The New England
`Journal
` Medicine
`of
`
`© Copyr ight, 2000, by the Massachusetts Medical Societ y
`
`VOLUME 343
`
`S
`
`E P T E M B E R
`
` 28, 2000
`
`NUMBER 13
`
`INTRAMUSCULAR INTERFERON BETA-1a THERAPY INITIATED DURING A FIRST
`DEMYELINATING EVENT IN MULTIPLE SCLEROSIS
`
`, M.D.,
` K
`.D., R. P
`, M.D., P
` H. S
`.D., J
`, M.D., P
` W. B
`, M.D., R
` D. J
`L
`INKEL
`HILLIP
`H
`IMON
`ACK
`H
`ECK
`OY
`ACOBS
`AWRENCE
`C
` M. B
`, P
`.D., T
` J. M
`, M.D., N
` A. S
`, M.D., P
` J. S
`, S
`.D.,
`ETER
`IMONIAN
`ANCY
`URRAY
`HOMAS
`ROWNSCHEIDLE
`AROL
`H
`LASOR
`C
`A
` W. S
`, M.D., P
`.D.,
`
` CHAMPS S
` G
`*
`LFRED
`ANDROCK
`H
`AND
`THE
`TUDY
`ROUP
`
`A
`BSTRACT
`Background
`Treatment with interferon beta has
`been shown to help patients with established multi-
`ple sclerosis, but it is not known whether initiating
`treatment at the time of a first clinical demyelinating
`event is of value.
`Methods
`We conducted a randomized, double-blind
`trial of 383 patients who had a first acute clinical de-
`myelinating event (optic neuritis, incomplete trans-
`verse myelitis, or a brain-stem or cerebellar syndrome)
`and evidence of prior subclinical demyelination on
`magnetic resonance imaging (MRI) of the brain. Af-
`ter initial treatment with corticosteroids, 193 patients
`were randomly assigned to receive weekly intramus-
`cular injections of 30 µg of interferon beta-1a and 190
`were assigned to receive weekly injections of place-
`bo. The study end points were the development of
`clinically definite multiple sclerosis and changes in
`findings on MRI of the brain. The trial was stopped
`after a preplanned interim efficacy analysis.
`Results
`During three years of follow-up, the cu-
`mulative probability of the development of clinically
`definite multiple sclerosis was significantly lower in
`the interferon beta-1a group than in the placebo group
`(rate ratio, 0.56; 95 percent confidence interval, 0.38
`to 0.81; P=0.002). As compared with the patients in
`the placebo group, patients in the interferon beta-1a
`group had a relative reduction in the volume of brain
`lesions (P<0.001), fewer new or enlarging lesions
`(P<0.001), and fewer gadolinium-enhancing lesions
`(P<0.001) at 18 months.
`Conclusions
`Initiating treatment with interferon
`beta-1a at the time of a first demyelinating event is
`beneficial for patients with brain lesions on MRI that
`indicate a high risk of clinically definite multiple scle-
`rosis. (N Engl J Med 2000;343:898-904.)
`©2000, Massachusetts Medical Society.
`
`898
`
`·
`
`September 28, 2000
`
`M
`
`ULTIPLE sclerosis is a chronic, inflam-
`matory, demyelinating disease of the
`central nervous system that most com-
`monly affects women, with an onset
`typically between 20 and 40 years of age. A diagno-
`sis of clinically definite multiple sclerosis requires the
`occurrence of at least two neurologic events consistent
`with demyelination that are separated both anatom-
`ically in the central nervous system and temporally.
`1
`Magnetic resonance imaging (MRI) of the brain, by
`identifying lesions consistent with the occurrence of
`demyelination, can add certainty to the diagnosis.
`2,3
`The presence of such MRI-identified lesions in a pa-
`tient with an isolated syndrome of the optic nerve (op-
`tic neuritis), spinal cord (incomplete transverse my-
`elitis), or brain stem or cerebellum of recent onset is
`associated with a high risk of clinically definite multi-
` When the cause is demyelination, all
`ple sclerosis.
`4-8
`three syndromes are presumed to have a common
`pathogenesis.
`Interferon-beta has demonstrated benefits in the
`treatment of patients with established multiple sclero-
`sis, including slowing the progression of physical dis-
` reducing the rate of clinical relapses,
` and
`ability,
`9,10
`9-11
`reducing the development of brain lesions, as assessed
`by MRI,
` and brain atrophy.
