This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Hopewell EX1031
`
`1
`
`

`

`36
`
`Proceedingsof the Association of American Physicians 111:1
`
`January/February1999
`
`sured by Scripps Neurological Rating Scale (SNRS;
`7) (in 10-point intervals). The stratified groups were
`then randomized in blocks of four to either the pla-
`cebo armor the cladribine arm.
`In all, 27 patients
`were randomized onto the cladribine arm and 25 onto
`the placebo arm. Throughoutthe study, patients, neu-
`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-
`ond year, and within 48 hror less of report by a pa-
`tient of a relapse. A clinical relapse was definedas the
`appearance of new symptomsor worsening of an ex-
`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 improvementlasting
`for at
`least 30 days, and the worsening must have
`lasted at least 24 hr and occurin the absenceoffever.
`Relapse severity was rated as follows: 1) mild re-
`lapse—decrease in SNRSof1-7; 2) moderate relapse
`—decrease in SNRS of 8-14; or 3) severe relapse—
`decrease in SNRSof 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. T1-weighted scans were obtained in
`the sagittal and axial planes. Axial scans of 3 mm
`thickness and zero interslice gaps were done about 10
`min after the intravenous injection of gadopentetate
`dimeglumine (Magnevist, Berlex Laboratories). Spe-
`cial attention was givento careful repositioning of pa-
`tients to guarantee reproducible slice positions. The
`regions of contrast enhancement on Tl-weighted
`scans were outlined by hand on filmed images. All
`scans were interpreted and marked by the same neuro-
`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-
`puter workstation [ANALYZE (8), Rochester, MN].
`Quantitation of MRIfindings involved the determina-
`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 oflesions 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-
`
`mination is a semiautomated quantitative technique
`adapted from Wicks etal. (9) and Filippi et al. (10).
`
`Drug Administration
`
`In contrastto our earlier study of intravenous cladrib-
`ine in progressive MS(5), the drug was administered
`subcutaneously because of greater ease of administra-
`tion and because it has now beenestablished that the
`pharmacological properties and response rates of
`cladribine in lymphoproliferative diseases are the
`sameif the drug is given either intravenously or sub-
`cutaneously (11). 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-
`tion sites, and given monthly for 6 monthsfor a total
`cumulative dose of 2.1 mg/kg of cladribine. A com-
`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-
`cebo dose was substituted. The study design included
`eight 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-
`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 andseverity of clinical relapses as
`judged by neurological examination; and 2) the num-
`bers of enhancing lesions on Tl-weighted MRI brain
`
`Table 1. Pretreatment safety criteria for monthly
`coursesof cladribine in multiple sclerosis
`
`1.
`
`Platelet count must be:
`a. 200,000 or higher, or
`b. Between 150,000 and 200,000 and represent more
`than 50% ofprevious pretreatmentplatelet count, or
`c. Between 125,000 and 150,000 and representat least
`80% ofprevious pretreatmentplatelet count
`2. Absolute granulocyte count must be greater than 1000
`3. Hemoglobin level must not have declined:
`a. More than 1.5 g/dl from previous monthly
`pretreatmentlevel, or
`b. 3 g/dl or more from baseline
`
`2
`
`

