`
`BioMed Central
`
`Open Access
`Research
`Effects of glatiramer acetate on fatigue and days of absence from
`work in first-time treated relapsing-remitting multiple sclerosis
`Tjalf Ziemssen*1, Josef Hoffman2, Rainer Apfel2 and Simone Kern1
`
`Address: 1MS Center, Neurological University Clinic, Technical University of Dresden, Dresden, Germany and 2TEVA Germany, Mörfelden,
`Germany
`
`Email: Tjalf Ziemssen* - Tjalf.Ziemssen@uniklinikum-dresden.de; Josef Hoffman - Josef.Hoffmann@teva.de;
`Rainer Apfel - Rainer.Apfel@teva.de; Simone Kern - Simone.Kern@uniklinikum-dresden.de
`* Corresponding author
`
`Published: 5 September 2008
`
`Health and Quality of Life Outcomes 2008, 6:67
`
`doi:10.1186/1477-7525-6-67
`
`This article is available from: http://www.hqlo.com/content/6/1/67
`
`Received: 16 May 2008
`Accepted: 5 September 2008
`
`© 2008 Ziemssen et al; licensee BioMed Central Ltd.
`This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
`which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
`
`Abstract
`Objectives: Treatment of multiple sclerosis patients with glatiramer acetate has been
`demonstrated a beneficial effect on disease activity. The objective of this prospective naturalistic
`study was to evaluate the impact of glatiramer acetate on fatigue and work absenteeism.
`Methods: 291 treatment-naïve patients with relapsing remitting multiple sclerosis were included
`and treated with glatiramer acetate for twelve months. Relapse rates, disability, fatigue symptoms,
`days of absence from work and adverse events were monitored. Fatigue was measured with the
`MFIS scale and with a visual analogue scale.
`Results: Total MFIS scores decreased by 7.6 ± 16.4 from 34.6 to 27.0 (p ≤ 0.001). Significant
`reductions were observed on all three subscales of the MFIS. Fatigue symptoms, assessed using a
`visual analogue scale, decreased by 1.04 ± 2.88 cm from 4.47 cm to 3.43 cm (p ≤ 0.001). The
`proportion of patients absent from work at least once was reduced by a factor of two from 65.1%
`to 30.1% (p ≤ 0.001). Tolerance to treatment was rated as very good or good in 78.3% of patients.
`Adverse effects, most frequently local injection site reactions, were reported in 15.1% of patients.
`Conclusion: Treatment with glatiramer acetate was associated with a significant improvement in
`fatigue symptoms and a marked reduction in absence from work. Treatment was well-tolerated.
`Such benefits are of relevance to overall patient well-being.
`
`Introduction
`Fatigue is a common symptom of multiple sclerosis [1-5],
`reported by around three-quarters of affected patients [3],
`and considered one of the most distressing symptoms of
`disease by over half [2]. Many patients experience debili-
`tating fatigue every day [2]. In multiple sclerosis, fatigue
`has a major detrimental impact on quality of life [6-8], is
`frequently associated with depression [9,10] and is a lead-
`ing cause of absence from work or impaired work per-
`
`formance [6,11,12]. The pathophysiology of fatigue in
`multiple sclerosis is poorly understood, but is likely to be
`multifactorial [13-16]
`
`Treatment of fatigue in multiple sclerosis is thus a major
`challenge, which cannot be adequately achieved at the
`present time. Both non-pharmacological and pharmaco-
`logical interventions have been proposed for the manage-
`ment of fatigue in multiple sclerosis patients [15,17],
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`although the benefits of drugs such as modafenil and
`amantadine have not been demonstrated unequivocally
`[18-20].
`
`Immunomodulatory treatments for relapsing-remitting
`multiple sclerosis, namely glatiramer acetate and the β-
`interferons, provide a marked reduction in relapse rates
`and in MRI markers of disease activity [21]. It is therefore
`of interest to explore whether such treatments might influ-
`ence fatigue symptoms as well. A retrospective chart
`review of 218 Canadian patients receiving an immu-
`nomodulatory treatment during the late 1990s revealed
`that fatigue improved over the six months following treat-
`ment initiation [22]. Of particular interest was the obser-
`vation that a significantly higher proportion of glatiramer
`acetate treated patients than β-interferon-treated patients
`improved by at least one standard deviation of the Fatigue
`Impact Scale (FIS).
