RAPID COMMUNICATION
`
`Phase III Dose-Comparison Study of
`Glatiramer Acetate for Multiple Sclerosis
`
`Giancarlo Comi, MD,1 Jeffrey A. Cohen, MD,2 Douglas L. Arnold, MD,3
`Daniel Wynn, MD,4 and Massimo Filippi, MD5 for the FORTE Study Group
`
`Objective: To evaluate the safety, tolerability, and efficacy of glatiramer acetate (GA) 40mg compared to a 20mg
`dose.
`Methods: Patients with multiple sclerosis (MS) with 1 documented relapse in 12 months prior to screening, or 2
`documented relapses in 24 months prior to screening, and Expanded Disability Status Scale (EDSS) score 0 to 5.5
`were enrolled. Patients were evaluated at screening, baseline, and at months 1, 2, 3, 6, 9, and 12. Primary endpoint
`was rate of confirmed relapses observed during 12-month study. Analysis was by intent-to-treat.
`Results: A total of 1,155 patients randomized to GA 20mg (n ¼ 586) or 40mg (n ¼ 569). The groups were well-
`matched at baseline on demographic, clinical, and magnetic resonance imaging (MRI) characteristics. The primary
`endpoint was similar in both groups (relative risk [RR] ¼ 1.07; 95% confidence interval [CI], 0.88–1.31; p ¼ 0.486)
`with mean annualized relapse rates (ARRs) of 0.33 for the 20mg group, 0.35 for the 40mg group, and 0.27 for
`patients from both groups who completed the entire 1-year treatment. A total of 77% of patients remained relapse-
`free in both groups. Both groups showed a reduction in mean number of gadolinium-enhancing and new T2 lesions
`over time with trend for faster reduction in the first trimester with the 40mg dose compared with 20mg dose. Both
`doses were well-tolerated with a safety profile similar to that observed in previous studies of 20mg GA.
`Interpretation: In relapsing-remitting MS patients, both the currently-approved GA 20mg and 40mg doses were safe
`and well-tolerated, with no gain in efficacy for the higher dose.
`
`ANN NEUROL 2011;69:75–82
`
`Glatiramer acetate (GA) is 1 of 7 disease modifying
`
`agents currently-approved to treat relapsing-remit-
`ting multiple sclerosis (RRMS). In 3 double-blind pla-
`cebo-controlled trials, subcutaneous (sc) GA at a once-
`daily 20mg dose significantly reduced relapse frequency,
`magnetic resonance imaging (MRI) disease activity, and
`burden.1–3 Additionally, it has been shown that GA 20mg
`is able to significantly reduce the rate of developing clini-
`cally definite multiple sclerosis (MS) and MRI activity in
`patients with a first demyelinating event suggestive of the
`disease.4 The efficacy of GA in MS is thought to result
`from induction of immune tolerance; ie, reduced T cell
`proliferation and a shift to a T helper 2 (Th2) cytokine
`profile.5 Reaching immune tolerance could depend on the
`dose and the frequency of administration of the mixture of
`polypeptides of GA, suggesting that higher doses of GA
`may be more efficacious in influencing disease course.
`
`Studies of GA administered by sc injection in RRMS
`used a 20mg daily dose, the currently-approved regimen.
`Small early studies provided little data regarding doses
`other than 20mg daily.6 A phase II dose-comparative study
`suggested 40mg given sc once daily was well tolerated and
`showed a trend for an increased effect on clinical and MRI
`activity in RRMS compared to the marketed dose.7 Based
`on these initial results, a double-blind, placebo-controlled
`trial was undertaken to determine whether a dose of 40mg
`is more effective than the currently available dose of 20mg
`in reducing relapse rate, MRI activity, and the accumula-
`tion of white matter lesion burden in patients with RRMS.
`
`Patients and Methods
`Patients
`Enrollment started in September 2006 and was completed in
`May 2007. Key inclusion criteria included: (1) age 18–55 years
`
`View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22316
`
`Received Jul 20, 2010, and in revised form Oct 19, 2010. Accepted for publication Oct 22, 2010.
`
`Address correspondence to Dr Comi, Institute of Experimental Neurology, Department of Neurology, University Vita-Salute, Scientific Institute
`SanRaffaele, Via Olgettina 48, 20132 Milan, Italy. E-mail: g.comi@hsr.it
`
`From the 1Institute of Experimental Neurology, Department of Neurology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy; 2Mellen Center
`U-10, Cleveland Clinic Foundation, Cleveland, OH; 3McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, Montreal, Canada;
`4Consultants in Neurology Multiple Sclerosis Center, Consultants in Neurology, Ltd, Northbrook, IL; 5Neuroimaging Research Unit, Institute of Experimental
`Neurology, Division of Neuroscience, Scientific Institute and University Hospital San Raffaele, Milan, Italy.
