Summary 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.
Summary Background Most patients with multiple sclerosis without previous optic neuritis have thinner retinal layers than healthy controls. We assessed the role of peripapillary retinal nerve fibre ...layer (pRNFL) thickness and macular volume in eyes with no history of optic neuritis as a biomarker of disability worsening in a cohort of patients with multiple sclerosis who had at least one eye without optic neuritis available. Methods In this multicentre, cohort study, we collected data about patients (age ≥16 years old) with clinically isolated syndrome, relapsing-remitting multiple sclerosis, and progressive multiple sclerosis. Patients were recruited from centres in Spain, Italy, France, Germany, Czech Republic, Netherlands, Canada, and the USA, with the first cohort starting in 2008 and the latest cohort starting in 2013. We assessed disability worsening using the Expanded Disability Status Scale (EDSS). The pRNFL thickness and macular volume were assessed once at study entry (baseline) by optical coherence tomography (OCT) and was calculated as the mean value of both eyes without optic neuritis for patients without a history of optic neuritis or the value of the non-optic neuritis eye for patients with previous unilateral optic neuritis. Researchers who did the OCT at baseline were masked to EDSS results and the researchers assessing disability with EDSS were masked to OCT results. We estimated the association of pRNFL thickness or macular volume at baseline in eyes without optic neuritis with the risk of subsequent disability worsening by use of proportional hazards models that included OCT metrics and age, disease duration, disability, presence of previous unilateral optic neuritis, and use of disease-modifying therapies as covariates. Findings 879 patients with clinically isolated syndrome (n=74), relapsing-remitting multiple sclerosis (n=664), or progressive multiple sclerosis (n=141) were included in the primary analyses. Disability worsening occurred in 252 (29%) of 879 patients with multiple sclerosis after a median follow-up of 2·0 years (range 0·5–5 years). Patients with a pRNFL of less than or equal to 87 μm or less than or equal to 88 μm (measured with Spectralis or Cirrus OCT devices) had double the risk of disability worsening at any time after the first and up to the third years of follow-up (hazard ratio 2·06, 95% CI 1·36–3·11; p=0·001), and the risk was increased by nearly four times after the third and up to the fifth years of follow-up (3·81, 1·63–8·91; p=0·002). We did not identify meaningful associations for macular volume. Interpretation Our results provide evidence of the usefulness of monitoring pRNFL thickness by OCT for prediction of the risk of disability worsening with time in patients with multiple sclerosis. Funding Instituto de Salud Carlos III.
Summary Background On the basis of various clinical and MRI measurements, the phase 3 Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study in patients with relapsing–remitting ...multiple sclerosis (RRMS) showed that short-course oral treatment with cladribine at cumulative doses of 3·5 and 5·25 mg/kg over 96 weeks was more effective than placebo. Achieving sustained freedom from disease activity is becoming a viable treatment goal in RRMS; we therefore aimed to assess the effects of cladribine on this composite outcome measure by doing a post-hoc analysis of data from the CLARITY study. Methods Freedom from disease activity is composed of three components that are commonly used individually as endpoints in clinical trials; it is defined as the patient having no relapse, no 3-month sustained change in expanded disability status scale (EDSS) score, and no new MRI lesions (no T1 gadolinium-enhancing or active T2 lesions) over a specified period. We assessed the effect of two doses of cladribine tablets versus placebo on the proportion of patients who were free from disease activity based on the individual components, all pair-wise combinations, and the composite of the three components (freedom from disease activity). Freedom from disease activity was analysed at 24, 48, and 96 weeks, and in subgroups of patients stratified according to baseline demographic and disease characteristics (age, disease duration, previous treatment with disease-modifying therapy, T1 gadolinium-enhancing lesion number, T2 lesion volume, EDSS score, number of previous relapses, and highly active disease). Findings Of the 1326 patients randomly assigned to treatment in the CLARITY study, 1192 were assessable for freedom from disease activity at 96 weeks. Over 24 weeks, 266 (67%) of 395 patients in the cladribine 3·5 mg/kg group and 283 (70%) of 406 in the cladribine 5·25 mg/kg group were free from disease activity, versus 145 (39%) of 373 in the placebo group (odds ratio OR 3·31, 95% CI 2·46–4·46 for the 3·5 mg/kg group; and 3·68, 2·73–4·97 for the 5·25 mg/kg group; both p<0·0001). Over 48 weeks, 208 (54%) of 384 patients in the cladribine 3·5 mg/kg group and 222 (56%) of 396 patients in the cladribine 5·25 mg/kg group were free from disease activity, versus 86 (24%) of 360 patients in the placebo group (OR 3·80, 2·77–5·22 for the 3·5 mg/kg group; 4·13, 3·02–5·66 for the 5·25 mg/kg group; both p<0·0001). Over 96 weeks, 178 (44%) of 402 patients in the cladribine 3·5 mg/kg group and 189 (46%) of 411 patients in the cladribine 5·25 mg/kg group were free from disease activity, versus 60 (16%) of 379 patients in the placebo group (OR 4·28, 3·05–6·02 for the 3·5 mg/kg group; 4·62, 3·29–6·48 for the 5·25 mg/kg group; both p<0·0001). The effects of cladribine tablets on freedom from disease activity were significant across all patient subgroups. Interpretation Treatment with cladribine tablets significantly increased the proportion of patients with sustained freedom from disease activity over 96 weeks compared with placebo. Sustained freedom from disease activity could become an important measure of therapeutic response in RRMS. Funding Merck Serono SA–Geneva, Switzerland; an affiliate of Merck, Darmstadt, Germany.
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