`
`In order to investigate further the potential impact of
`immunomodulatory treatment on fatigue in multiple
`sclerosis, we initiated a prospective, observational, non-
`interventional study to monitor fatigue in treatment-naive
`RRMS patients initiating therapy with glatiramer acetate
`under conditions of daily practice. The primary objective
`of study was to determine the impact of initiating treat-
`ment with glatiramer acetate on fatigue and absenteeism.
`Secondary objectives were to evaluate the effect of treat-
`ment on clinical and MRI outcomes and to determine the
`tolerability of treatment.
`
`Methods
`This study was a prospective, observational, non-interven-
`tional study of patients with relapsing remitting multiple
`sclerosis treated with glatiramer acetate conducted in Ger-
`many. 130 ambulatory and hospital neurologists partici-
`pated in the study. The study was performed between
`November 2002 and October 2004.
`
`Patients
`The study included patients with a diagnosis of relapsing-
`remitting multiple sclerosis by the McDonald criteria [23]
`who had not previously been treated with an immu-
`nomodulatory treatment and in whom the investigator
`had decided to initiate therapy with glatiramer acetate.
`Patients were followed for twelve months following treat-
`ment initiation.
`
`Clinical assessment
`Patients were evaluated at inclusion and after 3, 6, 9 and
`12 months of treatment. At each visit, patients underwent
`a full neurological assessment, any relapses occurring
`since the previous visit were ascertained and disability
`assessed with the Expanded Disability Status Scale (EDSS)
`[24]. Fatigue was assessed by the patient using a visual
`
`analogue scale scored from 0 (no fatigue) to 10 (maxi-
`mum possible fatigue) and with the Modified Fatigue
`Impact Scale (MFIS) [25] in its validated German transla-
`tion. This is a 21-item questionnaire which yields a total
`score ranging from 0 (no impact of fatigue) to 84 points
`(maximum impact of fatigue), as well as three subscales
`representing the physical (score range 0 to 36), cognitive
`(score range 0 to 40) and psychosocial (score range 0 to 8)
`dimensions of fatigue.
`
`Patients were questioned about any time spent off work
`due to their multiple sclerosis. Due to the study protocol,
`the reasons for work absentism (relapse, fatigue) could
`not be differentiated. Any adverse events occurring since
`the previous visit were recorded.
`
`Statistical analysis
`Number of work days lost and fatigue scores over the
`course of the study were evaluated with the Wilcoxon rank
`test. All comparisons were two-tailed and a p value of <
`0.05 was taken as being statistically significant.
`
`Ethics
`This study was conducted according to the Declaration of
`Helsinki (Hong Kong Amendment) and pertinent
`national legal and regulatory requirements. Each patient
`provided written, informed consent and was free to with-
`draw from the study at any time for any reason without
`consequences on the care provided.
`
`Results
`Study sample
`A total of 338 patients were included in the study. Of
`these, 53 were excluded from the analysis due to a proto-
`col violation (24 patients treated previously with an
`immunomodulatory therapy and 29 patients for whom
`certain data were recorded retrospectively) and 47 failed
`to provide complete questionnaire data. The study popu-
`lation thus consisted of 291 subjects (86.1% of included
`patients).
`
`The baseline demographic and disease variables of the
`study subjects are presented in Table 1. At inclusion, their
`median age was 36.9 years and 74.9% were female. The
`median time since diagnosis was 4.31 years. In the year
`preceding inclusion, patients had experienced a mean of
`1.71 relapses (retrospectively assessed) and their mean
`EDSS score at inclusion was 2.58. Forty patients (13.7%)
`discontinued treatment during the course of the study,
`principally due to the occurrence of an adverse event (six-
`teen patients).
`
`Clinical outcome
`Clinical outcome at the end of the study are presented in
`Table 2. Information on relapses was missing for 24
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`Table 1: Demographic and clinical characteristics of patients at
`inclusion
`
`in fifteen patients (5.2%) and a sustained increase of > 1
`point in three patients (1%).
