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`Cladribine in treatment of chronic progressive multiple sclerosis
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`J Zyroff, E Beutler R McMillan, JC Sipe, JS Romine, J A Koziol,
`
`Introduction
`Summary
`Although the primary cause of m ultiple clerosis (M ) is
`
`Chronic progressive multiple sclerosis (MS) is a severely
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`
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`unknown, there is circumstantial evidence to indicate that
`
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`disabling demyelinating disease in which autoimmune
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`autoimmune mechanisms play a major part in the attack of
`
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`processes seem to have a major role. The nucleoside drug
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`the body's own immunocytes on central nervous system
`
`cladribine is a potent lympholytic agent with few side-effects.
`myelin to cause the symptoms in MS.
`
`We have studied Its efficacy and safety in a randomised
`1.l developed cladribine
`Carson and colleagues
`(2-
`
`double-blind trial.
`
`
`chlorodeoxyadenosine) a a highly specific antilymphocyte
`
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`four 51 patients (48 entered as matched pairs) received
`
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`agent that mimics the accumulation of deoxynucleotides in
`
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`monthly courses of O 7 mg/kg cladribine or placebo (saline)
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`
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`adenosine deaminase deficiency. This drug has been found
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`given through a surgically implanted central line. Neurologists
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`to cause death of lymphocytes by apopcosis and co have
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`with no knowledge of which medication the patient was
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`
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`relatively low toxicity toward other tissues. Unlike most
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`
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`receiving examined the patients monthly and noted two rating
`
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`other antilymphocyte drugs, it is equally effective against
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`scale scores (Kurtzke and Scripps). Cerebrospinal fluid and
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`resting and dividing cells.
`
`
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`brain magnetic resonance imaging (MRI) examinations were
`The use of clachibine in chronic MS was considered after
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`done at 6 and 12 months. Average neurological scores.
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`
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`extensive experience had been obtained with the drug in the
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`demyelinated volumes on MRI, and concentrations of
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`
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`successful treatment oflymphoid leukaemias, notably hairy
`
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`oiigoclonal bands in cerebrospinal fluid were stable or
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`
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`cell leukaemia and lymphomas, and some success in the
`
`treatment of autoimmune haemolytic anaemia.3 i Because
`
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`
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`improved In the patients receiving cladrabine but continued to
`
`
`
`
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`deteriorate In patients on placebo. Mean paired (placebo
`
`
`of its relative safety and the long-lasting lympbopenfa
`
`
`minus matched cladribine) differences at 12 months relative
`
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`observed during its administration, we underto k a pilot
`
`
`to baseline were (SEO
`for the Kurtzke scores,
`
`
`
`study, treating 4 patients with chronic progressive MS with
`1 O
`4)
`-13·9
`
`
`(2 3) forthe Scripps scores, 4 57 (1 17) mlfor demyellnated
`
`
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`cladribine in J 990. Results were sufficiently encouraging
`
`
`for us to conduct a more extensive randomised, double
`
`
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`volumes. and 7 ·3 (3·3) arbitrary units for concentrations of
`
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`blind, placebo-controlled study in 51 patients with chronic
`
`oiigoclonal bands.
`
`progressive MS.
`
`
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`Cladribine was generally well tolerated and clinically
`
`occurred In only 1 patient, In whom severe
`
`significant toxicity
`
`Patients and methods
`
`
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`marrow suppression developed with complete recovery after
`51 p:uiencs, all of whom had clinkally definite or laboratory
`
`
`
`
`
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`several months. 1 patient died of newly acquired hepatitis 8,
`
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`
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`supponed definite chronic progressive MS6 for more than 2 years,
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`
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`an event unlikely o be related to cladrlbine. We conclude that
`
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`were entered imo the study. These patients had been followed at
`
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`the immunosuppressive drug cladriblne Influences favourably
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`
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`Scripps Clinic by the neurology group for between 6 months and J 0
`the course of chronic progressive
`
`MS.
`
`
`
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`years. The study plan risks, and potential benefits were explained
`
`
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`to each patient in derail, and all patients gave informed consent.
