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`Multiple Sclerosis Journltiple Sclerosis JournMultiple Sclerosis Journe Sclerosis Journe Sclerosis Journe Sclerosis JMultiple Sclerosis Journple Sclerosis JournMultiple Sclerosis Joule Sclerosis Journe Sclerosis Journe Sclero24458588585585555175511551771717117772777777777727772777227727603276600303760327666000333MuMMMMMuMMM Sclerosis Journosi Joiis Jouossis JournossiS is Jous J urrnalG Giovannoni P SoelbealG Giovannoni, P SoelbalG GiovannoalG Giovannoni, P SoelbealG Giovannoni, P SoelbealG Giovannoni, P Soelbaa G Giovannoni, P SoalG GiovannoG Giovannoni, P SoelbGiovannoni, P Soelbe, P SoelbeGiovannoni, P SoGiovannoni, P Sioo nnn , P Soelbennoni, P SoeeelGiovannoni, P Soelbnoni, P Soelberg Sorensenrg Sorensenrg Sorensensrg Sorensenrg Srg Sorensenrg Srg Sorg Srg Sororreen ennnSoorre
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`research-article2017
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`727603 MSJ0010.1177/1352458517727603Multiple Sclerosis JournalG Giovannoni, P Soelberg Sorensen66666660303030303030000303030303030030300330030003000000330300033330003330303666666033030303030303030303030300333300330300030000300 MSM
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`MULTIPLE
`SCLEROSIS MSJ
`JOURNAL
`
`Original Research Paper
`
`Safety and efficacy of cladribine tablets in
`patients with relapsing–remitting multiple
`sclerosis: Results from the randomized
`extension trial of the CLARITY study
`
`Gavin Giovannoni, Per Soelberg Sorensen, Stuart Cook, Kottil Rammohan, Peter Rieckmann,
`Giancarlo Comi, Fernando Dangond, Abidemi K Adeniji and Patrick Vermersch
`
`Abstract
`Background: In the 2-year CLARITY study, cladribine tablets significantly improved clinical and mag-
`netic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing–remitting multiple scle-
`rosis (MS).
`Objective: To assess the safety and efficacy of cladribine treatment in a 2-year Extension study.
`Methods: In this 2-year Extension study, placebo recipients from CLARITY received cladribine
`3.5 mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo, with blind
`maintained.
`Results: A total of 806 patients were assigned to treatment. Adverse event rates were generally similar
`between groups, but lymphopenia Grade ⩾ 3 rates were higher with cladribine than placebo (Grade 4
`lymphopenia occurred infrequently). In patients receiving cladribine 3.5 mg/kg in CLARITY and expe-
`riencing lymphopenia Grade ⩾ 3 in the Extension, >90% of those treated with cladribine 3.5 mg/kg and
`all treated with placebo in the Extension, recovered to Grade 0–1 by study end. Cladribine treatment in
`CLARITY produced efficacy improvements that were maintained in patients treated with placebo in
`the Extension; in patients treated with cladribine 3.5 mg/kg in CLARITY, approximately 75% remained
`relapse-free when given placebo during the Extension.
`Conclusion: Cladribine tablets treatment for 2 years followed by 2 years’ placebo treatment produced
`durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia
`or clinical worsening. No clinical improvement in efficacy was apparent following further treatment with
`cladribine tablets after the initial 2-year treatment period in this trial setting.
`
`Keywords: Relapsing–remitting multiple sclerosis, cladribine tablets, randomized trial, CLARITY
`Extension, safety, efficacy
`
`Date received: 20 December 2016; revised: 7 July 2017; accepted: 30 July 2017
`
`Introduction
`Cladribine is an oral, synthetic deoxyadenosine analog
`prodrug, which preferentially depletes lymphocytes
`by exploiting the kinase-to-phosphatase enzyme pro-
`file in these cells. This produces moderate and discon-
`tinuous reductions in T and B cells with relatively
`minor and transient effects on innate immune cells,
`such as neutrophils and monocytes.1 The dosing regi-
`men of cladribine tablets involves very short treatment
`periods relative to the length of clinical effect
`
`(8–10 days annually).2 In the Cladribine Tablets
`Treating Multiple Sclerosis Orally (CLARITY) study
`(ClinicalTrials.gov, NCT00213135), patients with
`active relapsing–remitting multiple sclerosis (RRMS)
`were randomized to placebo or one of two cumulative
`doses of cladribine tablets (3.5 or 5.25 mg/kg body
`weight) for 2 years; each dose showed significant
`benefits in rate of relapse, disability progression, and
`magnetic resonance imaging (MRI) measures.2 The
`most commonly reported adverse event (AE) was mild
`
`Multiple Sclerosis Journal
`
`2018, Vol. 24(12) 1594–1604
`
`DOI: 10.1177/
`https://doi.org/10.1177/1352458517727603
`1352458518727603
`https://doi.org/10.1177/1352458517727603
`© The Author(s), 2017.