` However, it is not
`9-12
`13
`known whether treatment of patients earlier in the
`course of multiple sclerosis is of value. Therefore, we
`designed a randomized, double-blind, placebo-con-
`
`From the Department of Neurology, State University of New York School
`of Medicine at Buffalo and Buffalo General Hospital, Buffalo (L.D.J., C.M.B.);
`the Jaeb Center for Health Research, Tampa, Fla. (R.W.B.); the Department
`of Radiology–MRI, University of Colorado Health Sciences Center, Den-
`ver (J.H.S.); the Mellen Center for Multiple Sclerosis Treatment and Research,
`Cleveland Clinic Foundation, Cleveland (R.P.K.); the Multiple Sclerosis Re-
`search Unit, Centre for Clinical Research, Victoria General Hospital, Queen
`Elizabeth II Health Sciences Centre, Halifax, N.S., Canada (T.J.M.); and
`Biogen, Cambridge, Mass. (N.A.S., P.J.S., A.W.S.). Address reprint requests
`to Dr. Jacobs at the Department of Neurology, Buffalo General Hospital,
`100 High St., Buffalo, NY 14203, or at ljacobs@kaleidahealth.org.
`*Other participants in the Controlled High-Risk Subjects Avonex Mul-
`tiple Sclerosis Prevention Study (CHAMPS) are listed in the Appendix.
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 22, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1030 PAGE 1
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`INTRAMUSCULAR INTERFERON BETA-1a THERAPY INITIATED DURING A FIRST DEMYELINATING EVENT
`
`trolled clinical trial to determine whether weekly in-
`tramuscular injections of interferon beta-1a (Avonex)
`in patients with a first demyelinating event and with
`MRI evidence of prior subclinical demyelination in
`the brain reduced the incidence of clinically definite
`multiple sclerosis.
`
`METHODS
`
`Patients
`The study was conducted at 50 clinical centers in the United
`States and Canada from April 1996 until March 2000. The pro-
`tocol and informed-consent forms were approved by the institu-
`tional review board at each site, and all patients gave written in-
`formed consent. Study oversight was provided by an independent
`data and safety monitoring committee.
`Eligible subjects were patients between the ages of 18 and 50
`who had a first isolated, well-defined neurologic event consistent
`with demyelination and involving the optic nerve (unilateral optic
`neuritis), spinal cord (incomplete transverse myelitis), or brain stem
`or cerebellum (brain-stem or cerebellar syndrome) that was con-
`firmed on ophthalmologic or neurologic examination. Patients also
`had to have two or more clinically silent lesions of the brain that
`were at least 3 mm in diameter on MRI scans and were charac-
`teristic of multiple sclerosis (at least one lesion had to be periven-
`tricular or ovoid). The onset of the visual or neurologic symptoms
`had to have been no more than 14 days before intravenous corti-
`costeroid therapy was started (as described below) and no more
`than 27 days before randomization. Patients with a prior neuro-
`logic or visual event consistent with the occurrence of demyelina-
`tion that lasted longer than 48 hours were excluded.
`
`Treatment Assignment and Monitoring
`All patients received 1 g of methylprednisolone per day intra-
`venously for 3 days, followed by 1 mg of prednisone per kilogram
`of body weight per day orally for 11 days and a 4-day period of
`tapering in which 20 mg was given on the first day, 10 mg on the
`second, 0 mg on the third, and 10 mg on the fourth. In order to
`achieve balance with respect to the number of lesions on T
`-weight-
`2
`ed MRI scans (two, three or four, five to seven, and eight or more)
`and the type of initial clinical event (optic neuritis, spinal cord
`syndrome, or brain-stem or cerebellar syndrome), we used a min-
`imization procedure
` to assign patients randomly in approxi-
`14
`mately equal numbers to the two treatment groups. The distri-
`bution of the treatment groups according to study site was what
`would be expected by chance (P=0.88). One group received 30 µg
`of interferon beta-1a (Avonex, Biogen) weekly by intramuscular
`injection, whereas the other group received a matching placebo.
`The treatment period was planned to be three years. Patients and
`site personnel were unaware of the treatment assignments.
`Treatment began after the course of intravenous methylpred-
`nisolone was completed while the patient was still receiving oral
`prednisone. To minimize the symptoms of the interferon-related
`influenza-like syndrome, patients were instructed to take 650 mg of
`acetaminophen before each injection and then every 6 hours after
`each injection for 24 hours during the first six months of treatment.