`
`Age (mean ± SD; years)
`
`36.9 ± 9.3
`
`Population (N = 291)
`
`Gender
`Women
`Men
`Missing data
`
`218 (74.9%)
`67 (23.0%)
`6 (2.1%)
`
`Time since diagnosis (mean ± SD; years)
`
`4.31 ± 5.47
`
`ARR since diagnosis (mean ± SD)
`No relapses
`Up to 2 relapses
`3–5 relapses
`More than 5 relapses
`
`3.82 ± 3.54
`14 (4.8%)
`111 (38.1%)
`100 (34.4%)
`57 (19.6%)
`
`ARR within previous 12 months (mean ± SD)
`
`1.71 ± 0.88
`
`EDSS at treatment initiation (mean ± SD)
`EDSS 0–2
`EDSS 3–5
`EDSS 6–7
`Missing data
`
`2.58 ± 1.44
`127 (43.6%)
`121 (41.6%)
`16 (5.5%)
`27 (9.3%)
`
`ARR: annualised relapse rate: EDSS: Expanded Disability Status Scale;
`SD: standard deviation.
`
`patients. Of the remaining 267 patients, 61 (22.8%) expe-
`rienced a single relapse during the twelve-month study
`period and 23 patients (8.6%) more than one relapse. The
`mean annual relapse rate during the year of treatment
`with glatiramer acetate was 0.46. The mean EDSS score at
`the end of the study was 2.45, representing a mean
`decrease from baseline of 0.55 points. The change in EDSS
`score between baseline and twelve months was statisti-
`cally significant (p < 0.05; Wilcoxon rank test). A sus-
`tained reduction in EDSS score of > 1 point was observed
`
`Table 2: Clinical outcome
`
`Relapses during study (n = 267)
`No relapse
`1 relapse
`2 relapses
`3 relapses
`4–5 relapses
`
`Mean EDSS scores (n = 235)
`Baseline
`Study end
`Change from baseline
`
`Population (N = 291)
`
`180 (67.4%)
`61 (22.8%)
`12 (4.5%)
`8 (3.0%)
`3 (1.1%)
`
`2.58 ± 1.45
`2.45 ± 1.52
`-0.13 ± 0.73*
`
`Data are presented as number of patients (%) for relapses and as
`mean ± SD for Expanded Disability Status Scale (EDSS) scores. The
`asterisk indicates a significant change from baseline (p < 0.05;
`Wilcoxon signed rank test).
`
`Fatigue
`Overall, 220 patients provided exploitable data from the
`MFIS questionnaire at both inclusion and study end.
`Measures were compared between the three-month
`period before inclusion and the last three months of the
`treatment period. Significant decreases were observed in
`the total score as well as in all three dimension scores of
`the MFIS (Table 3). Similarly, the VAS rating of fatigue was
`reduced by around one quarter following initiation of
`treatment with glatiramer acetate (Table 3), between base-
`line and study end
`
`Work absenteeism
`The number of days missed from work due to multiple
`sclerosis was evaluated in the patients who were in
`employment (72.9% of the study population). In the
`three month period preceding inclusion, 138 patients
`(65.1%) had taken at least one day off work (Tables 4 and
`5). This number decreased to 64 patients (30.1%) in the
`year following initiation of treatment with glatiramer ace-
`tate. The number of days lost was significantly lower in
`the second year (p ≤ 0.001; Wilcoxon rank test).
`
`Safety
`Safety was assessed in all 338 included patients. Overall,
`51 patients (15.1%) experienced at least one adverse event
`during the treatment period. These were most frequently
`injection site reactions or symptoms of a systemic imme-
`diate post-injection reaction such as dyspnoea or tachy-
`cardia. No single event was reported in more than ten
`patients. The immediate post-injection reaction was clas-
`sified as serious in one patient.
`
`Discussion
`In this study, immunomodulatory treatment of relapsing-
`remitting multiple sclerosis with glatiramer acetate was
`associated with a reduction in subjective perceptions of
`fatigue and with the numbers of days taken off work due
`to illness. We observed a reduction of approximately one-
`quarter in both MFIS scores and in a VAS measure of
`fatigue. These findings are consistent with an earlier retro-
`spective study, which also reported an improvement in
`fatigue measured with the FIS following initiation of glat-
`iramer acetate treatment in 24.8% of patients [22]. The
`two studies cannot, however, be directly compared due
`differences in methodology.
`
`The amelioration observed following treatment with glat-
`iramer acetate may be a non-specific consequence of
`improved overall disease status in treated patients or alter-
`natively result from a specific action of the medication on
`the pathophysiology of multiple sclerosis fatigue. For
`
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`Table 3: Fatigue ratings.