`
`Article reuse guidelines:
`sagepub.com/journals-
`permissions
`
`Correspondence to:
`G Giovannoni
`Department of Neurology,
`Blizard Institute, Barts
`and The London School of
`Medicine and Dentistry,
`Queen Mary University of
`London, 4 Newark Street,
`London E1 2AT, UK.
`g.giovannoni@qmul.ac.uk
`
`Gavin Giovannoni
`Department of Neurology,
`Blizard Institute, Barts
`and The London School of
`Medicine and Dentistry,
`Queen Mary University of
`London, London, UK
`
`Per Soelberg Sorensen
`Department of Neurology,
`Danish Multiple Sclerosis
`Center, Copenhagen
`University Hospital,
`Copenhagen, Denmark
`
`Stuart Cook
`Department of Neurology &
`Neurosciences, New Jersey
`Medical School, Rutgers,
`The State University of New
`Jersey, Newark, NJ, USA
`
`Kottil Rammohan
`Department of Neurosurgery,
`The Ohio State University
`Columbus, OH, USA
`
`Peter Rieckmann
`Department of Neurology,
`Neurologische Klinik,
`Akademisches Krankenhaus
`Sozialstiftung Bamberg,
`Bamberg, Germany
`
`Giancarlo Comi
`Department of Neurology
`and Institute of Experimental
`Neurology, Ospedale San
`Raffaele, Università Vita-
`Salute San Raffaele, Milan,
`Italy
`
`Fernando Dangond
`Abidemi K Adeniji
`Department of Neurology and
`Immunology, EMD Serono,
`Inc., Billerica, MA, USA
`
`Patrick Vermersch
`Department of Neurosurgery,
`CHU Lille, Université de
`Lille, Lille, France
`
`1594
`
`Merck 2035
`Hopewell v Merck
`IPR2023-00480
`
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`

`

`G Giovannoni, P Soelberg Sorensen et al.
`
`to moderate lymphopenia, reflecting the mode of
`action of cladribine.2
`
`Here, we report findings from the CLARITY Extension
`study (ClinicalTrials.gov, NCT00641537), which
`investigated long-term safety, tolerability, and clinical
`benefits following administration of placebo or a
`cumulative dose of cladribine tablets 3.5 mg/kg body
`weight in patients who had completed CLARITY. The
`design allowed assessment of the effects of 2 years’
`additional treatment with cladribine tablets beyond
`the 2-year CLARITY regimen and included an
`assessment of the duration of the therapeutic benefit
`by a comparison of 2 years’ treatment with cladribine
`tablets followed by 2 years of placebo, and 2 years’
`treatment with cladribine tablets followed by two
`additional years of cladribine tablets treatment. In
`addition, early vs late treatment was compared by
`including a group receiving 2 years’ placebo treatment
`followed by 2 years’ cladribine tablets treatment.
`
`Methods
`
`Patients
`Patients who completed the 2-year study period in
`CLARITY were eligible for the Extension if they
`had normal lymphocyte count and other normal
`hematological results within 28 days of the first
`planned dose
`(see Supplementary Materials).
`CLARITY Extension was not a pre-planned study,
`and as a consequence after completing CLARITY,
`there was a variable gap period before patients entered
`the Extension (the median gap duration for the
`overall population was 40.3 weeks). Patients who had
`received interferon beta or glatiramer acetate during
`the gap period had to discontinue their disease-
`modifying drug (DMD) therapy ⩾3 months before
`the first study day of the Extension.
`
`Randomization and masking
`the Extension were
`Patients who
`entered
`re-randomized using an interactive voice response
`system. Randomization and double-blinding followed
`CLARITY procedures2 (see Supplementary Materials).
`The on-study treatment groups were as follows:
`
`(cid:3)(cid:120) CC 8.75 mg/kg (cladribine tablets 5.25 mg/kg
`in CLARITY/cladribine
`tablets 3.5 mg/kg
`CLARITY Extension);
`(cid:3)(cid:120) PC 3.5 mg/kg (placebo in CLARITY/cladrib-
`ine tablets 3.5 mg/kg in CLARITY Extension).
`
`Procedures
`The study design is represented in Figure 1. Patients
`in CLARITY were randomized (1:1:1 ratio) to one of
`two cumulative doses of cladribine tablets or placebo,
`taking one or two cladribine 10-mg tablets (or match-
`ing placebo) daily over 4–5 days in either Weeks 1
`and 5 of Years 1 and 2 (to give a cumulative dose of
`3.5 mg/kg) or Weeks 1, 5, 9, and 13 of Year 1 and Weeks
`1 and 5 of Year 2 (giving a 5.25 mg/kg cumulative
`dose).2 In the 96-week CLARITY Extension study,
`eligible patients who received placebo in CLARITY
`were assigned to cladribine tablets 3.5 mg/kg, and
`patients treated with cladribine tablets in CLARITY
`were re-randomized (2:1) to cladribine tablets 3.5 mg/
`kg or placebo. Treating physicians supervised study
`drug administration and monitored safety assessments
`including laboratory parameters and were responsible
`for the recording and treatment of AEs and MS
`relapses, whereas separate evaluating physicians
`assessed neurological findings and relapses (each was
`blinded to treatment group assignment). The blind was
`maintained from CLARITY in all treatment arms dur-
`ing the Extension. All patients treated with cladribine
`tablets during the Extension received a cumulative
`dose of 3.5 mg/kg, administered in Weeks 1, 5, 48, and
`52 (only patients with Grade 0 or 1 lymphocyte counts
`were retreated at Weeks 48 and 52). The Extension
`was followed by a 24-week “supplemental follow-up”
`(SUPF) during which patients did not receive treat-
`ment with cladribine tablets but could receive DMDs.
