T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`original article
`
`A Placebo-Controlled Trial of Oral
`Cladribine for Relapsing Multiple Sclerosis
`Gavin Giovannoni, M.B., B.Ch., Ph.D., Giancarlo Comi, M.D., Stuart Cook, M.D.,
`Kottil Rammohan, M.D., Peter Rieckmann, M.D.,
`Per Soelberg Sørensen, M.D., D.M.Sc., Patrick Vermersch, M.D., Ph.D.,
`Peter Chang, Ph.D., Anthony Hamlett, Ph.D., Bruno Musch, M.D., Ph.D.,
`and Steven J. Greenberg, M.D., for the CLARITY Study Group*
`
`A bs tr ac t
`
`From Queen Mary University London,
`the Blizard Institute of Cell and Molecu-
`lar Science, Barts and the London School
`of Medicine and Dentistry, London (G.G.);
`the Institute of Experimental Neurology,
`Università Vita-Salute San Raffaele, Mi-
`lan (G.C.); the University of Medicine and
`Dentistry, New Jersey Medical School,
`Newark (S.C.); Ohio State University, Co-
`lumbus (K.R.); the University of British
`Columbia and Vancouver Coastal Health,
`Vancouver, BC, Canada (P.R.); Copenha-
`gen University Hospital, Rigshospitalet,
`Copenhagen (P.S.S.); the University of
`Lille–Nord de France, Lille, France (P.V.);
`and Merck Serono, Geneva (P.C., A.H.,
`B.M., S.J.G.). Address reprint requests to
`Dr. Giovannoni at the Neuroscience Cen-
`tre, Blizard Institute of Cell and Molecu-
`lar Science, 4 Newark St., Whitechapel,
`London E1 2AT, United Kingdom, or at
`g.giovannoni@qmul.ac.uk.
`
`*Other members of Cladribine Tablets
`Treating Multiple Sclerosis Orally
`(CLARITY) study group are listed in the
`Supplementary Appendix, available with
`the full text of this article at NEJM.org.
`
`This article (10.1056/NEJMoa0902533)
`was published on January 20, 2010, at
`NEJM.org.
`
`N Engl J Med 2010;362:416-26.
`Copyright © 2010 Massachusetts Medical Society.
`
`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 kilo-
`gram), 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 com-
`parisons), 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 sig-
`nificant 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 cladri-
`bine 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, respec-
`tively, 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.)
`
`416
`
`n engl j med 362;5 nejm.org february 4, 2010
`
`The New England Journal of Medicine
`Downloaded from nejm.org on September 11, 2022. For personal use only. No other uses without permission.
` Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`Merck 2026
`TWi v Merck
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`
`

`

`Oral Cladribine or Placebo for Relapsing Multiple Sclerosis
`
`Multiple sclerosis is a chronic and
`
`debilitating autoimmune disorder of the
`central nervous system, in which T and
`B cells are believed to play a major pathophysio-
`logical role.1-3 Treatment benefits and disease
`modification can be obtained with the currently
`approved parenteral immunomodulatory and im-
`munosuppressant therapies: interferon beta, glatir-
`amer acetate, mitoxantrone, and natalizumab.
`However, treatment responses are often less than
`complete, and concern regarding safety and side-
`effect profiles may limit the general use of these
`drugs. The need for parenteral administration may
`present relative or absolute barriers to access,
`limiting treatment adherence and long-term out-
`comes.4
`Intracellular accumulation of the active metabo-
`lite of cladribine, 2-chlorodeoxyadenosine triphos-
`phate, results in the disruption of cellular me-
`tabolism, the inhibition of DNA synthesis and
`repair, and subsequent apoptosis.5 Cladribine pref-
`erentially affects lymphocytes because these cells
`have a relatively high ratio of deoxycytidine kinase
`to 5(cid:2)-nucleotidase and are dependent on adeno-
`sine deaminase activity to maintain the equilibrium
`of cellular concentrations of triphosphorylated
`nucleotides. The accumulation of the cladribine
`nucleotide produces rapid and sustained reduc-
`tions in CD4+ and CD8+ cells and rapid, though
`more transient, effects on CD19+ B cells, with
`relative sparing of other immune cells.5-8 Cladri-
`bine also has been shown to cause a reduction in
`the levels of proinflammatory cytokines and se-
`rum and cerebrospinal fluid chemokines, in ad-
`hesion molecule expression, and in mononuclear-
`cell migration.5,9-13
`In the Cladribine Tablets Treating Multiple
`Sclerosis Orally (CLARITY) study, we investigat-
`ed the efficacy and safety of cladribine in a 96-
`week, phase 3, double-blind, placebo-controlled,
`multicenter trial involving patients with relaps-
`ing–remitting multiple sclerosis. The two doses
`of cladribine that we evaluated were based on
`the results of previous clinical studies that used
`a parenteral formulation of the drug in various
`regimens.7,14-16 In order to provide an extended
`interim hematopoietic recovery period before sub-
`sequent retreatment, we administered cladribine
`in short courses within separate 48-week peri-
`ods rather than administering the aggregate
`treatment as six to eight consecutive monthly
`courses.
