IMMUNOLOGICAL DISORDERS
`
`BioDrugs 1997 May: 7 (5): 386-393
`1173-8804/97/0005-0386/$04.00/0
`© Adis International Limited.All rights reserved.
`
`Cladribine
`Use in Therapy of Multiple Sclerosis
`
`John S. Romine," Jack C. Sipe, James A. Koziol,? Jack Zyroff,> Robert McMillanand
`Ernest Beutler?
`
`1 Division of Neurology, Scripps Clinic and Research Foundation, La Jolla, California, USA
`2 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla,
`California, USA
`3. Division of Radiology, Scripps Clinic and Research Foundation,La Jolla, California, USA
`
`Contents
`
`SUMMATY 386
`1. Results in Chronic Progressive Multiple Sclerosis 2.0. 388
`2. Adverse Effects... eeee 390
`3. Therapeutic Potential and Clinical Use6 ee 392
`
`
`Summary
`
`Cladribine is a novel drug that selectively depletes lymphocytes and may be
`able to destroy the activated immunocytes that damagethe central nervous system
`in multiple sclerosis. Our initial controlled studies have shown a beneficial, al-
`though temporary, dose-related effect of cladribine on the course of chronic pro-
`gressive multiple sclerosis.
`Peak improvement in median Scripps Neurological Rating Scale (SNRS)
`neurological performancescores, followed by gradual decline, occurred at month
`14 after initiation of treatment with a 2.8 mg/kg total dose and at month 7 after
`initiation of treatment with a 1.4 mg/kg total dose. A marked decrease in the
`presence of enhanced magnetic resonance imaging lesions was observed at both
`dose levels.
`Adverse effects are also dose-related. Mild segmental herpes zoster or tran-
`sient marrow suppression occurred in some patients treated at the higher total
`dose, whereas no problemsof this kind were observed at the lowertotal dose.
`It is our hope that studies that are presently under waywill establish cladribine
`as a practical therapeutic option for patients with all non-benign forms of multiple
`sclerosis.
`
`
`The fundamental cause of multiple sclerosis is
`still unknown,butthere is persuasive circumstan-
`tial evidence that
`immunopathological mecha-
`nisms play an importantrole in the inflammatory
`demyelination of the central nervous system (CNS)
`which is the hallmark ofthe disease.!!] Suppression
`and/or ‘modulation’ of the immunesystem is there-
`
`fore a rational means of therapy for multiple scle-
`rosis.{2]
`Although interferon-B has recently been shown
`to decrease the frequency andseverity of relapses
`in the relapsing-remitting form of multiple sclero-
`sis,3] no clearly satisfactory treatment by immuno-
`suppression or any other method has yet been
`
`Hopewell EX1046
`
`Hopewell EX1046
`
`1
`
`

