J Neurol (2014) 261:2101–2111
`DOI 10.1007/s00415-014-7446-0
`
`O R I G I N A L C O M M U N I C A T I O N
`
`A 2-year observational study of patients with relapsing-remitting
`multiple sclerosis converting to glatiramer acetate from other
`disease-modifying therapies: the COPTIMIZE trial
`
`Tjalf Ziemssen • Ovidiu A. Bajenaru • Adriana Carra´ • Nina de Klippel • Joa˜o C. de Sa´ • Astrid Edland •
`Jette L. Frederiksen • Olivier Heinzlef • Klimentini E. Karageorgiou • Rafael H. Lander Delgado •
`Anne-Marie Landtblom • Miguel A. Macı´as Islas • Niall Tubridy • Yossi Gilgun-Sherki
`
`Received: 17 January 2014 / Revised: 14 July 2014 / Accepted: 15 July 2014 / Published online: 14 August 2014
`Ó The Author(s) 2014. This article is published with open access at Springerlink.com
`
`Abstract Studies suggest that patients with relapsing-
`remitting multiple sclerosis (RRMS) who do not benefit
`from other disease-modifying treatments (DMTs) may
`benefit from converting to glatiramer acetate (GA). COP-
`TIMIZE was a 24-month observational study designed to
`assess the disease course of patients converting to GA
`20 mg daily from another DMT. Eligible patients had
`converted to GA and had received prior DMT for
`3–6 months, depending on the reasons for conversion.
`Patients were assessed at baseline and at 6, 12, 18, and
`24 months. In total, 672 patients from 148 centers world-
`wide were included in the analysis. Change of therapy to
`
`GA was prompted primarily by lack of efficacy (53.6 %) or
`intolerable adverse events (AEs; 44.8 %). Over a 24-month
`period, 72.7 % of patients were relapse free. Mean annual
`relapse rate decreased from 0.86 [95 % confidence interval
`(CI) 0.81–0.91] before the change to 0.32 (95 % CI
`0.26–0.40; p \ 0.0001) at last observation, while the pro-
`gression of disability was halted, as the Kurtzke Expanded
`Disability Status Scale (EDSS) scores remained stable.
`Patients improved significantly (p \ 0.05) on measures of
`fatigue, quality of life, depression, and cognition; mobility
`scores remained stable. The results indicate that changing
`RRMS patients to GA is associated with positive treatment
`outcomes.
`
`R. H. Lander Delgado: Deceased.
`
`T. Ziemssen (&)
`Neurologische Universita¨tsklinik, Klinikum Carl Gustav Carus,
`Fetscherstraße 74, 01307 Dresden, Germany
`e-mail: Tjalf.Ziemssen@uniklinikum-dresden.de
`
`O. A. Bajenaru
`Carol Davila University of Medicine and Pharmacy, Bucharest,
`Romania
`
`A. Carra´
`Hospital Britanico de Buenos Aires, Buenos Aires, Argentina
`
`N. de Klippel
`Virga Jessaziekenhuis, Hasselt, Belgium
`
`J. C. de Sa´
`Hospital de Santa Mari, Hasselt, Belgium
`
`A. Edland
`Central Hospital of Buskerud, Drammen, Norway
`
`J. L. Frederiksen
`Glostrup Hospital, University of Copenhagen, Glostrup,
`Denmark
`
`O. Heinzlef
`Tenon Hospital, Paris, France
`
`K. E. Karageorgiou
`General Hospital of Athens, Athens, Greece
`
`A.-M. Landtblom
`Department of Neurology and Department of Clinical and
`Experimental Medicine, University of Linko¨ping, Linko¨ping,
`Sweden
`
`A.-M. Landtblom
`Department of Medical Specialists and Department of Medicine
`and Health Sciences, Linko¨ping University, Motala, Sweden
`
`M. A. Macı´as Islas
`Central University of Guadalajara, Guadalajara, Jalisco, Mexico
`
`N. Tubridy
`School of Medicine and Medical Science, Dublin University,
`Dublin, Ireland
`
`Y. Gilgun-Sherki
`Teva Pharmaceuticals Industries Ltd, Petach Tikva, Israel
`
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`Keywords Disease-modifying therapy Glatiramer
`acetate Multiple sclerosis RRMS
`
`Introduction
`
`Multiple sclerosis (MS) is a chronic, progressive, autoim-
`mune diffuse inflammatory disease of the central nervous
`system [1]. Historically, the disease and the efficacy of MS
`treatments were measured by the extent to which clinical
`progression was slowed or halted, using relapse rates or the
`progression of disability [2, 3]. However, we now know
`that other considerations must also be taken into account,
`including fatigue, quality of life (QoL), etc. [4]. At least
`30 % of patients show a suboptimal response to first-line
`disease-modifying treatments (DMTs) for relapsing-remit-
`ting multiple sclerosis (RRMS) during the first year of
`treatment [5]. There are no acceptable criteria to guide
`physicians when converting from one first-line DMT to
`another, and such decisions are generally based on the
`physician’s judgment.