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`
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`Patients were matched according to age, sex, and severity of
`
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`disease and 24 pairs of patients were identified. Each pair was
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`randomised by the statistician (JAK) using random number tables'
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`
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`so that one patient was assigned 10 the group initially receiving
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`
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`cladribineand the other 10 the group o.riginally receiving placebo. 1
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`
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`other patient, for whom no suitable match was identified, was
`
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`s1aned on cladribine; this individual left the study after 8 months
`
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`
`
`on protocol. 2 patients, both initially assigned to clad.ribine, were
`
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`10s1 at 2 and 3 months: as di cussed below, I patieot died of acute
`
`B du.ring her second month on protocol and
`fulminating hepatitis
`
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`of a the other patient dropped out of the study at 3 months because
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`traumatic hip fracture. The loss of the e 2 patients seemed
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`
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`unarcributablc to cladribine so we recruited 2 additional matched
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`patients as replacemencs and assigned them to cladribine. I patient
`Department of Molecular and Experimental Medicine, Scripps
`
`
`
`
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`receiving placebo withdrew from the study after 4 months on
`
`Research Institute (JC S,pe MD, J S Romine MD, Pro( J A Koziol
`PhD,
`
`
`
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`pro1ocol for reasons unrelated to treatment, so we chose not to
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`
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`Prof R McMillan MD, Prof E Beutler MD); and Division ol Neurology and
`
`
`
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`replace this patient. The analyses reported here refer to the 24
`
`
`
`
`Department of Radiology, Scripps Clinic and Research Foundation
`
`
`
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`matched pairs of patients (table J), and exclude the 3 patients on
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`(JC Sipe, JS Romine, J Zyroff MD), La Jolla, Callfomla, USA
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`cladribinc who did no1 complete a full year of the study.
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`Panicipanis were permitted 10 continue medications 10 crcat
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`
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`Correspondence to: Prof Ernest Beutler, Department ot Molecular
`
`
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`troublesome symptoms of MS-cg, spasticity treated with
`
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`
`
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`and Experimental Medicine (SBR-3), Scripps Research Institute,
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`
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`baclofcn or bladder dy function with oxybutynin. Candidate
`
`10666 North Torrey Pines Road, La Jolla, CA 92037, USA
`
`Lancet1994;344:9-13
`
`EXHIBIT
`
`Vol 344 • July 2, l 994
`
`Merck2004
`9
`
`
`TWi vMerck
`
`
`IPR2023-00050
`
`
`
`THE LANCET
`
`
`Time
`Score
`
`Placebo
`Cladribine
`
`Epss
`Baseline
`6 mo
`12 mo
`
`SNRS
`69 5(2 2)
`69 5(21)
`Baseline
`73 7(27)
`65 3(2 3)
`6 mo
`
`
`62 6 (2 3)412 mo 74 8(2 1)
`
`47(03)
`45(04)
`44(04)
`
`46(03)
`5 0(0 3)
`56 (03)
`
`Table 2: Summary statistics from neurological examinations
`
`analysis and complete blood count. The unblinded investigators
`decided, on the basis of the blood count, whetherit was safe to
`proceed with the next dose of test medication. If these observers
`judged that the drug could be given safely, cladribine (or placebo)
`was administered by continuous 7-day intravenousinfusion at the
`rate of0-1 mg/kg daily. Ifnot, the counts were repeatedperiodically
`and the decision whether or not to continue was made; planned
`infusions were delayed in 4 patients receiving the drug and in 2
`patients on placebo.
`In theoriginal protocol six monthly doses were planned butthis
`was modified to four courses after the study began because the
`thrombocytopenia was more profound than expected in some
`patients.
`1 patient had already received five courses before the
`decision to reduce dosage had been made. | patient received only
`two courses and 2 patients only three because ofthrombocytopenia.
`All other patients were given four courses.
