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Publications (5)121.14 Total impact

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    ABSTRACT: OBJECTIVE: In Assessment of OraL Laquinimod in PrEventing ProGRession in Multiple SclerOsis (ALLEGRO), a phase III study in relapsing-remitting multiple sclerosis (RRMS), oral laquinimod slowed disability and brain atrophy progression, suggesting laquinimod may reduce tissue damage in MS. MRI techniques sensitive to the most destructive aspects of the disease were used to further investigate laquinimod's potential effects on inflammation and neurodegeneration. METHODS: 1106 RRMS patients were randomised 1:1 to receive once-daily oral laquinimod (0.6 mg) or placebo for 24 months. White matter (WM), grey matter (GM) and thalamic fractions were derived at months 0, 12 and 24. Also assessed were evolution of gadolinium-enhancing and/or new T2 lesions into permanent black holes (PBH); magnetisation transfer ratio (MTR) of normal-appearing brain tissue (NABT), WM, GM and T2 lesions; and N-acetylaspartate/creatine (NAA/Cr) levels in WM. RESULTS: Compared with placebo, laquinimod-treated patients showed lower rates of WM at months 12 and 24 (p=0.004 and p=0.035) and GM (p=0.004) atrophy at month 12 and a trend for less GM atrophy at month 24 (p=0.078). Laquinimod also slowed thalamic atrophy at month 12 (p=0.005) and month 24 (p=0.003) and reduced the number of PBH at 12 and 24 months evolving from active lesions (all p<0.05). By month 24, MTR decreased significantly in NABT (p=0.015), WM (p=0.011) and GM (p=0.034) in placebo-treated patients, but not in laquinimod-treated patients. WM NAA/Cr tended to increase with laquinimod and decrease with placebo at 24 months (p=0.179). CONCLUSIONS: Oral laquinimod may reduce (at least in the initial phase of treatment) some of the more destructive pathological processes in RRMS patients. TRIAL REGISTRATION: The ALLEGRO trial identifier number with clinicaltrials.gov is NCT00509145. KEYWORDS: MRI, Multiple Sclerosis
    Journal of neurology, neurosurgery, and psychiatry 01/2013; · 4.87 Impact Factor
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    ABSTRACT: Treatment options for patients suffering from progressive forms of multiple sclerosis (MS) remain inadequate. Mast cells actively participate in the pathogenesis of MS, in part because they release large amounts of various mediators that sustain the inflammatory network. Masitinib, a selective oral tyrosine kinase inhibitor, effectively inhibits the survival, migration and activity of mast cells. This exploratory study assessed the safety and clinical benefit of masitinib in the treatment of primary progressive MS (PPMS) or relapse-free secondary progressive MS (rfSPMS). Multicenter, randomized, placebo-controlled, proof-of-concept trial. Masitinib was administered orally at 3 to 6 mg/kg/day for at least 12 months, with dose adjustment permitted in event of insufficient response with no toxicity. The primary response endpoint was the change relative to baseline in the multiple sclerosis functional composite score (MSFC). Clinical response was defined as an increase in MSFC score relative to baseline of > 100%. Thirty-five patients were randomized to receive masitinib (N = 27) or placebo (N = 8). Masitinib was relatively well tolerated with the most common adverse events being asthenia, rash, nausea, edema, and diarrhea. The overall frequency of adverse events was similar to the placebo group, however, a higher incidence of severe and serious events was associated with masitinib treatment. Masitinib appeared to have a positive effect on MS-related impairment for PPMS and rfSPMS patients, as evidenced by an improvement in MSFC scores relative to baseline, compared with a worsening MSFC score in patients receiving placebo; +103% ± 189 versus -60% ± 190 at month-12, respectively. This positive, albeit non-statistically significant response was observed as early as month-3 and sustained through to month-18, with similar trends seen in the PPMS and rfSPMS subpopulations. A total of 7/22 (32%) assessable masitinib patients reported clinical response following 12 months of treatment (according to the modified intent-to-treat population, observed cases) compared with none in the placebo group. The Expanded Disability Status Scale remained stable for both treatment groups. These data suggest that masitinib is of therapeutic benefit to PPMS and rfSPMS patients and could therefore represent an innovative avenue of treatment for this disease. This exploratory trial provides evidence that may support a larger placebo-controlled investigation.