`

`Romine et al.: Cladribine in Relapsing-Remitting Multiple Sclerosis
`
`7
`
`| year. A
`scans. Outcomes were to be assessed at
`sample size of 25 patients per group would be suffi-
`cient to detect a decline in the annual rate of exacerba-
`tions,
`from |
`in the placebo group to 0.5 in the
`cladribine group, with a two-sided Poissontest at al-
`pha level 0.05 (12). Similarly, on the basis of findings
`from our chronic progressive MStrial, we postulated
`that the frequency of enhancinglesions in the placebo
`group would remain at 50% throughout the course of
`this study, whereas the frequency of enhancing le-
`sions in the cladribine-treated group would decline
`from 50% to <10% at | year. A sample size of 25 pa-
`tients per treatment group would be sufficient to de-
`tect a difference of 50% versus 10% with a powerof
`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 patientinitially randomized either to pla-
`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-
`riod. We present primary analyses—that is, analyses
`of the primary outcomesat | year—andidentify other
`analyses as secondary. Wedid not impute data values
`for any patient not observed out to 18 months.
`Comparisonofthe joint frequency and severity of
`relapses between the two treatment groups was under-
`taken using Mantel’s (13) extension of the Mantel-
`Haenszel procedure, here denoted Qy,. (Mantel’s pro-
`cedure can incorporate arbitrary scores for the degree
`of relapse, but we choseto score objectively by means
`of ranks based on drop in SNRSscore, separately in
`each monthly summarytable of relapses, as cross-
`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-
`formation as predictors ofclinical 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-
`ison of the frequency of enhancing lesions on T1-
`weighted MRI scansover time was done with McNe-
`mar’s test for paired data (within treatment groups)
`and Fisher exact test (between treatment groups); lo-
`gistic regression was also used to assess the signifi-
`cance of covariate information. A nonparametric re-
`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-
`sures since little change might be expected between
`the two groupsoverthe relatively short time frame of
`
`the study. Two-sided p valuesrelative to the null dis-
`tributions of the observedtest statistics are reported.
`Intrarater reliability of the determination of pres-
`ence of enhancing lesions on Tl-weighted MRI scans
`wasassessed by meansofa 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., 10; J.S., 10) 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-
`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-
`dently assessed by each examineronthe sameday. In-
`ter-rater agreement was high: the weighted k coeffi-
`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 asa differ-
`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 18 months,five patients
`on placebo withdrew: two patients movedout of state,
`two withdrew for unspecified reasons, and one with-
`drew because of worsening MS. Onepatient 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-
`riod. Figure | depicts the trial profile. During the pe-
`riod from 12 to 18 months, the blinding was removed
`from two cladribine patients and two placebopatients.
`
`3
`
`

`

`38
`
`Proceedings of the Association of American Physicians 11 1:1
`
`January/February 1999
`
`
`
`152 PATIENTS WITH PRESUMED
`RELAPSING-REMITTIING
`MULTIPLE SCLEROSIS
`WERE SCREENED
`
`
`
`
`
`100 NOT RANDOMIZED
`89 EXCLUSIONS
` 11 REFUSED CONSENT
`
`
`
`52 PATIENTS WITH
`RELAPSING-REMITTING
`
`MS WERE RANDOMIZED
`
`
`
`
`
`Table 2. Baseline demographic and clinical
`characteristics
`
`
`Placebo
` (n = 25)
`
`Cladribine
`(n = 27)
`
`Sex
`Male
`Female
`Race
`White
`Other
`Age(years)
`Mean
`25th percentile
`50th pecentile
`75th percentile
`Range
`Years with symptoms
`Mean
`25th percentile
`50th pecentile
`75th percentile
`Range
`Numberof exacerbations
`in previous year
`1
`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
`
`91
`3.5
`9
`12.5
`1-25
`
`13
`5
`7
`
`3.8
`2.5
`3.5
`3.3
`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
`32
`55
`2-6.5
`
`76.1
`66
`78.5
`86.5
`41-93
`
`27 CLADRIBINE
`
`1 WITHDRAWAL
`AT 4 MONTHS
`
`
`
`
`
`
`
`
`26 COMPLETED
`12 MONTHS
`
`25 FOLLOWED
`TO 18 MONTHS
`
`25 PLACEBO
`
`1 WITHDRAWAL
`AT 3 MONTHS
`
`24 COMPLETED
`12 MONTHS
`
`19 FOLLOWED
`TO 18 MONTHS
`
`
`
`
`
`
`Figure 1. Trial profile of the cladribine relapsing-remitting
`MSclinicaltrial.
`
`Because of potential bias, information from these pa-
`tients concerning their frequency and severity of ex-
`acerbations subsequent to the point of unblinding is
`not used in the calculation and comparison of exacer-
`bation rates between the two treatment groups.
`
`Demographic and Baseline Characteristics in the
`Two Treatment Groupsafter Randomization
`
`The two groups weresimilar in termsofbaseline clin-
`ical characteristics (Table 2). Each group had an ap-
`proximate 2:1
`female-to-male preponderance and
`comparable mean age, disease duration, and baseline
`EDSS. Patients randomized to cladribine therapy av-
`eraged a slightly greater number of exacerbations in
`the 12 months prior to study entry than patients ran-
`domized to placebo.
`
`EDSS, Extended Disability Status Score. SNRS, Scripps Neurolog-
`ical Rating Scale.
`
`Effect of Cladribine on Outcome Measures
`
`Figure 2 depicts the frequency and severity of exacer-
`bations for all patients enrolled in the study. We
`examined the joint distribution of frequency and se-
`verity over months 7 through 12 for treatment com-
`parisons: onthe basis of our prior experience (17), we
`expected the maximum immunosuppression on clad-
`ribine therapy would not be achieved prior to month
`7. Using the extended Mantel-Haenszel 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 (Qy = 2.30, 2p = .021). Over
`this period,
`the relapse rate in the cladribine group
`
`4
`
`