`Studies have shown that the three most common reasons
`why physicians in clinical practice convert an MS patient’s
`medication are lack of efficacy or suboptimal response, [5,
`6] intolerable drug-induced adverse events (AEs) [7, 8],
`and the development of neutralizing antibodies [9–11],
`which are known to block the biological activity of inter-
`feron (IFN) and natalizumab therapy [12]. It has been
`suggested that clinical observations such as relapse rate and
`disability or findings of magnetic resonance imaging (MRI)
`may be used to define criteria for converting from one
`DMT to another in clinical practice [12, 13]. One study
`analyzed whether the first relapse and time from the first to
`second relapse would be able to predict treatment failure
`[14]. However, none of these criteria has proved useful in
`determining whether a patient would benefit from a treat-
`ment change.
`Converting therapy within the IFN-b class may not
`always benefit the patient [15]. Patients who present with
`neutralizing antibodies during IFN treatment do not ben-
`efit from converting from one IFN to another or from
`continuous therapy with any subcutaneous IFN-b prepa-
`ration [15]. Conversely, studies have demonstrated that
`there is a clinical benefit in changing either from one
`class of first-line DMT to another or
`to second-line
`treatments [13, 16–18]. With some DMTs (e.g. natal-
`izumab, which is indicated for patients for whom IFN
`therapy has not been effective),
`the use of escalating
`doses has been proven to improve efficacy compared with
`converting to another DMT [19]. However, despite its
`efficacy profile, the safety and tolerability of natalizumab
`are a concern because of the risk of progressive multi-
`focal leukoencephalopathy (PML) [20].
`
`123
`
`The copolymer glatiramer acetate (GA; Copaxone) is
`approved as a 20-mg daily subcutaneous (s.c.) injection for
`reducing relapse frequency in patients with RRMS [21].
`Post-marketing experience with GA includes more than
`1.88 million patient-years of exposure and,
`in some
`patients, more than 20 consecutive years of treatment [22].
`Two prospective open-label studies have shown a benefi-
`cial effect of GA for subjects who did not benefit from
`previous sequential IFN treatment, either because of lack of
`perceived clinical effects or AEs [13, 17]. The COPTIM-
`IZE trial was designed to provide insight into patients’
`outcomes and attitudes toward converting to GA when
`another DMT is ineffective or
`intolerable. This also
`allowed investigators to assess the impact of the mild
`adverse effect profile of GA, which differs in many ways
`from other DMTs, and the positive impact of GA on QoL
`parameters [23–25].
`
`Methods
`
`Study design
`
`COPTIMIZE was a 2-year international, multicenter, pro-
`spective, non-interventional, longitudinal, and observational
`study conducted in 148 study centers across 19 countries.
`Included were patients who had converted from another
`DMT to GA 20 mg daily within 3–6 months of screening.
`An electronic case report form (eCRF) was completed
`by attending neurologists (investigators) to assess the dis-
`ease course and rationale for converting treatment to GA.
`Data were collected by means of standardized eCRF on a
`password-protected website, at baseline and then at
`6-month intervals for a total of five data collection time
`points over 24 months. Baseline assessment
`included
`patients’ demographic characteristics, MS disease history,
`reasons for changing medication, annualized relapse rate
`(ARR) in the 2 years before the conversion, expanded
`disability status scale (EDSS)/mobility score measured
`within 2 years before the conversion and at recruitment,
`MRI data, cognitive functions by Paced Auditory Serial
`Addition Test (PASAT) [26], and impact of fatigue on
`daily activities by Modified Fatigue Impact Scale (MFIS;
`the effects of fatigue on physical, cognitive, and psycho-
`social functioning) [27]. Patients answered 21 questions on
`fatigue severity, with scores ranging from ‘never’ (0) to
`‘highly’ (4), which denotes severe fatigue.