`

`Cladribine in Multiple Sclerosis
`
`387
`
`Table I. Completed and ongoingclinicaltrials of cladribine in the treatment of multiple sclerosis
`
`Numberof_Trial location Comments and references
`
`Trial=Type of Blinded/ Dosage and duration Route
`
`
`courses
`multiple
`crossover
`(daily dose x number
`sclerosis
`of days)
`cP
`0.087 mg/kg x 7
`
`1?
`
`No/no
`
`IV
`
`6
`
`Scripps
`
`Feasibility study in 4 patients in
`1990
`
`23
`
`CP
`
`Yes/yes
`
`0.1 mg/kg x 7
`
`3
`4?
`
`5°
`
`RR
`cP
`
`cP
`
`Yes/no
`Yes/no
`
`Yes/no
`
`0.1 mg/kg x 7
`0.05 mg/kg x 7
`0.07 mg/kg x 5
`0.07 mg/kg x 5
`
`0.05 mg/kg x 5
`
`IV
`
`IV
`IV
`sc
`Sc
`
`sc
`
`4
`
`1
`2
`6
`2 and6
`
`Scripps
`
`Scripps
`
`Scripps
`Multicentre in US
`and Canada
`
`Part | of double-blind crossover
`study!"
`Part ll of double-blind crossover
`study's!
`
`4
`
`Scripps
`
`Retreatment study of patients
`from trial 2!)
`
`Polish Academyof
`6
`sc
`5mg x 5
`Yes/no
`RR
`6°
`Science
`10mg x 5
`Oral
`a Completed study.
`b Ongoing study.
`Abbreviations: CP = chronic progressive; IV = intravenous; RR = relapsing remitting; SC = subcutaneous.
`
`found for patients with chronic progressive multi-
`ple sclerosis (CPMS). Previous trials of treatment
`in CPMS have involved broad-spectrum immuno-
`suppressive drugs such as cyclophosphamide!4!
`and methotrexate.'°! The modest benefit observed
`with these drugs has been generally counterbal-
`anced by concerns overtoxicity.
`One current hypothesis of multiple sclerosis
`pathogenesis is that activated T lymphocytes pass
`from the bloodstream into the multiple sclerosis
`plaques in the CNS. Theseactivated cells, regard-
`less of their immunespecificity, may directly or
`indirectly damage myelin and/or oligoden-
`drocytes. Therefore, the selective depletion of lym-
`phocytes in multiple sclerosis might be beneficial
`if it could be accomplished safely. For these
`reasons, a new type of drug, cladribine (2-
`chlorodeoxyadenosine, Leustatin®), was selected
`for trial in CPMS becauseofits properties of rela-
`tively selective production of lymphopenia with a
`favourable toxicity profile as compared with other
`antilymphocyte drugs.!°!
`Cladribine is an adenosine deaminase-resistant
`purine nucleoside that was developed by Carson et
`al.!”] at Scripps Clinic and Research Foundation.
`The drug was designed to simulate the immuno-
`deficient condition seen in the rare disorder of he-
`
`reditary adenosine deaminase deficiency by caus-
`ing high levels of deoxynucleotides to accumulate
`in lymphocytes, thus resulting in cell death. In con-
`trast with other antilymphocyte agents, cladribine
`has the ability to kill both resting and dividing
`cells.!8]
`The use of cladribine in CPMS wasconsidered
`
`following pioncering clinical studies with cladrib-
`ine at the Scripps Clinic in the treatment of various
`lymphoid neoplasms and leukaemia.!?! The most
`dramatic positive results were seen in hairy cell
`leukaemia, in which 86% of patients experienced
`a durable and complete remission after a single
`treatment with cladribine.!°! Cladribine is also
`
`presently under evaluation at our institution in a
`variety of autoimmune disorders,
`including
`Coomb’s positive haemolytic anaemia, immune
`thrombocytopenia, rheumatoid arthritis and in-
`flammatory boweldisease.
`The bioavailability of cladribine is the same by
`either continuous intravenous or intermittent sub-
`
`cutaneous administration, and is halved when
`given by the oral route.!!! A detailed discussion of
`the clinical pharmacokinetics of cladribine has
`been presented elsewhere.!!!!
`
`© Adis InternationalLimited. All rights reserved.
`
`BioDrugs 1997 May: 7 (5)
`
`2
`
`

`

`388
`
`Romine etal.
`
`25
`
`Initial cladribine
`
`
`
`EDSSscore
`
`
`
`SNRSscore NNh
`
`moB
`
`|
`
`|
`
`
`
`’
`
`
`
`25
`
`Initial placebo
`
`
`
`
`
`805
`
`
`
`7275 ~
`
`‘
`
`64 5
`
`56 5
`
`.
`
`Time (months)
`
`Fig. 1. Kurtzke Extended Disability Status Scale (EDSS)[top] and Scripps Neurological Rating Scale (SNRS) [bottom] scores of 48
`patients with chronic progressive multiple sclerosis treated with cladribine in a double-blind crossover study. The initial cladribine
`group(left) received cladribine 0.7 mg/kg as a continuous intravenous infusion over 7 days in each of 4 successive months. The
`initial placebo group(right) was given cladribine 0.7 mg/kg as thefirst monthly infusion in month 13, and 2 subsequent7-day infusions
`of 0.35 mg/kg in months 14 and 15. Medians(solid lines) and interquartile ranges (brokenlines), smoothed with the nonparametric
`procedure LOWESS, are shown.
`
`1. Results in Chronic Progressive
`Multiple Sclerosis
`
`An initial feasibility study with 4 patients in
`1990 was encouraging, and we subsequently con-
`ducted a double-blind crossoverstudy of the effect
`of cladribine in CPMS(table 1). To date, this is the
`only controlled study of cladribine in multiple scle-
`rosis to be completed; the results have been pub-
`lished in 2 parts.{!?.!3)
`In this study, 48 patients with CPMS were
`paired by age, gender and disease severity. Pair
`
`members were randomly assignedto receive either
`cladribine or placebo treatment via surgically im-
`planted venous access devices. Patients on the
`cladribine arm were given monthly 7-day continu-
`ous
`intravenous
`infusions of cladribine 0.1
`
`mg/kg/day (0.7 mg/kg/course) for a total of 4
`courses (total dose 2.8 mg/kg). Patients on the pla-
`cebo arm were given saline intravenously in an
`identical fashion. Double-blind masking was main-
`tained; patients, neurologists, neuroradiologists
`and nurses had no knowledge of which medication
`
`© Adis International Limited. All rights reserved.
`
`BioDrugs 1997 May; 7 (5)
`
`3
`
`