`
`Magnetic resonance imaging
`Magnetic resonance imaging (MRI) was performed on a 1:5 T
`General Electric Signa scanner. T2 and proton density weighted
`images were obtained using a conventional spin-echo sequence
`with repetition times of 2500 ms and echo delay times of 30 and 90
`ms. Sections were 4 mm thick with a 1 mm interslice gap. T1
`weighted scans were obtainedin thesagittal and axial planes. Axial
`scans of3 mm thickness and 0 interslice gap were done about 10 min
`after
`gadopentetate
`dimeglumine
`(Magnevist;
`Berlex
`Laboratories, Wayne, New Jersey, USA) injection to ensure
`optimal time for transmigration of the contrast agent across the
`blood-brain barrier. Special attention was given to careful
`repositioning of patients to guarantee reproducible slice positions.
`Regions of demyelination on proton density weighted scans and
`contrast enhancement on T1 weighted scans were outlined by hand
`SNRS
`
`78
`
`@ Cladribine
`
`O Placebo 75
`
`Score
`
`72
`
`69
`
`63
`
`60
`
`
` Placebo Cladribine
`16/8
`16/8
`Sex (F/M)
`22/2
`24/0
`Race (white/cther)
`42 7 (21-54)
`43 0 (28-53)
`Meanage (yr) (and range)
`
`Mean duration ofclinical symptomsof MS(yr) (andrange) 10 5 (2-31) 12 7 (4-24)
`
`Table 1: Demographic characteristics of paired patients at
`study entry
`
`patients were excluded if the serum creatinine was above 132
`umol/L or if the calculated creatinine clearance wasless than 80%
`of the age-adjusted normalvalue;ifserum transaminases or hepatic
`alkaline phosphatase were more than twice the upper limit of
`normal; or if the neutrophil count was below 1600/pL or platelet
`count was less than 130 000/nL. No woman nottaking adequate
`birth control measures or man planning to father a child for the
`duration ofthe study was included. Patients who weretreated with
`corticosteroids or other immunosuppressive medications such as
`cyclophosphamide, azathioprine, or cyclosporin within the
`previous 6 months or who appeared to have decreased marrow
`reserve as manifested by leukopenia or thrombocytopenia for more
`than
`6 weeks
`after
`conclusion
`of
`treatment’ with
`immunosuppressive agents were excluded. All patients had a
`central venous access device implanted for drug or placebo
`administration.
`
`Study design
`Theinvestigation was designed as a 2-year double-blind crossover
`study. This design was ethically necessary because of the need for
`surgically implanted central venous lines. However, the protocol
`stipulated analysis as a parallel study after 1 year, crossover being
`decided at that time. The primary endpoint was neurological
`improvement, andsince significant improvement was achieved at
`the end of | year this portion of the study was concluded at that
`time.
`
`Evaluation
`The examining neurologists, nurses, and patients were blinded to
`the treatmentassignments. An unblinded investigator (EB or RM)
`monitored all the laboratory studies and patients’ complaints and
`illnesses, if any. Every patient was examined monthly by the same
`neurologist for the first year of the study. Two neurological
`assessments,the Scripps Neurologic Rating Scale (SNRS)* and the
`Kurtzke Expanded Disability Status Scale (EDSS),’ were scored at
`every examination, and at each visit blood was taken for chemical
`EDSS
`
`@ Cladribine
`O Placebo
`
`a6
`
`4.5
`
`5.0
`
`23
`
`5.5
`
`—x—m_xm0 2 4 6 8 10 12
`
`
`
`
`
`
`
`
`Month
`
`
`
`
`
`Figure 1: ChangesIn the Kurtzke (EDSS) and Scripps (SNRS)rating scores
`Mean (SE bars) shown.
`
`
`10
`
`Vol 344 + July 2, 1994
`
`
`
`EDSS
`
`0.5
`
`
`
`
`
`Paireddifferences(placebo-—cladribine)
`
`0.5
`
`1.0
`
`156
`
`THE LANCET
`
`SNRS
`
`°
`
`w@
`
`a
`
`©
`
`-12
`
`415
`
`0
`
`2
`
`4
`
`6
`Month
`
`8
`
`10
`
`12
`
`0
`
`2
`
`4
`
`6
`Month
`
`8
`
`10
`
`12
`
`Figure 2: Differences between Kurtzke (EDSS) and Scripps (SNRS)rating scores In matched pairs (placebo minus cladribine)
`Mean paired differences (SE bars) shown. Paired differences were significantly greater than zero (EDSS p<0 01, SNRS p<0O 001).