`
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`FIGURE: Patient disposition during the course of the study. Of patients on GA 20mg and on GA 40mg, 91% and 86% com-
`pleted the study, respectively, while 9% and 14%, respectively, were ET. ET 5 terminated early from the study; GA 5 glatir-
`amer acetate.
`
`inclusive; (2) a diagnosis of RRMS8,9; (3) Expanded Disability
`Status Scale (EDSS) score 0–5.5; and (4) at least 1 documented
`relapse in the 12 months prior to screening, at least 2 docu-
`mented relapses in the 24 months prior to screening, or 1 docu-
`mented relapse between 12 and 24 months prior to screening
`with at least 1 documented gadolinium-enhancing (GdE) lesion
`on an MRI scan performed within 12 months prior to screening.
`Key exclusion criteria included: (1) a clinical relapse or steroid
`treatment within 30 days prior to screening; (2) previous treat-
`ment with immunomodulators within the last 2 months; or (3)
`immunosuppressive treatments within the last 6 months and pre-
`vious use of GA or natalizumab. The protocol and consent docu-
`ments were approved by the institutional review boards and ethics
`committees of the participating centers. Patients provided written
`informed consent prior to undergoing any study-related proce-
`dures. This study is registered, as number NCT00337779.
`
`Treatment
`Patients were treated with a daily sc dose of a single prefilled
`syringe of either GA 20mg or GA 40mg. Labeling and packag-
`ing for the doses were identical.
`
`Design
`The trial was a multicentre, randomized, double-blind, parallel-
`group, dose-comparison study lasting 12 months. The study
`was conducted in 20 countries worldwide, with a total of 136
`sites. The randomization procedure employed a 1:1 assignment
`ratio, and a scheme using blocks stratified by center.
`For trial purposes, a month was defined as 30 6 4 days.
`At each study site, a treating neurologist was responsible for the
`overall medical management of patients including safety moni-
`toring. An examining neurologist performed a standardized
`neurological examination, and assessed Timed 25-Foot Walk
`(T25FW), Functional System and EDSS scores (Neurostatus,
`L. Kappos, MD, Department of Neurology, University Hospi-
`tal, Basel, Switzerland) at scheduled and unscheduled visits. All
`patients underwent evaluations
`including vital
`signs
`(blood
`
`pressure, pulse, and temperature), adverse events, and concomi-
`tant medications, at screening (month 1), baseline (month 0),
`months 1, 2, 3, and every 3 months thereafter; and safety labo-
`ratory assessments (hematology, serum biochemistry, and urinal-
`ysis) at screening, baseline, and months 1, 3, 6, 9, and 12.
`Neurological examinations were performed every 3 months and
`MRI scans at baseline and month 12. A ‘‘frequent MRI cohort’’
`of patients from 38 sites performed additional scans at months
`1, 2, 3, 6, and 9. After completion of 12 months of double-
`blind treatment, both treatment groups were assigned to open
`label treatment with GA 40mg for an additional 12 months.
`A relapse was defined as the appearance of 1 or more
`new neurological abnormalities or the reappearance of 1 or
`more previously observed neurological abnormalities. An event
`was counted as a relapse only when the subject’s symptoms
`were accompanied by objective changes in the examining neu-
`rologist’s assessment corresponding to an increase of at least 0.5
`points on the EDSS, 1 grade in 2 or more Functional System
`scores, or 2 grades in 1 Functional System score. Isolated
`changes in bowel, bladder, and cognitive function did not qual-
`ify as relapses. The treating neurologist determined whether the
`change in symptoms qualified as an on-study relapse, which
`could be treated at the discretion of the treating neurologist
`with a standard 1g dose of intravenous (iv) methylprednisolone
`for a maximum 5 consecutive days.
`The Steering Committee supervised the conduct of the
`study. An independent Data Monitoring Committee met 3
`times during the trial, in person or via teleconference, to review
`study conduct as well as blinded safety data. Unblinded safety
`data were provided to the Data Monitoring Committee upon
`their request by an unblinded statistician not directly involved
`in the trial. Serious adverse events were reported to the Data
`Monitoring Committee members on a monthly basis.
`
`Outcome Measures
`The primary efficacy outcome measure was the rate of con-
`firmed relapses during the 12-month double-blind phase.
`
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`Secondary outcome measures included, in a hierarchical order
`for statistical analysis, the cumulative number of GdE lesions at
`months 3, 6, 9, and 12 (frequent MRI cohort), and the num-
`ber of new T2 lesions at month 12 compared to baseline scan.
