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`Proceedings of the Association of American Physicians 111:1
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`January/February 1999
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`84. Berkenbosch F., van Oers J., del Rey A., et al. Corti(cid:173)
`cotropin-releasing factor-producing neurons in the rat
`activated by interleukin-I. Science 238: 524-536, 1987.
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`matory mediator-induced hypothalamic-pituitary-adre(cid:173)
`nal axis activation is defective in streptococcal cell wall
`arthritis-susceptible Lewis rats. Proc. Natl. Acad. Sci.
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`adrenalectomy in patients with Cushing's syndrome due
`to an adrenocortical aden~ma. N. Engl. J. Med. 322:
`1708-1712, 1990.
`87. Amino N. and Miyai K. Post-partum autoimmune endo-
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`crine syndromes. In: Davies T.F. (ed). Autoimmune En(cid:173)
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`247-272.
`88. Altemus M., Deuster P.A., Galliven E., et al. Suppres(cid:173)
`sion of hypothalamic-pituitary-adrenal axis responses to
`stress in lactating women. J. Clin. Endocrinol. Metab.
`80:2954-2959, 1995.
`89. Gunnison A.F., Weideman P.A., and Sobo M. En(cid:173)
`hanced inflammatory response to acute ozone exposure
`in rats during pregnancy and lactation. Fimdam. Appl
`Toxicol. 19: 607-612, 1992.
`90. Ahima R.S., Prabakaran D., Mantzoros C., et al. Role of
`leptin in the neuroendocrine response to fasting. Nature
`382: 250-252, 1996.
`
`A Double-Blind, Placebo-Controlled,
`Randomized Trial of Cladribine in Relapsing-Remitting
`Multiple Sclerosis
`
`John S. Romine,* Jack C. Sipe,* James A. Koziol,* Jack Zyroff,t and Ernest Beutler'
`*Di vision of Neurology and 'Department of Radiology, Scripps Clinic, and 'Department of Molecular and
`Experimental Medicine, The Scripps Research Institute, La Jolla, CA
`
`We conducted an 18-month, placebo-controlled, double-blind study to evaluate cladribine in the treatment of
`52 patients with rel~psing-remitting multiple sclerosis. Patients received either placebo or cladribine 0.07 mg/
`kg/day by. subcutafleous injection for 5 consecutive days as six monthly courses for a total cumulative dose of
`2.1 mg/kg. Analysis of results revealed a statistically significant favorable effect of cladribine on the joint fre(cid:173)
`quency and severity of rel.apses and magnetic resonance imaging (MRI) findings. MRI-enhancing lesions were
`completely suppressed in the cladribine patients by the sixth month of treatment. Mild segmental herpes zoster
`occurred in two cladribine-treated patients and one patient receiving placebo. Otherwise, there were no side ef(cid:173)
`fects or adverse events. We conclude that c1adribine shows promise as a treatment for relapsing-remitting mul(cid:173)
`tiple sclerosis.
`
`A lthough the cause and cure of multiple sclerosis
`
`(MS) remains unknown, it is generally accepted
`that immunological mechanisms play an important
`role in the inflammatory demyelination of the central
`nervous system that is the pathological hallmark of
`the disease. For this reason, current approaches to the
`treatment of MS patients are focused on modulation
`or suppression of the immune system.
`The drug cladribine
`[2-chlorodeoxyadenosine
`(2-CdA), Mylinax, Ortho McNeil, Raritan, NJ] is a se(cid:173)
`lective immunosuppressive molecule synthesized by
`Carson to mimic the immunodeficiency state seen in
`hereditary adenosine deaminase deficiency (]). It is a
`purine nucleoside with chlorine substituted for hydro(cid:173)
`gen at the 2 position of the purine ring. This makes the
`molecule resistant to adenosine deaminase, leading to
`accumulation of deoxynucleotides and selective killing
`of lymphocytes with relatively little toxicity in other
`tissues (2). The drug is used widely as a treatment for
`lymphoid malignancies and is especially effective in
`hairy cell leukemia (3,4). Because of positive results
`from our therapeutic trial of cladribine in progressive
`MS (5,6), we undertook this study to evaluate claddb(cid:173)
`ine in patients with the relapsing-remitting form of MS.
`
`Key words: immunosuppression; 2-chlorodeoxyadenosine.