`Assessments at 6-month intervals included relapses
`within the previous 6 months and the EDSS/mobility score;
`the EDSS assessment was performed via the Neurostatus
`e test [28]. Confirmed progression (i.e. worsening of the
`EDSS from baseline to final examination) was defined as
`an increase of one point if the baseline EDSS score was
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`J Neurol (2014) 261:2101–2111
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`
`between 0 and 5, and by an increase of 0.5 points if the
`baseline score was [5.0. Changes in function were asses-
`sed by the Functional Assessment of Multiple Sclerosis
`(FAMS) [29]. Scores on the FAMS range between 0.00 and
`176.00 points, with an increase in score indicating an
`increase in functional abilities. Depression was measured
`by the Center for Epidemiological Studies Depression
`Scale (CES-D) [30]. CES-D scores ranged from 0 to 60
`points, with higher scores indicating more symptoms of
`depression during the past week.
`
`Patients
`
`To be included, patients had to have a diagnosis of RRMS,
`to have converted to GA within 3 months before recruit-
`ment, and to have available ARR and EDSS data acquired
`in the year before inclusion. Patients could have been
`treated with any DMT for up to 6 months before the
`treatment conversion, if the change was due to unverified
`drug inefficacy or AEs.
`Patients were classified based on their individual pre-
`medication: ‘de novo’ patients had not received any phar-
`maceutical MS medication,
`‘converter’ patients had
`received another kind of DMT before recruitment, and
`‘post-chemotherapy’ patients had received chemothera-
`peutic medication before recruitment.
`
`Study endpoints
`
`The primary study endpoint was disease course of subjects
`converted from one DMT class (IFN) to another (GA) as
`measured by ARR before and after the conversion, annu-
`alized rate of deterioration (ARD: rate of deterioration as
`measured by mean EDSS), and mobility score in the year
`before and following the change to GA.
`Secondary endpoints included reasons for changing
`DMT; characteristics of patients failing to benefit from
`previous DMT; QoL changes measured by FAMS follow-
`ing GA conversion; impact of fatigue on daily activities,
`measured by the MFIS; change in rates of depression as
`evaluated by CES-D; and changes in AEs before and after
`the conversion to GA.
`This study was conducted in accordance with the 18th
`World Medical Assembly (Helsinki) recommendations and
`amendments, as well as guidelines for Good Epidemiology
`Practice. Patients’ personal data and investigator data
`included in the sponsor database were treated in compli-
`ance with all local applicable laws and regulations.
`
`Statistical analyses
`
`The intention-to-treat cohort, consisting of all enrolled
`subjects who took at least one dose of GA, was used for all
`
`efficacy and safety assessments. Descriptive procedures
`were used to represent data. Tests of significance (signed
`rank test and binomial test) were used to measure changes
`in efficacy parameters from baseline to final examination.
`Wilcoxon signal rank was used within groups for EDSS,
`MFIS, QoL, CES-D, and PASAT (excluding ARR).
`Kruskal–Wallis was used between groups for EDSS.
`Poisson regression within and between groups was used for
`ARR. ARR and ARD before and after the conversion was
`analyzed using repeated measures analysis of covariance
`using the maximum likelihood ratio. Log transformation
`was implemented to the ARR and ARD to establish if there
`was a significant deviation of ARR and ARD from nor-
`mality (i.e. if p \ 0.001 on the Shapiro–Wilk test).
`
`Results
`
`Patient disposition
`
`A total of 672 patients were enrolled in the study. Data on
`555 patients (82.6 %) were available at 365 days, and data
`on 423 (63.0 %) were available at 730 days. The mean
`duration of observation was 594.7 days [±standard devia-
`tion (SD) = 221.3] in 634 patients who had one or more
`examinations. Table 1 details patient demographics and
`disease characteristics.
`
`Baseline demographics and patient classification
`
`Demographics and disease characteristics are shown in
`Table 1. Of the 672 patients enrolled, 640 (95.2 %) were
`classified as ‘converter’ patients (had received other DMT
`before enrollment), and the efficacy analysis was restricted
`to these patients. Nine (1.3 %) were classified as ‘post-
`chemotherapy’ patients, and 23 patients (3.4 %) were
`missing classification data. In converted patients, a change
`of therapy to GA was prompted primarily by lack of effi-
`cacy (343/640; 53.6 %) or
`intolerable AEs (287/640;
`44.8 %), caused by the corresponding premedication.