`
`Me thods
`
`Patients
`From April 20, 2005, to January 18, 2007, we re-
`cruited patients from 155 clinical centers in 32
`countries (for details, see the Supplementary Ap-
`pendix, available with the full text of this article
`at NEJM.org). Patients were eligible if they had re-
`ceived a diagnosis of relapsing–remitting multiple
`sclerosis (according to the McDonald criteria),17
`had lesions consistent with multiple sclerosis on
`magnetic resonance imaging (MRI) (according to
`the Fazekas criteria),18 had had at least one relapse
`within 12 months before study entry, and had a
`score of no more than 5.5 on the Kurtzke Expanded
`Disability Status Scale (EDSS, which ranges from
`0 to 10, with higher scores indicating a greater
`degree of disability).19
`Patients were excluded from the study if two
`or more previous disease-modifying therapies had
`failed or if they had received immunosuppressive
`therapy at any time before study entry or cytokine-
`based therapy, intravenous immune globulin ther-
`apy, or plasmapheresis within 3 months before
`study entry. Patients were also excluded if they had
`abnormal results on hematologic testing (a plate-
`let or neutrophil count below the lower limit of
`the normal range or a leukocyte count of half the
`lower limit of the normal range) within 28 days
`before study entry, had a disorder that could com-
`promise immune function (including systemic
`disease or infection with the human immunode-
`ficiency virus or human T-cell lymphotropic virus),
`or had had a relapse within 28 days before study
`entry. For any patient who had received a disease-
`modifying drug for multiple sclerosis, a washout
`period of at least 3 months before study entry was
`required.
`
`Study Design
`Eligible patients were assigned in an approximate
`1:1:1 ratio to receive one of two cumulative doses
`of cladribine over 96 weeks (either 3.5 mg or
`5.25 mg per kilogram of body weight) or match-
`ing placebo. Randomization was performed with
`the use of a central system and a computer-gen-
`erated treatment randomization code, with dynam-
`ic allocation by site in permuted blocks of six. The
`study drugs were administered orally as short
`courses, each consisting of one or two 10-mg
`cladribine tablets or matching placebo given once
`daily for the first 4 or 5 days of a 28-day period.
`
`n engl j med 362;5 nejm.org february 4, 2010
`
`417
`
`The New England Journal of Medicine
`Downloaded from nejm.org on September 11, 2022. For personal use only. No other uses without permission.
` Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`In the first 48-week treatment period, patients
`received either two courses of cladribine, followed
`by two courses of placebo (in the 3.5-mg group);
`four courses of cladribine (in the 5.25-mg group);
`or four courses of placebo (in the placebo group),
`starting at day 1 and at weeks 5, 9, and 13 (8 to
`20 days of treatment). In the second 48-week pe-
`riod, both cladribine groups received two cours-
`es of cladribine, and the placebo group received
`two courses of placebo, starting at weeks 48 and
`52 (8 to 10 days of treatment) (Fig. 1 in the Sup-
`plementary Appendix). After week 24, rescue ther-
`apy with subcutaneous interferon beta-1a (at a dose
`of 44 μg three times per week) was available if
`a patient had more than one relapse or a sustained
`increase in the EDSS score.
`The study was conducted in accordance with
`relevant clinical guidelines (see the Supplementary
`Appendix). All patients provided written informed
`consent.
`
`consistent with a relapse. Evaluators at a central
`neuroradiology center assessed MRI evaluations
`in a blinded fashion.
`Neurologic examinations included the EDSS
`evaluation,19 which was conducted at the prestudy
`evaluation and at day 1 and at weeks 13, 24, 36,
`48, 60, 72, 84, and 96. MRI scans were obtained
`at the prestudy evaluation and at weeks 24, 48, and
`96. Clinical laboratory tests, including chemical
`and hematologic analyses and urinalysis, were
`performed by a central laboratory at frequent in-
`tervals during the 96-week study (for details, see
`the Supplementary Appendix). For suspected re-
`lapses occurring between study visits, patients
`were required to attend the study site within 7 days
`after the onset of neurologic symptoms for ob-
`jective assessment by the evaluating physician in
`a blinded fashion. Relapses could be treated with
`intravenous corticosteroids at the discretion of the
`treating physician.