`Address correspondence and reprint requests to: John S. Romine,
`M.D., Division of Neurology, MS313, Scripps Clinic, 10666 North
`Torrey Pines Road, La Jolla, CA 92037.
`
`Received 18 September 1998; Accepted 23 September 1998.
`
`METHODS
`Patient Selection
`The study subjects were 52 patients with clinically
`definite relapsing-remitting MS for at least 1 year. All
`patients had a history of two or more relapses in the
`previous 2 years and Extended Disability Status Score
`(EDSS) scores of 6.5 or less at time of study entry.
`The majority of patients had been followed at Scripps
`Clinic. Exclusion criteria included: 1) prior treatment
`with an immunosuppressive drug within 3 months;
`2) a serum creatinine of> 1.5 mg/dl; 3) serum gluta(cid:173)
`mic-oxaloacetic transaminase/serum glutamic-pyruvic
`transaminase or alkaline phosphatase elevated to twice
`the upper limit of normal; 4) baseline neutrophil counts
`of <1600/µJ or platelet counts of <130,000/µJ; and
`5) previous total lymphoid irradiation or prior exten(cid:173)
`sive myelosuppressive chemotherapy.
`The study plan, risks, and potential benefits were
`explained to each patient in detail. All patients gave
`informed consent to participate in the study.
`
`Study Design
`An 18-month, randomized, placebo-controlled, dou(cid:173)
`ble-blind study was conducted in the facilities of the
`General Clinical Research Center (GCRC) of Scripps
`Clinic. After completion of screening evaluations, 52
`patients were stratified according to gender, age (in
`IO-year intervals), and degree of disability as mea-
`
`Copyright© 1999,Proceedings oftlte Association of American Pltysicialls, Volume 111, Number 1, pp. 35-44
`
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`

`36
`
`Proceedings of the Association of American Physicians 111:1
`
`January/February 1999
`
`Romine et al.: Cladribine in Relapsing-Remitting Multiple Sclerosis
`
`37
`
`~
`
`sured by Scripps Neurological Ratino Scale (SNRS·
`,
`7) (in JO-point intervals). The stratified groups were
`then randomized in blocks of four to either the pla(cid:173)
`cebo arm or the cladribine arm. In all, 27 patients
`were randomized onto the cladribine arm and 25 onto
`the placebo arm. Throughout the study, patients, neu(cid:173)
`rologists, nurses, and the neuroradiologist remained
`blinded to treatment assignment. A pharmacist was
`informed of patient assignment by code in order to
`dispense placebo or the appropriate dose of cladribine
`to each patient.
`In all patients, clinical neurological exams plus
`SNRS and EDSS rating scales were performed at
`baseline and repeated by the same neurologist every
`month for the first year, every 3 months for the sec(cid:173)
`ond year, and within 48 hr or less of report by a pa(cid:173)
`tient of a relapse. A clinical relapse was defined as the
`appearance of new symptoms or worsening of an ex(cid:173)
`isting symptom, attributable to MS and accompanied
`by objective worsening of neurological findings. To
`be scored as a relapse the alterations must have been
`preceded by disease stability or improvement lasting
`for at least 30 days, and the worsening must have
`lasted at least 24 hr and occur in the absence of fever.
`Relapse severity was rated as follows: ]) mild re(cid:173)
`lapse-decrease in SNRS of 1-7; 2) moderate relapse
`-decrease in SNRS of 8-14; or 3) severe relapse(cid:173)
`decrease in SNRS of 15 or greater.
`Magnetic resonance imaging (MRI) of the brain
`was performed on a 1.5 T Signa scanner (General
`Electric, Milwaukee, WI) for each patient at baseline,
`and then monthly for the first year and every 6 months
`the second year. Tl-weighted scans were obtained in
`the sagittal and axial planes. Axial scans of 3 mm
`thickness and zero interslice gaps were done about 1 0
`min aft~r the intravenous injection of gadopentetate
`dimeglumine (Magnevist, Berlex Laboratories). Spe(cid:173)
`cial attention was given to careful repositioning of pa(cid:173)
`tients to guarantee reproducible slice positions. The
`regions of contrast enhancement on Tl-weiohted
`scans were outlined by hand on filmed images. All
`scans were interpreted and marked by the same neuro(cid:173)
`radiologist (J.Z.), who had no knowledge of patient
`treatment assignment. These were then duplicated by
`a technologist using the taped raw data and a com(cid:173)
`puter workstation [ANALYZE (8), Rochester, MN].