`Rate of brain volume changes defined as the percentage brain
`volume changes from baseline to month 12 was an exploratory
`endpoint.
`
`MRI Scanning and Analysis
`The Neuroimaging Research Unit in Milan, Italy, served as the
`MRI analysis centre (MRI-AC). Before a site could enroll study
`participants they were required to image a volunteer patient
`with definite MS twice with repositioning according to a strict
`study imaging protocol using imagers with minimum field
`strength of 1.0T. Conventional or fast spin echo (repetition
`time [TR] ¼ 2200–3000ms, echo time [TE] ¼ 15–50/80–
`120ms, echo train length ¼ 4–6, slice thickness ¼ 3mm, and
`contiguous axial slices ¼ 44) sequences were used to obtain
`proton density and T2-weighted images. Conventional spin
`echo T1-weighted images (TR ¼ 600–650ms, TE ¼ 10–20ms)
`with the same scan geometry were obtained 5 minutes after
`injection of 0.1mmol/kg of gadolinium. A series of axial, coro-
`nal, and sagittal images was obtained to create an axial reference
`scan for subsequent careful repositioning of each patient at the
`follow-up session. Axial slices were positioned to run parallel to
`a line joining the most inferioanterior and inferioposterior parts
`of the corpus callosum.
`Image quality was reviewed at the MRI-AC using prede-
`termined criteria. The identification of GdE and T2-hyperin-
`tense lesions was done by consensus of 2 experienced observers.
`The number of total and new GdE lesions and new T2-hyper-
`intense lesions were counted. The identified lesions were then
`outlined by trained technicians using a semiautomated segmen-
`tation technique based on local thresholding (Jim 4.0; Xinapse
`System, Leicester, UK) and lesion volumes were calculated auto-
`matically. Percentage brain volume changes and cross-sectional
`normalized brain volumes were measured on postcontrast T1-
`weighted images, with Structural Image Evaluation of Normal-
`ized Atrophy (SIENA) software and a cross-sectional method
`(SIENAX) (available from the FMRIB Software Library, Oxford
`University, Oxford, UK; http://www.fmrib.ox.ac.uk/analysis/
`research/siena/siena), as described elsewhere.10
`
`Statistical Analysis
`A total of 980 patients equally randomized to the 2 study arms
`was expected to provide 90% power to detect a 30% difference in
`relapse rate during the double-blind phase, based on the following
`assumptions: (1) expected 1-year relapse-rate of a virtual placebo
`arm equal to 0.7; (2) annual relapse rate reduction by treatment
`with GA 20mg ¼ 30% compared with placebo to 0.49; and (3)
`annual relapse rate reduction by treatment with GA 40mg ¼
`30% compared to GA 20mg to 0.343 relapses per year.
`All efficacy and safety analyses were performed on the
`intent-to-treat cohort, defined as all randomized patients. For
`analysis of the primary efficacy endpoint, a baseline-adjusted,
`quasilikelihood
`(overdispersed)
`Poisson
`regression
`was
`
`Comi et al: GA Dose-Comparison Trial for RRMS
`
`employed. An offset based on the log of subject’s exposure was
`employed to adjust the number of relapses to rates. Prior num-
`ber of relapses, baseline EDSS, subject’s exposure and centers
`were included in the model as covariates. Also, an alternative
`primary analysis was considered,
`the analysis of covariance
`(ANCOVA), utilizing normal
`approximation large
`sample
`theory, in case the randomization distribution simulation did
`not confirm the statistical significance of the quasilikelihood
`Poisson regression. Secondary efficacy end points were analyzed
`in a hierarchical order using a baseline-adjusted negative bino-
`mial regression. Baseline GdE lesion counts and center effect
`were used as covariates in the model in addition to the treat-
`ment effect. Brain volume changes were analyzed by applying
`an ANCOVA that compared the adjusted means of the percent-
`age changes in brain volumes detected between groups. The
`number of patients withdrawing early due to adverse events,
`and patients who were free of relapses during study were com-
`pared for treatment effects using the chi square test, and time
`to withdrawal was analyzed by a log-rank test.
`
`Results
`Patients Disposition
`A total of 1,262 patients were considered for this study,
`107 (8.5%) of whom were screening failures. The vast
`majority of
`the screening failures
`(80.4%) occurred
`because the patients did not meet the inclusion/exclusion
`criteria. The others withdrew consent (14.0%), and 5.6%
`were not
`randomized due to other
`reasons, mainly
`related to scheduling issues. A total of 1,155 eligible
`patients were randomized either to GA 20mg (n ¼ 586)
`or 40mg (n ¼ 569). A total of 1,024 patients (88.7%)
`completed the double-blind phase. Premature termina-
`(p ¼
`tion from the double-blind phase was higher
`0.0071) in the GA 40mg arm (79 patients; 13.9%) com-
`pared to GA 20mg arm (52 patients; 8.9%) (Fig). The
`reasons for early termination are summarized in Table 1.