`
`Endpoints
`Safety and clinical endpoints, including amendments,
`are described in the Supplementary Materials. Clinical
`endpoints included the annualized relapse rate (ARR),
`the proportion of patients free of qualifying relapses,
`time to first qualifying relapse, and time to confirmed
`Expanded Disability Status Scale (EDSS) progression.
`
`(cid:3)(cid:120) CP 3.5 mg/kg (cladribine tablets 3.5 mg/kg in
`CLARITY/placebo in CLARITY Extension);
`(cid:3)(cid:120) CP 5.25 mg/kg (cladribine tablets 5.25 mg/kg
`in CLARITY/placebo in CLARITY Extension);
`(cid:3)(cid:120) CC 7 mg/kg (cladribine tablets 3.5 mg/kg in
`CLARITY/cladribine
`tablets 3.5 mg/kg
`in
`CLARITY Extension);
`
`Statistical analysis
`No sample size calculation was made as enrollment
`was limited to eligible patients from CLARITY.
`No hypotheses were pre-specified in the original
`protocol, but an amendment specified a benefit/
`risk analysis and a 2.5% significance level for the
`interim and final analyses. Efficacy endpoints were
`
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`Multiple Sclerosis Journal 24(12)
`
`Figure 1. Study design. Each short course of treatment comprised one or two 10-mg cladribine tablets taken once daily
`for four or five consecutive days or an equivalent number of matching placebo tablets. There was a variable interval
`between the treatment periods in the CLARITY and Extension studies.
`CP 3.5 mg/kg: cladribine tablets 3.5 mg/kg in CLARITY followed by placebo in CLARITY Extension; CP 5.25 mg/kg: cladribine
`tablets 5.25 mg/kg in CLARITY followed by placebo in CLARITY Extension; CC 7 mg/kg: cladribine tablets 3.5 mg/kg in CLARITY
`followed by cladribine tablets 3.5 mg/kg in CLARITY Extension; CC 8.75 mg/kg: cladribine tablets 5.25 mg/kg in CLARITY followed
`by cladribine tablets 3.5 mg/kg in CLARITY Extension; PC 3.5 mg/kg: placebo in CLARITY followed by cladribine tablets 3.5 mg/kg in
`CLARITY Extension; SUPF, supplemental follow-up.
`
`exploratory and all determinations of significance
`were nominal; a p value ⩽0.025 was considered
`nominally significant.
`
`To investigate potential incremental effects of extended
`treatment during the Extension, comparisons between
`groups included CP 3.5 mg/kg vs PC 3.5 mg/kg (early
`vs late treatment with the 3.5 mg/kg dose), CC 7 mg/kg
`vs CP 3.5 mg/kg, CC 8.75 mg/kg vs CP 5.25 mg/kg
`(192 weeks of treatment vs 96 weeks of treatment), and
`CC 7 mg/kg + CC 8.75 mg/kg (combined data for
`patients who received treatment with cladribine tablets
`in CLARITY and CLARITY Extension) vs CP 3.5 mg/
`kg + CP 5.25 mg/kg (combined data for placebo in
`Years 3 and 4).
`
`The intention-to-treat (ITT) population, which com-
`prised patients randomized or assigned to treatment in
`the Extension, was analyzed for efficacy. The safety
`population, which included patients who received
`⩾one dose of study medication and had follow-up
`safety data, was analyzed for safety. Patients who had
`completed CLARITY but were not eligible for treat-
`ment in the Extension were followed for safety only
`(SAFUP population).
`
`Results
`
`Patients
`the
`into
`There were 1326 patients randomized
`CLARITY trial, of which, 1184 completed (89.3%). Of
`the 1184 that completed the CLARITY trial, 867 were
`enrolled in the Extension (73.2%, from 16 January
`2008 to 20 July 2009). Of the 867 enrolled in the
`Extension, 61 comprised the SAFUP population, and
`806 were randomized or assigned to treatment. The
`CLARITY study consisted of a total of 155 study sites;
`however, 22 fewer study sites were involved in
`CLARITY Extension. In total, there were five treat-
`ment groups in CLARITY Extension (CP 3.5 mg/kg,
`n = 98; CP 5.25 mg/kg, n = 92; CC 7 mg/kg, n = 186;
`CC 8.75 mg/kg, n = 186; and PC 3.5 mg/kg, n = 244).