`We assessed compliance with the protocol by reviewing the pa-
`tients’ diaries and counting the number of empty vials that were
`returned. Each center was instructed to report all adverse events
`during the first six months of treatment, but thereafter to report
`only serious adverse events, as well as depression, seizures, cardiac
`events, and injection-site reactions, whether or not they were se-
`rious. An influenza-like syndrome was defined as the presence of
`influenza-like symptoms, fever, or chills. Every six months, blood
`was obtained for hematologic and serum chemical tests and phys-
`ical examinations were performed. Laboratory values that exceeded
`prespecified ranges were considered abnormal. Serum was assayed
`for the presence of neutralizing antibodies every six months; we
`report the incidence of titers greater than or equal to 1:20 — the
`
`level that has been associated with reduced biologic activity of in-
`terferon beta-1a.
`15
`Study Procedures and End Points
`At the end of the first month (and again at the end of the second
`month, if the patient’s condition was not considered to be stable
`or improving at month 1), each patient was examined by a treat-
`ing and an examining neurologist, both of whom were unaware
`of the patient’s treatment assignment. Subsequent examinations
`were scheduled at month 6 and every six months thereafter; ad-
`ditional examinations were performed within seven days after a pa-
`tient reported new visual or neurologic symptoms. The treating
`neurologist was responsible for asking the patient about adverse
`events and visual or neurologic symptoms, whereas the examining
`neurologist performed a structured neurologic examination with-
`out knowledge of the patient’s history during or before the study.
`The primary prespecified end point was the development of
`clinically definite multiple sclerosis. For patients whose condition
`was neurologically stable or improving one month after the initi-
`ation of treatment with the study drug, the end point was defined
`as the occurrence of either a new visual or neurologic event or pro-
`gressive neurologic deterioration. The former required documen-
`tation of a new clinical abnormality consistent with the patient’s
`report of neurologic or visual symptoms that lasted more than 48
`hours and that were attributable to a part of the central nervous
`system that differed from that of the initial episode at study entry.
`The latter was defined as an increase from month 1 of at least 1.5
`points in the score on the Expanded Disability Status Scale.
` On
`16
`this scale, scores range from 0 to 10, with higher scores indicating
`more severe disability. A patient whose initial demyelinating event
`was clinically worse one month after the initiation of treatment was
`considered to have reached the primary end point if either further
`worsening was documented at two months or the patient withdrew
`from the study before completing two months of treatment. All
`end points were confirmed by a central end-point committee whose
`members were unaware of the patients’ treatment assignments.
`Patients in whom clinically definite multiple sclerosis developed
`discontinued treatment and were withdrawn from the study. Pa-
`tients who discontinued treatment but who did not reach the end
`point were encouraged to return for follow-up assessments.
`Findings on MRI of the brain served as a secondary prespecified
`end point. A screening MRI of the brain was performed to deter-
`mine the patients’ eligibility. Unenhanced T
`-weighted and en-
`2
`hanced T
`-weighted MRI scans of the brain were obtained with use
`1
`of a standardized protocol at base line and at months 6, 12, and
`18 in patients who were still in the study at those times. The base-
`line scan was obtained four or more days after the patient completed
`the course of intravenous methylprednisolone but while the patient
`was still receiving oral prednisone. MRI of the brain was not per-
`formed after 18 months because of the expectation that the rate
`of clinical outcomes would differ between treatment groups (since
`patients were withdrawn from the trial on receipt of a diagnosis
`of clinically definite multiple sclerosis) and could therefore skew
`the interpretation of the results. All scans that could be evaluated
`were graded at a central reading center without knowledge of the
`patients’ treatment assignments. The number of new or enlarging
`lesions and the volume of lesions on T
`-weighted MRI scans and
`2
`the number of gadolinium-enhancing lesions on T
`-weighted MRI
`1
`scans were assessed according to a standardized method.
`Statistical Analysis
`We calculated that 380 patients would be needed for the study,
`given an estimated three-year rate of clinically definite multiple scle-
`rosis in the placebo group of 50 percent, a relative effect of treat-
`ment of 33 percent, a 5 percent probability of a type I error (two-
`tailed), and a power of 80 percent. The calculation was adjusted
`to allow for 15 percent of the patients to be withdrawn or lost to
`follow-up before the development of clinically definite multiple scle-
`rosis. Primary analyses included all randomized patients and fol-
`lowed the intention-to-treat principle. All reported P values are
`two-tailed.