`[Note: The number of patients who changed to GA due to a
`lack of efficacy (343) and the number that changed due to
`AEs (287) sums to 630, not 640, as there are multiple
`reasons aside from these two that were cited by patients for
`changing therapy]. In the majority of converted patients
`(553/640; 86.4 %), only a single DMT agent had been used
`before the conversion to GA therapy. Eighty patients
`(12.5 %) had received two DMT agents, and six patients
`(0.9 %) had received three DMT agents before the change
`to GA. One patient (0.2 %) was missing information on
`number of prior DMT treatments received.
`Of the patients converted, documentation on type of
`DMT was available for 617 patients and missing for 23
`
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`J Neurol (2014) 261:2101–2111
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`Table 1 Baseline demographics and disease characteristics
`
`Characteristics
`
`Patients with data Overall
`
`672
`
`672
`
`615
`
`632
`
`625
`
`660
`
`Female gender, n (%)
`
`Mean age, years (SD)
`
`Mean duration of disease since
`onset, mo (SD)
`
`Mean time since MS diagnosis, mo
`(SD)
`
`Median ARR measured over the
`past 2 years before GA (SD)
`
`Distribution of patients by ARR
`range, n (%)
`\1
`C1 and \3
`C3
`
`Clinical type of MS, n (%)
`
`657
`
`RRMS with incomplete
`remissions
`
`RRMS with complete remission
`
`Clinically isolated syndrome
`
`Other
`
`Mean EDSS score measured over
`the past 2 years before GA (SD)
`
`Mean EDSS score at time of
`conversion (SD)
`
`Mobility score, n (%)
`
`878
`
`600
`
`595
`
`Asymptomatic
`Able to walk unaided [500 m
`Able to walk unaided
`for \500 m
`Walking with unilateral support
`
`Walking with bilateral support
`
`Need of wheelchair outdoors
`
`MRI data available, n (%)
`
`672
`
`476 (70.8)
`
`39.9 (10.2)
`
`97.2 (78.9)
`
`69.7 (61.3)
`
`0.86 (0.67)
`
`329 (49.9)
`
`318 (48.2)
`
`13 (2.0)
`
`264 (40.2)
`
`383 (58.3)
`
`1 (0.2)
`
`9 (1.4)
`
`2.8 (1.7)
`
`3.0 (1.9)
`
`111 (18.7)
`
`336 (56.5)
`
`60 (10.1)
`
`51 (8.6)
`
`22 (3.7)
`
`15 (2.5)
`
`193 (41.0)
`
`ARR annualized relapse rate, EDSS Expanded Disability Status Scale,
`GA glatiramer acetate, MRI magnetic resonance imaging, MS multiple
`sclerosis, RRMS relapsing-remitting multiple sclerosis, SD standard
`deviation
`
`patients. Most patients converted (589/617) (95.5 %) had
`received IFN-b before converting (Fig. 1).
`Table 2 details the baseline disease characteristics of
`those patients who were converted because of lack of
`efficacy or because of AEs. The clinical type of disease,
`disease activity over the past 2 years, and the decision to
`convert were significantly different between these two
`groups. A greater proportion of patients who converted
`because of lack of efficacy presented with RRMS with
`incomplete remissions, while most who converted because
`of AEs had RRMS with complete remissions. Exacerba-
`tions tended to be rare in both groups. However, exacer-
`bations of disease were more frequent in those who were
`converted because of lack of efficacy, while stable disease
`
`123
`
`was more prominent in those who were converted because
`of AEs. While, in most cases, the decision to convert was
`made solely by the patient’s physician, a mutual decision
`was more common among the patients who converted
`because of AEs (Table 2). The majority of patients who
`converted because of AEs discontinued IFN therapy
`because of flu-like symptoms [180/287 (62.7 %); Table 3].
`Among the nine patients classified as being ‘post-che-
`motherapy’, the most common reasons for converting were
`worsening of EDSS (n = 7) and severity of relapses
`(n = 4), followed by high lesion load on MRI (n = 2) and
`a high relapse rate (n = 1). Multiple reasons for converting
`could be recorded for a single patient. All nine patients had
`undergone
`escalation
`therapy,
`seven
`had
`received
`mitoxantrone, one had received cyclophosphamide, and
`one cyclophosphamide followed by IFN.