`The most common reason was adverse events (mainly
`injection site reactions), which was reported for 4.8% of
`the discontinued patients on GA 20mg vs 9.0% on GA
`40mg.
`
`Baseline Characteristics
`The 2 groups were well-matched on demographic, clini-
`cal, and MRI baseline characteristics (Table 2).
`
`Efficacy Results
`
`PRIMARY ENDPOINT. No difference between the
`groups was observed in the mean number of confirmed
`relapses during the double-blind phase (0.28 6 0.58 for
`patients on GA 20mg and 0.27 6 0.54 for patients on
`GA 40mg); mean annualized number of confirmed relap-
`ses was 0.33 6 0.81 for patients on GA 20mg,
`
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`ANNALS of Neurology
`
`TABLE 1: Reasons for Early Termination
`
`Reasons
`
`GA 20mg(n 5 586)
`
`GA 40mg(n 5 569)
`
`All
`
`Adverse events
`
`Subject withdrew consent
`
`Failed to return/lost to follow-up
`
`Request of investigator
`
`Pregnancy
`
`Sponsor’s decision
`
`Noncompliance
`
`Death
`aTraffic accident. GA ¼ glatiramer acetate.
`
`Number
`
`52
`
`28
`
`10
`
`6
`
`3
`
`3
`
`1
`
`1
`
`%
`
`8.9
`
`4.8
`
`1.7
`
`1.0
`
`0.5
`
`0.5
`
`0.2
`
`0.2
`
`Number
`
`79
`
`51
`
`12
`
`5
`
`6
`
`2
`
`1
`
`1
`1a
`
`%
`
`13.9
`
`9.0
`
`2.1
`
`0.9
`
`1.1
`
`0.4
`
`0.2
`
`0.2
`
`0.2
`
`p
`
`0.007
`
`0.005
`
`0.617
`
`0.799
`
`0.290
`
`0.677
`
`0.983
`
`0.983
`
`0.234
`
`compared to 0.35 6 0.99 for patients on GA 40mg (risk
`ratio ¼ 1.07; 95% CI, 0.88–1.31; p ¼ 0.486). The alter-
`native ANCOVA analysis, yielded similar results: p ¼
`0.872 adjusted for center, and p ¼ 0.844 adjusted for
`country (Table 3). Similar proportions of patients were
`free of relapses: 77.0% in the GA 40mg arm and 77.6%
`in the GA 20mg arm.
`
`SECONDARY AND EXPLORATORY ENDPOINTS. The
`analysis of the cumulative number of GdE lesions was
`carried out for a subset of patients that included 126
`patients on GA 20mg and 108 patients on GA 40mg
`(frequent MRI cohort). In this cohort, there were more
`GdE lesions at baseline in the 40mg arm (2.5 6 5.8)
`compared to the low-dose group (1.5 6 3.4, p ¼
`
`TABLE 2: Baseline Characteristics of Enrolled Patients
`
`0.081). On the scans performed at months 3, 6, 9, and
`12, in patients of this cohort, the mean number of GdE
`lesions was similar in both arms (Table 4). The mean
`number of GdE lesions at month 3 decreased compared
`with baseline by 21.9% (p ¼ 0.172) in the GA 20mg
`arm and by 37.6% (p ¼ 0.012) in the GA 40mg arm,
`and further decreased significantly at month 6 compared
`to baseline (57.3%, p ¼ 0.0007) in the GA 20mg arm
`and 69.2% (p < 0. 0001) in the GA 40mg arm. These
`reductions of MRI activity were maintained with 70.8%
`reduction at the end of the 9 months in the GA 20mg
`group and a reduction by 72.2% in the GA 40mg group
`compared to baseline (p < 0.0001). The cumulative
`number of GdE lesions at months 3, 6, 9, and 12 was
`higher in the high dose group (3.49 vs 2.83), but this
`
`Characteristics
`
`Age (yr)
`
`Gender (% F)
`
`Time from first symptom (yr)
`
`Time from diagnosis (yr)
`
`p
`
`0.959
`
`0.906
`
`0.608
`
`0.258
`
`0.022
`
`0.152
`
`0.888
`
`0.880
`
`GA 40mg(n 5 569)a
`GA 20mg(n 5 586)a
`36.3 6 9.0, 36.3
`36.3 6 9.0, 36.0
`71.5
`71.8
`6.5 6 6.7, 4.2
`6.3 6 6.5, 4.3
`3.3 6 4.8, 1.0
`3.0 6 4.0, 1.0
`1.4 6 0.7, 1.0
`1.5 6 0.7, 1.0
`2.0 6 1.0, 2.0
`2.0 6 1.0, 2.0
`2.2 6 4.8, 0
`2.2 6 6.9, 0
`9.8 6 10.4, 6.5
`9.7 6 12.4, 5.8
`2.1 6 1.1, 2.0
`2.2 6 1.2, 2.0
`EDSS score
`0.773
`All p values are derived from t test, except for gender p value which was derived from the log-likelihood chi-square test.