`
`on filmed images. All scans were interpreted and marked by the
`same neuroradiologist (JZ) who had no knowledge of treatment
`protocols. ‘These were then duplicated by a technologist using the
`taped raw data and a computer work station (CEMAX,Santa
`Clara, California). Pixel counts for each slice were converted into
`volumes by a volume rendering software program. All
`the
`volumetric analyses were done by the same technologist.
`
`Cerebrospinal fluid (CSF) examination
`CSF was
`tested
`for
`total protein and immunoglobulin
`concentration, and samples were frozen for assessment of changes
`in oligoclonal bands. At the end of one year the baseline and 6 and
`12 month samples of CSF were labelled with **I-albumin and
`concentrated 40-fold in a Centricon-10 (Amicon) centrifugal
`concentrators, and electrophoresis was performed on Corning high
`resolution protein agarose plates. After staining with acid violet,
`the strips were scanned with a Zeineh soft
`laser scanning
`densitometer (Biomed Instruments, Fullerton, California). The
`height of oligoclonal bands was measured in millimetres as
`arbitrary units by a technician with no knowledgeof the treatment.
`The radioactivity of the albumin band was determinedto correct
`for
`inter-sample differences
`in concentration and sample
`application, When the concentration of any samplein a series was
`150%, or more of any other sample electrophoresis was repeated,
`the volumes applied being changed so that nearly the same amounts
`of each original CSF was applied to the gel. A reliability
`experiment, on 12 random samples run on three different gels,
`yielded an intra-class correlation coefficient’® of 0-95 for the
`replicates across the gels.
`
`Statistical methods
`The design was a double-blind crossover trial, with one planned
`interim analysis at 12 months, before crossover. Our primary
`endpoint was neurological improvement as assessed by the two
`rating scales. Our pilot study suggested that, relative to placebo,
`cladribine would improve the status of patients with chronic
`progressive MS. We estimated that a samplesize of 44 patients (22
`per arm) would be sufficient to detect a 15%, SNRS improvement
`in patients on cladribine if there was no improvement on placebo,
`with a statistical power of 0-90 and a one-sided statistical test at
`conventional alphalevel 0-05. Our stopping rule at 12 months was
`
`significant improvement in the SNRSfor the cladribine group
`comparedwith the placebo arm,at an alpha level of 0:01. Since this
`improvementwasachieved,the statistical analysis was done as fora
`conventional randomised parallel design.
`Comparisons between treatment arms were based on the
`underlying matching of 24 pairs of patients; the last available
`observations were carried forward for the patient who had not
`completed 12 monthsin the study. Similar analyses were done in
`which these missing data remained missing and in which they were
`modelled under the representation that
`they were missing at
`random. Also, an unpaired, intent-to-treat analysis was done on
`data from all 51 patients; and a paired analysis incorporating data
`from the 2 cladribine patients lost by month 3 wasalso undertaken,
`All additional analyses yielded results similar to those reported
`here.
`Summary statistics are based on the 24 matchedpairs of patients
`and are reported as mean (and standard error, SEM). The paired
`differences in neurological scores were analysed with a non-
`parametric repeated measures analysis of variance.** Other paired
`comparisons between the treatment arms were made with both
`parametric and non-parametric one-sample procedures, with
`two-sided p values reported throughout.
`
`Results
`Neurological examinations
`Both examining neurologists (JR and JS) participated in a
`study of inter-rater and intra-rater reliability. 20 patients
`(10 primarily followed by each neurologist) were
`independently assessed by each examiner on the same day.