`These patients comprised the ITT population and quali-
`fied for the safety population. In CLARITY Extension,
`806 patients were treated, of which 738 (91.6%) com-
`pleted the 2-year study (Figure 2), and 636 (78.9%)
`entered the SUPF. The characteristics of patients who
`entered the Extension were similar across groups at
`baseline, except that patients who had received placebo
`in CLARITY showed evidence of greater disease activ-
`ity (Table 1). The characteristics of patients who did or
`
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`

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`G Giovannoni, P Soelberg Sorensen et al.
`
`Figure 2. Patient disposition during the CLARITY Extension study. Seven patients received rescue therapy during the
`2-year treatment period (CP 3.5 mg/kg, n = 3 (3.1%); CP 5.25 mg/kg, n = 2 (2.2%); CC 7 mg/kg, n = 1 (0.5%); PC 3.5 mg/
`kg, n = 1 (0.4%)).
`AE: adverse event; CP 3.5 mg/kg: cladribine tablets 3.5 mg/kg in CLARITY followed by placebo in CLARITY Extension; CP 5.25 mg/
`kg: cladribine tablets 5.25 mg/kg in CLARITY followed by placebo in CLARITY Extension; CC 7 mg/kg: cladribine tablets 3.5 mg/kg in
`CLARITY followed by cladribine tablets 3.5 mg/kg in CLARITY Extension; CC 8.75 mg/kg: cladribine tablets 5.25 mg/kg in CLARITY
`followed by cladribine tablets 3.5 mg/kg in CLARITY Extension; PC 3.5 mg/kg: placebo in CLARITY followed by cladribine tablets
`3.5 mg/kg in CLARITY Extension; SUPF: supplemental follow-up.
`
`did not enter CLARITY Extension at baseline of the
`CLARITY study were also similar (Supplementary
`Table 1). The gap between CLARITY and the Extension
`varied within each group but was distributed similarly
`across the treatment groups. Relapses during the gap
`period were not qualified by an evaluating physician.
`There were no major differences between groups in
`disease management during the gap period with few
`patients receiving other DMDs (Table 1). Details for
`concomitant DMD use during the gap between
`CLARITY and Extension and during the SUPF are
`shown in the Supplementary Materials.
`
`Safety outcomes
`The incidence of AEs was generally similar between
`groups (Table 2), and most AEs were classified as
`mild or moderate. There were 89 (11.0%) treatment
`discontinuations due
`to AEs
`(Table 2 and
`Supplementary Table 2) but only 11 (1.4%) patients
`withdrew from the study due to AEs (not shown).
`During the Extension, the frequency of lymphopenia
`and leukopenia was higher in patients treated with
`cladribine tablets compared with placebo recipients.
`For patients who received cladribine tablets 3.5 mg/kg
`in both CLARITY and the Extension, the treatment
`
`discontinuation rate due to lymphopenia and the inci-
`dence of lymphopenia AEs was somewhat elevated
`compared to patients who had received placebo in
`CLARITY and cladribine tablets in the Extension
`(Table 2). The majority of patients in each treatment
`group had no platelet toxicity, and among patients
`with decreased platelet count, most cases were Grade
`1 or 2 in severity. One patient in each of the CC 7 mg/kg
`and CC 8.75 mg/kg groups had ⩾Grade 3 platelet
`toxicity, but there were none in any other group (not
`shown). A total of 94 (11.7%) patients experienced
`⩾one serious adverse event (SAE), including
`infections and infestations (n = 16, 2.0%), and
`gastrointestinal disorders (n = 8, 1.0%).
`
`AEs of special interest
`Lymphopenia events of Grade ⩾ 3 were reported in all
`treatment groups, including approximately 6% of
`patients treated with placebo (Table 3). No patients in
`either the CP 3.5 or 5.25 mg/kg group experienced
`Grade 4 lymphopenia. In the CP 3.5 mg/kg group,
`five patients experienced Grade ⩾ 3 lymphopenia,
`and all recovered to Grade 0–1 lymphocyte counts
`during the Extension, with a mean (standard
`deviation (SD)) time to recovery of 41.0 (33.5) days
`
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`

`Multiple Sclerosis Journal 24(12)
`
`Table 1. Baseline demographics and disease characteristics of treatment groups in CLARITY Extension (ITT population).
`
`Age, years
`Female, n (%)
`White, n (%)
`Weight, kg
`Prior DMD within 3 months of
`Study Day 1, n (%)
`DMD use between CLARITY and
`Extension, n (%)
`Number who relapsed between
`CLARITY and Extension,a n (%)
`Disease duration,b years
`Median EDSS score (min.; max.)
`Number of T1 Gd+ lesions
`T1 Gd+ lesion volume, mm3
`Number of T1 hypointense lesions
`T1 hypointense lesion volume,
`mm3 × 103
`T2 lesion volume, mm3 × 103
`Mean gap between studies,c weeks
`Median gap between studies,c
`weeks (min.; max.)