`

`Romineet al.: Cladribine in Relapsing-Remitting Multiple Sclerosis
`
`39
`
`Placebo
`
`EDSS
`
`x
`x
`
`x
`x
`
`“Keone:
`arose en
`
`ccommsnszcamsrnesee
`
`seers
`x
`
`a
`
`x
`
`eX
`a
`
`xX
`
`x
`
`x
`
`x
`
`65
`
`6
`
`5
`Ai
`35
`
`a
`
`25
`
`2
`
`.
`
`
`
`
`
`Xo
`oe
`
`
`
`~X
`.
`
`x
`
`x
`
`x
`
`
`T
`T
`T
`T
`TT
`T
`T
`0
`3
`6
`9
`12
`15
`18
`Months on Protocol
`
`Cladribine
`
`| EDss
`es
`
`
`
`
` Figure 2. Event charts for frequency and
`
`"
`x
`
`stratseccerqureeresstnnarleenoanene
`x
`XK
`
`xX
`a
`
`oo
`
`cawte
`
`ii
`
`x
`
`6
`5.5
`
`5
`45
`4
`35
`
`seRORS
`
`Xe
`
`z
`
`“X% =
`x
`
`cen ee
`
`:
`x
`2
`
`aex
`oe
`
`x
`
`
`
`severity of exacerbations over the course
`of the study in placebo-treated and cladri-
`bine-treated patients.
`Within treatment groups, patients are or-
`dered in terms of decreasing EDSSscoresat
`baseline; patients with identical EDSS scores
`at baseline are ordered by numbers of new
`exacerbations. Mild, moderate, or severe ex-
`acerbations are denoted by progressively
`heavier X’s.
`
`Months on Protocol
`
`18
`
`was 0.77 per year [95% confidenceinterval (CI), 0.37—
`1.41], compared to 1.67 per yearin 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-
`tors of relapse over months 7 through 12 (with fewer
`
`relapses being associated with cladribine therapy,
`lower EDSS scores at baseline, and fewer exacerba-
`tionsin the yearpriorto start of treatment). In second-
`ary analyses, we foundthat the reduction in the distri-
`bution of frequency and severity of exacerbations in
`the cladribine group relative to the placebo group is
`sustained at 18 months: Qy = 2.59, 2p = .010 over
`
`5
`
`