`Inter-rater agreement? washigh: the weighted « coefficient
`was 0:976 for EDSS and 0-828 for SNRS. Inter-rater
`agreement on the EDSS was 100% for all sets of
`examinations when agreement wasdefined as a difference
`less than or equal to 1-0. This compared favourably with
`agreements reported in otherclinical trials of therapeutic
`agents in MS." Inter-rater agreement on the SNRS was
`85°%,, with agreementdefined as difference of no more than
`10 points. Separately, 18 patients (JR, 8, and JS, 10) were
`assessed by the same examiner twice on the same day, the
`period between examinations ranging from 135 to 240 min.
`
`Vol 344 = July 2, 1994
`
`ll
`
`
`
`THE LANCET
`
`Time
`
`Baseline
`6 mo
`12 mo
`
`Mean (SE) volume (mL)
`Placebo
`18 32 (2 85)
`20 91 (3 37)
`22 46 (3 39)
`
`Cladribine
`23 46 (4 35)
`24 35 (4 81)
`22 66 (4 32)
`
`Table 3: Total lesion volumes (MRI)
`
`Intra-rater agreement on the EDSS wasperfect; weighted k
`coefficients of agreement between the two SNRSscores
`were 0-978 (JR) and 0-998 (JS).
`SNRS and EDSS scores are shown in figure 1 with
`summary statistics in table 2. Both scores indicated
`progressive deterioration in patients
`randomised to
`placebo. Modest improvementin mean scores was foundin
`patients
`on
`cladribine. The
`average matched-pair
`differences (placebo minus cladribine) in scores during the
`study are shown in figure 2. A distribution-free procedure"
`was used to assess whetherindividual paired differences
`were consistently positive or negative. These directional
`statistics were highly significant (y?,=8°38, p<0-:004 for
`EDSS,y?, = 13:26, p< 0-001 for SNRS). The meanpaired
`differences in EDSS and SNRS scores at 6 monthsare 0-6
`(0-3) and —8-9 (2:2), with respective 95% confidence
`intervals of 0-1-2 and — 13-5 to — 4-3), At 12 months, the
`mean paired differences in EDSS and SNRSscoresare 1:3
`(0-3)and — 12-5(2-0), respective 95%, Cls being 0-6—-2-0.and
`— 16:7 to — 8:2.
`We also analysed the numberof patients experiencing a
`change in EDSS scoreof 1 or more points at 1 year. Among
`the 23 patients receiving placebo who were evaluable at 12
`months the EDSS score of 7 of them had progressed by at
`least 1 point, the score had improved (decreased) at least a
`point in only 1, and 15 patients remained within 1 point of
`baseline. Among the 24 evaluable patients receiving
`cladribine, the EDSS score of only | patient had worsened
`by at least a point, the EDSS had improved (decreased) by
`at least a point in 4 patients, and 19 patients had an EDSS
`score that changedless than 1 point. These proportionsare
`significantly different (p < 0-02, Terpstra-Jonckheeretest).
`
`concentrations at baseline and at 6 months and 12 months
`averaged 29-9 (4-2), 26-5 (3-4), and 25-0 (3:3) a significant
`decline (F, ,,=5-17, P < 0-02). Corresponding valuesfor the
`placebo group were 26-2 (3-8), 29-9 (3-8), and 29-9 (4-7), a
`modest but non-significant increase (F,,,= 1°81, p=0:18).