`
`CP 3.5 mg/kg
`(n = 98)
`
`40.7 (10.7)
`67 (68.4)
`96 (98.0)
`67.93 (14.89)
`0
`
`2 (2.0)
`
`9 (9.2)
`
`10.07 (6.74)
`2.5 (0.0; 6.5)
`0.27 (0.96)
`18.45 (68.14)
`13.53 (13.39)
`2.39 (3.15)
`
`CP 5.25 mg/kg
`(n = 92)
`
`40.8 (9.6)
`59 (64.1)
`90 (97.8)
`70.53 (15.16)
`0
`
`CC 7 mg/kg
`(n = 186)
`
`40.6 (10.5)
`124 (66.7)
`181 (97.3)
`68.91 (14.09)
`0
`
`CC 8.75 mg/kg
`(n = 186)
`
`PC 3.5 mg/kg
`(n = 244)
`
`41.4 (10.1)
`125 (67.2)
`180 (96.8)
`68.56 (14.01)
`0
`
`41.6 (9.6)
`156 (63.9)
`240 (98.4)
`70.68 (15.56)
`3 (1.2)
`
`0
`
`0
`
`0
`
`4 (1.6)
`
`8 (8.7)
`
`17 (9.1)
`
`18 (9.7)
`
`46 (18.9)
`
`12.30 (8.01)
`2.5 (0.0; 6.5)
`0.10 (0.49)
`19.78 (108.84)
`13.72 (15.84)
`3.50 (7.47)
`
`10.41 (7.13)
`2.5 (0.0; 6.5)
`0.31 (1.56)
`43.46 (245.13)
`11.46 (12.66)
`1.95 (2.68)
`
`11.85 (7.85)
`2.5 (0.0; 6.5)
`0.31 (1.29)
`49.19 (266.98)
`12.96 (14.66)
`2.37 (3.66)
`
`10.80 (6.80)
`3.0 (0.0; 6.5)
`0.77 (1.85)
`132.30 (415.18)
`13.28 (14.35)
`2.31 (3.97)
`
`18.57 (19.05)
`41.16 (26.13)
`41.29 (0.1; 116.0)
`
`16.95 (18.17)
`41.19 (25.86)
`43.07 (0.3; 112.9)
`
`13.69 (14.39)
`42.08 (25.37)
`41.43 (0.4; 115.3)
`
`15.76 (14.55)
`39.97 (23.89)
`39.50 (0.9; 111.0)
`
`16.43 (13.81)
`41.99 (27.47)
`39.71 (0.3; 118.0)
`
`ITT: intention-to-treat; CP 3.5 mg/kg: cladribine tablets 3.5 mg/kg in CLARITY followed by placebo in CLARITY Extension; CP 5.25 mg/kg: cladribine tablets
`5.25 mg/kg in CLARITY followed by placebo in CLARITY Extension; CC 7 mg/kg: cladribine tablets 3.5 mg/kg in CLARITY followed by cladribine tablets
`3.5 mg/kg in CLARITY Extension; CC 8.75 mg/kg: cladribine tablets 5.25 mg/kg in CLARITY followed by cladribine tablets 3.5 mg/kg in CLARITY Extension;
`PC 3.5 mg/kg: placebo in CLARITY followed by cladribine tablets 3.5 mg/kg in CLARITY Extension; DMD: disease-modifying drug; EDSS: Extended
`Disability Status Scale; Gd+: gadolinium-enhancing.
`Data are shown as mean (standard deviation (SD)), unless stated otherwise.
`aRelapses during the gap period were not qualified by an evaluating physician.
`bTime from first attack.
`cDuration of the gap between the last visit date in the CLARITY treatment period and the randomization date in CLARITY Extension.
`
`(min.–max.: 14–85 days). In the CP 5.25 mg/kg group,
`four of the six patients who had Grade ⩾ 3 lymphope-
`nia recovered, with a mean time to Grade 0–1 recovery
`of 34.9 (11.7) days (min.–max.: 26–51 days); lympho-
`cyte count data were incomplete for the other two
`patients. The two groups treated with cladribine tablets
`in both CLARITY and the Extension (CC 7 and CC
`8.75 mg/kg) showed the highest incidence of Grade ⩾ 3
`lymphopenia (40.9% and 53.2%, respectively) and
`longest median time to recovery to Grade 0–1 lympho-
`penia (212 and 168 days, respectively) during the
`Extension. The incidence rates of infections and infes-
`tations showed no clear relation to total dose received
`(Table 3), with the exception of the herpes zoster
`infection rate which was higher in the CC 8.75 mg/kg
`group (4.8%) than the other groups (CC 7 mg/
`kg = 1.1%, CP 3.5 mg/kg = 2.0%, CP 5.25 mg/kg = 1.1%,
`and PC 3.5 mg/kg = 2.0%; Table 3). The single case of
`“pulmonary mycosis” resulted from an erroneous cod-
`ing of the reported term “pulmonary mycoplasmosis”;
`this event was non-serious, mild, and considered
`
`unrelated to study medication by the investigator. There
`were no cases of aspergillus in CLARITY Extension.