`
`Volume 343 Number 13
`
`·
`
`899
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 22, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1030 PAGE 2
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`The New England Journal of Medicine
`
`The cumulative probability of clinically definite multiple scle-
`rosis was calculated for each group according to the Kaplan–Meier
`product-limit method and compared with use of the Mantel log-
`rank test, beginning after one month of treatment (since by defini-
`tion the end point could not be reached before one month). Data
`on patients in whom clinically definite multiple sclerosis did not de-
`velop were censored on the date they were last seen by the treating
`neurologist at either a scheduled or unscheduled visit. Unadjust-
`ed and adjusted rate ratios were determined from a proportional-
`hazards model. Differences in the size of effects in subgroups clas-
`sified according to the initial clinical event and the number of brain
`lesions on T
`-weighted MRI scans at screening were assessed sep-
`2
`arately with use of interaction terms in the proportional-hazards
`model. The data on the volume of lesions and the number of le-
`sions on MRI were evaluated with the use of the Mann–Whitney
`rank-sum test.
`The trial was terminated in March 2000 at the recommenda-
`tion of the data and safety monitoring committee after the single
`preplanned interim analysis of efficacy. This analysis revealed that
`treatment with interferon beta-1a was significantly better than treat-
`ment with placebo and met the stopping guidelines, which in-
`cluded a P value of 0.029.
`RESULTS
`Base-Line Characteristics
`Between April 1996 and April 1998, 383 patients
`were enrolled in the trial: 193 were randomly assigned
`to the interferon beta-1a group and 190 to the pla-
`cebo group. The base-line characteristics of the two
`groups were similar (Table 1).
`
`Development of Clinically Definite Multiple Sclerosis
`and Brain Lesions on MRI
`The cumulative probability of the development of
`clinically definite multiple sclerosis during the three-
`year follow-up period was significantly lower in the
`interferon beta-1a group than in the placebo group
`(rate ratio, 0.56; 95 percent confidence interval, 0.38
`to 0.81; P=0.002) (Fig. 1). At three years, the cu-
`mulative probability was 35 percent in the interferon
`beta-1a group and 50 percent in the placebo group.
`After adjustment for age, type of initial event, the
`volume of lesions on T
`-weighted MRI scans, and
`2
`the number of gadolinium-enhancing lesions on
`T
`-weighted scans, the effect of treatment with inter-
`1
`feron beta-1a appeared to be stronger (adjusted rate
`ratio, 0.49; 95 percent confidence interval, 0.33 to
`0.73; P<0.001). The effect of treatment was similar
`among subgroups classified according to the type of
`initial event (P=0.49 for the interaction) and the
`-weighted MRI scan at
`number of lesions on the T
`2
`screening (P=0.88 for the interaction).
`The diagnosis of clinically definite multiple sclero-
`sis was the result of a second acute demyelinating
`event in all but five patients. One patient in each
`group had progressive neurologic worsening during
`the first two months of the study treatment, and one
`patient in the interferon beta-1a group and two pa-
`tients in the placebo group had progressive neuro-
`logic disability without an acute exacerbation. Cor-
`ticosteroids were prescribed for a neurologic event
`that did not qualify as clinically definite multiple scle-
`
`900
`
`·
`
`September 28, 2000
`
`rosis in the case of 9 patients in the interferon beta-
`1a group (3 of whom later met the criteria for clin-
`ically definite multiple sclerosis) and 22 patients in the
`placebo group (7 of whom later met the criteria).
`The changes in the volume of brain lesions on
`T
`-weighted MRI scans differed significantly between
`2
`the interferon beta-1a group and the placebo group
`at 6 months (P<0.001), 12 months (P=0.004), and
`18 months (P<0.001) (Table 2). At 18 months, the
`median increase in lesion volume was 1 percent in the
`interferon beta-1a group, as compared with 16 percent
`in the placebo group. At 6, 12, and 18 months, there
`were also fewer new or enlarging lesions on T
`-weight-
`2
`ed MRI scans (P=0.001, P<0.001, and P<0.001,
`respectively) and fewer gadolinium-enhancing lesions
`on T
`-weighted scans (P=0.03, P=0.02, and P<
`1
`0.001, respectively) in the interferon beta-1a group
`than in the placebo group (Table 2). As compared
`with the placebo group, the interferon beta-1a group
`had 42 percent fewer gadolinium-enhancing lesions
`at 6 months, 55 percent fewer at 12 months, and 67
`percent fewer at 18 months.