`
`Baseline
`
`On treatment
`
`Mean Change
`
`p
`
`MFIS Total score (n = 220)
`Physical dimension score
`Cognitive dimension score
`Psycho-social dimension score
`
`34.6 ± 18.7
`17.6 ± 9.1
`13.9 ± 9.2
`3.1 ± 2.1
`
`27.0 ± 18.6
`13.5 ± 9.0
`11.2 ± 8.6
`2.4 ± 2.0
`
`-7.6 ± 16.4
`-4.1 ± 8.1
`2.7 ± 8.0
`-0.7 ± 2.0
`
`VAS score (n = 198)
`
`4.47 ± 2.53
`
`3.43 ± 2.55
`
`-1.04 ± 2.88
`
`p ≤ 0.001
`p ≤ 0.001
`p ≤ 0.001
`p ≤ 0.001
`
`p ≤ 0.001
`
`Fatigue over three months was measured with the Modified Fatigue Impact Scale (MFIS) and with a visual analogue scale (VAS). Data are presented
`as mean ± SD for those patients providing exploitable data both at inclusion and at study end. Probabilities were calculated with the Wilcoxon rank
`test.
`
`example, it has been suggested that fatigue may be aggra-
`vated by the production of high levels of pro-inflamma-
`tory cytokines [26,27]. The ability of glatiramer acetate to
`attenuate the secretion and activity of these cytokines
`within the central nervous system [28,29] may provide
`such a specific mechanism. Others have proposed, on the
`basis of magnetic resonance spectroscopy (MRS) findings,
`that fatigue may be associated with axonal injury in the
`cortex rather than inflammatory white matter lesions per
`se [30]. In a recent trial, Tedeschi et al. could demonstrate
`that among MS patients with low disability those with
`high-fatigue show higher white and gray matter atrophy
`and higher lesion load. They suggest that in MS, inde-
`pendent of disability, white and gray matter atrophy is a
`risk factor to have fatigue [31]. In additon, a recent trial of
`Rocca et al. using functional imaging in MS patients with
`fatigue and interferon beta-1a treatment pointed out that
`an abnormal recruitment of the fronto-thalamic circuitry
`is associated with interferon-induced fatigue in MS
`patients [32]. In contrast to the interferon's, the specific
`action of glatiramer acetate to improve MRS markers of
`axonal injury in multiple sclerosis might contribute to a
`reduction in fatigue [33,34].
`
`We also observed a dramatic reduction of over fifty per-
`cent in the number of patients who needed to take time
`off work due to their multiple sclerosis. This is consistent
`with findings from an American study, which also
`
`Table 4: Number of days missing from work in the previous year
`at baseline and one year after start of treatment.
`
`Baseline
`
`After 12 Months
`
`N
`
`76
`26
`39
`32
`50
`68
`0
`
`%
`
`26.1%
`8.9%
`13.4%
`11.0%
`17.2%
`23.4%
`0%
`
`N
`
`148
`27
`14
`8
`18
`62
`14
`
`%
`
`50.9%
`9.3%
`4.8%
`2.8%
`6.2%
`21.3%
`4.8%
`
`No
`≤ 5 days
`6–10 days
`11–20 days
`> 20 days
`Not in employment
`Missing information
`
`reported a marked decrease in days off work in patients
`treated with glatiramer acetate [35], but less so with beta-
`interferons. This is an important functional effect of treat-
`ment since the ability to hold down a job satisfactorily is
`critical for self-esteem and because, in certain countries
`such as the USA, remaining in full-time employment is an
`important determinant of obtaining insurance for reim-
`bursement of treatment costs.
`
`Again, the impact of glatiramer acetate on time off work
`may be an indirect consequence of reduced relapse fre-
`quency, although the data from the US study showing a
`differential effect on time off work between glatiramer
`acetate and β-interferons would argue against this. Alter-
`natively, the observed effect may be secondary to a reduc-
`tion in fatigue, which has been identified in other studies
`to be a major reason why patients with multiple sclerosis
`need to take time off work [11,12]. Finally, it should be
`noted that the low incidence of debilitating side-effects
`reported with glatiramer acetate [36] means that patients
`are unlikely to need to take time off work due to treatment
`side-effects.
`
`The strength of this study include the naturalistic design,
`which means that the findings can probably be general-
`ised to standard care, at least in Europe, with confidence,
`the prospective nature of the data collection and the rela-
`tively large numbers of patients evaluated. Limitations
`include the absence of a comparator group against which
`the magnitude of the observed treatment effects could be
`assessed, and data collection during physician consulta-
`tions rather than with patients' diaries, which may have
`introduced some degree of anamnestic error into the find-
`ings. The absence of a control group might overestimate
`the improvement in fatigue symptoms. As a placebo
`group is probably not ethical it will be further of interest
`to compare prospectively the benefit on fatigue in a group
`of naive MS patients treated with GA vs. a group treated
`with IFN-beta in a next study.