`
`Efficacy of GA
`
`ARR
`
`Data on ARRs before converting to GA and during the study
`were available for 625 patients. The majority of these
`patients [n = 458/625 (73.3 %)] experienced less than 0.25
`relapses/year while receiving GA therapy (Fig. 2). Overall,
`patients experienced a significant reduction in the mean
`number of relapses from baseline while on GA therapy from
`0.86 to 0.32 (mean change -0.54; p \ 0.0001 Chi squared;
`Fig. 3). Reductions in ARR from baseline were significant
`regardless of whether patients converted because of lack of
`efficacy or AEs (mean change -0.66 and -0.36, respec-
`tively; p \ 0.0001 in both groups; Fig. 3). However, the
`decrease in ARR was significantly greater in patients con-
`verting for lack of efficacy versus AEs (p = 0.0021).
`
`Confirmed EDSS change
`
`Data on 399 patients with at least one confirmed EDSS pro-
`gression after baseline examination were evaluated. The
`proportion of patients without confirmed progression (343/
`399 patients, 86.0 %) was significantly higher than with
`confirmed progression (56/399 patients; 14.0 %; p \ 0.0001,
`binominal-test with H0 proportion = 50 %). When analyzed
`by reason for conversion only, patients who converted
`because of intolerable AEs had a significant increase in EDSS
`from baseline (?0.17; p = 0.0265, Fig. 4a) but there was no
`significant difference between the values in the two groups.
`
`Mobility score
`
`A total of 542 patients had at least one mobility score after
`the baseline examination. The majority of patients
`(n = 348; 64.2 %) did not experience any worsening in
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`2105
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`36.5
`
`30.3
`
`28.7
`
`2.1
`
`1.8
`
`0.7
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Previously Recieved DMT, %
`Proportion of Patients who
`
`J Neurol (2014) 261:2101–2111
`
`Fig. 1 Type of disease-
`modifying therapy used by
`patients before converting to
`glatiramer acetate in patients
`with previous type known
`(n = 617). IFN interferon, i.m
`intramuscular, i.v. intravenous,
`s.c subcutaneous
`
`Table 2 Disease characteristics of patients converted to glatiramer
`acetate because of lack of efficacy or adverse events (n = 630)
`
`Characteristics
`
`Lack of
`efficacy
`(n = 343)
`
`Adverse
`events
`(n = 287)
`
`p value
`
`Clinical disease type over the past 2 years, %
`
`\0.0001
`
`significantly from baseline to final examination, with a
`difference of -3.59 points ±15.05, p \ 0.0001; Table 4.
`The reduction in fatigue was greater in patients who con-
`verted because of lack of efficacy (-6.01 points from
`baseline; p = 0.0006), compared with those who converted
`because of AEs (-2.16 points; p = NS; Fig. 4b).
`
`RRMS with complete
`remissions
`
`RRMS with incomplete
`remissions
`
`Other
`
`30.1
`
`67.5
`
`2.4
`
`Activity of disease over the past 2 years, %
`
`Stable MS
`Exacerbations rare (\1
`relapse/year)
`Slow progression (\ 1
`point increase in EDSS in
`the last year)
`
`Frequent exacerbations (C1
`relapse/year)
`
`Fast progression (C1 point
`increase in EDSS in the
`last year)
`
`8.9
`
`35.9
`
`16.1
`
`31.5
`
`3.2
`
`Could not be classified
`
`4.4
`
`Decision to convert therapy made by, %
`
`Physician
`
`Patient
`
`Both
`
`86.2
`
`2.8
`
`10.9
`
`50.3
`
`49.3
`
`0.5
`
`23.7
`
`47.3
`
`9.4
`
`16.3
`
`1.0
`
`2.5
`
`59.9
`
`7.4
`
`32.7
`
`\0.0001
`
`\0.0001
`
`EDSS Expanded Disability Status Scale, MS multiple sclerosis, RRMS
`relapsing remitting MS
`
`mobility A total of 103 (19.0 %) patients reported better
`mobility, while 91 (16.8 %) reported worse mobility. The
`difference in the numbers of patients showing improve-
`ment or worsening was not significant by binominal test
`with H0 proportion = 50 % (p = NS).
`
`Impact on fatigue
`
`Data on 287 patients with MFIS scores were available for
`evaluation. Overall, mean MFIS scores
`decreased
`
`Change in QoL
`
`A total of 218 patients had available QoL data at baseline
`and at the final examination.