`
`Study Oversight
`The protocol was reviewed and approved by the
`local review board or ethics committee at each
`study center. An independent data and safety
`monitoring board reviewed the study conduct and
`all safety data. Data were gathered by an indepen-
`dent commercial research organization and ana-
`lyzed by the sponsor (Merck Serono) in accordance
`with the statistical plan. MRI data were analyzed
`by an independent commercial research organi-
`zation at a central reading center. The authors were
`involved in all stages of development and final-
`ization of the manuscript and were assisted by an
`independent medical-writing-services agency paid
`by Merck Serono. The first draft of the manuscript
`was cowritten by the lead academic author and a
`representative of the sponsor, with the medical-
`writing-services agency providing support as di-
`rected. The authors vouch for the completeness
`and accuracy of the data and analyses.
`
`Study Procedures
`To maintain the double-blind nature of the study,
`all patients within a weight range received the same
`number of tablets (cladribine or matched placebo).
`In addition, at each study site, a treating physician
`reviewed clinical laboratory results and assessed
`treatment-emergent adverse events and safety in-
`formation, and an independent evaluating physi-
`cian who was unaware of study-group assignments
`performed neurologic examinations and deter-
`mined whether a clinical event fulfilled criteria
`
`Primary and Secondary End Points
`The primary end point was the rate of relapse at
`96 weeks. A relapse was defined as an increase of
`2 points in at least one functional system of the
`EDSS or an increase of 1 point in at least two
`functional systems (excluding changes in bowel
`or bladder function or cognition) in the absence
`of fever, lasting for at least 24 hours and to have
`been preceded by at least 30 days of clinical sta-
`bility or improvement.
`Key clinical secondary efficacy end points were
`the proportion of patients who were relapse-free
`and the time to sustained progression of disabil-
`ity, which was defined as the time to a sustained
`increase (for at least 3 months) of at least 1 point
`in the EDSS score or an increase of at least 1.5
`points if the baseline EDSS score was 0. Addi-
`tional clinical efficacy end points included the
`time to the first relapse and the proportion of
`patients receiving rescue therapy with interfer-
`on beta-1a. Secondary MRI end points were the
`mean number of lesions per patient per scan at
`96 weeks for gadolinium-enhancing T1-weighted
`lesions, active T2-weighted lesions, and combined
`unique lesions, which were defined as new gado-
`linium-enhancing T1-weighted lesions or new
`nonenhancing or enlarging T2-weighted lesions
`(without double-counting).
`The safety assessment included a review of the
`incidence of treatment-emergent adverse events
`in each study group, physical examination, and
`laboratory measurements. A strict protocol was
`
`418
`
`n engl j med 362;5 nejm.org february 4, 2010
`
`The New England Journal of Medicine
`Downloaded from nejm.org on September 11, 2022. For personal use only. No other uses without permission.
` Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`

`

`Oral Cladribine or Placebo for Relapsing Multiple Sclerosis
`
`established for the management of hematologic
`events (see the Supplementary Appendix).
`
`Statistical Analysis
`We determined that 1290 patients (approximately
`430 in each group) were required to provide a pow-
`er of 90% to detect a clinically meaningful rela-
`tive reduction of 25% in the relapse rate in the
`cladribine groups, as compared with the placebo
`group, at 96 weeks (the primary end point). This
`
`was calculated with the use of a two-sided t-test
`on the assumption that a mean number of 2.1 re-
`lapses would occur in the placebo group, that the
`standard deviation for the number of relapses in
`each group would be 2.02, that the proportion of
`patients who could not be evaluated would be 10%,
`and that the two-sided type I error rate for the
`comparison between each cladribine group and the
`placebo group would be 2.5%.