`Quantitation of MRI findings involved the determina(cid:173)
`tion of lesion areas on the consecutive sections of the
`Tl-weighted scans as interpreted by one of two
`skilled technologists, then calculation of volumes by
`assuming homogeneity of lesions across the sections.
`Initially, the taped raw data from the individual scans
`were read into a volume-rendering software program,
`ANALYZE, running on a Hewlett-Packard 712/60
`workstation. Our methodology for lesion area deter-
`
`0
`
`mination is a semiautomated quantitative technique
`adapted from Wicks et al. (9) and Filippi et al. (10).
`
`Drug Administration
`
`In contrast to our earlier study of intravenous cladrib(cid:173)
`ine in progressive MS (5), the drug was administered
`subcutaneously because of greater ease of administra(cid:173)
`tion and because it has now been established that the
`pharmacological properties and response rates of
`cladribine in lymphoproliferative diseases are the
`same if the drug is given either intravenously or sub(cid:173)
`cutaneously (II). Each patient received a course of
`five consecutive daily subcutaneous injections of
`cladribine, 0.07 mg/kg/day or an equivalent volume
`of saline placebo, fractionated into two or three injec(cid:173)
`tion sites, and given monthly for 6 months for a total
`cumulative dose of 2.1 mg/kg of cladribine. A com(cid:173)
`plete blood count was obtained before each monthly
`course of treatment and reviewed by the pharmacist,
`and the next dose of cladribine was given only if
`blood count safety criteria were met according to an
`algorithm designed for this purpose by one of us
`(E.B.; Table 1). If these criteria were not met, a pla(cid:173)
`cebo dose was substituted. The study design included
`eigh~ monthly courses. The last two courses ordinarily
`consisted of placebo, but if a drug dose had been
`omitted because of blood count inadequacy, then ac(cid:173)
`tive drug could be given at month 7 or 8 instead of
`placebo.
`
`Statistical Considerations
`
`Two primary outcome measures were identified: 1)
`the joint frequency and severity of clinical relapses as
`judged by neurological examination; and 2) the num(cid:173)
`bers of enhancing lesions on Tl-weighted MRI brain
`
`Table 1. Pretreatment safety criteria for monthly
`courses of cladribine in multiple sclerosis
`
`I. Platelet count must be:
`a. 200,000 or higher, or
`b. Between 150,000 and 200,000 and represent more
`than 50% of previous pretreatment platelet count, or
`c. Between 125,000 and 150,000 and represent at least
`80% of previous pretreatment platelet count
`2. Absolute granulocyte count must be oreater than 1000
`3. Hemoglobin level must not have declined:
`a. More than l .5 g/dl from previous monthly
`pretreatment level, or
`b. 3 g/dl or more from baseline
`
`scans. Outcomes were to be assessed at I year. A
`sample size of 25 patients per group would be suffi(cid:173)
`cient to detect a decline in the annual rate of exacerba(cid:173)
`tions, from I in the placebo group to 0.5 in the
`cladribine group, with a two-sided Poisson test at al(cid:173)
`pha level 0.05 (12). Similarly, on the basis of findings
`from our chronic progressive MS trial, we postulated
`that the frequency of enhancing lesions in the placebo
`group would remain at 50% throughout the course of
`this study, whereas the frequency of enhancing le(cid:173)
`sions in the cladribine-treated group would decline
`from 50% to < I 0% at I year. A sample size of 25 pa(cid:173)
`tients per treatment group would be sufficient to de(cid:173)
`tect a difference of 50% versus I 0% with a gower of
`0.90, using a two-sided binomial test at alpha level
`0.05.
`Our analyses were intent-to-treat, in that all data
`from every patient initially randomized either to pla(cid:173)
`cebo or to cladribine are included and reported for
`that initial treatment group. Blinded observations
`were undertaken up to 18 months from baseline (trial
`entry); hence, information is reported out to this pe(cid:173)
`riod. We present primary analyses-that is, analyses
`of the primary outcomes at I year-and identify other
`analyses as secondary. We did not impute data values
`for any patient not observed out to 18 months.