`aValues are mean 6 SD; median.EDSS ¼ Expanded Disability Status Scale; F ¼ female; GA ¼ glatiramer acetate; GdE ¼ gado-
`linium-enhancing; SD ¼ standard deviation.
`
`Number of relapses in the previous year
`
`Number of relapses in the previous 2 years
`
`Number of GdE lesions
`
`Volume of T2 lesions (ml)
`
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`TABLE 3: Results of Primary and Secondary Endpoints
`
`Comi et al: GA Dose-Comparison Trial for RRMS
`
`Analysis
`
`Annualized relapse rate
`
`Relapse free patients (%)
`
`Number of GdE lesions at month 12
`
`Number of new T2 lesions at month 12
`
`GA 20 mg(n 5 586)3
`0.33 6 0.81; 0.0
`77.6 6 17.4
`0.68 6 2.30; 0
`2.87 6 6.57; 1.0
`0.58
`
`GA 40 mg(n 5 569)3
`0.35 6 0.99; 0.0
`77.0 6 17.7
`0.54 6 1.77; 0
`2.72 6 8.36; 0
`0.53
`
`p
`
`0.486b
`1.000c
`d
`
`d
`
`0.423
`
`Percent brain volume changes (%)
`3Values are mean 6 SD; median.
`bPoisson regression.
`cLog likelihood chi square.
`dNegative binomial regression model did not converge.AG ¼ glatiramer acetate; GdE ¼ gadolinium-enhancing; SD ¼ standard
`deviation.
`
`difference was not significant p ¼ 0.091), and was not
`supported by the results of the number of GdE lesions in
`the entire study population.
`In the entire study population at month 12, the
`mean number of GdE lesions per patient was 0.68 in the
`20mg group and 0.54 in the 40mg group (21%). The
`mean number of new T2 lesions at month 12 was similar
`in the 2 treatment groups: 2.87 in the GA 20mg group
`and 2.72 in the GA 40mg group (see Table 3). Percent
`brain volume changes were similar in both groups with a
`mean of 0.58% in the GA 20mg arm and of 0.53% in
`the GA 40mg arm (p ¼ 0.423).
`
`in the GA 20mg arm, 615
`injection site reactions
`(79.3%) were classified as mild by the investigators, 145
`(18.7%) were moderate, and only 16 (2%) were classified
`as severe. Similarly, out of the total 824 reports of injec-
`tion site reactions in the GA 40mg arm, 628 (76.2%)
`were mild, 175 (21.2%) were moderate, and 21 (2.6%)
`were severe. The incidence of immediate postinjection
`reactions was low: 36 patients (6.1%) in GA 20mg and
`43 patients (7.6%) in GA 40mg. There were no safety
`concerns in either treatment group with regards to labo-
`ratory results, electrocardiogram (ECG) and vital signs.
`
`Safety Results
`The safety profile of both doses was similar to that
`observed in previous studies of GA 20mg. Both doses
`were well-tolerated with only 25 cases (4.3%) of severe
`adverse events in the GA 20mg arm and 24 (4.3%) in
`the GA 40mg arm. A similar incidence rate was also seen
`for injection site reactions: 336 patients (55.6%) in GA
`20mg and 330 patients (58%) in GA 40mg, the majority
`of which were mild. Out of a total of 776 reports of
`
`Discussion
`The safety and efficacy of GA at the currently-approved
`20mg daily dose are supported by 3 placebo-controlled
`trials,1–3 a meta-analysis of these studies,11 2 long-term
`follow-up studies,12,13 and postmarketing experience.