`

`40
`
`Proceedings of the Association of American Physicians 111:1
`
`January/February 1999
`
`the l-year period from month 7 through month 18.
`Overthis extended period, the exacerbationrate in the
`cladribine group was 0.66 per year (95%CI, 0.37—
`1.05) compared to 1.34 per year in the placebo group
`(95% CI, 0.90-1.93).
`Figure 3 compares the frequency andseverity 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 wasstriking improvementin 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 oractive drug.
`Wheninjections were stopped, the frequency of re-
`lapses in the placebo group returned to its baseline,
`pretreatment frequency, but the frequency and sever-
`ity of relapses continued to decline in the patients who
`received cladribine.
`MRIresults (Fig. 4, Table 3) revealed complete
`suppression of enhancinglesions 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-
`hancing lesions at 12 months relative to baseline in
`the cladribine group (2p < .0003 by McNemar’s test).
`In contrast, there is a slight increase in the occurrence
`
`of enhancing lesions at 12 monthsrelative to baseline
`in the placebo group (2p = .109 by McNemar’s test);
`and,
`the frequency of enhancing lesions is signifi-
`cantly greater at 12 months in the placebo group than
`in the cladribine group (2p = .0001 by Fisher exact
`test). In secondary analyses, we find a significant re-
`duction in the frequency of enhancing lesions experi-
`enced by the cladribine group relative to baseline al-
`ready at month 7 and persisting at month 18 (2p <
`.0005 by McNemar’s test at each time point). More-
`over, the frequency of enhancing lesions in the pla-
`cebo groupis already significantly greater than that in
`the cladribine group by 7 months (2p = .0001 by
`Fisher) and remains so at 18 months (2p = .002 by
`Fisher). No significant predictors of enhancing lesion
`presence other than treatment were found by logistic
`regression.
`Wefound nosignificant differences between the
`treatment groups in either EDSS or SNRSscores, 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-
`tal herpes zoster that occurred in two cladribine-
`
`
`
`2-Cda
`
`Ml Severe
`Moderate
`Mild
`Unknown
`
`
`
`2.5 ;
`
`
`
`RateofExacerbationsperYear
`
` 1to6
`
`2-Cda
`
`Placebo
`
`ms
`
`©6Placebo
`
`2-Cda
`
`2-Cda
`
`|
`
`4
`
`|
`
`7 tol2
`
`13 to18
`
`Months
`
`Figure 3. Rates of exacerbations for the
`two treatmentgroups.
`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-
`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 peryear.
`
`6
`
`

`

`Romineet al.: Cladribine in Relapsing-Remitting Multiple Sclerosis
`
`41
`
`Cladribine
`
`Placebo
`
`Yo
`
`80
`
`~~
`
`= 60
`
`- 40
`|
`|
`|
`|
`] 20
`|
`|
`
`mm?
`
`500 —
`
`-
`
`1
`
`od
`
`400
`
`300
`
`0>c
`
`Qo
`
`O
`=
`2 200
`oO
`=
`3
`=
`Lu
`
`100
`
`
`
`
`
`uv
`oO@
`4
`#Q
`
`oO
`o.uU
`
`Q3
`
`s =
`
`°o
`
`%
`
`»o 80
`
`T
`
`~
`
`ar
`
`NK
`_—
`
`mm?
`
`500 ; > tT T
`|
`|
`
`400
`
`300
`
`200
`
`100
`
`
` 0
`
`.=:
`Zs
`5a,
`_*
`ono
`\ ae
`|
`it) oe pidgesas|0
`0
`3
`6
`9
`12
`15
`18
`12
`15
`9
`18
`
`Month
`
`Month
`
`Figure 4. Average volumesof enhancinglesions on T1-weighted scans (bars,left vertical axis), and proportions of patients with enhanc-
`ing lesions (dots, right vertical axis), for the two treatment groups overthe courseof the trial.
`Averages and proportions were computed onthe basisofall available MRIdata at each time point. Standarderrorbars 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-
`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 * 10°/wl. The average platelet
`count in the cladribine group declined modestly to a
`low of >200 x 10*/y1 at 6 months, and the average
`hemoglobin to a low of >13.5 g/dl at 11 months, but
`there were no individual cases ofsignificant thrombo-
`
`Table 3. Presence of enhancing lesions by MRI over
`the courseof the trial
`
`Placebo
`
`Cladribine
`
`‘
`Time
`
`Lesions
`
`absent
`
`Lesions
`
`present
`
`Lesions
`
`absent
`
`Lesions
`
`present
`
`Baseline
`7 months
`12 months
`18 months
`
`13
`10
`15
`25
`11
`13
`25
`16
`7
`22,
`10
`9
`
`
`14
`0
`0
`2
`
`Note: Onecladribine patient did not have an MRI during month 7,
`one placebo patient and onecladribine patient did not have an MRI
`during month 12, and onecladribine 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-
`tively low toxicity from cladribine, we began studies
`in 1990 with progressive MS patients in the hopethat
`depletion of immunocytes might be beneficial. Be-
`cause initial observations were encouraging, we un-
`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-
`logical performance scores and on MRIfindings was
`documented inpatients treated with cladribine (5,6).
`A multicenter trial has subsequently been con-
`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-
`logical performance scores in the placebo arm and
`therefore no significant differences were seen be-
`tween cladribine and placebo-treated groups. This
`study was probably underpowereddueto inclusion of
`more patients with advanced disability (18). How-
`ever, marked suppression of enhancing MRI lesions
`with cladribine treatment was confirmed in the pro-
`
`7
`
`