`The intention-to-treat population included all
`
`Table 1. Demographic and Clinical Characteristics of the Patients at Baseline (Intention-to-Treat Population).*
`
`Variable
`
`Age — yr
`Mean
`Range
`Female sex — no. (%)
`Mean weight — kg
`Race — no. (%)†
`White
`Black
`Other
`Previous therapy with any disease-modifying drug —
`no. (%)‡
`Disease duration from first onset — yr
`Mean
`Range
`EDSS score¶
`0 — no. (%)
`1 — no. (%)
`2 — no. (%)
`3 — no. (%)
`4 — no. (%)
`≥5 — no. (%)
`Mean score
`Gadolinium-enhancing T1-weighted lesions
`Patients with lesions — no. (%)
`Mean no. of lesions∥
`Mean volume of T2-weighted lesions — mm3
`
`Placebo
`(N = 437)
`
`38.7±9.9
`18–64
`288 (65.9)
`70.3±15.4
`
`429 (98.2)
`1 (0.2)
`7 (1.6)
`142 (32.5)
`
`8.9±7.4
`0.4–39.5
`
`13 (3.0)
`70 (16.0)
`127 (29.1)
`96 (22.0)
`83 (19.0)
`48 (11.0)
`2.9±1.3
`
`Cladribine
`
`3.5 mg/kg
`(N = 433)
`
`5.25 mg/kg
`(N = 456)
`
`37.9±10.3
`18–65
`298 (68.8)
`68.1±14.6
`
`425 (98.2)
`2 (0.5)
`6 (1.4)
`113 (26.1)
`
`7.9±7.2§
`0.3–42.3
`
`12 (2.8)
`75 (17.3)
`133 (30.7)
`108 (24.9)
`71 (16.4)
`34 (7.9)
`2.8±1.2
`
`39.1±9.9
`18–65
`312 (68.4)
`69.3±14.8
`
`446 (97.8)
`4 (0.9)
`6 (1.3)
`147 (32.2)
`
`9.3±7.6
`0.4–35.2
`
`11 (2.4)
`80 (17.5)
`119 (26.1)
`108 (23.7)
`84 (18.4)
`54 (11.8)
`3.0±1.4
`
`128 (29.3)
`0.8±2.1
`14,287.6±13,104.8
`
`138 (31.9)
`1.0±2.7
`14,828.0±16,266.8
`
`147 (32.2)
`1.0±2.3
`17,202.1±17,467.7
`
`* Plus–minus values are means ±SD. Percentages may not total 100 because of rounding.
`† Race was determined by the investigators.
`‡ The most commonly used drugs were intramuscular interferon beta-1a (Avonex, 11.2% of patients), subcutaneous in-
`terferon beta-1b (Betaseron, 10.6% of patients), subcutaneous interferon beta-1a (Rebif, 9.4% of patients), and subcu-
`taneous glatiramer acetate (Copaxone, 6.5% of patients).
`§ P = 0.005 for the overall comparison among the three groups.
`¶ Scores on the Expanded Disability Status Scale (EDSS) range from 0 to 10, with higher scores indicating a greater de-
`gree of disability.
`∥ All imaging findings were based on all images that could be evaluated.
`
`n engl j med 362;5 nejm.org february 4, 2010
`
`419
`
`The New England Journal of Medicine
`Downloaded from nejm.org on September 11, 2022. For personal use only. No other uses without permission.
` Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`patients who underwent randomization, and the
`safety population included all patients who re-
`ceived at least one dose of a study drug and for
`whom follow-up safety data were available. The
`primary efficacy measurement was analyzed with
`the use of a Poisson regression model including
`effects for treatment and region and the log of
`time in the study as the offset variable. The study
`
`groups were compared by means of an approxi-
`mate chi-square test on the basis of Wald statis-
`tics and Hochberg’s step-up method for multiple
`comparisons to protect the type I error.
`For patients who received rescue therapy, the
`primary and secondary efficacy analyses included
`the prerescue data and imputed data from the time
`of rescue onward, according to prespecified meth-
`
`Table 2. Clinical and Imaging End Points and Relapses during the 96-week Study (Intention-to-Treat Population).*
`
`End Point
`
`Relapse rate (primary end point)
`
`Annualized relapse rate (95% CI)
`
`Relative reduction in annualized relapse rate for cladribine vs.