`This first large, 12-month multicentre, randomized, dou-
`ble-blind, parallel-group dose-comparison trial of GA
`demonstrated that, over 12 months, there is no gain in
`efficacy with a double dose of GA compared to the
`
`TABLE 4: Results of Number of GdE Lesions Over Time—Frequent MRI Cohort
`
`GdE Lesions
`
`Number of GdE lesions at baseline
`
`Number of GdE lesions at mo 3
`
`Number of GdE lesions at mo 6
`
`Number of GdE lesions at mo 9
`
`Number of GdE lesions at mo 12
`
`GA 20mg(n 5 126)a
`GA 40mg(n 5 108)a
`1.48 6 3.41
`2.47 6 5.83
`1.21 6 2.61 (21.9, p ¼ 0.172)
`1.64 6 3.91 (37.6, p ¼ 0.012)
`0.65 6 1.56 (57.3, p ¼ 0.0007)
`0.76 6 2.19 (69.2, p < 0.0001)
`0.45 6 1.27 (70.8, p < 0.0001)
`0.72 6 2.11 (72.2, p < 0.0001)
`0.75 6 3.30 (48.9, p ¼ 0.103)
`0.79 6 2.91 (69.0, p ¼ 0.004)
`2.83 6 6.58
`3.49 6 8.19
`Cumulative number of GdE lesions
`0.091
`during 12 mo
`aValues are mean 6 SD (% change from baseline, p value). GA ¼ glatiramer acetate; GdE ¼ gadolinium-enhancing; MRI ¼ mag-
`netic resonance imaging; SD ¼ standard deviation.
`
`p
`
`0.082
`
`0.325
`
`0.666
`
`0.208
`
`0.904
`
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`currently-approved 20mg dose. There were no differences
`between the 2 doses
`in relapse rate, proportion of
`patients free from relapses, various MRI markers of dis-
`ease activity or rates of brain volume change. The clinical
`and MRI measures of disease activity during study were
`greatly reduced in both arms compared to the corre-
`sponding prestudy and baseline values.
`The annualized relapse rate on study was 0.33 in the
`GA 20mg dose group and 0.35 in the GA 40mg dose group,
`values which are very low compared to those in the pivotal
`trial of GA,2 but close to that observed for GA in the more
`recent ‘‘Rebif vs Glatiramer Acetate in Relapsing MS Dis-
`ease’’ (REGARD) (0.29) and ‘‘Betaferon Efficacy Yielding
`Outcomes of a New Dose’’ (BEYOND) (0.34) studies.14,15
`MRI analyses support the conclusion that both doses
`of GA were equally effective in this study. The mean num-
`ber of GdE lesions decreased at the end of the study com-
`pared to baseline by about 70% in both treatment groups.
`The onset of the reduction of MRI activity appeared to
`occur earlier than expected based on the previous analysis
`of the European-Canadian MRI trial.3 The analysis of new
`T2 lesions formation in the frequent MRI cohort con-
`firmed that onset of action of GA on MRI activity started
`before 3 months from onset of treatment. The degree of
`progression of brain volume changes observed with both
`doses of GA is modestly lower than the values observed for
`GA in the BEYOND trial and in the European-Canadian
`MRI trial.3,15 Although comparisons across studies should
`be always considered with great caution, the MRI protocol
`was the same and the analysis was performed by the same
`MRI analysis center. The lower increase in brain volume
`changes observed in this study could be explained by the
`potential neuroprotective effect of available immunomodu-
`latory treatments in early MS.10,15,16
`in RRMS
`trials
`In recently completed clinical
`patients, the on-study relapse rate has been lower than that
`observed in earlier clinical trials. This behavior has been
`explained by the concurrence of several factors, including:
`(1) changing patterns of diagnosis and the so-called Will
`Rogers phenomenon;17 (2) the availability for recruitment
`of a less active population (because most patients are
`treated early, as reflected by the low EDSS and the short
`duration of disease (3 years) in the recruited population
`compared to earlier clinical trials; (3) lacking placebo group
`(added effect of drug and positive expectations); and (4)
`the fact that more active patients often are no longer con-
`sidered candidates for clinical trials for ethical reasons. This
`change in the characteristics of the disease in a clinical trial
`setting, mirrored by the low relapse rate of the placebo
`arms in recent trials,18 combined with the notion that early
`treatment with immunomodulatory drugs has better effi-
`cacy than delayed treatment,4,19 may suggest that the effi-
`
`cacy in terms of reduction in clinical and MRI activity
`achieved in recent trials is more similar than different com-
`pared with the previous clinical trials.
`Since patients in this trial tended to be more active
`than the patients treated with GA in the BEYOND and
`REGARD trials, as revealed by the higher mean number
`of GdE lesions at baseline (2.2 in this study vs 1.8 or
`1.65 in the BEYOND and REGARD, respectively), one
`might have expected higher relapse rates during this
`study compared to those. However, this was not the case.
`The proportion of clinically active patients was
`low
`(22.4%) in the GA 20mg group compared to 38% in
`the GA arm of the REGARD and 41% in the GA arm
`of the BEYOND trials, even considering that the num-
`bers relate to 1-year follow-up only.
`Treatment with GA was safe and tolerable, consistent
`with the safety and tolerability profile already observed in
`previous studies. Less than 5% of the patients discontinued
`treatment in the 20mg group because of adverse effects.
