Background: A 24-week phase II trial has shown that 0·3 mg of laquinimod given daily to patients with relapsing-remitting multiple sclerosis was well tolerated and reduced the formation of active lesions. We assessed the effect of oral daily 0·3 and 0·6 mg laquinimod on MRI-monitored disease activity in a 36-week double-blind, placebo-controlled phase IIb study. Methods: The study was done in 51 centres in nine countries. Inclusion criteria were one or more relapses in the year before entry and at least one gadolinium enhancing (GdE) lesion on screening MRI. Of 720 patients screened, 306 eligible patients were enrolled. Patients, aged 18-50 years, were randomly assigned to placebo (n=102), laquinimod 0·3 mg a day (n=98), or 0·6 mg a day (n=106). Brain MRI scans and clinical assessments were done at week -4, baseline, and monthly from week 12 to week 36. The primary outcome was the cumulative number of GdE lesions at weeks 24, 28, 32, and 36. The principal analysis of the primary endpoint was done on the intention-to-treat cohort. This study is registered with ClinicalTrials.gov, number NCT00349193. Findings: Compared with placebo, treatment with laquinimod 0·6 mg per day showed a 40·4% reduction of the baseline adjusted mean cumulative number of GdE lesions per scan on the last four scans (simple means 4·2 [SD 9·2] vs 2·6 [5·3], p=0·0048); treatment with 0·3 mg per day showed no significant effects (3·9 [5·5] vs placebo, p=0·6740). Both doses of laquinimod were well tolerated, with some transient and dose-dependent increases in liver enzymes. A case of Budd-Chiari syndrome-ie, a thrombotic venous outflow obstruction of the liver-occurred after 1 month of exposure in a patient with underlying hypercoagulability who received 0·6 mg laquinimod. Anticoagulant treatment resulted in a decline of liver enzymes to normal without any clinical signs of hepatic decompensation. Interpretation: In patients with relapsing-remitting multiple sclerosis, 0·6 mg per day laquinimod significantly reduced MRI-measured disease activity and was well tolerated. Funding: Teva Pharmaceutical Industries.
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