`

`Cladribine in Multiple Sclerosis
`
`389
`
`a patient was receiving. Patients were examined
`monthly and 2 neurological performance scores
`were recorded [Kurtzke Extended Disability Status
`Scale (EDSS)!'4! and Scripps Neurological Rating
`Scale (SNRS)!!5I].
`Over [2 months, analysis of SNRS and EDSS
`scores showedprogressive deterioration during the
`first year in patients receiving placebo, while the
`median SNRSand EDSS scores of patients receiv-
`ing cladribine improved modestly. Absolute
`changesin neurological scores were favourable in
`both EDSS (p = 0.013 at 12 months) and SNRS
`(p = 0.001 at 12 months) scoring systems(fig. 1).
`Statistical significance in favour of cladribine was
`also established when 12 months of data were an-
`alysed by Kaplan-Meier time-to-failure plots (fig.
`2),13]
`Blinding was maintained and the study was con-
`tinued for a second yearof treatment and observa-
`tion. However, patients were crossed over to oppo-
`
`site treatment arms. Patients treated with cladrib-
`
`ine in the first year received placebo in the second
`year, and vice versa. However,
`the dosage of
`cladribine was reduced to one-half of that given
`during the first year. The reduced total dose of
`cladribine [.4 mg/kg was administered by contin-
`uous intravenous infusion in divided doses as fol-
`
`lows: 0.7 mg/kg for the first monthly course, 0.35
`mg/kg for the second and third courses, and saline
`placebo for the fourth course. Patients who had
`received cladribine in the first year were given 4
`monthly infusions of saline placebo.
`Results from the second yeararealsoillustrated
`in figure |. Comparison of data from years | and 2
`of the study reveals that patients who hadfirst re-
`ceived placebo and then crossed over to treatment
`with the lowerdose of cladribine (1.4 mg/kg) show
`a trend of improvement in SNRSscoressimilar to
`that seen in patients treated with the full (2.8
`mg/kg) dose. Similar comparison also suggests
`
`@ Initial cladribine
`
`@
`
`initial placebo
`
`SNRSchange= -10
`
`1.0
`
`0.9 4
`
`0.8 5
`
`0.7 4
`
`
`
`a “T
`2
`4
`6
`
`T
`8
`
`—
`10
`
`i
`12
`
`0
`
`EDSSchange = 1.0
`
`Hf
`
`
`
`1.0
`
`0.9 4
`
`os -
`
`07 4
`
`06 4
`
`2 2
`
`Q°a
`
`Ty
`2
`
`0
`
`T
`4
`
`TT
`6
`
`T TT
`8
`10
`12
`
`Time (months)
`
`Fig. 2. Kaplan-Meiertime-to-failure plots of patients with chronic progressive multiple sclerosis treated with cladribine in a double-blind
`crossoverstudy. (Left) Time to failure as defined by an increase of Kurtzke Extended Disability Status Scale (EDSS) score by 1.0
`point on at least 2 consecutive months, considering the first month of change asthe time of event. (Right) Timeto failure as defined
`by a decrease of Scripps Neurological Rating Scale (SNRS) score by 10 points on at least 2 consecutive months, considering the
`first month of change as the time of event. The difference in time to failure estimated by log-rank statistics was significant for both
`scoring systemsin favourof cladribine (EDSS,p = 0.0148; SNRS,p = 0.001).
`
`© Adis International Limited.All rights reserved.
`
`BioDrugs 1997 May; 7 (5)
`
`4
`
`