`The “fungal infection” was considered non-serious,
`and no specific location was reported.
`
`Overall, 11/806 (1.4%) patients from the safety popu-
`lation developed a malignancy or unspecified tumor
`(see Supplementary Table 3). No cases of progressive
`multifocal leukoencephalopathy (PML) occurred dur-
`ing the Extension. Three deaths occurred during the
`Extension: two in the CP 3.5 mg/kg group (one drown-
`ing and one unknown cause) and one in the CC 7 mg/
`kg group (craniocerebral injury). All were considered
`unrelated or unlikely to be related to treatment with
`cladribine tablets (Table 2).
`
`Efficacy outcomes
`During the Extension, ARR were broadly similar
`across treatment groups (Table 4), and between-group
`
`1598
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`Table 2. Overview of safety outcomes, including treatment-emergent adverse events reported in 5% or more of patients.
`
`CP 3.5 mg/kg
`(n = 98)
`
`CP 5.25 mg/kg
`(n = 92)
`
`CC 7 mg/kg
`(n = 186)
`
`CC 8.75 mg/kg
`(n = 186)
`
`PC 3.5 mg/kg
`(n = 244)
`
`All patients
`(N = 806)
`
`G Giovannoni, P Soelberg Sorensen et al.
`
`71 (77.2)
`8 (8.7)
`0
`4 (4.3)
`
`149 (80.1)
`25 (13.4)
`1 (0.5)
`26 (14.0)
`
`1 (1.1)
`
`22 (11.8)
`
`74 (75.5)
`16 (16.3)
`2 (2.0)
`3 (3.1)
`
`0
`
`All AEs
`SAEs
`Deathsa
`AEs leading to treatment
`discontinuationb
`Lymphopeniac leading to
`treatment discontinuation
`Ten most frequently reported AEs (of those reported in 5% or more of patients)
` Lymphopenia
`9 (9.2)
`7 (7.6)
`68 (36.6)
` Nasopharyngitis
`19 (19.4)
`15 (16.3)
`22 (11.8)
` Headache
`20 (20.4)
`16 (17.4)
`21 (11.3)
` Back pain
`9 (9.2)
`9 (9.8)
`16 (8.6)
`
`Influenza
`11 (11.2)
`10 (10.9)
`16 (8.6)
` Upper respiratory tract infection
`8 (8.2)
`9 (9.8)
`17 (9.1)
` Urinary tract infection
`6 (6.1)
`4 (4.3)
`17 (9.1)
` Leukopenia
`1 (1.0)
`2 (2.2)
`19 (10.2)
` Pain in extremity
`8 (8.2)
`6 (6.5)
`10 (5.4)
` Bronchitis
`6 (6.1)
`7 (7.6)
`1 (0.5)
`
`149 (80.1)
`23 (12.4)
`0
`30 (16.1)
`
`194 (79.5)
`22 (9.0)
`0
`26 (10.7)
`
`637 (79.0)
`94 (11.7)
`3 (0.4)
`89 (11.0)
`
`23 (12.4)
`
`17 (7.0)
`
`63 (7.8)
`
`76 (40.9)
`28 (15.1)
`25 (13.4)
`18 (9.7)
`23 (12.4)
`20 (10.8)
`16 (8.6)
`20 (10.8)
`10 (5.4)
`12 (6.5)
`
`69 (28.3)
`45 (18.4)
`38 (15.6)
`28 (11.5)
`17 (7.0)
`19 (7.8)
`17 (7.0)
`12 (4.9)
`11 (4.5)
`17 (7.0)
`
`229 (28.4)
`129 (16.0)
`120 (14.9)
`80 (9.9)
`77 (9.6)
`73 (9.1)
`60 (7.4)
`54 (6.7)
`45 (5.6)
`43 (5.3)
`
`CP 3.5 mg/kg: cladribine tablets 3.5 mg/kg in CLARITY followed by placebo in CLARITY Extension; CP 5.25 mg/kg: cladribine tablets 5.25 mg/kg in
`CLARITY followed by placebo in CLARITY Extension; CC 7 mg/kg: cladribine tablets 3.5 mg/kg in CLARITY followed by cladribine tablets 3.5 mg/kg in
`CLARITY Extension; CC 8.75 mg/kg: cladribine tablets 5.25 mg/kg in CLARITY followed by cladribine tablets 3.5 mg/kg in CLARITY Extension; PC 3.5 mg/
`kg: placebo in CLARITY followed by cladribine tablets 3.5 mg/kg in CLARITY Extension; AE: adverse event; SAE: serious adverse event.
`Data shown as n (%).
