Elsevier

The Lancet Neurology

Volume 10, Issue 4, April 2011, Pages 329-337
The Lancet Neurology

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Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis

https://doi.org/10.1016/S1474-4422(11)70023-0Get rights and content

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.

Introduction

The accepted primary endpoints in phase 3 studies of therapies for relapsing-remitting multiple sclerosis (RRMS) are the rate of clinical relapses and the progression of disability, as measured by the expanded disability status scale (EDSS).1 These are commonly supported by secondary endpoints based on MRI measurements, which are a sensitive way of assessing the effect of treatment on inflammatory activity. In a post-hoc analysis of data from the AFFIRM trial, Havrdova and colleagues2 defined a composite efficacy parameter—freedom from disease activity—that incorporates clinical and radiological measures of disease activity, which they used to measure treatment success with natalizumab in RRMS.2 With the advent of effective biological therapies, freedom from disease activity has become an achievable outcome of treatment in another immune-mediated inflammatory disease, rheumatoid arthritis.3 Similarly, in multiple sclerosis, the growing number of therapies with new mechanisms of action and improved efficacy has increasingly made maintaining a comprehensive treatment response over an extended time period an expectation of therapy.

Cladribine, a synthetic deoxyadenosine analogue, induces a preferential and sustained reduction in numbers of circulating peripheral T and B lymphocytes,4 which are immune cells that have an important pathophysiological role in multiple sclerosis.5, 6, 7 This mechanism provides the rationale for use of a short-course annual dosing regimen of cladribine tablets as an oral multiple sclerosis therapy. The phase 3, double-blind, placebo-controlled, 96-week Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study8 (ClinicalTrials.gov number NCT00213135) assessed the efficacy and safety of cladribine for RRMS. In the CLARITY study, treatment with cladribine resulted in relative reductions in the annualised relapse rate by 55–58%, in risk of 3-month sustained EDSS progression by 31–33%, and in number of MRI active lesions per patient per scan by 73–88%, compared with placebo.8 Lymphopenia was the most common adverse event in patients treated with cladribine (reported in 21·6% and 31·5% of patients in the cladribine 3·5 mg/kg and 5·25 mg/kg groups, respectively, versus 1·8% in the placebo group), as was anticipated on the basis of the mechanism of action of cladribine. Infections or infestations were reported in 42·5%, 47·7%, and 48·9% of patients in the placebo, cladribine 3·5 mg/kg, and 5·25 mg/kg groups, respectively, with over 99% of events rated as mild or moderate in severity. 20 (2·3%) patients treated with cladribine developed herpes zoster; all cases were dermatomal in nature and no case was disseminated.8, 9

We report post-hoc analyses of data from the CLARITY study, investigating the early and sustained effects of treatment with cladribine tablets on individual and composite measures of disease activity-free status in patients with RRMS.

Section snippets

Patients and procedures

The methods of the CLARITY study have been published previously.8 Here we focus on information specific to this analysis.

Eligible patients had a diagnosis of RRMS according to the McDonald criteria,10 at least one relapse in the 12 months before study entry, MRI lesions consistent with multiple sclerosis in accordance with the Fazekas criteria,11 and an EDSS score of 0–5·5.12 Patients were excluded if two or more disease-modifying drugs had previously failed because of a lack of efficacy, or if

Results

1326 patients recruited from 155 clinical centres in 32 countries were randomly assigned to receive placebo (n=437), cladribine tablets 3·5 mg/kg (n=433), or cladribine tablets 5·25 mg/kg (n=456). 380 (87%) patients in the placebo group, 398 (92%) patients in the cladribine 3·5 mg/kg group, and 406 (89%) patients in the cladribine 5·25 mg/kg group completed the 96-week study. Treatment groups were generally well balanced with regard to baseline characteristics (webappendix p 2), although the

Discussion

Treatment with oral cladribine resulted in significant improvements in clinical and radiological efficacy outcomes, with significantly more patients remaining free from relapse, free from 3-month sustained EDSS progression and free from MRI lesion activity when treated with cladribine tablets versus placebo over 96 weeks. The treatment benefit was consistent across all pair-wise combinations of component measures that were tested. When all three component measures of disease activity were taken

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