`
`Completeness of Follow-up
`Follow-up was discontinued early for a reason oth-
`er than the development of clinically definite multi-
`ple sclerosis in 30 of the 193 patients in the interfer-
`on beta-1a group (16 percent) and in 27 of the 190
`patients in the placebo group (14 percent). The mean
`(±SD) duration of follow-up for the remaining pa-
`tients in whom clinically definite multiple sclerosis
`had not developed and who were still being followed
`when the trial was stopped or who had completed the
`3-year final examination was 30.9±4.9 months in
`the interferon beta-1a group and 30.6±5.1 months
`in the placebo group, and the respective rates of com-
`pleted visits were 99.4 percent and 99.5 percent. All
`of these patients completed at least 22 months of
`follow-up.
`
`Adverse Events, Development of Neutralizing Antibodies,
`and Compliance
`During the first six months, an influenza-like syn-
`drome was reported by 54 percent of the patients in
`the interferon beta-1a group and by 26 percent of
`the patients in the placebo group (P<0.001). De-
`pression was the only other adverse event whose in-
`cidence was at least 5 percentage points higher in the
`interferon beta-1a group than in the placebo group
`(incidence, 20 percent and 13 percent; P=0.05). Se-
`rious adverse events, none of which were attributed
`to treatment, occurred in 12 patients in the interferon
`beta-1a group and 19 patients in the placebo group.
`Neutralizing antibodies were detected in less than
`1 percent of patients in the interferon beta-1a group
`at 12 and 18 months and in 2 percent at 24 and 30
`months.
`Treatment was discontinued because of an adverse
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 22, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`MYLAN PHARMS. INC. EXHIBIT 1030 PAGE 3
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`

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`INTRAMUSCULAR INTERFERON BETA-1a THERAPY INITIATED DURING A FIRST DEMYELINATING EVENT
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`T
`
`ABLE
`
` 1.
`
` B
`
`ASE
`
`-L
`
`INE
`
` C
`
`HARACTERISTICS
`
`
`
`OF
`
`
`
`THE
`
` P
`
`ATIENTS
`
`.*
`
`C
`HARACTERISTIC
`
`Female sex — no. (%)
`Age — yr
`Race or ethnic group — no. (%)
`White
`Black
`Hispanic
`Asian
`Other
`Type of initial event — no. (%)
`Optic neuritis
`Spinal cord syndrome
`Brain-stem or cerebellar syndrome
`Duration of symptoms before initiation of intravenous
`methylprednisolone — days
`Median
`25th and 75th percentiles
`Duration of symptoms at initiation of study treatment —
`days
`Median
`25th and 75th percentiles
`-weighted MRI screening — no. (%)
`No. of brain lesions on T
`2
`
`23
`
`
`
`I
`NTERFERON
`B
`-1a
`ETA
`G
`ROUP
`(N=193)
`
` P
`A
`ATIENTS
`LL
`(N=383)
`
`
`
`289 (75)
`33±7
`
`141 (73)
`33±8
`
`330 (86)
`31 (8)
`10 (3)
`2 (1)
`10 (3)
`
`192 (50)
`83 (22)
`108 (28)
`
`166 (86)
`15 (8)
`4 (2)
`0
`8 (4)
`
`95 (49)
`41 (21)
`57 (30)
`
`
`
`P
`LACEBO
`G
`ROUP
`(N=190)
`
`148 (78)
`33±7
`
`164 (86)
`16 (8)
`6 (3)
`2 (1)
`2 (1)
`
`97 (51)
`42 (22)
`51 (27)
`
`8
`5, 12
`
`8
`5, 12
`
`9
`5, 12
`
`19
`16, 23
`
`66 (17)
`125 (33)
`81 (21)
`111 (29)
`
`20
`16, 23
`
`33 (17)
`64 (33)
`41 (21)
`55 (28)
`
`19
`16, 23
`
`33 (17)
`61 (32)
`40 (21)
`56 (29)
`
`†
`
`2051
`1003, 4622
`
`2279
`1247, 4719
`
`1850
`860, 4064
`
`254 (70)
`57 (16)
`51 (14)
`32 (8)
`
`121 (66)
`36 (20)
`26 (14)
`18 (9)
`
`133 (74)
`21 (12)
`25 (14)
`14 (7)
`
`–4
`5–7
`»8
`Volume of lesions on base-line T
`2
`Median
`25th and 75th percentiles
`No. of gadolinium-enhancing brain lesions on base-line
`-weighted MRI — no. (%)†‡
`T
`1
`
`-weighted MRI — mm
`3
`
`01>
`
`1
`Family history of multiple sclerosis — no. (%)
`
`*Plus–minus values are means ±SD. There were no significant differences between groups. Seven
`patients (three in the interferon beta-1a group and four in the placebo group) did not meet all eli-
`gibility criteria: one patient began intravenous methylprednisolone 15 days after the onset of symp-
`toms, two patients underwent randomization more than 27 days after the onset of symptoms, two
`patients were older than 50 years at the time of randomization, one patient had pale optic disks at
`base line, and one patient was found after randomization to have a vascular cause of the initial event
`rather than demyelination.