`Comparison of the joint frequency and severity of
`relapses between the two treatment groups was under(cid:173)
`taken using Mantel's (13) extension of the Mantel(cid:173)
`Haenszel procedure, here denoted QM- (Mantel's pro(cid:173)
`cedure can incorporate arbitrary scores for the degree
`of relapse, but we chose to score objectively by means
`of ranks based on drop in SNRS score, separately in
`each monthly summary table of relapses, as cross(cid:173)
`classified by treatment group.) A stratified version of
`Mantel's test and a general linear model with Poisson
`link (that is, a Poisson regression model; 14) were
`also used to evaluate the significance of covariate in(cid:173)
`formation as predictors of clinical relapse. Confidence
`intervals for relapse rates were calculated under the
`assumption that the numbers of events followed a
`Poisson distribution in each treatment group. Compar(cid:173)
`ison of the frequency of enhancing lesions on Tl(cid:173)
`weighted MRI scans over time was done with McNe(cid:173)
`mar' s test for paired data (within treatment groups)
`and Fisher exact test (between treatment groups); lo(cid:173)
`gistic regression was also used to assess the signifi(cid:173)
`cance of covariate information. A nonparametric re(cid:173)
`peated measures analysis of variance procedure (15)
`was used to compare neurological performance scores
`(EDSS and SNRS) between the two treatment groups
`over the course of the study. The EDSS and SNRS
`scores were considered to be secondary outcome mea(cid:173)
`sures since little change might be expected between
`the two groups over the relatively short time frame of
`
`the study. Two-sided p values relative to the null dis(cid:173)
`tributions of the observed test statistics are reported.
`Intrarater reliability of the determination of pres(cid:173)
`ence of enhancing lesions on Tl-weighted MRI scans
`was assessed by means of a test-retest of 20 scans by
`the examining neuroradiologist (J.Z.). Discrepancies
`between the two independent evaluations were 15%
`(3/20). In a similar spirit, both examining neurologists
`(J.R. and J.S.) participated in a study of inter-rater and
`intrarater reliability, with regard to the neurological
`rating scales. Twenty patients (J.R., IO; J.S., IO) were
`assessed by the same examiner twice on the same day,
`the period between examinations ranging from 135
`min to 240 min. Intrarater agreement for one exam(cid:173)
`iner (J.S.) on the EDSS was perfect; the weighted K
`coefficient of agreement (16) for the other examiner
`was 0.997. The weighted K coefficients of agreement
`between the paired SNRS scores were 0.999 for both
`examiners. Separately, 20 patients were indepen(cid:173)
`dently assessed by each examiner on the same day. In(cid:173)
`ter-rater agreement was high: the weighted K coeffi(cid:173)
`cient of association was 0.990 for the EDSS and 0.957
`for the SNRS. Inter-rater agreement on the EDSS was
`100% for all sets of examinations when agreement
`was defined as a difference of less than or equal to
`1.0, and 95% when agreement was defined as a differ(cid:173)
`ence of less than or equal to 0.5. Inter-rater agreement
`on the SNRS was 95% when agreement was defined
`as a difference of no more than 10 points, and 90%
`when agreement was defined as a difference of no
`more than 5 points.
`
`RESULTS
`Trial Considerations
`There was one withdrawal on the placebo arm at 3
`months (conversion disorder complicating assessment
`of underlying MS), and one withdrawal on the
`cladribine arm at 4 months (patient moved out of
`state); all of the remaining patients received standard
`intervention without deviations, as specified in the
`protocol. Thus, 26 cladribine patients and 24 placebo
`patients were available for evaluation at 12 months.
`During the period from 12 to I 8 months, five patients
`on placebo withdrew: two patients moved out of state,
`two withdrew for unspecified reasons, and one with(cid:173)
`drew because of worsening MS. One patient receiving
`cladribine also withdrew because of worsening MS.
`Thus, 25 cladribine patients and 19 placebo patients
`were available for evaluation the entire 18-month pe(cid:173)
`riod. Figure 1 depicts the trial profile. During the pe(cid:173)
`riod from I 2 to 18 months, the blinding was removed
`from two cladribine patients and two placebo patients.