`

`42
`
`Proceedings of the Association of American Physicians 111:1
`
`January/February 1999
`
`
`0 Ss 1
`
`
`
`EDSSScore
`
`|
`
`|
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`_ail
`es
`3.5} TTL ALA
`
`=—i
`/ I
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`
`
`Iit|\
`
`%&
`
`4.0 - Nee
`il |
`|
`0 Cladribine
`45+
`||
`3 Placebo
`J
`1
`|
`
`|
`
`1
`
`8
`
`|
`
`i
`
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`
`10 12 14
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`16
`
`18
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`
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`2
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`4
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`6
`
`
`
`
`
`SNRS
`
`Score
`
`70
`
`oO Cladribine
`a Placebo
`iL.
`1
`|
`
`l
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`
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`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14 16 18
`
`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 nosignificant tox-
`icity was observed.
`The results in relapsing-remitting MS, as re-
`ported in the current 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-
`jections; the relapse frequency dropped to about one
`half in both groups of patients.
`In the second 6
`months, however, when noinjections 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-
`tients who had received drug continued to enjoy rela-
`tive freedom from exacerbations, an effect that con-
`tinued into the second yearof the study.
`Ourprimary analysesare predicated on outcomes
`at | 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-
`one. Twopatients, 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-
`sults of our primary analyses at | year, comparing the
`joint frequency and severity of exacerbations between
`
`the treatment groups, and comparing the frequencies
`of enhancinglesions, are insensitive to the loss of in-
`formation from these patients. With regard to the sec-
`ond primary end point, the presence of enhancingle-
`sions of Tl-weighted scans, it is clear from Table 3
`that even under
`the least
`favorable scenario for
`cladribine—no enhancinglesionsin the placebo with-
`drawal, but enhancinglesions in the cladribine with-
`drawal—the favorable outcomeof cladribine therapy
`relative to placebo at
`| year would remain over-
`whelmingly significant. The lack of any demonstrable
`difference in neurological disability (EDSS and
`SNRS scores) between the cladribine and placebo
`groupsis of uncertain significance since neither treat-
`mentgroup, including the placebo group, showedsig-
`nificant worsening overthe duration of the study.
`The
`almost complete
`suppression of MRI-
`enhancinglesions with cladribineis a very robust treat-
`ment effect similar to that previously reported with
`cladribine in progressive MS(5,6,18) and exceeding
`the effect of interferon beta-la (19). Since enhance-
`ment of MRIlesions is thought to reflect active dis-
`ease (20), the question arises as to how somecladribine-
`treated patients continued to have clinical relapses,
`but with no apparent
`lesion enhancement onserial
`MRIscans.
`The mechanism of action of the beneficial effect
`of cladribine on MSis presumably related to the se-
`lective and sustained depletion of lymphocytes. In a
`previous study of cladribine in chronic progressive
`
`8
`
`