`†MRI was performed at least four days after the patient completed the course of intravenous meth-
`ylprednisolone, while the patient was receiving oral prednisone.
`‡A total of 362 patients had MRI scans that could be evaluated (183 in the interferon beta-1a
`group and 179 in the placebo group).
`
`event in one patient in the interferon beta-1a group
`(<1 percent) and in seven patients in the placebo
`group (4 percent). Treatment was stopped early for
`other reasons in 37 patients in the interferon beta-1a
`group (19 percent; 7 were lost to follow-up, 1 died in
`an automobile accident, 2 had disease activity, and 27
`asked to withdraw or withdrew for other reasons)
`and in 28 patients in the placebo group (15 percent;
`9 were lost to follow-up, 4 had disease activity, and
`15 asked to withdraw or withdrew for other reasons).
`Treatment was not discontinued in any patient be-
`cause of an abnormal laboratory value. The treat-
`
`ment assignment was revealed in the case of one pa-
`tient who became pregnant.
`Ninety-three percent of the patients in the inter-
`feron beta-1a group and 99.5 percent of the patients
`in the placebo group took the study medication at
`least 80 percent of the time; 88 percent and 94 per-
`cent, respectively, were at least 90 percent compliant.
`
`DISCUSSION
`The results of our trial add to the indications for
`interferon beta-1a in the treatment of multiple scle-
`rosis. In addition to the previously demonstrated ben-
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`Volume 343 Number 13
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`The New England Journal of Medicine
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`Downloaded from nejm.org on January 22, 2015. For personal use only. No other uses without permission.
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` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
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`The New England Journal of Medicine
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`50
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`40
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`30
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`20
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`10
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`Clinically Definite MS (%)
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`0
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`1
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`4
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`7
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`10
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`13
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`22
`19
`16
`Months
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`25
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`28
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`31
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`34
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`37
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`Interferon beta-1a group
`No. at riskK
`Clinically definite MSK
`Early withdrawal from studyK
`Followed until end of study
`Placebo group
`No. at riskK
`Clinically definite MSK
`Early withdrawal from studyK
`Followed until end of study
`
`193K
`9K
`7
`
`177K
`6K
`7
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`164K
`7K
`6
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`151K
`5K
`3
`
`143K
`3K
`1
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`190K
`18K
`7
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`165K
`13K
`6
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`146K
`7K
`0
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`139K
`4K
`4
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`131K
`6K
`1
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`139K
`4K
`4K
`19
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`112K
`0K
`0K
`0
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`112K
`2K
`1K
`36
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`124K
`8K
`1K
`17
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` 98K
`6K
`1K
`1
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` 90K
`3K
`5K
` 24
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`73K
`4K
`0K
`0
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`58K
`1K
`0K
`3
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`69K
`3K
`0K
`25
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`54K
`6K
`2K
`20
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`41K
`3K
`0K
`2
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`26K
`0K
`0K
`1
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`36K
`0K
`1K
`1
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`25K
`1K
`0K
`0
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`Figure 1.
` Kaplan–Meier Estimates of the Cumulative Probability of the Development of Clinically Definite Multiple Scle-
`rosis (MS) According to Treatment Group.