`

`390
`
`Romine etal.
`
`oO 4 TT
`
`
`60-7
`
`40-
`
`304
`
`2074
`
`104
`
`c2 8
`
`Do
`&oO
`x=c
`a
`oO
`
`sZ
`
`B
`
`a<2
`
`&
`
`@&
`
`5
`se 97
`an
`
`@ Initial cladribine
`Hf Initial placebo
`4 Start cladribine
`
`ing lesions at baseline. At 18 and 24 monthsafter
`initiation of treatment with cladribine 2.8 mg/kg
`total dose, no patient had lesion enhancement. In
`patients treated initially with placebo, lesion en-
`hancement persisted at the same percentage level
`at months 6 and 12, but after treatment with
`cladribine 1.4 mg/kg total dose, lesion enhance-
`ment was subsequently observed in only a single
`patient.
`
`2. Adverse Effects
`
`As of June 1995, a total of 125 multiple sclerosis
`patients (both chronic progressive and relaps-
`ing/remitting multiple sclerosis) have been treated
`at Scripps Clinic. The adverse events observed to
`that date in association with cladribine treatment
`are summarised in table I]. Most patients had no
`obvious drug-related symptomsor signs in associ-
`ation with the administration of cladribine. How-
`ever, 8 patients, all treated with the full 2.8 mg/kg
`dose, developed mild segmental herpes zoster. No
`other opportunistic infections occurred. 3 patients
`treated with the 2.8 mg/kg dose developedtransient
`bone marrow suppression with low platelet counts;
`2 of these patients required hospitalisation for red
`cell and platelet transfusion. One patient died of
`acute fulminant hepatitis B during the second
`month on cladribine, an event previously reported
`and considered to be probably unrelated to treat-
`ment.{!21
`The details of the effect of cladribine on blood
`counts in these patients are reported elsewhere.!!7)
`As expected, profound and prolonged lymphocyte
`depletion (most notably CD4+ cells) occurred in
`cladribine-treated patients; other blood cellular
`components were less affected. Granulocyte
`counts showed only a minor decline and the aver-
`age haemoglobin level declined moderately, with
`significant anaemia due to transient bone marrow
`suppression in only a single patient. However, red
`cells generally became macrocytic, especially at
`the higher dose levels. Average platelet counts de-
`clined to a low of around1.5 x 109/L, with recovery
`to near normal levels by 12 monthsafter treatment.
`Monocyte counts dropped within days of drug ad-
`
`Baseline
`
`6
`
`12
`
`18
`
`24
`
`Time (months)
`
`Fig. 3. Proportion of patients with enhancing lesions over the
`course of a double-blind crossoverstudy of cladribine treatment
`of chronic progressive multiple sclerosis. The difference was
`significant in favour of cladribine at 12 and 24 months(p < 0.001
`by McNemar’stest).
`
`that stabilisation of disease may be of shorter du-
`ration with the lower dose of cladribine. Peak im-
`provement of median SNRSscores, followed by
`gradual decline, occurred at month 14 after initia-
`tion of treatment with the 2.8 mg/kg total dose and
`at month 7 after initiation of treatment with the 1.4
`mg/kg total dose. Statistical analysis of the vari-
`ance of paired differences in EDSS and SNRS
`scores from year 2 of the study again confirmed
`significant treatment effects in favour of cladrib-
`ine,{!61
`Magnetic resonance imaging brain scans were
`obtained after intravenous gadopentetate dimeg-
`lumineat baseline and at 6, 12, 18 and 24 months.
`Volumetric
`analysis
`of
`demyelinated
`(T-
`weighted) lesions revealed no significant differ-
`ences between the cladribine and placebo groups.
`However, a highly significant difference in favour
`of cladribine was documented when the numberof
`‘active’ lesions (lesions enhanced by gadopentet-
`ate) were analysed (fig. 3). Approximately one-half
`of the-patients in both the initial cladribine-treated
`and the initial placebo-treated groups had enhanc-
`
`© Adis InternationalLimited.All rights reserved.
`
`BioDrugs 1997 May;7 (5)
`
`5
`
`