`in QoL score of 5.94
`A significant
`improvement
`(±31.57; p = 0.0227) from baseline to final examination
`was reported (Table 4). QoL improved regardless of the
`reasons for treatment conversion. Greater improvement
`was observed in patients who converted because of AEs
`(?10.81 points from baseline; p = 0.0120), compared with
`those who converted because of lack of efficacy (?6.62
`points; p = NS; Fig. 4c).
`
`Depression
`
`Data on 299 patients were available for evaluation. There
`was a significant improvement overall in the depression
`score following the conversion to GA therapy (-
`1.50 ± 10.84 from baseline; Table 4). Improvement was
`most commonly observed in patients who were converted
`because of lack of efficacy (-4.48 points from baseline;
`p \ 0.0001). No improvement was reported in those who
`converted because of AEs (?0.58 points; p = NS; Fig. 4d).
`
`Cognition changes
`
`In the 72 patients for whom cognition (PASAT) data were
`available, scores improved by a mean of 4.29 ± 9.28
`(p \ 0.0001; Table 4).
`Improvement
`in cognition was
`observed in patients who converted because of AEs (?3.26
`points from baseline; p = 0.0088), as well as in those who
`converted because of lack of efficacy (?4.33 points from
`
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`Table 3 Reasons for
`discontinuing interferon
`treatment before study entry
`among patients converted to
`glatiramer acetate because of
`intolerable adverse events
`(n = 287)
`
`Patients responded with up to
`three possible reasons
`
`Reason
`
`Flu–like
`symptoms
`
`Subjective
`
`Skin reactions
`
`Blood work
`
`Others
`
`Not specified
`
`Patients,
`n (%)
`
`180 (62.7)
`
`83 (28.9)
`
`51 (17.8)
`
`29 (10.1)
`
`64 (22.3)
`
`2 (0.7)
`
`baseline; p = NS; Fig. 4e). Both baseline and final scores
`were notably higher in the group that converted because of
`AEs (Fig. 4e).
`
`Patient reporting of efficacy
`
`Among the 660 patients with available data, only 49
`patients (7.4 %; p \ 0.0001)
`reported that GA was
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`J Neurol (2014) 261:2101–2111
`
`less effective than their previous DMT, while signif-
`icantly more patients [348 (52.7 %)] reported that GA
`treatment was more effective than their previous
`DMT,
`and
`263
`patients
`(39.9 %)
`reported
`no
`difference.
`
`Safety and tolerability
`
`A total of 196 AEs occurred in 104 patients [15.5 % of
`all patients (n = 672)], with the majority of events
`deemed probably [104 events in 56 patients (8.3 %)] or
`possibly related to GA therapy [45 events in 26 patients
`(3.8 %)]. Most common AEs by preferred term and sys-
`tem organ class are shown in Table 5 in addition to AEs
`by severity reported. 174 of all 672 patients (25.9 %)
`terminated GA treatment during the observation period.
`Table 6 details the physician- and patient-reported reasons
`for termination.
`
`Pre-conversion
`
`Post-conversion
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
` Within ARR Quartile, %
`Adjusted Percent of Patients
`
`Fig. 2 Distribution of
`annualized relapse rates (ARRs)
`before and during glatiramer
`acetate therapy (n = 625).