`a Three deaths reported: two in the cladribine tablets/placebo (3.5 mg/kg) group (one drowning; one unknown cause) and one in the continuous cladribine tablets
`(7 mg/kg) group (craniocerebral injury). All cases were considered unrelated, or unlikely to be related, to the study medication.
`b Overall incidences of AEs (n (% out of all patients)) leading to treatment discontinuation in ⩾2 patients, by System Organ Class (SOC) or preferred term, in the
`Extension study (safety population) were as follows: 62 (7.7%) blood and lymphatic disorders; 10 (1.2%) investigations; 4 (0.5%) infections and infestation;
`3 (0.4%) pregnancy, puerperium, and perinatal conditions; 3 (0.4%) skin and subcutaneous tissue disorders; 2 (0.2%) general disorders and administration-site
`conditions; 2 (0.2%) respiratory, thoracic, and mediastinal disorders.
`cMain event (preferred term) leading to treatment discontinuation.
`
`comparisons confirmed that there were no significant
`differences (Table 5). Proportions of relapse-free
`patients were also comparable across treatment
`groups. At the end of the CLARITY study, approxi-
`mately 80% of patients who received cladribine tab-
`lets 3.5 mg/kg were relapse-free.2 In patients from the
`group that received placebo in the Extension (i.e. the
`CP 3.5 mg/kg group), approximately 75% remained
`relapse-free at 120 weeks (Table 4). No significant
`differences in time to first qualifying relapse (relative
`to first dose) were seen between treatment groups
`during the Extension (Figure 3). However, there was
`a consequence to delaying treatment with cladribine
`tablets; when CLARITY and the Extension phase
`were considered together, the shortest time to first
`qualifying relapse was seen in patients treated with
`placebo in CLARITY and cladribine tablets 3.5 mg/kg
`in the Extension (PC 3.5 mg/kg, Supplementary
`Figure 1). The proportions of patients who did not
`experience 3-month confirmed EDSS progression
`
`ranged from 72.4% (CP 3.5 mg/kg group) to 78.3%
`(CP 5.25 mg/kg group), with no clear pattern of differ-
`ences between treatment groups (Table 4). Median
`EDSS scores by visit and treatment groups during
`CLARITY and CLARITY Extension are shown in
`Supplementary Figure 2.
`
`In an effort to evaluate the longitudinal effect of clad-
`ribine on ARR, we compared the same groups of
`patients from the end of CLARITY to the end of
`CLARITY Extension. The only difference was
`observed in the PC 3.5 mg/kg group. Compared with
`placebo treatment during CLARITY (ARR 0.26), a
`significant reduction was seen when these patients
`received cladribine tablets 3.5 mg/kg during the
`Extension (ARR 0.10; 60.7% relative reduction,
`p < 0.0001). This difference in ARR was comparable
`to that seen between patients who received placebo
`and the group treated with cladribine tablets 3.5 mg/kg
`during the CLARITY study (57.6% relative reduction,
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`Multiple Sclerosis Journal 24(12)
`
`Table 3. Overview of AEs of special interest (safety population).
`
`CP 3.5 mg/kg
`(n = 98)
`
`CP 5.25 mg/kg
`(n = 92)
`
`CC 7 mg/kg
`(n = 186)
`
`CC 8.75 mg/kg
`(n = 186)
`
`PC 3.5 mg/kg
`(n = 244)
`
`41.0 (33.5)
`22.00
`14–85
`
`34.9 (11.7)
`31.50
`26–51
`
`6 (6.5)
`0 (0.0)
`4 (66.7)
`
`Incidence of lymphopenia (CTCAE Grade 3 or 4) and time to recovery
`5 (5.1)
` Patients with Grade 3 or 4 lymphopeniaa
` Patients with Grade 4 lymphopenia
`0 (0.0)
`5 (100.0)
`
` Patients who recovered from Grade 3 or 4
`lymphopeniab
` Mean (SD) time to recoveryc (days)
` Median time to recovery (days)
` Min.–max. time to recovery (days)
`AEs and SAEs from SOC infections and infestations
`44 (47.8)
`48 (49.0)
` Any AE from SOC infections and infestations
`2 (2.2)
`2 (2.0)
` Serious AEs from SOC infections and infestations
`Infections of interest in System Organ Class preferred terms (serious and non-serious)
` Herpes zoster
`2 (2.0)
`1 (1.1)
` Oral herpes
`2 (2.0)
`3 (3.3)
` Herpes simplex
`1 (1.0)
`0
` Herpes virus infection
`1 (1.0)
`0
` Genital herpes