`

`Cladribine in Multiple Sclerosis
`
`39]
`
`TableII. Adverse events in 125 multiple sclerosis patients treated with cladribine*
`Event dueto cladribine
`Total dose of
`Adverse
`Age (y)/
`Treated as partof Cause
`
`event cladribine (mg/kg)__treatment?gender study protocol?
`
`
`Death
`
`40/F
`
`43/F
`3t/F
`471M
`
`Marrow suppression
`43/F
`67/F
`
`Infections
`
`Yes
`
`Yes
`Yes
`No
`
`Yes
`No
`
`Acute hepatic necrosis secondary to
`hepatitis B
`Suicide
`Drowning in pool
`Quadriplegia and respiratory failure
`secondary to progressive multiple
`sclerosis
`
`Cladribine®
`Cladribine®
`
`1.4
`
`2.8
`2.8
`21
`
`2.8
`2.1
`
`Unlikely
`
`No
`No
`No
`
`Yes
`Yes
`
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`No
`Yes
`Yes
`
`Yes
`
`Streptococcal pharyngitis
`Herpes zoster
`Herpes zoster
`Herpes zoster
`Herpes zoster
`Herpeszoster
`Herpes zoster
`Herpes zoster
`Herpeszoster
`
`Cladribine
`
`A/F
`43/F
`57/F
`39/M
`46/F
`5S1/F
`47/M
`50/F
`52/F
`Thrombocytopenia
`4 patients
`Revision of Portacath
`No
`28
`Portacath malfunction
`Yes
`58/F
`No
`2.8
`Portacath malfunction
`Yes
`43/F
`No
`2.8
`Portacath maifunction
`Yes
`40/F
`
`Yes No Pneumothorax 2.8
`
`
`40/F
`a_ Patients treated from 1990 to June 1995.
`
`2.8
`2.8
`2.8
`2.8
`2.8
`2.8
`2.8
`2.8
`2.8
`
`2.8
`
`No
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`Yes
`
`Yes
`
`b
`c
`
`Previous treatment with carbamazepine and phenytoin.
`Previous treatment with chlorambucil.
`
`Abbreviations: F = female; M = male; y = years.
`
`ministration, with rebound to near normal levels
`within | month.
`
`Jn summary, the adverse effects seen in this
`group of multiple sclerosis patients are dose-re-
`lated. All episodes of mild herpes zoster and occa-
`sional episodes of transient marrow suppression
`occurred In association with the 2.8 mg/kg dose,
`while none occurredin patients treated with the 1.4
`mg/kg dose. Two ofthe patients with temporary
`marrow suppression had been previously treated
`with potentially marrow-suppressive drugs, one
`with carbamazepine and phenytoin, the other with
`chlorambucil. This would suggest that the risk of
`
`marrow suppression from cladribine is increased
`after previous treatment with drugs, such as those
`above, which can reduce the size of the haemo-
`poietic stem cell pool.
`Previous studies of cladribine treatment of pa-
`tients with neoplastic disorders have shown that
`increasing doses ofcladribine are associated with
`an increased incidence of thrombocytopenia as
`well as marrow suppression with pancytopenia. At
`total doses 5 to 10 times that used for hairy cell]
`leukaemia (as part of preparation for bone marrow
`transplantation),
`renal dysfunction and CNS
`toxicity were observed, the latter manifested as
`
`©Adis internationalLimited. All rights reserved
`
`BioDrugs 1997 May;7 (5)
`
`6
`
`