`placebo — %†
`
`P value‡
`
`Relapse-free rate
`
`Patients without relapse — no. (%)
`
`Odds ratio for cladribine vs. placebo (95% CI)§
`
`P value¶
`
`Relapse at 96 weeks
`
`No. of relapses — no. of patients (%)
`
`0
`
`1
`
`2
`
`3
`
`Placebo
`(N = 437)
`
`Cladribine
`
`3.5 mg/kg
`(N = 433)
`
`5.25 mg/kg
`(N = 456)
`
`0.33 (0.29–0.38)
`
`0.14 (0.12–0.17)
`
`0.15 (0.12–0.17)
`
`57.6
`
`<0.001
`
`54.5
`
`<0.001
`
`266 (60.9)
`
`345 (79.7)
`
`360 (78.9)
`
`2.53 (1.87–3.43)
`
`2.43 (1.81–3.27)
`
`<0.001
`
`<0.001
`
`266 (60.9)
`
`109 (24.9)
`
`44 (10.1)
`
`15 (3.4)
`
`3 (0.7)
`
`345 (79.7)
`
`69 (15.9)
`
`13 (3.0)
`
`5 (1.2)
`
`1 (0.2)
`
`360 (78.9)
`
`77 (16.9)
`
`13 (2.9)
`
`5 (1.1)
`
`1 (0.2)
`
`≥4
`
`P value∥
`
`Need for rescue therapy
`
`<0.001
`
`<0.001
`
`Patients receiving rescue therapy — no. (%)
`
`Odds ratio for cladribine vs. placebo (95% CI)§
`
`27 (6.2)
`
`11 (2.5)
`
`9 (2.0)
`
`0.40 (0.19–0.81)
`
`0.31 (0.14–0.66)
`
`P value¶
`
`Time to first relapse
`
`15th Percentile of time to event — mo**
`
`Hazard ratio for cladribine vs. placebo (95% CI)††
`
`P value††
`
`Time to 3-mo sustained change in EDSS score
`
`10th Percentile of time to event — mo**
`
`Hazard ratio for cladribine vs. placebo (95% CI)††
`
`P value††
`
`Patients without a 3-mo sustained change in EDSS score
`
`Patients with no change — no. (%)
`
`Odds ratio for cladribine vs. placebo (95% CI)§
`
`P value¶
`
`420
`
`4.6
`
`0.01
`
`13.4
`
`0.003
`
`13.3
`
`0.44 (0.34–0.58)
`
`0.46 (0.36–0.60)
`
`<0.001
`
`<0.001
`
`10.8
`
`13.6
`
`13.6
`
`0.67 (0.48–0.93)
`
`0.69 (0.49–0.96)
`
`0.02
`
`0.03
`
`347 (79.4)
`
`371 (85.7)
`
`387 (84.9)
`
`1.55 (1.09–2.22)
`
`1.46 (1.03–2.07)
`
`0.02
`
`0.03
`
`n engl j med 362;5 nejm.org february 4, 2010
`
`The New England Journal of Medicine
`Downloaded from nejm.org on September 11, 2022. For personal use only. No other uses without permission.
` Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`

`

`Oral Cladribine or Placebo for Relapsing Multiple Sclerosis
`
`Table 2. (Continued.)
`
`End Point
`
`Lesion activity on brain MRI
`
`Gadolinium-enhancing T1-weighted lesions
`
`Mean no.
`
`Relative reduction — %
`
`Active T2-weighted lesions
`
`Mean no.
`
`Relative reduction — %
`
`Combined unique lesions
`
`Mean no.
`
`Relative reduction — %
`
`P value‡‡
`
`Placebo
`(N = 437)
`
`0.91
`
`1.43
`
`1.72
`
`Cladribine
`
`3.5 mg/kg
`(N = 433)
`
`5.25 mg/kg
`(N = 456)
`
`0.12
`
`85.7
`
`0.38
`
`73.4
`
`0.43
`
`74.4
`
`0.11
`
`87.9
`
`0.33
`
`76.9
`
`0.38
`
`77.9
`
`<0.001
`
`<0.001
`
`* EDSS denotes Expanded Disability Status Scale, and MRI magnetic resonance imaging.
`† The relative reduction in the annualized relapse rate was calculated as the ratio of the difference in the annualized relapse rate between
`the placebo group and the cladribine group to the annualized relapse rate in the placebo group.
`‡ The P value was based on a Wald chi-square test from an analysis of the number of relapses with the use of a Poisson regression model
`with fixed effects for treatment and region and the log of time in the study as an offset variable.
`§ Odds ratios and associated 95% confidence intervals were estimated with the use of a logistic-regression model with fixed effects for
`study group and region.
`¶ The P value was based on a Wald chi-square test from an end-point analysis with the use of a logistic-regression model with fixed effects
`for study group and region.
`∥ The P value was based on a Cochran–Mantel–Haenszel test with adjustment for the baseline number of relapses.
`** The 10th and 15th percentile values were estimated from the Kaplan–Meier survival curve.
`†† The hazard ratio, 95% confidence intervals, and P values were based on a Cox proportional-hazards model with fixed effects for study
`group and region.
`‡‡ The P value is for all comparisons with placebo for imaging measurements and was based on a nonparametric analysis-of-covariance
`model on ranked data with fixed effects for study group and region and the number of gadolinium-enhancing T1-weighted lesions at base-
`line as a covariate.
`
`ods in the statistical analysis plan. For the primary
`end point, imputed data were derived only from
`patients in the placebo group.