`0
`0
` Varicella
`0
`0
` Candidiasis
`0
`0
` Fungal infection
`0
`0
` Hepatitis B
`1 (1.0)
`0
`0
`0
` Pulmonary mycosisd
` Tuberculosis (pulmonary)
`0
`0
`
`76 (40.9)
`5 (2.7)
`69 (90.8)
`
`99 (53.2)
`6 (3.2)
`89 (89.9)
`
`61 (25.0)
`1 (0.4)
`50 (82.0)
`
`256.7 (239.7)
`212.00
`8–1184
`
`241.80 (216.1)
`168.00
`7–799
`
`160.2 (160.4)
`111.3
`5–701
`
`91 (48.9)
`2 (1.1)
`
`87 (46.8)
`3 (1.6)
`
`110 (45.1)
`7 (2.9)
`
`2 (1.1)
`3 (1.6)
`1 (0.5)
`0
`0
`0
`1 (0.5)
`1 (0.5)
`0
`0
`0
`
`9 (4.8)
`4 (2.2)
`0
`0
`1 (0.5)
`0
`0
`0
`0
`1 (0.5)
`1 (0.5)
`
`5 (2.0)
`1 (0.4)
`2 (0.8)
`2 (0.8)
`0
`1 (0.4)
`0
`0
`0
`0
`0
`
`CP 3.5 mg/kg: cladribine tablets 3.5 mg/kg in CLARITY followed by placebo in CLARITY Extension; CP 5.25 mg/kg: cladribine tablets 5.25 mg/kg in
`CLARITY followed by placebo in CLARITY Extension; CC 7 mg/kg: cladribine tablets 3.5 mg/kg in CLARITY followed by cladribine tablets 3.5 mg/kg in
`CLARITY Extension; CC 8.75 mg/kg: cladribine tablets 5.25 mg/kg in CLARITY followed by cladribine tablets 3.5 mg/kg in CLARITY Extension; PC 3.5 mg/
`kg: placebo in CLARITY followed by cladribine tablets 3.5 mg/kg in CLARITY Extension; CTCAE: Common Terminology Criteria for Adverse Events; SD:
`standard deviation; AE: adverse event; SOC: System Organ Class.
`Data shown as n (%), unless otherwise specified.
`aDefined as an absolute lymphocyte count in CTCAE Grade 3–4 after initiating the Extension study.
`bReturn of absolute lymphocyte count to CTCAE Grade 0 or 1.
`cAnalysis conditional on a patient having a recovery event (recovery to CTCAE Grade 0/1) within the observation time of the study.
`d The single case of “pulmonary mycosis” resulted from an erroneous coding of the reported term pulmonary mycoplasmosis; this event was non-serious, mild
`and considered unrelated to study medication by the investigator.
`
`p < 0.001).2 There were no clear relationships between
`the length of the gap period and the following: ARR,
`proportion of relapse-free patients, time to first quali-
`fying relapse, or time to 3-month confirmed EDSS
`progression (data not shown). Data relating to MRI
`outcomes are the subject of a separate report.
`
`Discussion
`Overall, the safety and tolerability in CLARITY
`Extension were comparable with CLARITY, with
`lymphopenia the most frequently reported AE and the
`most frequent reason for treatment discontinuation,
`consistent with previous studies of cladribine tablets in
`RRMS.2 In CLARITY Extension, the majority of lym-
`phopenia events were classified as mild or moderate,
`
`and the majority of patients who experienced lympho-
`penia Grade ⩾ 3 actually experienced Grade 3 only.
`Furthermore, the majority of patients who experienced
`lymphopenia Grade ⩾ 3 recovered to Grade 0–1 lym-
`phopenia by the end of the Extension. With the higher
`cumulative doses, the percentage of patients with
`Grade ⩾ 3 lymphopenia increased along with the time
`to recovery. Post-hoc analysis showed that in patients
`treated with cladribine tablets 3.5 mg/kg in CLARITY
`and cladribine
`tablets 3.5 mg/kg
`in CLARITY
`Extension according to the treatment guidelines (i.e.
`Grade 0 lymphocyte count at the start of CLARITY
`and Grade 0–1 at the start of Years 2, 3, and 4), no
`cases of Grade 4 lymphopenia were seen at the end of
`any treatment year. Furthermore, >85% of patients had
`recovered to Grade 0–1 lymphopenia by the end of
`
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`

`

`G Giovannoni, P Soelberg Sorensen et al.
`
`Table 4. Summary of clinical efficacy endpoints.
`
`CP 3.5 mg/kg
`(n = 98)
`
`CP 5.25 mg/kg
`(n = 92)
`
`CC 7 mg/kg
`(n = 186)
`
`CC 8.75 mg/kg
`(n = 186)
`
`PC 3.5 mg/kg
`(n = 244)
`
`0.15 (0.09, 0.21)
`68 (75.6)
`
`0.13 (0.08, 0.19)
`61 (75.3)
`
`0.10 (0.06, 0.13)
`134 (81.2)
`
`0.12 (0.08, 0.16)
`132 (76.7)
`
`0.10 (0.07, 0.13)
`180 (79.6)
`
`71 (72.4)
`
`72 (78.3)
`
`144 (77.4)
`
`142 (76.3)
`
`185 (75.8)
`
`Annualized relapse rate (97.5% CI)
`Proportion of patients qualifying
`relapse-free, n (%)
`Proportion of patients who remained
`free of c