`The cumulative probability of the development of clinically definite multiple sclerosis during the three-year follow-up
`period was significantly lower in the interferon beta-1a group than in the placebo group (P=0.002 by the Mantel log-
`rank test). The numbers of patients at risk are the numbers in whom clinically definite multiple sclerosis had not devel-
`oped at the beginning of each three-month period. The end point was assessed beginning at one month, since accord-
`ing to the protocol that was the earliest possible time at which the end point could be reached. The “early-withdrawal”
`row indicates the number of patients in whom multiple sclerosis did not develop and whose follow-up ended before
`the study ended. Data were censored at the time of a patient’s last completed neurologic examination.
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`efit of interferon beta in patients with established
`multiple sclerosis,
` our results show that once-week-
`9-13
`ly intramuscular injections of interferon beta-1a, ini-
`tiated at the time of a first clinical demyelinating
`event, are beneficial in patients who have MRI evi-
`dence of prior subclinical demyelination in the brain.
`In our study of 383 patients, interferon beta-1a re-
`duced the rate of development of clinically definite
`multiple sclerosis within three years by about half.
`Findings on MRI scans of the brain provided addi-
`tional objective support for the observation that the
`effects of treatment with interferon beta-1a were rap-
`id and sustained. Interferon beta-1a was well tolerat-
`ed, with no serious treatment-related adverse effects.
`The base-line characteristics of the two groups were
`similar, and there was no evidence of confounding
`in the analyses. The percentage of patients who were
`withdrawn from the study for reasons other than the
`development of clinically definite multiple sclerosis
`was similar in the two groups. Most patients contin-
`ued treatment until their protocol-specified follow-
`
`up concluded, and the rates of compliance were good
`in both groups. The occurrence of the influenza-like
`syndrome related to interferon beta-1a therapy could
`have provided some patients with a clue to the treat-
`ment assignment, but given that the examining neu-
`rologist was unaware of the patients’ histories and
`that a separate, central end-point committee was used
`to verify all outcomes, this possibility should not have
`appreciably biased the results.
`Because approved treatments for multiple sclerosis
`are available, we could not ethically keep patients in
`their assigned groups once clinically definite multiple
`sclerosis was diagnosed. Thus, the trial design could
`not provide any direct data on the long-term effect
`of interferon beta-1a on the rate of exacerbations or
`the progression of disability. However, the beneficial
`effects seen on MRI scans of the brain provide indi-
`rect evidence of a long-term benefit of treatment.
`A prior longitudinal study of patients with acute iso-
`lated demyelinating events found that the volume and
`-weighted MRI scans
`number of brain lesions on T
`2
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`902
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`·
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`September 28, 2000
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`The New England Journal of Medicine
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`Downloaded from nejm.org on January 22, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
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`MYLAN PHARMS. INC. EXHIBIT 1030 PAGE 5
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`INTRAMUSCULAR INTERFERON BETA-1a THERAPY INITIATED DURING A FIRST DEMYELINATING EVENT
`
`T
`
`ABLE
`
` 2.
`
`F
`
` MRI S
`-W
` T
`
`-W
` T
`
`CANS
`EIGHTED
`AND
`EIGHTED
`ON
`INDINGS
`1
`2
` 6, 12,
` 18 MONTHS OF TREATMENT.*
`AND
`AFTER
`
`
`
`OF
`
`
`
`THE
`
` B
`
`RAIN
`
`,
`
`VARIABLE
`
`6 MONTHS
`INTERFERON
`BETA-1a
`GROUP