`In the analysis of secondary end points, the
`proportions of patients who were relapse-free and
`progression-free were analyzed with the use of a
`logistic-regression model that included study-
`group and region effects, and odds ratio and 95%
`confidence intervals were estimated for each study
`group. The three study groups were compared
`with the use of an approximate chi-square test on
`the basis of Wald statistics. The time to the first
`relapse and the time to a 3-month sustained
`change in the EDSS score were analyzed with the
`use of a Cox proportional-hazards model that in-
`cluded study-group and region effects, and the
`hazard ratio for the time to the first relapse and
`the time to a 3-month sustained change in the
`EDSS score in each group and associated 95%
`
`confidence intervals were estimated. Kaplan–Meier
`plots of the time to the first relapse and the time
`to a 3-month sustained change in the EDSS score
`were also generated.
`Secondary end points that were related to le-
`sion counts on MRI were analyzed with the use of
`a nonparametric analysis-of-covariance model on
`ranked data with effects for study group and re-
`gion adjusted for baseline counts of gadolinium-
`enhancing T1 lesions. To protect the overall fami-
`ly-wise type I error rate of 5%, dose groups that
`differed significantly from placebo for the pri-
`mary efficacy measures were compared with pla-
`cebo for the three secondary MRI measurements
`with the use of a hierarchical testing procedure
`that was based on the Hochberg procedure. The
`sequential testing of the measurements was car-
`ried out only if the test for the previous measure-
`ment was significant.
`
`n engl j med 362;5 nejm.org february 4, 2010
`
`421
`
`The New England Journal of Medicine
`Downloaded from nejm.org on September 11, 2022. For personal use only. No other uses without permission.
` Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`Sensitivity analyses were conducted to assess
`the effect of baseline differences in disease char-
`acteristics on efficacy outcome measures. The re-
`sults of these analyses are not reported here, since
`no material effects were shown. No interim analy-
`ses were conducted for this study.
`
`R esults
`
`Patients
`The demographic and clinical characteristics of
`the intention-to-treat population of 1326 patients
`was generally well balanced across the three study
`groups, although patients receiving 3.5 mg of
`cladribine per kilogram had a shorter mean du-
`ration of disease (P = 0.005 for the overall com-
`parison) (Table 1). Almost one third of patients had
`previously received disease-modifying therapy.
`Overall, 1184 patients (89.3%) completed the 96-
`week study (91.9% in the cladribine 3.5-mg group,
`89.0% in the cladribine 5.25-mg group, and 87.0%
`in the placebo group) (Fig. 2 in the Supplemen-
`tary Appendix). A total of 1165 patients (87.9%)
`completed treatment (91.2%, 86.2%, and 86.3%,
`respectively). The mean time of participation in the
`study was 89.4 weeks (91.0, 89.4, and 87.8 weeks,
`respectively).
`
`Primary and Secondary End Points
`The annualized relapse rate at 96 weeks was sig-
`nificantly reduced in both cladribine groups, as
`compared with the placebo group (0.14 in the
`cladribine 3.5-mg group and 0.15 in the cladri-
`bine 5.25-mg group, vs. 0.33 in the placebo group),
`for relative reductions of 57.6% and 54.5%, respec-
`tively (P<0.001 for both comparisons) (Table 2 and
`Fig. 1A and 1C). The proportion of patients who
`remained relapse-free at 96 weeks was significantly
`higher in both cladribine groups (79.7% and 78.9%,
`respectively), as compared with the placebo group
`(60.9%) (P<0.001 for both comparisons) (Table 2).
`In addition, the time to the first relapse was lon-
`ger in both cladribine groups (hazard ratio in the
`3.5-mg group, 0.44; 95% confidence interval [CI],
`0.34 to 0.58; P<0.001; and hazard ratio in the
`5.25-mg group, 0.46; 95% CI, 0.36 to 0.60; P<0.001
`for both comparisons) (Table 2 and Fig. 1B). These
`improvements were achieved with a reduction in
`the odds of receiving rescue therapy with interferon
`beta-1a in the cladribine 3.5-mg group (60%) and
`the cladribine 5.25-mg group (69%), as compared
`with placebo (P = 0.01 and P = 0.003, respectively)
`(Table 2).
`
`During the 96-week study, there was a relative
`reduction in the risk of 3-month sustained pro-
`gression of disability in both cladribine groups,
`as compared with placebo, with a 33% reduction
`in the cladribine 3.5-mg group (hazard ratio, 0.67;
`95% CI, 0.48 to 0.93; P = 0.02) and a 31% reduction
`in the cladribine 5.25-mg group (hazard ratio,
`0.69; 95% CI, 0.49 to 0.96; P = 0.03) (Table 2 and
`Fig. 1D). There were corresponding increases in
`the odds for remaining free of 3-month sustained
`disability progression in both cladribine groups,
`as compared with placebo (P = 0.02 for the 3.5-mg
`group and P = 0.03 for the 5.25-mg group) (Ta-
`ble 2).