`
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`38
`
`Proceedings of the Association of American Physicians 111:1
`
`January/February 1999
`
`Romine et al.: Cladribinc in Relapsing-Remitting Multiple Sclerosis
`
`39
`
`152 PATIENTS WITH PRESUMED
`RELAPSING-REMITTING
`MULTIPLE SCLEROSIS
`WERE SCREENED
`
`Table 2. Baseline demographic and clinical
`characteristics
`
`Placebo
`(n = 25)
`
`Cladribine
`(n = 27)
`
`JOO NOT RANDOMIZED
`89 EXCLUSIONS
`11 REFUSED CONSENT
`
`52 PATIENTS WITH
`RELAPSING-REMITTING
`MS WERE RANDOMIZED
`
`i
`27 CLADRIBINE
`
`l
`
`I WITHDRAWAL
`AT4MONTHS
`
`t
`
`26 COMPLETED
`12 MONTHS
`
`t
`
`25 FOLLOWED
`TO IS MONTHS
`
`t
`25PLACEBO
`
`t
`
`I WITHDRAWAL
`AT3MONTHS
`
`t
`
`24 COMPLETED
`12MONTHS
`{
`19FOLLOWED
`TO 18MONTHS
`
`Figure I. Trial profile of the cladribinc relapsing-remitting
`MS clinical trial.
`
`Because of potential bias, information from these pa(cid:173)
`tients concerning their frequency and severity of ex(cid:173)
`acerbations subsequent to the point of unb1inding is
`not used in the calculation and comparison of exacer(cid:173)
`bation rates between the two treatment groups.
`
`Demographic and Baseline Characteristics in the
`Two Treatment Groups after Randomization
`
`The two groups were similar in terms of baseline clin(cid:173)
`ical characteristics (Table 2). Each group had an ap(cid:173)
`proximate 2: 1 female-to-male preponderance and
`comparable mean age, disease duration, and baseline
`EDSS. Patients randomized to cladribine therapy av(cid:173)
`eraged a slightly greater number of exacerbations in
`the 12 months prior to study entry than patients ran(cid:173)
`domized to placebo.
`
`Sex
`Male
`Female
`Race
`White
`Other
`Age (years)
`Mean
`25th percentile
`50th pecentile
`75lh percentile
`Range
`Years with symptoms
`Mean
`25th percentile
`50th pecentile
`75th percentile
`Range
`Number of exacerbations
`in previous year
`I
`2
`3 or4
`Baseline EDSS
`Mean
`25th percentile
`50th pecentile
`75th percentile
`Range
`Baseline SNRS
`Mean
`25th percentile
`50th pecentile
`75th percentile
`Range
`
`7
`18
`
`25
`0
`
`39.8
`36.5
`41
`44
`31-52
`
`9.1
`3.5
`9
`12.5
`1-25
`
`13
`5
`7
`
`3.8
`2.5
`3.5
`5.3
`2-6.5
`
`75.8
`67
`75.5
`86
`54-98
`
`9
`18
`
`24
`3
`
`43.4
`38.5
`44.5
`49.5
`30-52
`
`10.2
`4.5
`8
`12.5
`1-29
`
`5
`16
`6
`
`3.9
`2.3
`5.5
`5.5
`2-6.5
`
`76.1
`66
`78.5
`86.5
`41-93
`
`EDSS, Extended Disability Status Score. SNRS, Scripps Neurolog(cid:173)
`ical Rating Scale.
`
`Effect of Cladribine on Outcome Measures
`
`Figure 2 depicts the frequency and severity of exacer(cid:173)
`bations for all patients enrolled in the study. We
`examined the joint distribution of frequency and se(cid:173)
`verity over months 7 through 12 for treatment com(cid:173)
`parisons: on the basis of our prior experience ( 17), we
`expected the maximum immunosuppression on clad(cid:173)
`ribine therapy would not be achieved prior to month
`7. Using the extended Mantel-Haensze1 procedure, we
`found that there is a statistically significant reduction
`in the frequency and severity of exacerbations in the
`cladribine group compared to the placebo group over
`months 7 through 12 (Q,, = 2.30, 2p = .021). Over
`this period, the relapse rate in the cladribine group
`
`EOSS
`
`I
`
`G5
`
`Placebo
`
`X
`
`X
`
`"----.x--.-
`
`X
`
`0
`
`3
`
`6
`
`9
`
`12
`
`15
`
`18
`
`Months on Protocol
`
`Cladribine
`
`EOSS
`
`GS
`
`S.5
`
`X
`
`0
`
`3
`
`6
`
`9
`
`12
`
`15
`
`18
`
`Months on Protocol
`
`Figure 2. Event charts for frequency and
`severity of exacerbations over the course
`of the study in placebo-treated and cladri(cid:173)
`bine-treated patients.