`
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`Table 5: Development of the different groups at baseline (No work absentism, less than 5 days,...) one year after start of treatment
`with glatiramer acetate using the same categories (No work absentism, less than 5 days,...).
`
`Baseline
`
`No work absentism ≤ 5 days absent
`
`6–10 days absent
`
`11–20 days absent
`
`> 20 days absent Not in employment
`
`After 12 Months
`
`No work absentism
`≤ 5 days absent
`6–10 days absent
`11–20 days absent
`> 20 days absent
`Not in employment
`
`N
`
`59
`6
`4
`2
`0
`3
`
`%
`
`21.3%
`2.2%
`1.4%
`0.7%
`0%
`1.1%
`
`N
`
`15
`8
`1
`2
`0
`0
`
`%
`
`5.4%
`2.9%
`0.4%
`0.7%
`0%
`0%
`
`N
`
`20
`8
`3
`1
`3
`2
`
`%
`
`7.2%
`2.9%
`1.1%
`0.4%
`1.1%
`0.7%
`
`N
`
`23
`1
`2
`2
`1
`1
`
`%
`
`8.3%
`0.4%
`0.7%
`0.7%
`0.4%
`0.4%
`
`N
`
`22
`4
`4
`1
`13
`4
`
`%
`
`7.9%
`1.4%
`1.4%
`0.4%
`4.7%
`1.4%
`
`N
`
`9
`0
`0
`0
`1
`52
`
`%
`
`3.3%
`0%
`0%
`0%
`0.4%
`18.8%
`
`Conclusion
`In conclusion, this non-interventional prospective study
`demonstrated that treatment with glatiramer acetate was
`associated with a reduction in patient-reported fatigue rat-
`ings and in days missing from work, concomitant with an
`improvement in clinical manifestations of disease activity.
`These functional outcomes are of critical importance for
`overall patient well-being.
`
`Competing interests
`JH and RA are employed by TEVA Germany. TZ has
`received honoraria and financial compensation by Bayer
`Healthcare, Biogen Idec, Merck Serono, Pfizer, Sanofi-
`Aventis and Teva. SK has received honoraria and financial
`compensation by Bayer Healthcare, Biogen Idec, Sanofi-
`Aventis and Teva. Research Projects of TZ and SK were
`funded by the Roland-Ernst-Foundation, Robert-Pfleger-
`Foundation, Sanofi-Aventis/TEVA and Bayer Healthcare.
`In the MS center Dresden, clinical studies are performed
`for Bayer Healthcare, Biogen Idec, BioMS, Genzyme,
`Glaxo Smith Kline, Sanofi-Aventis and Teva.
`
`Authors' contributions
`RA, JH and TZ were responsible for the conception of the
`study. TZ drafted the article. All authors contributed to the
`interpretation of the results and revising the article for
`important intellectual content. All authors read and
`approved the final manuscript.
`
`Acknowledgements
`This was an investigator-driven, only observational study supported by an
`unrestricted grant by TEVA Germany, purveyors of glatiramer acetate. The
`unrestricted grant was spent for the production of the study material, dis-
`tribution, compensation of the subinvestigator, collecting the data by a clin-
`ical research associate and statistical analysis. TZ and SK received no
`financial compensation for their role in the study and manuscript prepara-
`tion.
`
`References
`Krupp LB, Pollina DA: Mechanisms and management of fatigue
`1.
`in progressive neurological disorders. Current opinion in neurol-
`ogy 1996, 9(6):456-460.
`Fisk JD, Pontefract A, Ritvo PG, Archibald CJ, Murray TJ: The
`impact of fatigue on patients with multiple sclerosis. The
`Canadian journal of neurological sciences 1994, 21(1):9-14.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`Freal JE, Kraft GH, Coryell JK: Symptomatic fatigue in multiple
`sclerosis. Arch Phys Med Rehabil 1984, 65(3):135-138.
`Vercoulen JH, Hommes OR, Swanink CM, Jongen PJ, Fennis JF,
`Galama JM, Meer JW van der, Bleijenberg G: The measurement of
`fatigue in patients with multiple sclerosis. A multidimen-
`sional comparison with patients with chronic fatigue syn-
`drome and healthy subjects. Archives of neurology 1996,
`53(7):642-649.
