via an interactive voice response system in a 1:1:1:1 ratio, stratified by geographical region, to receive weekly subcutaneous injections with atacicept (25, 75, or 150 mg) or placebo. Both patients and study personnel were masked to treatment assignment. The primary endpoint was the change in mean number of gadolinium-enhancing lesions on T1-weighted MRI per patient per scan between weeks 12 and 36. Efficacy endpoints were analysed in the intention-to-treat population. Patients who completed week 36 were eligible to participate in a long-term extension study (ATAMS EXT), consisting of a double-blind phase followed by an open-label phase, for a total study time of up to 5 years. The study was terminated early after the independent data and safety monitoring board noted an increased annualised relapse rate with atacicept. The protocol was subsequently amended to include a 60-week safety follow-up, to allow treatment with approved multiple sclerosis drugs, and to change the primary endpoint to gadolinium-enhancing T1 lesions per scan during the entire double-blind period of ATAMS. Both the trial and the extension are registered with ClinicalTrials.gov, numbers NCT00642902 (ATAMS) and NCT00853762 (ATAMS EXT). Findings Between April 23, 2008, and early study termination on Sept 11, 2009, 255 patients were randomly assigned: 63 to placebo, 63 to atacicept 25 mg, 64 to 75 mg, and 65 to 150 mg. 90 (35%) patients completed the week 36 treatment visit, 26 (10%) discontinued before study termination (including one who dropped out before receiving study treatment), and 139 (55%) discontinued because of study termination. During the double-blind period of ATAMS, annualised relapse rates were higher in the atacicept groups than in the placebo group (atacicept 25 mg, 0·86, 95% CI 0·43–1·74; 75 mg, 0·79, 0·40–1·58; 150 mg, 0·98, 0·52–1·81; placebo, 0·38, 0·17–0·87). Mean numbers of gadolinium-enhancing T1 lesions per scan were similar in all groups (25 mg, 2·26, 0·97–5·27; 75 mg, 2·30, 1·08–4·92; 150 mg, 2·49, 1·18–5·27; placebo, 3·07, 1·40–6·77). Seven patients (one taking placebo and six atacicept) discontinued treatment because of adverse events. One death occurred in the placebo group. During the safety follow-up, immunoglobulin concentrations and B-cell counts returned towards predose values and annualised relapse rates in the atacicept groups decreased until they were similar to that of the placebo group Interpretation Increased clinical disease activity associated with atacicept suggests that the role of B cells and humoral immunity in multiple sclerosis is complex. For studies that explore therapeutic immunomodulation in multiple sclerosis, rigorous monitoring for negative effects on clinical and MRI outcomes is warranted. Funding Merck Serono (Merck KGaA) and EMD Serono (Merck KGaA).
    The Lancet Neurology 01/2014; · 23.92 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background In pivotal phase 3 studies, fingolimod treatment initiation was associated with a transient reduction in heart rate (HR). Atrioventricular (AV) conduction delays, which were typically asymptomatic, were detected in a small minority of patients. Objective We report the first-dose effects of fingolimod in patients who switched from injectable therapies during the Evaluate Patient OutComes (EPOC) study (ClinicalTrials.gov Identifier: NCT01216072). Methods This was a phase 4, 6-month, randomized, active-comparator, open-label, multicenter study. It included over 900 fingolimod-treated patients with relapsing multiple sclerosis, with subgroups of individuals who were receiving common concomitant HR-lowering medications or had pre-existing cardiac conditions (PCCs). Vital signs were recorded hourly for 6 hours post-dose. A 12-lead electrocardiogram was obtained at baseline and at 6 hours post-dose. Results A transient decrease in mean HR and blood pressure occurred within 6 hours of the first fingolimod dose. The incidence of symptomatic bradycardia was low (1%); eight patients reported dizziness and there was one case each of fatigue, palpitations, dyspnea, cardiac discomfort, and gait disturbance. These symptomatic events were typically mild or moderate in severity and all resolved spontaneously, without intervention or fingolimod discontinuation. Conclusion First-dose effects in patients with PCCs and in those receiving concomitant HR-lowering medications were consistent with effects observed in the overall study population and with results from previous clinical trials. The EPOC study provides additional data demonstrating the transient and generally benign nature of fingolimod first-dose effects on HR and AV conduction in a large population that is more representative of patients encountered in routine clinical practice than in the pivotal trials.
    Multiple Sclerosis and Related Disorders. 01/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Infusion of PDA-001, a preparation of mesenchymal-like cells derived from full-term human placenta, is a new approach in the treatment of patients with multiple sclerosis. Objective This safety study aimed to rule out the possibility of paradoxical exacerbation of disease activity by PDA-001 in patients with multiple sclerosis. Methods This was a phase 1b, multicenter, randomized, double-blind, placebo-controlled, 2-dose ranging study including patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis. The study was conducted at 6 sites in the United States and 2 sites in Canada. Patients were randomized 3:1 to receive 2 low-dose infusions of PDA-001 (150×106 cells) or placebo, given 1 week apart. After completing this cohort, subsequent patients received high-dose PDA-001 (600×106 cells) or placebo. Monthly brain magnetic resonance imaging scans were performed. The primary end point was ruling out the possibility of paradoxical worsening of MS disease activity. This was monitored using Cutter's rule (≥5 new gadolinium lesions on 2 consecutive scans) by brain magnetic resonance imaging on a monthly basis for six months and also the frequency of multiple sclerosis relapse. Results Ten patients with relapsing-remitting multiple sclerosis and 6 with secondary progressive multiple sclerosis were randomly assigned to treatment: 6 to low-dose PDA-001, 6 to high-dose PDA-001, and 4 to placebo. No patient met Cutter's rule. One patient receiving high-dose PDA-001 had an increase in T2 and gadolinium lesions and in Expanded Disability Status Scale score during a multiple sclerosis flare 5 months after receiving PDA-001. No other patient had an increase in Expanded Disability Status Scale score >0.5, and most had stable or decreasing Expanded Disability Status Scale scores. With high-dose PDA-001, 1 patient experienced a grade 1 anaphylactoid reaction and 1 had grade 2 superficial thrombophlebitis. Other adverse events were mild to moderate and included headache, fatigue, infusion site reactions, and urinary tract infection. Conclusion PDA-001 infusions were safe and well tolerated in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis patients. No paradoxical worsening of lesion counts was noted with either dose.
    Multiple Sclerosis and Related Disorders. 01/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: The Latin American MS Experts’ Forum has developed practical recommendations on the initiation and optimization of disease-modifying therapies in patients with relapsing-remitting multiple sclerosis (RRMS). The recommendations reflect the unique epidemiology of MS and the clinical practice environment in Latin American countries. Treatment response may be evaluated according to changes in relapses; progression, as assessed by the Expanded Disability Status Scale and the Timed 25-foot Walk; and lesion number on magnetic resonance imaging. Follow-up assessments are recommended every six months, or annually for stable patients. Cognitive function should be evaluated in all RRMS patients at baseline and annually thereafter. These recommendations are intended to assist clinicians in Latin America in developing a rational approach to treatment selection and sequencing for their RRMS patients.
    Journal of the neurological sciences 01/2014; · 2.32 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The REbif FLEXible dosing in early MS (REFLEX) study compared several brain MRI outcomes in patients presenting with clinically isolated syndromes suggestive of multiple sclerosis and treated with two dose-frequencies of subcutaneous interferon (IFN) β-1a or placebo. Patients were randomised (1:1:1) to IFN β-1a, 44 µg subcutaneously three times a week or once a week, or placebo three times a week for up to 24 months. MRI scans were performed every 3 months, or every 6 months if the patient developed clinically definite multiple sclerosis. End points analysed included: number of combined unique active lesions per patient per scan; numbers and volumes of new T2, T1 hypointense and gadolinium-enhancing (Gd+) lesions per patient per scan; and brain volume. 517 patients were randomised (intent-to-treat population: subcutaneous IFN β-1a three times a week, n=171; subcutaneous IFN β-1a once a week, n=175; placebo, n=171). Combined unique active lesions were lower in patients treated with subcutaneous IFN β-1a versus placebo (mean (SD) lesions per patient per scan: three times a week 0.6 (1.15); once a week 1.23 (4.26); placebo 2.70 (5.23); reduction versus placebo: three times a week 81%; once a week 63%; p<0.001) and with three times a week versus once a week (48% reduction; p=0.002). The mean numbers of new T2, T1 hypointense and Gd+ lesions were all significantly lower in the two active treatment arms compared with placebo (p≤0.004 for three times a week or once a week) and in the three times a week group compared with once a week (p≤0.012). Both subcutaneous IFN β-1a 44 µg regimens improved MRI outcomes versus placebo, with the three times a week regimen having a more pronounced effect than once a week dosing. clinicaltrial.gov identifier, NCT00404352.
    Journal of neurology, neurosurgery, and psychiatry 11/2013; · 4.87 Impact Factor