`Within treatment groups, patients are or(cid:173)
`dered in terms of decreasing EDSS scores at
`baseline; patients with identical EDSS scores
`at baseline are ordered by numbers of new
`exacerbations. Mild, moderate, or severe ex(cid:173)
`acerbations are denoted by progressively
`heavier X's.
`
`was 0.77 per year [95% confidence interval (Cl), 0.37-
`1.41], compared to 1.67 per year in the placebo group
`(95% CI, 1.02-2.57). With Poisson regression, we
`identified treatment along with two other covariates,
`baseline EDSS and number of exacerbations in the
`year prior to start of treatment, as significant predic(cid:173)
`tors of relapse over months 7 through 12 (with fewer
`
`relapses being associated with cladribine therapy,
`lower EDSS scores at baseline, and fewer exacerba(cid:173)
`tions in the year prior to start of treatment). In second(cid:173)
`ary analyses, we found that the reduction in the distri(cid:173)
`bution of frequency and severity of exacerbations in
`the cladribine group relative to the placebo group is
`sustained at 18 months: Q" = 2.59, 2p = .010 over
`
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`Proceedings of the Association of American Physicians 111:1
`
`January/February 1999
`
`Romine ct al.: Cladribine in Relapsing-Remitting Multiple Sclerosis
`
`41
`
`the I-year period from month 7 through month I 8.
`Over this extended period, the exacerbation rate in the
`cladribine group was 0.66 per year (95% Cl, 0.37-
`1.05) compared to 1.34 per year in the placebo group
`(95% Cl, 0.90-1.93).
`Figure 3 compares the frequency and severity of
`relapses at 6-month intervals during the study with the
`frequency of relapses in the 12 months preceding
`treatment with drug or placebo. It is apparent that
`there was striking improvement in the first 6 months
`of the study, when injections of placebo or cladribine
`were being given 5 days of each month, regardless of
`whether the patients received placebo or active drug.
`When injections were stopped, the frequency of re(cid:173)
`lapses in the placebo group returned to its baseline,
`pretreatment frequency, but the frequency and sever(cid:173)
`ity of relapses continued to decline in the patients who
`received cladribine.
`MRI results (Fig. 4, Table 3) revealed complete
`suppression of enhancing lesions after study month 6
`in the cladribine group, whereas lesion enhancement
`persisted in the placebo group. Formally, with regard
`to the primary outcome measure at 12 months, there is
`a highly significant decrease in the occurrence of en(cid:173)
`hancing lesions at 12 months relative to baseline in
`the c!adribine group (2p < .0003 by McNemar' s test).
`In contrast, there is a slight increase in the occurrence
`
`of enhancing lesions at 12 months relative to baseline
`in the placebo group (2p = . !09 by McNemar's test);
`and, the frequency of enhancing lesions is signifi(cid:173)
`cantly greater at 12 months in the placebo group than
`in the cladribine group (2p = .000 I by Fisher exact
`test). In secondary analyses, we find a significant re(cid:173)
`duction in the frequency of enhancing lesions experi(cid:173)
`enced by the cladribine group relative to baseline al(cid:173)
`ready at month 7 and persisting at month I 8 (2p <
`.0005 by McNemar' s test at each time point). More(cid:173)
`over, the frequency of enhancing lesions in the pla(cid:173)
`cebo group is already significantly greater than that in
`the cladribine group by 7 months (2p = .000 I by
`Fisher) and remains so at I 8 months (2p = .002 by
`Fisher). No significant predictors of enhancing lesion
`presence other than treatment were found by logistic
`regression.
`We found no significant differences between the
`treatment groups in either EDSS or SNRS scores, the
`secondary outcome parameters, over 18 months (p > .5
`for each; Fig. 5).
`
`Adverse Events and Side Effects
`
`Infections were limited to an episode of mild segmen(cid:173)
`tal herpes zoster that occurred in two cladribine-
`
`2,5
`
`2-Cdo
`
`Pklc:obo
`
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`
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`
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`.0
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`0
`0
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`w
`0
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`0
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`
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`
`severe
`•
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`-
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`
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`
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`
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`
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`
`,
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`i'.
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`
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`
`'·
`
`-12 to 0
`
`1 to 6
`
`7 to12
`Months
`
`13to18
`
`Figure 3. Rates of exacerbations for the
`two treatment groups.