`

`392
`
`Romineet al.
`
`paraparesis or quadraparesis usually occurring sev-
`eral weeks after cladribine treatment.!®!8!9] No
`such neurological or renal toxicity has been seen in
`any of the thousandsofpatients with lymphoid ma-
`lignancies treated with cladribine at lower doses
`comparable with those used in our multiple sclero-
`sis studies.
`There are other possible adverse effects which
`have not yet been seen with cladribine but which
`are of concern. The possibility over the long term
`for induction of a neoplastic disorder after treat-
`ment with cladribine is a consideration, since the
`drug is incorporated into DNA.At the present time
`there has been no obviousincrease in the frequency
`of secondary neoplasms occurring in over 5000
`cancerpatients treated worldwide with cladribine,
`although the possibility of such a phenomenonhas
`not been excluded since no formal study has been
`performed. Likewise,the use of cladribine together
`with other immunosuppressive drugs, including
`high-dosage corticosteroids, should be approached
`with caution since the additive immunosuppressive
`effect of such a combination could lead to a higher
`incidence of herpes zoster or other opportunistic
`infections. Although this problem has not been ob-
`served with cladribine, it should be considered a
`possibility in view of the reported occurrence of an
`increased incidence of Listeria infection in cancer
`patients treated with fludarabine, a purine nucleo-
`side drugrelated to cladribine, plus prednisone.!2°!
`
`3. Therapeutic Potential and
`Clinical Use
`
`The evaluation of cladribine as a treatment for
`multiple sclerosisis still in progress. At this time it
`is not licensed for the treatment of multiple sclero-
`sis and remains an experimental therapy best lim-
`ited to clinical trials. Whether ornot it proves to be
`a practical treatment for multiple sclerosis will de-
`pend on the results of several ongoing studies
`which are presently under wayat sites including
`Scripps, a multicentre trial in the US and Canada,
`and the Polish Academy of Science!!! (table 1.
`These studies include further controlled trials with
`CPMSpatients as well as patients with the relaps-
`
`Table Ill. Pretreatment safety criteria for monthly courses of
`cladribine in multiple sclerosis
`Platelet count must be:
`22.0 x 10"/L or
`
`4.5 to 2.0 x 10"'/L and >50% of previous pretreatmentplatelet
`count or
`
`1.25 to 1.5 x 10"/L and >80%of previous pretreatment
`platelet count
`Absolute granulocyte count must be >10°/L
`Haemoglobin level must not have declined by:
`>15 g/L from previous monthly pretreatmentlevel or
`>30 g/L from baseline
`
`ing/remitting form of multiple sclerosis. Since the
`beneficial effect of a single course of cladribine in
`CPMSpatients is not permanent, a current study of
`the safety and efficacy of retreatment with cladrib-
`ine will be especially important.
`At our institution, current trials with cladribine
`in multiple sclerosis are now proceeding with the
`subcutaneous route of administration rather than
`
`the more invasive continuous intravenous method
`
`used in earlier studies. Subcutaneous cladribineis
`
`well tolerated and producesnolocal reaction at in-
`jection sites. Because cladribine solutions are cur-
`rently available only at a concentration of 1 mg/ml,
`the total volume for each daily dose is normally
`divided into 2 or 3 subcutaneousinjection sites in
`the abdomenorthigh to prevent administration of
`too large a volume at | site. A preparation more
`suitable for clinical use, which contains Smg of
`cladribine per ml, is now in clinicaltrial.
`We do not enter into a study any multiple scle-
`rosis patient who has abnormal baseline haema-
`tological, hepatic or renal functions. Individual
`monthly treatments of cladribine are given only if
`certain pretreatment blood countsafety criteria are
`met, as outlined in table III. If treatment safety cri-
`teria are not met, then the treatment is withheld for
`that monthly cycle and given the following month
`if blood countcriteria are met at that time. Com-
`plete blood counts are also checked periodically in
`the 8 weeks after completionof the cladribinetreat-
`mentcycle.
`
`© Adis InternationalLimited.All rights reserved.
`
`BioDrugs 1997 May; 7 (5)
`
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`

`Cladribine in Multiple Sclerosis
`
`393
`
`10.
`
`Liliemark J, Albertioni F, Hassan M, ct al. Onthe bioavailability
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`. Liliemark J. The clinical pharmacokinetics of cladribine. Clin
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`. Sipe JC, Romine JS, Koziol JA, et al. Cladribine in treatment
`of chronic progressive multiple sclerosis. Lancet 1994; 344
`(8914): 9-13
`. Beutler E, Sipe JC, RomineJS, et al. The treatment of chronic
`progressive multiple sclerosis with cladribine. Proc Natl Acad
`Sci USA 1996; 93: 1716-20
`. Kurtzke JF. Rating neurologic impairmentin multiple sclerosis:
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`33: 1444-52
`. Sipe JC, Knobler RL, Braheny SL,et al. A neurologic rating
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`. Sipe JC, Romine JS, ZyroffJ, et al. Treatment of multiple scle-
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`20.
`
`21.
`
`Acknowledgements
`
`The authors acknowledge the outstanding work of Caro-
`lyn Koumaras, R.N., in clinical coordination, Kathleen Rom-
`ine, R.N., in patient recruitment, and the nursing and support
`staff of the General Clinical Research Center at Scripps
`Clinic. This work was supported by National Institutes of
`Health grants NS 30218 and RRO0833, FDA Grant FD-R-
`000280,
`the Stein Endowment Fund and the Jose Garate
`Memorial Fund for M.S. Research.
`
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`Correspondence and reprints: Dr John S. Romine, Division
`of Neurology, Scripps Clinic and Research Foundation,
`10666 North Torrey Pines Road, MS313, La Jolla, CA 92037,
`USA.
`
`© Adis International Limited. All rights reserved.
`
`BioDrugs 1997 May: 7 (8)
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