`Cladribine treatment resulted in significant re-
`ductions in measures of MRI activity, as compared
`with placebo. Patients in the cladribine 3.5-mg
`group and cladribine 5.25-mg group had fewer le-
`sions per patient per scan than those in the pla-
`cebo group for gadolinium-enhancing T1 lesions
`(mean number, 0.12 and 0.11, respectively, vs.
`0.91), active T2 lesions (mean number, 0.38 and
`0.33, respectively, vs. 1.43), and combined unique
`lesions (mean number, 0.43 and 0.38, respectively,
`vs. 1.72) (P<0.001 for all comparisons vs. placebo)
`(Table 2).
`
`Adverse Events
`Lymphocytopenia (mostly graded as mild or mod-
`erate) was reported more frequently among pa-
`tients receiving cladribine than among those re-
`ceiving placebo (Table 3). Severe neutropenia (as
`rated by the investigators) was reported in three
`patients receiving cladribine (one in the 3.5-mg
`group and two in the 5.25-mg group), with severe
`thrombocytopenia and pancytopenia in one of
`the patients in the latter group, who also had an
`exacerbation of latent tuberculosis (see the Sup-
`plementary Appendix). There were no cases of se-
`vere anemia. The effects of cladribine on lym-
`phocyte counts in the first and second 48-week
`periods are presented in Table 4. Figure 3 in the
`Supplementary Appendix shows the effects of
`therapy on lymphocyte and neutrophil counts over
`the duration of the study. Maximal effects on lym-
`phocyte, neutrophil, and platelet counts and he-
`moglobin levels are presented, according to labo-
`ratory criteria of the National Cancer Institute’s
`Common Terminology Criteria for Adverse Events,
`in Table 1 in the Supplementary Appendix.
`Infections or infestations were reported in
`47.7% of the patients in the cladribine 3.5-mg
`group, 48.9% of those in the cladribine 5.25-mg
`
`422
`
`n engl j med 362;5 nejm.org february 4, 2010
`
`The New England Journal of Medicine
`Downloaded from nejm.org on September 11, 2022. For personal use only. No other uses without permission.
` Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`

`

`Oral Cladribine or Placebo for Relapsing Multiple Sclerosis
`
`(cid:2) (cid:2)(cid:9)(cid:9)(cid:13)(cid:4)(cid:8)(cid:7)(cid:14)(cid:6)(cid:5)(cid:1)(cid:3)(cid:6)(cid:8)(cid:4)(cid:10)(cid:11)(cid:6)(cid:1)(cid:3)(cid:4)(cid:12)(cid:6)
`
`(cid:23)
`
`(cid:32)(cid:7)(cid:42)(cid:6)(cid:1)(cid:12)(cid:43)(cid:1)(cid:24)(cid:7)(cid:44)(cid:11)(cid:12)(cid:1)(cid:3)(cid:6)(cid:8)(cid:4)(cid:10)(cid:11)(cid:6)
`
`Cladribine 5.25 mg/kg
`P<0.001
`
`Cladribine 3.5 mg/kg
`P<0.001
`
`Placebo
`
`12
`
`24
`
`36
`
`48
`
`60
`
`72
`
`84
`
`96
`
`(cid:38)(cid:6)(cid:6)(cid:45)(cid:11)
`
`100
`
`75
`
`50
`
`25
`
`0
`
`0
`
`(cid:3)(cid:6)(cid:8)(cid:4)(cid:10)(cid:11)(cid:6)(cid:1)(cid:16)(cid:15)(cid:17)
`
`(cid:30)(cid:4)(cid:12)(cid:7)(cid:6)(cid:9)(cid:12)(cid:11)(cid:1)(cid:46)(cid:7)(cid:12)(cid:40)(cid:1)(cid:28)(cid:43)