`The number of exacerbations for the year
`prior to initiation of treatment was obtained
`from the patient's history. Over the course of
`the trial itself, exacerbations were docu(cid:173)
`mented by the neurologist and classified as
`mild, moderate, or severe as explained in the
`text. For purposes of comparison, rates are
`presented as relapses per year.
`
`Cladribine
`
`Placebo
`
`3 mm
`---.--~-~--.-----,---.-780
`
`500
`
`%
`
`(I)
`
`400
`
`,,,
`E ::,
`0
`>
`C:
`0
`·;;;
`;!l
`0) 200
`C ·o
`C:
`0
`,,:;
`C:
`LU
`
`300
`
`JOO
`
`\
`
`~ ,
`\
`
`60
`
`40
`
`20
`
`3 mm
`
`400
`
`300
`
`200
`
`100
`
`' /
`
`...
`
`•
`T
`- .
`
`I•
`
`%
`
`vv~ 60
`
`40
`
`'
`~ 20
`
`.·
`
`12
`
`15
`
`18
`
`0
`
`Month
`
`0
`0
`
`3
`
`6
`
`.
`.
`
`9
`
`Month
`
`Figure 4. Average volumes of enhancing lesions on Tl-weighted scans (bars, left vertical _axis), and proportions of patients with enhanc-
`ing lesions (dots, right vertical axis), for the two treatment groups over the course of the tr~al.
`.
`Averages and proportions were computed on the basis of all available MRI data at each time point. Standard error bars are also given for the MRI
`volumes.
`
`treated patients and in one patient receiving placebo.
`Acyclovir was administered orally in each case.
`Cladribine-treated patients experienced no side ef(cid:173)
`fects that might have led to unblinding of patients or
`examining neurologists. Average lymphocyte counts
`in the cladribine group declined as expected to a nadir
`at 7 months of 0.4 X 103/µ,I. The average platelet
`count in the cladribine group declined modestly to a
`low of >200 X I 03/µ,I at 6 months, and the average
`hemoglobin to a low of> 13.5 g/dl at 11 months, but
`there were no individual cases of significant thrombo-
`
`Table 3. Presence of enhancing lesions by MRI over
`the course of the trial
`
`Placebo
`
`Cladribine
`
`Time
`
`Lesions
`absent
`
`Lesions
`present
`
`Lesions
`absent
`
`Lesions
`present
`
`Ba:-.eline
`7 months
`12 months
`18 months
`
`15
`13
`7
`9
`
`IO
`II
`16
`IO
`
`13
`25
`25
`22
`
`14
`0
`0
`2
`
`Note: One cladribine patient did not have an MRI during month 7,
`one placebo patient and one cladribine patient did not have an MRI
`during month 12, and one cladribine patient did not have an MRI at
`month 18.
`
`cytopenia, anemia, granulocytopenia, or generalized
`marrow suppression (Fig. 6).
`
`DISCUSSION
`In view of the long-lasting lymphopenia and rela(cid:173)
`tively low toxicity from cladribine, we began studies
`in 1990 with progressive MS patients in the hope that
`depletion of immunocytes might be beneficial. Be(cid:173)
`cause initial observations were encouraging, we un(cid:173)
`dertook a 2-year, placebo-controlled, double-blind
`study in 51 patients in which cladribine (total dose =
`2.8 mg/kg) or placebo was administered during the
`first year via a central venous access device using a
`portable infusion pump. A favorable effect on neuro(cid:173)
`logical performance scores and on MRI findings was
`documented in patients treated with cladribine (5,6).
`A multicenter trial has subsequently been con(cid:173)
`ducted in 159 patients with progressive MS using
`cladribine subcutaneously at a total dose of 2.1 mg/
`kg. Unexpectedly, there was no worsening of neuro(cid:173)
`logical performance scores in the placebo arm and
`therefore no significant differences were seen be(cid:173)
`tween cladribine and placebo-treated groups. This
`study was probably underpowered due to inclusion of
`more patients with advanced disability (18). How(cid:173)
`ever, marked suppression of enhancing MRI lesions
`with cladribine treatment was confirmed in the pro-
`
`Petitioner TWi Pharms., Inc.