`Among the matchedpairs, the placebo patients tended to
`have higher values than their counterparts on cladribine:
`The mean paired difference (placebo minus matched
`cladribine)
`in
`relative
`oligoclonal
`immunoglobulin
`concentrations at 6 monthsrelative to baseline is 4-3 (2-0)
`(95% CI 0-1-8-5); at 12 months it was 7:3 (3-3) (95% CI
`0-5-14-1),
`
`Side-effects and complications
`In general, cladribine was well-tolerated byall patients and
`there were no untoward side-effects or symptoms in MS
`patients that could have systematically affected the double-
`blindednessof the protocol. Marrow suppression occurred
`in several patients but wasclinically significant in only l,a
`patient who wasalso taking large doses of phenytoin for
`trigeminal neuralgia. This patient’s marrow function
`recovered fully over a period of several months after
`conclusion of therapy with cladribine. Details of the
`haematological data collected in this study are summarised
`elsewhere. '*
`Two serious medical events occurred. A 40-year-old
`woman received her second dose of cladribine when her
`blood count and blood chemistry, including liver function
`tests, were normal. Hepatitis B serology had been negative
`on study entry. 3 daysafter the infusion, she presented with
`fever, abdominal pain, and transaminase levels exceeding
`15 000 U/mL. Peripheral blood counts were normalexcept
`for modest lymphopenia. There was a history of probable
`exposure to hepatitis B infection, and liver biopsy revealed
`acute necrosis that was demonstrated to be due to hepatitis
`B virus. Theclinical course was fulminant, and the patient
`died 5 days after admission. The fulminant course is
`unlikely to be related to cladribine (see Discussion). A
`second patient developed abdominal pain and low grade
`fever 2 weeks after conclusion of her second course of
`placebo. She declined hospital admission and did not attend
`for follow-up the next day. 2 days later she was admitted to
`the hospital with severe lower abdominal pain, decreased
`bowel sounds, and rebound tenderness. Surgery was
`considered, but a culture revealed Salmonella enteritidis in
`her stools, and the patient responded promptly to antibiotic
`therapy.
`2 patients who hadreceived cladribine had mild episodes
`of herpes zoster restricted to one or two dermatomes, and
`these subsided rapidly on treatmentwith oral acyclovir.
`
`MRIdata analyses
`Summary statistics relating to demyelinated and enhancing
`volumes are given in table 3. Paired differences (placebo
`minuscladribine) ofdemyelinated volumesat 6 months and
`at 12 months, relative to baseline values, were different
`from zero (T?, ,,= 17-01, p< 0-002). This can beattributed
`primarily to the changes at 12 monthsrelative to baseline.
`The meanpaired difference (placebo minuscladribine) in
`demyelinated volumes at 6 monthsrelative to baseline was
`1-47 (1:32) mL (95% CI — 1-26 to 4-19); at 12 monthsthe
`mean difference was 4-42 (1-10) (95% CI 2-16-6-69).
`We dichotomised the enhancing volume findings by
`calling the elimination of enhancing volumes or their
`Immunosuppressive therapy in MS_has previously
`continued absence a favourable outcomeandlabelling the
`involved treatment primarily with cyclophosphamide,
`emergence of or continued presence of enhancing volumes
`azathioprine,
`and cyclosporin. Evidence of modest
`as an unfavourable outcome. A paired analysis of the
`efficacy’ has been tempered bysignificant side-effects in
`12-month findingsrelative to baseline yields 13 pairs with
`some patients on long-term therapy. Plasmapheresis and
`jointly
`favourable outcomes,
`3 pairs with
`jointly
`lymphocytapheresis have been tried but there is no clear
`unfavourable outcomes,| pair with placebo favourable and
`evidence of sustained clinical benefit.© Monoclonal
`cladribine unfavourable, and 10 pairs with placebo
`antibodies directed against specific T-cell subsets have also
`unfavourable, cladribine favourable (p <0:001, McNemar
`been used in MS but the primary obstacle to long-term
`test).
`treatment has been the development of antibody to the
`monoclonal.'? Although interferon beta has been found to
`be effective in relapsing-remitting MS—with significant
`reductions in exacerbationrate, in severity of exacerbations
`
`CSF examination
`The numberof oligoclonal bands did not change in any
`patient. For the cladribine group,
`relative oligoclonal
`”
`
`12
`
`Vol 344 + July 2, 1994
`
`
`
`THE LANCET
`
`lesions—no satisfactory
`and in accumulation of MRI
`treatmenthas been found for progressive MS.
`Cladribine in our study was associated with highly
`significant improvementsin neurological ratings. The MS
`status of patients on placebo continued to decline, and this
`neurological deterioration was notonly significant but also
`was sufficiently severe to affect the patients’ disability
`status.
`
`that the drug maybe given by the much more convenient
`subcutaneous route,?* and in future trials this is what we
`plan to use. Preliminary results suggest that a lower doseis
`less likely to produce marrow suppression andis effective.