    BMC Neurology 06/2012; 12:36. · 2.56 Impact Factor
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    ABSTRACT: BACKGROUND: Two proof-of-concept clinical trials have provided evidence that laquinimod reduces disease activity in patients with relapsing-remitting multiple sclerosis. METHODS: We conducted a randomized, double-blind, phase 3 study at 139 sites in 24 countries. A total of 1106 patients with relapsing-remitting multiple sclerosis were randomly assigned in a 1:1 ratio to receive oral laquinimod at a dose of 0.6 mg once daily or placebo for 24 months. The primary end point was the annualized relapse rate during the 24-month period. Secondary end points included confirmed disability progression (defined as an increase in the score on the Expanded Disability Status Scale that was sustained for at least 3 months) and the cumulative number of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted magnetic resonance imaging. RESULTS: Treatment with laquinimod as compared with placebo was associated with a modest reduction in the mean (±SE) annualized relapse rate (0.30±0.02 vs. 0.39±0.03, P=0.002) and with a reduction in the risk of confirmed disability progression (11.1% vs. 15.7%; hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.91; P=0.01). The mean cumulative numbers of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted images were lower for patients receiving laquinimod than for those receiving placebo (1.33±0.14 vs. 2.12±0.22 and 5.03±0.08 vs. 7.14±0.07, respectively; P<0.001 for both comparisons). Transient elevations in alanine aminotransferase levels to greater than three times the upper limit of the normal range were observed in 24 patients receiving laquinimod (5%) and 8 receiving placebo (2%). CONCLUSIONS: In this phase 3 study, oral laquinimod administered once daily slowed the progression of disability and reduced the rate of relapse in patients with relapsing-remitting multiple sclerosis. (Funded by Teva Pharmaceutical Industries; ClinicalTrials.gov number, NCT00509145.). Comment in Oral laquinimod for multiple sclerosis. [N Engl J Med. 2012] New and old: notable drug developments for clinical practice. [J Neurol. 2012]
    New England Journal of Medicine 01/2012; 366(11):1000-1009. · 54.42 Impact Factor
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    ABSTRACT: To evaluate the prevalence of prior inflammatory events in patients consulting for a first inflammatory neurological event and improve early diagnosis of multiple sclerosis. During the initial visit, the neurologist gave patients a self-administered questionnaire containing 72 questions regarding previous symptoms lasting >24 h. During the follow-up visit, the neurologist validated the symptoms and collected information about the current attack. The cohort included 178 patients (74% women, mean age (SD) 33.7 (10.1) years). The main reason for the initial visit was visual disturbance and sensory troubles in limbs. Mean (SD) global Expanded Disability Status Scale score was 1.4 (1.1), 46% of brains MRIs were positive according to Barkhof-Tintoré criteria, 41% had abnormal white blood cell count in cerebrospinal fluid and 71% had immunoglobin G oligoclonal bands. Prior symptoms suggestive of demyelination were reported by 79 patients (44%), validated by the neurologist for 70% (55 patients) and identified only by the neurologist in four patients. Sequelae were observed in 14 patients with validated prior symptoms (26%). The self-administered questionnaire showed an overall sensitivity of 93% and specificity of 80% for identifying patients with prior symptoms suggestive of demyelination. A patient-administered questionnaire subsequently validated by the neurologist demonstrated that 33% of patients consulting for a first demyelinating event had prior symptoms suggestive of central nervous system demyelination that had gone unnoticed, and almost 70% had either sequelae of prior demyelination or McDonald criteria for dissemination in space. Such a questionnaire could be a useful tool for earlier diagnosis of multiple sclerosis.
    Journal of neurology, neurosurgery, and psychiatry 03/2011; 82(3):323-5. · 4.87 Impact Factor
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    ABSTRACT: BACKGROUND: Cladribine provides immunomodulation through selective targeting of lymphocyte subtypes. We report the results of a 96-week phase 3 trial of a short-course oral tablet therapy in patients with relapsing-remitting multiple sclerosis. METHODS: We randomly assigned 1326 patients in an approximate 1:1:1 ratio to receive one of two cumulative doses of cladribine tablets (either 3.5 mg or 5.25 mg per kilogram of body weight) or matching placebo, given in two or four short courses for the first 48 weeks, then in two short courses starting at week 48 and week 52 (for a total of 8 to 20 days per year). The primary end point was the rate of relapse at 96 weeks. RESULTS: Among patients who received cladribine tablets (either 3.5 mg or 5.25 mg per kilogram), there was a significantly lower annualized rate of relapse than in the placebo group (0.14 and 0.15, respectively, vs. 0.33; P<0.001 for both comparisons), a higher relapse-free rate (79.7% and 78.9%, respectively, vs. 60.9%; P<0.001 for both comparisons), a lower risk of 3-month sustained progression of disability (hazard ratio for the 3.5-mg group, 0.67; 95% confidence interval [CI], 0.48 to 0.93; P=0.02; and hazard ratio for the 5.25-mg group, 0.69; 95% CI, 0.49 to 0.96; P=0.03), and significant reductions in the brain lesion count on magnetic resonance imaging (MRI) (P<0.001 for all comparisons). Adverse events that were more frequent in the cladribine groups included lymphocytopenia (21.6% in the 3.5-mg group and 31.5% in the 5.25-mg group, vs. 1.8%) and herpes zoster (8 patients and 12 patients, respectively, vs. no patients). CONCLUSIONS: Treatment with cladribine tablets significantly reduced relapse rates, the risk of disability progression, and MRI measures of disease activity at 96 weeks. The benefits need to be weighed against the risks. (ClinicalTrials.gov number, NCT00213135.) 2010 Massachusetts Medical Society Comment in Oral cladribine and fingolimod for relapsing multiple sclerosis. [N Engl J Med. 2010] Oral therapy for multiple sclerosis--sea change or incremental step? [N Engl J Med. 2010] ACP Journal Club. Oral cladribine was more effective than placebo for relapsing-remitting multiple sclerosis. [Ann Intern Med. 2010] Oral cladribine and fingolimod for relapsing multiple sclerosis. [N Engl J Med. 2010]
    New England Journal of Medicine 01/2010; 362(5):416-426. · 54.42 Impact Factor