`This almost doubled with the 40mg dose. Injection site
`reactions remained the most commonly reported adverse
`event, with similar incidence rate in both doses of GA.
`Also the immediate postinjection reactions incidence rate
`were similar in the 2 groups.
`In conclusion, this study confirms that the double
`dose when administered daily showed no gains in efficacy
`(based on annualized relapse rate [ARR] and MRI meas-
`ures over 1 year), indicating it has no role in treatment
`of early, mildly affected RRMS patients.
`
`Acknowledgments
`This research was supported by a grant from Teva Phar-
`maceutical industries, Ltd.
`We thank the patients and site personnel involved
`in this study. We also thank Dr D. Ladkani (Teva Phar-
`maceutical Industries, Ltd.) for his assistance in the prep-
`aration of this manuscript.
`Preliminary results were presented in the World
`Congress on Treatment and Research in Multiple Sclero-
`sis Congress in September 2008 in Montreal, Canada.
`
`Potential Conflicts of Interest
`G.C. has received grants from Teva Pharmaceuticals; has
`received personal compensation for participating in advisory
`boards and acting as consultant from Teva Pharmaceuticals,
`Novartis, Sanofi-Aventis, Merck-Serono, and Bayer Schering;
`and has received honoraria for speaking activities from Teva
`Pharmaceuticals, Novartis, Serono Symposia International
`Foundation, Sanofi-Aventis, Merck-Serono, Biogen-Dompe`,
`and Bayer Schering. J.A.C. received personal compensation for
`serving as a consultant or speaker from Biogen Idec, Eli Lilly,
`
`80
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`Mylan Pharms. Inc. Exhibit 1017 Page 6
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`

`
`Genzyme, Novartis, and Teva Pharmaceuticals; and has
`received or has pending grants from Biogen Idec, Genzyme,
`Immune Tolerance Network, Novartis, Teva Pharmaceuticals,
`the U.S. Department of Defense, NIAID, and the National
`MS Society. M.F. has received grants or has grants pending
`from Bayer-Schering, Biogen-Dompe`, Genmab, Merck-
`Serono, Teva Pharmaceuticals, Fondazione Italiana Sclerosi
`Multipla (FISM), and Fondazione Mariani; has received
`compensation as a speaker from Teva Pharmaceuticals, Merck-
`Serono, Bayer-Schering, Biogen-Dompe`, and Genmab; has
`acted as a consultant for Teva Pharmaceuticals, Merck-Serono,
`Bayer-Schering, Biogen-Dompe`, Genmab, and Pepgen; has
`been a board member of Teva Pharmaceuticals and Genmab;
`has been paid for developing educational presentations from
`Bayer-Schering Pharma, Biogen-Dompe`, Genmab, Merck-
`Serono, and Teva Pharmaceuticals; and has had travel expenses
`covered or reimbursed from Teva Pharmaceuticals, Biogen-
`Dompe`, Merck-Serono, Sanofi-Aventis, Genmab, and Bayer-
`Schering. D.L.A. received personal compensation from Biogen
`Idec, Genentech, Novartis; has received honoraria from Biogen
`Idec, Biogen Idec Canada, CD-Pharma Interactive Medical
`Production, EMD Serono Canada, Genentech, MS Forum,
`Sanofi Aventis, Serono Symposia International Foundation,
`Teva Neuroscience Inc., and Vertex Pharmaceuticals; holds a
`patent (Method of Evaluating the Efficacy of Drug on Brain
`Nerve Cells); has served as a paid consultant for Biogen Idec;
`has received research support from Biogen Idec, Canadian
`Institutes of Health Research, Multiple Sclerosis Society of
`Canada, Multiple Sclerosis Scientific Research Foundation; has
`consulted for Consulting: Bayer HealthCare Pharmaceuticals
`Inc., Eisai Medical Research Inc., Elan Pharmaceuticals Inc.,
`Eli Lilly & Co., and GlaxoSmithKline; and has stock options
`from NeuroRx Research, Inc. D.W. has received support to
`travel to investigator meeting and advisory board meetings; has
`received fees for Steering Committee Membership; has
`received consultant and speaker compensation from Teva
`Pharmaceuticals, EMD Serono, Genzyme, Avanir Pharma-
`ceuticals, Accorda, BioMS, Pfizer, Allergan, Cephalon,
`GlaxoSmithKline, Questcor, and Forest Laboratories; has
`received grants or has grants pending from Teva Pharmaceu-
`ticals, EMD Serono, Biogen Idec, Avanir, BioMS, Pfizer, Ono,
`Eli Lilly, Abbott, Facet, Opexa, UCB, Elan, National Multiple
`Sclerosis Society, and the National Institutes of Health; and has
`received payment for development of educational presenta-
`tions from Teva Pharmaceuticals, EMD Serono, Acorda
`Genzyme, and the Chicago Center for Neurological Care
`and Research. Consultants in Neurology has received research
`support from Teva Neuroscience, Pfizer, EMD Serono, Biogen
`Idec, Avanir, BioMS, Pfizer, Ono, Eli Lilly, Abbott Facet,
`Opexa, UCB, Elan, the National MS Society, and the NIH.