`Patients with a very high
`annualized relapse rate
`terminated glatiramer acetate
`treatment after a short period of
`observation because of relapses
`
`ARR Quartile
`
`1.02
`
`0.86
`
`0.69
`
`0.32
`
`0.36
`
`0.33
`
`Baseline
`
`Final Follow-up
`
`Overall (n=625)*
`
`Lack of efficacy (n=343)
`
`Adverse events (n=287)
`
`1.5
`
`1.3
`
`1.1
`
`0.9
`
`0.7
`
`0.5
`
`0.3
`
`0.1
`
`-0.1
`
`ARR, relapses/year
`
`Fig. 3 Change in annualized relapse rate (ARR) in all patients
`receiving glatiramer acetate (GA) therapy (n = 625) and in patients
`with known reason for the conversion to GA (Asterisk denotes that the
`overall number of patients with ARR data does not equal the sum of
`
`the number of patients who converted to GA due to lack of efficacy
`and adverse events because of double counting of patients who
`reported both reasons for converting). All reductions in ARR within
`groups were statistically significant (p \ 0.0001)
`
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`
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`

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`J Neurol (2014) 261:2101–2111
`
`2107
`
`32.89
`30.45
`
`P=0.0006
`
`28.29
`26.88
`
`Lack of efficacy
`
`Adverse events
`
`Baseline
`
`Examination
`
`Final
`
`40
`
`35
`
`30
`
`25
`
`20
`
`15
`
`10
`
`05
`
`b
`
`Fatigue score
`
`d
`
`25
`
`20
`
`3.47
`
`2.30
`
`3.45
`
`2.47
`
`P=0.0265
`
`Lack of efficacy
`
`Adverse events
`
`Baseline
`
`Examination
`
`Final
`
`108.79
`102.32
`
`P=0.0120
`
`115.41
`113.13
`
`5.0a
`
`4.5
`
`4.0
`
`3.5
`
`3.0
`
`2.5
`
`2.0
`
`1.5
`
`1.0
`
`0.5
`
`0.0
`
`EDSS Score
`
`c
`
`140
`
`120
`
`100
`
`17.87
`16.56
`
`P<0.0001
`
`17.14
`
`13.39
`
`P=0.0022
`
`Lack of efficacy
`
`Adverse events
`
`Baseline
`
`Examination
`
`Final
`
`15
`
`10
`
`5
`
`0
`
`Depression score
`
`Lack of efficacy
`
`Adverse events
`
`Baseline
`
`Examination
`
`Final
`
`40.35
`
`30.39
`
`P=0.0088
`
`43.61
`
`34.72
`
`Lack of efficacy
`
`Adverse events
`
`Baseline
`
`Final
`
`Examination
`
`80
`
`60
`
`40
`
`20
`
`0
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Quality of life score
`
`e
`
`Cognition score
`
`Fig. 4 a Change in Expanded Disability Status Scale (EDSS) score
`in patients converted to glatiramer acetate, by the reason for the
`conversion. b Change in fatigue score (Modified Fatigue Impact
`Scale) in patients converted to glatiramer acetate, by the reason for
`the conversion. c Change in quality of
`life score (Functional
`Assessment of Multiple Sclerosis) in patients converted to glatiramer
`
`acetate, by the reason for the conversion. d Change in depression
`score (Center for Epidemiological Studies Depression Scale) in
`patients converted to glatiramer acetate, by the reason for the
`conversion. e Change in cognition score (paced auditory serial
`addition test) in converting patients by the reason for the conversion
`
`Discussion
`
`It is reported that patients with RRMS frequently convert
`DMT because their original
`therapy is not optimally
`effective or produces intolerable AEs [6, 7, 9, 12, 17–19];
`those were the main reasons for converting to GA therapy
`in this study. Depending on the reasons for converting, lack
`of efficacy or adverse reactions, patients may have a
`greater or lesser response to the new agent.
`ARR is an important indication of the inflammatory
`component of MS. In the COPTIMIZE study, ARR
`
`was significantly reduced from baseline after convert-
`ing to GA, both in patients who converted because of
`lack of efficacy and those who converted because of
`AEs.
`No significant changes in EDSS scores were observed in
`patients who were converted to GA therapy. However, it is
`important to note that following the conversion to GA, a
`greater proportion of patients had no confirmed progres-
`sion, as measured by the EDSS; only modest changes in
`EDSS scores from baseline were observed. Subgroup
`analysis revealed EDSS scores to be higher at both baseline
`
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`J Neurol (2014) 261:2101–2111
`
`Table 4 Change in secondary efficacy endpoints from baseline to final observation of all patients irrespective of previous treatment or reason for
`conversion
`
`Scale, mean (95 % CI)
`
`Patients with data (n)
`
`Baseline
`
`Final
`
`Fatigue, MFIS
`
`Quality of life, FAMS
`
`Depression, CES-D
`
`Cognition, PASAT
`
`287
`
`218
`
`299
`
`72
`
`31.94 (29.67–34.22)
`
`28.36 (26.00–30.72)
`
`102.67 (97.78–107.57)
`
`108.61 (103.43–113.80)
`
`16.13 (14.85–17.40)
`
`37.46 (33.93–40.99)
`
`14.63 (13.38–15.88)
`
`41.75 (37.79–45.71)
`
`p value
`
`\0.0001
`0.0227
`
`0.0111
`\0.0001
`
`CES-D Center for Epidemiological Studies Depression Scale, CI confidence interval, FAMS Functional Assessment of Multiple Sclerosis, MFIS
`Modified Fatigue Impact Scale, PASAT paced auditory serial addition test
`
`and final examination among those converted because of
`lack of efficacy rather than AEs.
