A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis.
BACKGROUND
Cladribine provides immunomodulation through selective targeting of lymphocyte subtypes. We report the results of a 96-week phase 3 trial of a short-course 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.)
Giovannoni
Gavin
G
Queen Mary University London, the Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, United Kingdom. g.giovannoni@qmul.ac.uk
Comi
Giancarlo
G
Cook
Stuart
S
Rammohan
Kottil
K
Rieckmann
Peter
P
Soelberg Sørensen
Per
P
Vermersch
Patrick
P
Chang
Peter
P
Hamlett
Anthony
A
Musch
Bruno
B
Greenberg
Steven J
SJ
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001921:Brain / Q000473:pathology; D017338:Cladribine / Q000009:adverse effects / Q000627:therapeutic use*; D004185:Disability Evaluation; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006562:Herpes Zoster / Q000209:etiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D057194:Intention to Treat Analysis; D008231:Lymphopenia / Q000139:chemically induced; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000473:pathology; D055815:Young Adult
D007166:Immunosuppressive Agents; D017338:Cladribine