`Schwid SR, Covington M, Segal BM, Goodman AD: Fatigue in mul-
`tiple sclerosis: current understanding and future directions.
`J Rehabil Res Dev 2002, 39(2):211-224.
`Amato MP, Ponziani G, Rossi F, Liedl CL, Stefanile C, Rossi L: Quality
`of life in multiple sclerosis: the impact of depression, fatigue
`and disability. Multiple sclerosis (Houndmills, Basingstoke, England)
`2001, 7(5):340-344.
`Janardhan V, Bakshi R: Quality of life in patients with multiple
`sclerosis: the impact of fatigue and depression. Journal of the
`neurological sciences 2002, 205(1):51-58.
`Lobentanz IS, Asenbaum S, Vass K, Sauter C, Klosch G, Kollegger H,
`Kristoferitsch W, Zeitlhofer J: Factors influencing quality of life
`in multiple sclerosis patients: disability, depressive mood,
`fatigue and sleep quality. Acta neurologica Scandinavica 2004,
`110(1):6-13.
`Flachenecker P, Kumpfel T, Kallmann B, Gottschalk M, Grauer O,
`Rieckmann P, Trenkwalder C, Toyka KV: Fatigue in multiple scle-
`rosis: a comparison of different rating scales and correlation
`to clinical parameters. Multiple sclerosis (Houndmills, Basingstoke,
`England) 2002, 8(6):523-526.
`10. Tellez N, Rio J, Tintore M, Nos C, Galan I, Montalban X: Does the
`Modified Fatigue Impact Scale offer a more comprehensive
`assessment of fatigue in MS? Multiple sclerosis (Houndmills, Basing-
`stoke, England) 2005, 11(2):198-202.
`Jackson MF, Quaal C, Reeves MA: Effects of multiple sclerosis on
`occupational and career patterns. Axone (Dartmouth, NS) 1991,
`13(1):16-17. 20-12.
`Smith MM, Arnett PA: Factors related to employment status
`changes in individuals with multiple sclerosis. Multiple sclerosis
`(Houndmills, Basingstoke, England) 2005, 11(5):602-609.
`13. Comi G, Leocani L, Rossi P, Colombo B: Physiopathology and
`treatment of fatigue in multiple sclerosis. Journal of neurology
`2001, 248(3):174-179.
`14. Krupp LB: Fatigue in multiple sclerosis: definition, pathophys-
`iology and treatment. CNS drugs 2003, 17(4):225-234.
`15. Kesselring J, Thompson AJ: Spasticity, ataxia and fatigue in mul-
`tiple sclerosis. Bailliere's clinical neurology 1997, 6(3):429-445.
`16. Kern S, Ziemssen T: Brain immune communication psychone-
`uroimmunology of multiple sclerosis. Mult Scler 2007.
`17. Zifko UA: Management of fatigue in patients with multiple
`sclerosis. Drugs 2004, 64(12):1295-1304.
`Pucci E, Branas P, D'Amico R, Giuliani G, Solari A, Taus C: Amanta-
`dine for fatigue in multiple sclerosis. Cochrane database of sys-
`tematic reviews (Online) 2007:CD002818.
`19. Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP,
`Nagaraja HN: Efficacy and safety of modafinil (Provigil) for the
`treatment of fatigue in multiple sclerosis: a two centre phase
`2 study. Journal of neurology, neurosurgery, and psychiatry 2002,
`72(2):179-183.
`
`9.
`
`11.
`
`12.
`
`18.
`
`Page 5 of 6
`(page number not for citation purposes)
`
`MYLAN INC. EXHIBIT NO. 1045 Page 5
`
`
`
`Health and Quality of Life Outcomes 2008, 6:67
`
`http://www.hqlo.com/content/6/1/67
`
`20.
`
`27.
`
`Stankoff B, Waubant E, Confavreux C, Edan G, Debouverie M, Rum-
`bach L, Moreau T, Pelletier J, Lubetzki C, Clanet M: Modafinil for
`fatigue in MS: a randomized placebo-controlled double-blind
`study. Neurology 2005, 64(7):1139-1143.
`21. Corboy JR, Goodin DS, Frohman EM: Disease-modifying Thera-
`pies for Multiple Sclerosis. Current treatment options in neurology
`2003, 5(1):35-54.