`As our understanding of MS improves, it has become
`clearer that symptoms beyond disability scores, such as
`EDSS, are important [23]. For example, fatigue in MS has
`been correlated not only with neurodegenerative processes
`that cause functional reorganization resulting in increased
`metabolic demands [31, 32], but also, recently, with dis-
`turbance in central neuronal pathways [33]. Interestingly,
`in one study, patient-reported fatigue was observed to
`significantly improve after converting to GA, consistent
`with previous reports of increased improvement of fatigue
`symptoms with GA use [26, 34]. Similarly, cognition,
`correlating with cortical atrophy in MS patients [35],
`improved significantly from baseline after converting to
`GA. Cognitive symptoms in MS have been associated with
`cortical atrophy [35], but it is important to remember that
`such symptoms in many patients can vary over time and be
`a result of fatigue. Of course, patients who improve after
`switching from IFN to GA may do so because they no
`longer experience the typical flu-like side effects that
`increase fatigue. Patients also improved significantly on
`measures of QoL and depression, while mobility scores
`remained stable. Improvements in QoL were more pro-
`nounced in those who converted because of AEs versus
`lack of efficacy, which is consistent with intolerable AEs,
`which significantly impact QoL, being eliminated or
`reduced after conversion to GA.
`Depression scores significantly improved during GA
`treatment in patients who converted due to lack of efficacy,
`but were unchanged in those who converted because of
`AEs. Improved scores in patients previously experiencing a
`lack of efficacy may have been due to a heightened con-
`fidence in the ability of their new regimen to slow disease
`progression.
`Taken together, the decrease in ARR and lack of EDSS
`progression observed in patients who converted to GA
`therapy represent
`significant
`real-world improvements
`attained by RRMS patients whose disease was not ade-
`quately controlled by their previous DMT. This is an
`important finding, because it points to the ability of GA to
`
`123
`
`modify patient progression on a real-world level, as mea-
`sured by clinical relapses and other patient-reported out-
`comes, including fatigue and depression.
`Of the 672 patients included in the study, AEs occurred
`in 15.5 % of patients. These AEs were mainly attributable
`to injection-site reactions or pain. Because neurodegener-
`ative activity is observed in MS patients even in early
`stages of the disease [36], it is important to establish rig-
`orous algorithms to optimize treatment in those responding
`sub-optimally to their original
`therapy. Should mono-
`therapy not prove optimal, combining a DMT with another
`treatment could provide an additive effect to control dis-
`ease progression [37].
`This observational study reflects both the limitations and
`advantages inherent in such a study design. Regression to
`the mean has been shown to be a common occurrence in
`longitudinal studies of MS patients with high levels of
`disease activity and may present a limitation in the present
`study given that there is no comparison to a matched
`control cohort [38]. This phenomenon would suggest that
`patients switching to GA as a consequence of the limited
`efficacy of prior therapy will tend to return to the average
`disease state over time, potentially accounting for reduc-
`tions in the ARR rate. Other
`limitations include the
`potential for information or classification bias [39]. How-
`ever, well-designed observational studies with appropriate
`statistical techniques provide valuable information, with
`high generalizability. Further, the overall sample size was
`relatively small, and sample sizes were not consistent
`throughout the different assessments (i.e. the same number
`of patients may not have been examined for fatigue as for
`cognition, etc.). Thus,
`it was not possible to pool
`the
`patients across all parameters. Further, because of the
`observational nature of this study, there was a fairly high
`dropout rate and considerable variability in the availability
`of patient data for different endpoints. However,
`the
`dropout rate included not only patients who left the study
`but also patients who had to be excluded from the study
`because of missing data from the participating sites. Nev-
`ertheless, the results of observational studies can be used to
`demonstrate
`real-world clinical outcomes,
`including
`
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`2109
`
`Table 5 Most frequently reported adverse events by preferred term
`and by system organ class (n = 672)
`
`Table 5 continued
`
`Adverse events
`
`Adverse events
`
`Patients,
`n (%)
`
`Number of
`events
`
`Patients,
`n (%)
`
`Number of
`events
`
`Total reported adverse events
`
`104 (15.5)
`
`196
`
`By system organ class (frequency of cases C3)
`
`General disorders and administration
`site conditions
`
`50 (7.4)
`
`78
`
`Nervous system disorders
`
`19 (2.8)
`
`Skin and subcutaneous tissue disorders
`
`18 (2.7)
`
`Psychiatric disorders
`
`Respiratory, thoracic and me