`

`Romineet al.: Cladribine in Relapsing-Remitting Multiple Sclerosis
`
`43
`
`
`
`4
`
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`
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`
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`o Cladribine
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`ee
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`
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`
`4
`
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`:
`
`
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`
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`
`Platelets
`Lymphocytes
`
`
`T a5TT T T T T T T
`
`
`
`
`
`
`
`
`25 ooo 1 t
`
`275 +
`
`250} i
`
`i
`
`«225+
`
`wo}
`
`175+
`
`_
`2a;
`
`&%
`
`© Cladribine
`+
`© Placebo
`po
`0
`2
`4
`6
`8
`10 12 14 16
`18
`
`o Cladribine
`oa Placebo
`lt 4
`0.0
`2
`4
`6
`8
`0
`
`1 —
`1
`de
`10 12 14 16 18
`
`Month
`
`Month
`
`Figure 6. Serial blood cell counts over the course ofthetrial.
`Solid symbols indicate when drug was administered. Means and standard error bars are shown.
`
`there was an approximately four-fold de-
`MS (6),
`MS (6) would indicate that beneficial effect should
`eventually decline and would not be expectedto last
`crease in the CD4/CD8“helper/suppressor” ratio and
`much beyond 2 years. The lengthy but impermanent
`an approximately five-fold reduction of CD25-acti-
`duration of effect of cladribine meansthat retreatment
`vated T and B lymphocytes, which lasted for many
`will be necessary if cladribine is to becomea practical
`months after a 4-month course of the drug. By com-
`long-term therapy for MS. At present, there are few
`parison, treatment of MS with the general immuno-
`data on the safety of long-term retreatment with
`suppressive drugs cyclophosphamide (21) or chlor-
`
`ambucil (22) producedarelatively transient two-fold cladribine in a nonmalignant disease such as MS.
`Twenty-four patients from our initial study of cladrib-
`decline in the CD4/CD8 ratio. This difference sug-
`gests that cladribine may have a more potent immuno-
`ine in chronic progressive MS have been retreated
`(0.07 mg/kg X 5 days X 4 courses) because ofa re-
`suppressive effect in MS than other drugs.
`The duration ofthe beneficial effect on relapsing
`currence of disease worsening. There were no in-
`MSafter a course of cladribine could not be deter-
`stances of marrow suppression or thrombocytopenia
`in these patients, but 6 (25%) developed herpes zoster
`mined from this study since the patients were un-
`with a second course of cladribine as compared to 2 of
`blinded after 18 months. However, an estimate based
`on observations of cladribine in chronic progressive
`51 (4%) with the first treatment. Repeated treatment
`
`9
`
`

`

`44
`
`Proceedings of the Association of American Physicians 111:1
`
`January/February 1999
`
`logic rating scale (NRS) for use in multiple sclerosis.
`Neurology 34: 1368-1372, 1984.
`. Biomedical Imaging Resource: Mayo Foundation. Ana-
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`. Wicks D.A.G., Tofts P.S., Miller D.H., et al. Volume
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`
`raises long-term toxicity issues including: 1) suscepti-
`bility to opportunistic infection; 2) marrow stemcell
`depletion; and 3) an increase in the incidence of ma-
`lignancy, known to occur in association with other
`long-term immunosuppressive treatments (23).
`Since currently available treatments for relapsing
`MS are only partially effective and because,
`in the
`case of interferons, there is concern that the beneficial
`effect may be lost due to induction of neutralizing an-
`tibodies (24), new treatments need to be developed. In
`this regard, cladribine shows promiseasa relatively
`safe andat least temporarily effective treatment in re-
`ducing the frequency and severity of MS exacerba-
`tions and in suppressing new contrast-enhancing MRI
`lesions.
`
`ACKNOWLEDGMENTS
`
`The authors gratefully acknowledge the outstanding
`work of Carolyn Koumaras, R.N,in clinical coordina-
`tion, Kathleen Romine, R.N.,
`in patient recruitment,
`and the nursing and support staff of the General Clini-
`cal Research Center at Scripps Clinic. This study was
`done underthe investigator-initiated IND no. 36773.
`It was supported by the Stein Endowment Fund,
`Grant RRO00833
`from the National
`Institutes of
`Health, Johnson & Johnson Pharmaceutical Research
`Institute, SFP-1004, and the Garate Memorial Fund
`for Multiple Sclerosis Research. This is publication
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