`
`Comi et al: GA Dose-Comparison Trial for RRMS
`
`Appendix: FORTE Study Group
`Study Committees
`
`CORE CLINICAL STEERING COMMITTEE. Giancarlo
`Comi (PI), Jeffrey A. Cohen (PI), Massimo Filippi, Doug-
`las L. Arnold, Daniel Wynn. The MRI Analysis Center,
`Neuroimaging Research Unit, San Raffaele Scientific Insti-
`tute, Milan, Italy. Massimo Filippi; Maria A. Rocca, Elisa-
`betta Stefania Perego, Martina Absinta, Sarlota Mesaros,
`Roberto Vuotto, Paolo Misci, Melissa Petrolini.
`
`DATA SAFETY MONITORING COMMITTEE. Patricia
`Coyle (Chair), Jerry Wolinsky, Jack Antel, Scott Zam-
`vil, Paul Feigin.
`
`Study Sites
`Argentina: A.J. Carra, R.J. Bettinelli, G.G. Luetic, C.A.
`Vrech; Belgium: B.D.P. Dubois; Canada: L. Metz, A.
`Bar-Or, V. Bhan, M. Myles; Czech Republic: E. Havr-
`dova, E. Ehler, P. Kanovsky, R. Talab, O. Zapletalova;
`Estonia: K. Gross-Paju, P. Taba; Finland: I. Elovaara, J.
`P. Era¨linna, E. Kinnunen, K. Koivisto, M. Reunanen;
`France: B.Brochet, W. Camu, P. Damier, G. Defer; Ger-
`many: H. Tumani, E. Becker, T. Buettner, H.C. Diener,
`P. Franz, J. Haas, C. Heesen, F. Heidenreich, H.W.
`Koelmel, G.Reifschneider, K. Retzlaff, F. Thoemke, T.
`Ziemssen; Hungary: C. Rozsa, L. Bartos, A. Csanyi, I.
`Deme, S. Komoly, G. Panczel, M. Simo; Israel: A.
`Achiron, R. Milo;
`Italy: G. Comi, R.Bergamaschi,
`A.Bertolotto, R. Capra, D. Caputo, P.Cavalla, D. Cen-
`tonze, S.Cottone, N. De Stefano, C. Gasperini, G.
`Mancardi, L. Provinciali, S. Ruggieri, E. Scarpini, M.
`Zaffaroni; Latvia: M. Metra; Lithuania: R. Kizlaitiene,
`A. Vaitkus; Netherlands:C.P. Zwanikken, R.M.M. Hup-
`perts, P.J.H. Jongen; Poland: A. Szczudlik, W. Fryze, Z.
`Kazibutowska, K. Pierzchaa, J. Pniewski, R. Podemski,
`A. Ste˛pien´ ; Romania: O. Bajenaru, A.Campeanu,
`I.
`Marginean, C.D. Popescu, I. Toldisan; Russia: A. Boiko,
`A. Gustov, N. Malkova, S. Perfilyev, I. Poverennova, M.
`Saykhunov, A. Shutov, A. Skoromets, N. Spirin, I. Sto-
`lyarov, L.Volkova; Spain: A. Rodriguez-Antigu¨edad, T.
`Arbizu, R. Arroyo, J. Barcena, B. Casanova, O. Ferna´n-
`dez, X. Montalban, L. Ramio´ , A. Saiz-Hinarejos,; UK:
`B. Sharrack, E. Silber, C. Young; USA: M. Agius, G.
`Birnbaum, D. Campagnolo, K. Chaudhary, J. Cohen,
`C. Ford, E. Fox, A. Goodman, B. Green, A.Gupta, B.
`Hughes, A. Javed, D. Jeffery, L. Kasper, M. Kaufman,
`O. Khan, K. Kresa-Reahl, T. Leist, S. Lynch, C. Marko-
`witz, D. Mattson, H. Moses, B. Parks, G. Parry, T. Phil-
`lips, M. Picone, K. Rammohan, S. Rizvi, W. Royal, S.
`Scarberry, C. Sheppard, V. Simnad, B. Thrower, R.
`Whitham, D. Wynn.
`
`January 2011
`
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`Mylan Pharms. Inc. Exhibit 1017 Page 7
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`ANNALS of Neurology
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`References
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