`
`PLACEBO
`GROUP
`
`12 MONTHS
`INTERFERON
`BETA-1a
`GROUP
`
`PLACEBO
`GROUP
`
`18 MONTHS
`INTERFERON
`BETA-1a
`GROUP
`
`PLACEBO
`GROUP
`
`¡123
`¡653, 254
`145
`<0.001
`
`40
`¡175, 624
`145
`
`102
`¡375, 573
`134
`
`214
`¡45, 1238
`120
`
`0.004
`
`28
`¡576, 397
`119
`<0.001
`
`313
`5, 1140
`109
`
`82 (50)
`63 (41)
`60 (36)
`46 (30)
`23 (14)
`43 (28)
`165
`152
`1.5±2.7
`2.8±4.3
`0.01
`
`65 (44)
`32 (25)
`56 (38)
`47 (37)
`28 (19)
`47 (37)
`149
`126
`2.1±3.3
`4.0±5.0
`<0.001
`
`62 (47)
`22 (18)
`41 (31)
`47 (39)
`29 (22)
`50 (42)
`132
`119
`2.1±3.2
`5.0±7.7
`<0.001
`
`115 (70)
`93 (61)
`27 (16)
`16 (11)
`23 (14)
`43 (28)
`165
`152
`0.9±2.3
`1.5±3.1
`0.03
`
`100 (68)
`28 (19)
`19 (13)
`147
`0.7±2.0
`0.02
`
`71 (57)
`20 (16)
`33 (27)
`124
`1.6±3.8
`
`109 (81)
`66 (58)
`13 (10)
`23 (20)
`12 (9)
`25 (22)
`134
`114
`0.4±1.5
`1.4±3.6
`<0.001
`
`T2-weighted MRI scans
`Change in volume of lesions — mm3
`Median
`25th and 75th percentiles
`No. of patients
`P value
`No. of new or enlarging lesions —
`no. (%)
`
`01
`
`–3
`»4
`No. of patients
`Mean no. of lesions
`P value
`T1-weighted MRI scans
`No. of gadolinium-enhancing
`lesions — no. (%)
`
`01>
`
`1
`No. of patients
`Mean no. of lesions
`P value
`
`*Plus–minus values are means ±SD. The Mann–Whitney rank-sum test was used to calculate P values.
`
`both at the time of the initial demyelinating event
`and subsequently were predictive of the degree of
`neurologic disability 10 years after the initial event.
`7,8
`There has been controversy about the importance
`of performing MRI of the brain at the time of a first
`acute demyelinating event, particularly in patients who
`present with optic neuritis, since a clinical diagnosis
`of this syndrome generally can be established with-
`out ancillary testing.
` The results of our study provide
`17
`justification for obtaining MRI scans of the brain at
`the time of a first event to determine whether there
`is further evidence of multiple sclerosis. Our results
`indicate that once-weekly treatment with intramus-
`cular interferon beta-1a is beneficial in patients who
`are deemed to be at high risk for clinically definite
`multiple sclerosis because they have subclinical de-
`myelinating lesions on MRI of the brain. Our study
`does not provide the long-term follow-up data re-
`quired to determine whether early initiation of treat-
`ment has long-term effects. However, the weight of
`current knowledge suggests that preventing or delay-
`ing a second attack of multiple sclerosis and reducing
`the progression of central nervous system demyelin-
`ation as demonstrated on MRI scans of the brain
`will have long-term clinical benefits.
`
`Supported by Biogen.
`
`Drs. Jacobs, Beck, Simon, Kinkel, Brownscheidle, and Murray are paid
`consultants to Biogen.
`
`APPENDIX
`Other participants in the study were as follows: Clinical Centers — Uni-
`
`
`versity of Toronto: P. O’Connor, P. Fleming, T. Gray; Buffalo General Hos-
`pital: C. Miller, R. Bakshi, F. Munschauer; Cleveland Clinic Foundation:
`D. Bolibrush, J. Cohen; Ottawa General Hospital: M. Freedman, U. Webb,
`H. Rabinowicz; Foothills Hospital: L. Metz, A. Davis, R. Ranawaya; Van-
`couver Hospital and Health Sciences Center: S. Hashimoto, W. Morrison,
`J. Oger; University of Maryland Hospital: H. Panitch, K. Costello, C. Bev-
`er; Multiple Sclerosis Center at Shepherd: W. Stuart, D. Court, D. Stuart;
`Georgetown University Hospital: C. Tornatore, D. Bartlett, J. Richert;
`Hôpital Notre Dame: P. Duquette, R. Dubois, G. Bernier; Allegheny Neu-
`rological Associates: T. Scott, L. Pappert, J. Brillman; Medical College of
`Virginia, Richmond Eye and Ear Hospital: W. Fenton, III, T. Anderson, J.
`Astruc; Salt Lake City Veterans Affairs Medical Center: J. Rose, J. Kline, J.
`Burns; Victoria General Hospital: P. Weldon, F. Bhan; University of Iowa
`College of Medicine: M. Wall, L. Vining, T. Grabowski; New York Hospi-
`tal–Cornell Medical Center: B. Apatoff, K. Arapello, J. Friedman; Univer-
`sity of Pennsylvania Medical Center: S. Galetta, D. Pfohl, G.