`Cladribine may becomea useful agent for the management
`of chronic progressive MS.
`Supported by FDA grant FD-R-000280 and NIH grants NS30218 and
`RRO00833, the Sam Stein and Rose Stein Charitable Trust Fund, and a
`grant from the R W Johnson Pharmaceutical Research Institute. This
`work could not have been done without the outstanding assistance of
`Carolyn Koumaras, and otherstaff of the General Clinical Research
`Center.
`
`In a double-blind study the aim is for both patients and
`evaluating physicians to be blinded to the treatment being
`given but sometimesthere are clues that make blindingless
`than perfect, For example, although the studyofinterferon
`was blinded'*"? this agent does cause malaise, among other
`References
`prominentside-effects, and some patients may have known
`whether or not they were on active drug. With cladribine
`1 Carson DA, Wasson DB, Taetle R, Yu A. Specific toxicity of
`2-chlorodeoxyadenosine toward resting and proliferating human
`there are no such clues* but unexpected thrombocytopenia
`lymphocytres. Blood 1983; 62: 737-43.
`did lead to a delay in drug dosage in some patients, 4 on
`2 Carson DA, Wasson DB, Beutler E. Antileukemic and
`active drug and 2 on placebo. This may have provided a clue
`immunosuppressiveactivity of 2-chloro-2’-deoxyadenosine. Proc Natl
`Acad Sci USA 1984; 81: 2232-36.
`to the patient and,possibly, the neurologist that active drug
`3 Piro LD. 2-Chlorodeoxyadenosine treatment of lymphoid
`was being given but exclusion of data on these 6 patients
`malignancies. Blood 1992; 79: 843-45.
`does not affect the significance of the findings. Moreover,
`4 Beutler E, Piro LD, Saven A, et al, 2-chlorodeoxyadenosine (2-CdA): a
`the neuroradiologist knew nothing about
`the drugs
`potent chemotherapeutic and immunosuppression nucleoside. Leuk
`administered and the MRI data indicate that new oractive
`Lymphoma 1991; §: 1-8.
`5 Beutler E. Cladribine (2-chlorodeoxyadenosine). Lancet 1992; 340:
`MSlesions decreasedin patients on cladribine. The overall
`952-56.
`volume of demyelinated lesions did not significantly
`6 Poser CM, Paty DW,Scheinberg L, et al. New diagnostic criteria for
`change.In addition, there wasa significant differencein the
`multiple sclerosis: Guidelines for research protocols. Ann Neurol 1983;
`13: 227-31.
`concentration of oligoclonal protein in the CSF of patients
`7 Snedecor GW, Cochran WG.Statistical methods. Ames: Iowa State
`on cladribine.
`University Press, 1980: 464.
`In general, cladribine was well tolerated, but marrow
`8 Sipe JC, Knobler RL, Braheny SL, Rice GP, Panitch HS, Oldstone
`suppression with platelet counts below 80000/pL was
`MB.A neurologic rating scale (NRS)for use in multiple sclerosis.
`Neurology 1984; 34: 1368-72.
`documented in 4 patients and between 80000/pL and
`9 Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An
`100 000 in another 3.** The frequencyof thrombocytopenia
`expandeddisability status scale (EDSS). Neurology 1983; ; 33: 1444-52.
`was high enough forusto plan an additionaltrial at a lower
`10 Snedecor GW, Cochran WG.Statistical methods. Ames: Iowa State
`dose,
`including also patients with remitting relapsing
`University Press, 1980: 24344.
`disease. The death from hepatitis B requires comment.
`Koziol JA, Maxwell DA.A distribution-free test for paired growth
`curve analyses with application to an animal tumor immunotherapy
`Liver damage in chronic hepatitis B seems to have an
`experiment. Stat Med 1983; 1: 83-89.
`immunological mechanism?°
`and
`treatment with
`12 Cohen J. Weighted kappa: nominal scale agreement with provision for
`immunosuppressive drugs seems to ameliorate the course
`scaled disagreementofpartial credit. Psychol Bull 1968; 70: 213-20.