`EX1016, Page 4 of 6
`
`

`

`42
`
`Proceedings of the Association of American Physicians 111:1
`
`January/February 1999
`
`Romine ct al.: Cladribinc in Relapsing-Remitting Multiple Sclerosis
`
`43
`
`Hemoglobin
`
`MCV
`
`!ll]l
`
`3.5
`
`~
`0
`0
`"'
`~ 4.0
`w
`
`80
`
`~
`0
`0
`
`"' ~
`35 75
`
`4.5
`
`o Cladribine
`□ Placebo
`
`70
`
`o Cladribine
`□ Placebo
`
`0 2 4 6
`
`8 10 12 14 16 18
`
`0
`
`2 4
`
`6
`
`8 10 12 14 16 18
`
`Month
`
`Month
`
`Figure 5. Changes in the Kurtzke (EDSS) and Scripps (SNRS) rating scores.
`Solid symbols indicate when cladribine was administered. Means and pointwise standard error bars are shown.
`
`gressive MS multicenter study and no significant tox(cid:173)
`icity was observed.
`The results in relapsing-remitting MS, as re(cid:173)
`ported in the cun-ent study, indicate that cladribine
`given subcutaneously at a total dosage of 2.1 mg/kg
`appears to be safe and effective in reducing the rate
`and severity of clinical exacerbations for at least the
`relatively short duration of the study. Particularly
`striking was the placebo effect noted in the first 6
`months of our study, when patients were receiving in(cid:173)
`jections; the relapse frequency dropped to about one
`half in both groups of patients. In the second 6
`months, however, when no injections were given but
`after immunosuppression had been achieved in the
`drug-treated group, the relapse frequency returned to
`baseline in patients who had received placebo, but pa(cid:173)
`tients who had received drug continued to enjoy rela(cid:173)
`tive freedom from exacerbations, an effect that con(cid:173)
`tinued into the second year of the study.
`Our primary analyses are predicated on outcomes
`at 1 year following randomization. During this period,
`all patients received the treatment to which they had
`been randomized; that is, treatment allocation and
`treatment actually received were identical for every(cid:173)
`one. Two patients, one randomized to placebo and the
`other to cladribine, withdrew from the study during
`the first year. Hence, the attrition rate was <5% on
`each arm over the formal length of the trial. The re(cid:173)
`sults of our primary analyses at I year, comparing the
`joint frequency and severity of exacerbations between
`
`the treatment groups, and comparing the frequencies
`of enhancing lesions, are insensitive to the loss of in(cid:173)
`formation from these patients. With regard to the sec(cid:173)
`ond primary end point, the presence of enhancing le(cid:173)
`sions of Tl-weighted scans, it is clear from Table 3
`that even under the least favorable scenario for
`cladribine-no enhancing lesions in the placebo with(cid:173)
`drawal, but enhancing lesions in the cladribine with(cid:173)
`drawal-the favorable outcome of cladribine therapy
`relative to placebo at 1 year would remain over(cid:173)
`whelmingly significant. The lack of any demonstrable
`difference in neurological disability (EDSS and
`SNRS scores) between the cladribine and placebo
`groups is of uncertain significance since neither treat(cid:173)
`ment group, including the placebo group, showed sig(cid:173)
`nificant worsening over the duration of the study.
`The almost complete suppression of MRI(cid:173)
`enhancing lesions with cladribine is a very robust treat(cid:173)
`ment effect similar to that previously reported with
`cladribine in progressive MS (5,6,18) and exceeding
`the effect of interferon beta-I a (19). Since enhance(cid:173)
`ment of MRI lesions is thought to reflect active dis(cid:173)
`ease (20), the question arises as to how some cladribine(cid:173)
`treated patients continued to have clinical relapses,
`but with no apparent lesion enhancement on serial
`MRI scans.
`The mechanism of action of the beneficial effect
`of cladribine on MS is presumably related to the se(cid:173)
`lective and sustained depletion of lymphocytes. In a
`previous study of cladribine in chronic progressive
`
`14.5
`
`'o 14.0
`
`'"
`
`13.5 -
`
`13.0
`
`275
`
`o Cladrlblno
`a Placebo
`
`0 2 4 6 8 10 12 14 16 18
`
`Month
`
`Platelets
`
`250
`
`'b
`
`• '
`" 225
`
`200
`
`175
`
`o Cladribine
`o Placebo
`
`0 2 4 6 8 10 12 14 16 18
`Month
`
`94
`
`92
`
`~ 90
`E
`~
`
`88
`
`86
`
`2.5
`
`2.0
`
`• 1.5
`.....
`'e
`" 1.0
`
`0.5
`
`0.0
`
`o Cladrlblne
`a Placebo
`
`0
`
`2 4
`
`6
`