A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis

Gavin Giovannoni, Giancarlo Comi, Stuart Cook, Kottil W Rammohan, Peter Rieckmann, Per Soelberg Sørensen, Patrick Vermersch, Peter Chang, Anthony Hamlett, Bruno Musch, Steven J. Greenberg

Research output: Contribution to journalArticle

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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-ourse 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.).

Original languageEnglish
Pages (from-to)416-426
Number of pages11
JournalNew England Journal of Medicine
Volume362
Issue number5
DOIs
StatePublished - Feb 4 2010
Externally publishedYes

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Cladribine
Multiple Sclerosis
Placebos
Tablets
Recurrence
Magnetic Resonance Imaging
Confidence Intervals
Relapsing-Remitting Multiple Sclerosis
Lymphopenia
Immunomodulation
Herpes Zoster
Body Weight
Lymphocytes
Brain
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Giovannoni, G., Comi, G., Cook, S., Rammohan, K. W., Rieckmann, P., Sørensen, P. S., ... Greenberg, S. J. (2010). A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. New England Journal of Medicine, 362(5), 416-426. https://doi.org/10.1056/NEJMoa0902533

A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. / Giovannoni, Gavin; Comi, Giancarlo; Cook, Stuart; Rammohan, Kottil W; Rieckmann, Peter; Sørensen, Per Soelberg; Vermersch, Patrick; Chang, Peter; Hamlett, Anthony; Musch, Bruno; Greenberg, Steven J.

In: New England Journal of Medicine, Vol. 362, No. 5, 04.02.2010, p. 416-426.

Research output: Contribution to journalArticle

Giovannoni, G, Comi, G, Cook, S, Rammohan, KW, Rieckmann, P, Sørensen, PS, Vermersch, P, Chang, P, Hamlett, A, Musch, B & Greenberg, SJ 2010, 'A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis', New England Journal of Medicine, vol. 362, no. 5, pp. 416-426. https://doi.org/10.1056/NEJMoa0902533
Giovannoni, Gavin ; Comi, Giancarlo ; Cook, Stuart ; Rammohan, Kottil W ; Rieckmann, Peter ; Sørensen, Per Soelberg ; Vermersch, Patrick ; Chang, Peter ; Hamlett, Anthony ; Musch, Bruno ; Greenberg, Steven J. / A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. In: New England Journal of Medicine. 2010 ; Vol. 362, No. 5. pp. 416-426.
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AU - Sørensen, Per Soelberg

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N2 - Background: Cladribine provides immunomodulation through selective targeting of lymphocyte subtypes. We report the results of a 96-week phase 3 trial of a short-ourse 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.).

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