Fast track — ArticlesSustained 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
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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2022, Autoimmunity ReviewsCitation Excerpt :Oral cladribine is given in 2 five days courses in the first year and 2 five courses in the second year for a total of 20 days of treatment. Cladribine appears to work by depleting peripheral circulating auto-reactive B and T cells with decreases in absolute lymphocyte count, CD4+ T cell count and CD8+ T cell count correlating with MRI outcome in RRMS [98]. CD4+ T cells decrease after the 1st course reaching a nadir of 48–55% reduction from baseline [99] and 60% reduction after the 2nd course [76].
Monitoring of safety and effectiveness of cladribine in multiple sclerosis patients over 50 years
2022, Multiple Sclerosis and Related Disorders
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For other members see the webappendix