Publication Stats

4k Citations
1,169.38 Total Impact Points

Institutions

  • 2012–2014
    • Ottawa Hospital Research Institute
      Ottawa, Ontario, Canada
    • Icahn School of Medicine at Mount Sinai
      Manhattan, New York, United States
    • Universität Basel
      Bâle, Basel-City, Switzerland
    • Claude Bernard University Lyon 1
      Villeurbanne, Rhône-Alpes, France
  • 1997–2014
    • University of Ottawa
      • • Department of Medicine
      • • Department of Biochemistry, Microbiology and Immunology
      • • Division of Medical Oncology
      Ottawa, Ontario, Canada
  • 2013
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
    • University of Texas Health Science Center at Houston
      • Department of Neurology
      Houston, TX, United States
    • Università degli Studi di Siena
      Siena, Tuscany, Italy
  • 2011–2013
    • University of Toronto
      • Saint Michael's Hospital
      Toronto, Ontario, Canada
    • Ospedale di San Raffaele Istituto di Ricovero e Cura a Carattere Scientifico
      Milano, Lombardy, Italy
  • 2011–2012
    • Università degli Studi di Genova
      • Dipartimento di Medicina sperimentale (DIMES)
      Genova, Liguria, Italy
  • 2002–2012
    • The Ottawa Hospital
      • Department of Neurology
      Ottawa, Ontario, Canada
  • 1990–2012
    • McGill University
      • • Neuroimmunology Unit
      • • Department of Neurology and Neurosurgery
      Montréal, Quebec, Canada
    • Université de Montréal
      • Department of Medicine
      Montréal, Quebec, Canada
  • 2010
    • The University of Calgary
      Calgary, Alberta, Canada
    • University of Colorado Colorado Springs
      Colorado Springs, Colorado, United States
  • 2007–2010
    • Carleton University
      • Department of Psychology
      Ottawa, Ontario, Canada
    • SickKids
      • Division of Neurology
      Toronto, Ontario, Canada
  • 2007–2009
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
  • 2008
    • Barrow Neurological Institute
      Phoenix, Arizona, United States
  • 2007–2008
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2006
    • The National Institute of Neurology and Neurosurgery
      Tlalpam, The Federal District, Mexico
  • 2005
    • Multiple Sclerosis Society of Canada
      Ottawa, Ontario, Canada
  • 1992
    • Wayne State University
      • Department of Neurology
      Detroit, MI, United States