`13 Goodkin DE, Cookfair D, Wende K,et al. Inter- and intrarater scoring
`of both acutely acquired and chronic hepatitis. ““Rebound”
`agremmentusing grades 1-0 to 3-5 of the Kurtzke Expanded Disability
`exacerbation
`of
`infection
`may
`occur
`when
`Status Scale (EDSS). Neurology 1992; ; 42: 859-63.
`immunosuppression is withdrawn?!? but our patient had
`14 Beutler E, Koziol J, McMillan R, Sipe JC, Romine JS, Carrera CJ.
`fulminating hepatic necrosis during and immediately after
`Marrow suppression produced by repeated doses of cladribine. Acta
`the infusion of cladribine. Cladribine has no known liver
`haematol 1994; 91: 10-15.
`15 Weiner HL, Hafler DA. Immunotherapy in multiple sclerosis. Ann
`toxicity and liver-function tests of the other patients in this
`Neurol 1988; 23: 211-22.
`study revealed no difference between drug and placebo
`16 ‘Tindall R. A closer look at plasmapheresis in multiple sclerosis: the
`patients. More than 1000 patients have received cladribine
`cons. Neurology 1988; 38: 53-56.
`at this institution, and atleast 1 has developedviral hepatitis
`17 Hafler DA, Weiner HL. Immunosuppression with monoclonal
`antibodies in multiple sclerosis. Neurology 1988; 38: 42-47.
`with a benign course. Over 5000 patients have received this
`18 Duquette P, Girard M, Despault L, Dubois R,et al. Interferon
`drug worldwide and no other case of fulminant hepatitis
`beta-1b is effective in relapsing-remitting multiple sclerosis I. Clinical
`infection has been recorded.
`Indeed, a patient with
`results of a multicenter, randomized, double-blind, placebo-controlled
`trial. Neurology 1993; 43: 655-67.
`subfulminant hepatitis C from blood transfusion given 18
`19 Paty DW, Li DKB.Interferon beta-Ib is effective in relapsing-
`days earlier showed rapid recovery in the face of the
`remitting multiple sclerosis II, MRI analysis results of a multicenter,
`cladribine therapy.2* We consider it unlikely that
`the
`randomized double-blind, placebo-controlled trial. Neurology 1993;;
`43: 622-67.
`fulminant course in our patient wasrelated to cladribine.
`20 Moriyama T, Guilhot S, Klopchin K,et al. Immunobiology and
`Cladribine is incorporated into DNA.' Althoughourfirst
`pathogenesis of hepatocellular injury in hepatitis B virus transgenic
`patients were treated a decade ago? most had far advanced
`mice. Science 1990; 248: 361-64.
`leukaemia or lymphomaanddid not survive long enough to
`Lau JY, Bird GL, Gimson AE, Alexander GJ, Williams R. ‘Treatment
`permit assessment of long-term toxicity or oncogenicity.
`of HBVreactivation after withdrawal of immunosuppression. Lancer
`1991; 337: 802.
`Large numbersof patients with hairy cell leukaemia have
`22 Lueg E, Heathcote J. Dangers of immunosuppression therapy in
`been treated in the past 5 years, but these generally received
`hepatitis B virus carriers. Can Med Assoc J 1992; 147: 1155-58.
`2wv
`a total dose of only 0:7 mg/kg body weight. Noneof the 4
`Schirmer M, Vogel W, Thaler J, et al. Subfulminant hepatitis C ina
`patient with hairy-cell leukemia during treatment with cladribine. Exp
`patients with MS wetreated with a total dose of 2-5 mg/kg 4
`Hematol 1993; 21: 1091.
`years ago in a pilot study has had adverse effects long-term.
`24 Liliemark J, Albertioni F, Hassan M, Juliusson G. On the
`In this study surgical implantation of a catheter was
`bioavailability of oral and subcutaneous 2-chloro-2’-deoxyadenosine in
`required because no information abouttheefficacy of other
`humans;alternative routes of administration. 7 Clin Oncol 1992; 10:
`1514-18.
`routes of administration was available. We now recognise
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