`22. Metz LM, Patten SB, Archibald CJ, Bakker JI, Harris CJ, Patry DG, Bell
`RB, Yeung M, Murphy WF, Stoian CA, et al.: The effect of immu-
`nomodulatory treatment on multiple sclerosis fatigue. Jour-
`nal of neurology, neurosurgery, and psychiatry 2004, 75(7):1045-1047.
`23. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin
`FD, McFarland HF, Paty DW, Polman CH, Reingold SC, et al.: Rec-
`ommended diagnostic criteria for multiple sclerosis: guide-
`lines from the International Panel on the diagnosis of
`multiple sclerosis. Annals of neurology 2001, 50(1):121-127.
`24. Kurtzke JF: Rating neurologic impairment in multiple sclero-
`sis: an expanded disability status scale (EDSS). Neurology 1983,
`33(11):1444-1452.
`25. Multiple Sclerosis Council for Clinical Practice Guidelines: Fatigue
`and multiple sclerosis: evidence-based management strate-
`gies for fatigue in multiple sclerosis. Washington DC: Paralyzed
`Veterans of America; 1998:1-33.
`26. Heesen C, Nawrath L, Reich C, Bauer N, Schulz KH, Gold SM:
`Fatigue in multiple sclerosis: an example of cytokine medi-
`ated sickness behaviour? Journal of neurology, neurosurgery, and psy-
`chiatry 2006, 77(1):34-39.
`Flachenecker P, Bihler I, Weber F, Gottschalk M, Toyka KV, Rieck-
`mann P: Cytokine mRNA expression in patients with multiple
`sclerosis and fatigue. Multiple sclerosis (Houndmills, Basingstoke, Eng-
`land) 2004, 10(2):165-169.
`28. Ziemssen T, Kumpfel T, Klinkert WE, Neuhaus O, Hohlfeld R: Glat-
`iramer acetate-specific T-helper 1- and 2-type cell lines pro-
`duce BDNF: implications for multiple sclerosis therapy.
`Brain-derived neurotrophic factor.
` Brain 2002, 125(Pt
`11):2381-2391.
`29. Ziemssen T, Reichmann H: Non-motor dysfunction in Parkin-
`son's disease. Parkinsonism & related disorders 2007, 13(6):323-332.
`30. Tartaglia MC, Narayanan S, Francis SJ, Santos AC, De Stefano N, Lapi-
`erre Y, Arnold DL: The relationship between diffuse axonal
`damage and fatigue in multiple sclerosis. Archives of neurology
`2004, 61(2):201-207.
`31. Tedeschi G, Dinacci D, Lavorgna L, Prinster A, Savettieri G, Quat-
`trone A, Livrea P, Messina C, Reggio A, Servillo G, et al.: Correlation
`between fatigue and brain atrophy and lesion load in multi-
`ple sclerosis patients independent of disability. Journal of the
`neurological sciences 2007, 263(1–2):15-19.
`32. Rocca MA, Agosta F, Colombo B, Mezzapesa DM, Falini A, Comi G,
`Filippi M: fMRI changes in relapsing-remitting multiple sclero-
`sis patients complaining of fatigue after IFNbeta-1a injec-
`tion. Human brain mapping 2007, 28(5):373-382.
`33. Khan O, Mackenzie M, Shen Y, Zak I, Latif Z, Caon C: Combined
`Brain MTR and H-MRS Multi-Modality Approach To Investi-
`gate Mechanism of Action of Interferon Beta and Glatiramer
`Acetate in RRMS. Neurology 2007.
`34. Khan O, Shen Y, Bao F, Caon C, Tselis A, Latif Z, Zak I: Long-Term
`Study of Brain (1)H-MRS Study in Multiple Sclerosis: Effect
`of Glatiramer Acetate Therapy on Axonal Metabolic Func-
`tion and Feasibility of Long-Term (1)H-MRS Monitoring in
`Multiple Sclerosis. J Neuroimaging 2007.
`Lage MJ, Castelli-Haley J, Oleen-Burkey MA: Effect of immu-
`nomodulatory therapy and other factors on employment
`loss time in multiple sclerosis. Work (Reading, Mass) 2006,
`27(2):143-151.
`36. Ziemssen T, Neuhaus O, Hohlfeld R: Risk-benefit assessment of
`glatiramer acetate in multiple sclerosis. Drug Saf 2001,
`24(13):979-990.
`
`35.
`
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