`
`(cid:32)(cid:47)(cid:20)(cid:1)(cid:4)(cid:12)(cid:1)(cid:3)(cid:7)(cid:11)(cid:45)
`Placebo
`Cladribine
`3.5 mg/kg
`Cladribine
`5.25 mg/kg
`
`437
`
`424
`
`399
`
`373
`
`355
`
`333
`
`315
`
`304
`
`304
`
`433
`
`424
`
`407
`
`389
`
`379
`
`364
`
`355
`
`347
`
`347
`
`456
`
`447
`
`425
`
`404
`
`388
`
`375
`
`363
`
`350
`
`350
`
`54.5% reduction
`P<0.001
`
`57.6% reduction
`P<0.001
`
`0.33
`
`0.14
`
`0.15
`
`Placebo
`(N=437)
`
`Cladribine
`3.5 mg/kg
`(N=433)
`
`Cladribine
`5.25 mg/kg
`(N=456)
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0.0
`
`(cid:2)(cid:9)(cid:9)(cid:13)(cid:4)(cid:8)(cid:7)(cid:14)(cid:6)(cid:5)(cid:1)(cid:3)(cid:6)(cid:8)(cid:4)(cid:10)(cid:11)(cid:6)(cid:1)(cid:3)(cid:4)(cid:12)(cid:6)
`
`(cid:24)
`
`(cid:22)(cid:13)(cid:42)(cid:13)(cid:8)(cid:4)(cid:12)(cid:7)(cid:45)(cid:6)(cid:1)(cid:28)(cid:43)(cid:19)(cid:1)(cid:43)(cid:38)(cid:1)(cid:3)(cid:6)(cid:8)(cid:4)(cid:10)(cid:11)(cid:6)(cid:11)
`
`(cid:25)
`
`(cid:32)(cid:7)(cid:42)(cid:6)(cid:1)(cid:12)(cid:43)(cid:1)(cid:30)(cid:44)(cid:43)(cid:39)(cid:44)(cid:6)(cid:11)(cid:11)(cid:7)(cid:43)(cid:9)
`
`Placebo
`
`Cladribine 5.25 mg/kg
`P=0.03
`
`25
`
`20
`
`15
`
`10
`
`(cid:26)(cid:25)(cid:35)(cid:35)(cid:1)(cid:34)(cid:48)(cid:47)(cid:43)(cid:48)(cid:6)(cid:11)(cid:11)(cid:7)(cid:47)(cid:9)(cid:1)(cid:16)(cid:15)(cid:17)
`
`Placebo
`
`Cladribine 5.25 mg/kg
`
`252
`
`114
`
`109
`
`300
`
`250
`
`200
`
`150
`
`100
`
`5
`
`0
`
`Cladribine 3.5 mg/kg
`P=0.02
`
`0
`
`12
`
`24
`
`36
`
`48
`
`60
`
`72
`
`84
`
`96
`
`(cid:38)(cid:6)(cid:6)(cid:45)(cid:11)
`
`(cid:34)(cid:4)(cid:12)(cid:7)(cid:6)(cid:9)(cid:12)(cid:11)(cid:1)(cid:50)(cid:7)(cid:12)(cid:44)(cid:1)(cid:21)(cid:19)(cid:31)(cid:47)(cid:1)(cid:24)(cid:47)(cid:9)(cid:42)(cid:7)(cid:48)(cid:46)(cid:6)(cid:5)
`
`(cid:32)(cid:47)(cid:20)(cid:1)(cid:4)(cid:12)(cid:1)(cid:3)(cid:7)(cid:11)(cid:45)
`Placebo
`Cladribine
`3.5 mg/kg
`Cladribine
`5.25 mg/kg
`
`437
`
`424
`
`399
`
`373
`
`355
`
`333
`
`315
`
`304
`
`304
`
`433
`
`424
`
`407
`
`389
`
`379
`
`364
`
`355
`
`347
`
`347
`
`456
`
`447
`
`425
`
`404
`
`388
`
`375
`
`363
`
`350
`
`350
`
`Cladribine 3.5 mg/kg
`
`12
`
`24
`
`36
`
`48
`
`60
`
`72
`
`84
`
`96
`
`(cid:38)(cid:6)(cid:6)(cid:45)(cid:11)
`
`12
`
`4 5
`
`33
`
`19
`
`13
`
`30
`
`19
`
`16
`
`33
`
`15
`
`14
`
`34
`
`9
`
`15
`
`17
`
`8
`
`10
`
`50
`
`21
`
`30
`
`39
`
`13
`
`11
`
`50
`
`0
`
`0
`
`(cid:24)(cid:13)(cid:46)(cid:13)(cid:8)(cid:4)(cid:12)(cid:7)(cid:49)(cid:6)(cid:1)(cid:32)(cid:47)(cid:20)(cid:1)(cid:47)(cid:42)(cid:1)(cid:3)(cid:6)(cid:8)(cid:4)(cid:10)(cid:11)(cid:6)(cid:11)
`
`(cid:32)(cid:47)(cid:20)(cid:1)(cid:4)(cid:12)(cid:1)(cid:3)(cid:7)(cid:11)(cid:45)
`Placebo
`Cladribine
`3.5 mg/kg
`Cladribine
`5.25 mg/kg
`
`Figure 1. Efficacy Outcome Measures Relating to Relapse and Progression of Disability during the 96-Week Study Period (Intention