A longitudinal observational study of a cohort of patients with relapsing remitting multiple sclerosis treated with glatiramer acetate

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1 European Journal of Neurology 2007, 14: doi: /j x A longitudinal observational study of a cohort of patients with relapsing remitting multiple sclerosis treated with glatiramer acetate M. Debouverie a,b, T. Moreau c, C. Lebrun d, O. Heinzlef e, F. Brudon f and J. Msihid g a Hoˆpital Central, CHU Nancy, Nancy, France; b Faculte de Me decine, Nancy Universite, EA 4003, Nancy, France; c Hoˆpital Ge ne ral, CHU, Dijon, France; d Hoˆpital Pasteur, CHU, Nice, France; e Hoˆpital Poissy-St-Germain-en Laye, France; f Clinique du Tonkin, Villeurbanne, France; and g GECEM, Montrouge, France Keywords: glatiramer acetate, immunomodulatory treatment, b-interferon, observational study, relapsing remitting multiple sclerosis, treatment switch Received 24 April 2007 Accepted 23 August 2007 Immunomodulatory treatments for relapsing remitting multiple sclerosis (RRMS) are not efficacious or tolerated in all patients. It is important to evaluate alternative classes of treatment in patients failing first-line therapy. The objective of this prospective observational study was to evaluate the efficacy and safety of glatiramer acetate in patients, to whom b-interferons could not be administered. The study included patients with RRMS who were intolerant to or had contraindications to b-interferon. After initiation of glatiramer acetate treatment, follow-up visits were made every 3 months, when data on neurologist-ascertained relapses and disability [Expanded Disability Status Scale (EDSS) score] were collected. Tolerability was evaluated by spontaneous adverse event reporting. Overall, 205 patients were studied and 113 (55.1%) treated for at least 4 years. The proportion of patients presenting over three relapses per year decreased from 51.2% to 8.4% in the 2 years following treatment initiation. Over 5 years of treatment, mean annualized relapse rates and mean EDSS scores remained stable ( relapses/year and 3.6 ± ± 2.1 respectively). Adverse events were reported by 179 patients, leading to discontinuation of treatment in 10 patients. Patients with RRMS to whom b-interferons cannot be prescribed can benefit from treatment with glatiramer acetate. Introduction Glatiramer acetate (Teva Pharmaceutical Industries Ltd, Kansas City, MO, USA) is a synthetic polypeptide mixture of four amino acids designed to mimic amino acid motifs of myelin basic protein, and has been developed for the treatment of multiple sclerosis (MS) [1]. Glatiramer acetate is assumed to act by inducing a population of regulatory T cells (T H 2 cells) that migrate to inflammatory sites in the central nervous system, where they are activated by cross-reacting myelin antigens to exert a beneficial ÔbystanderÕ effect [2]. There is also evidence that these activated T cells can be stimulated to release a brain-derived neurotrophic factor, which may be able to promote neuronal repair in MS [3,4]. In randomized, placebo-controlled trials in relapsing remitting multiple sclerosis (RRMS) patients, glatiramer acetate has been shown to reduce relapse rates and to slow down disease progression [5 7], as well as to reduce lesion load and lesion activity, as observed in magnetic resonance imaging (MRI) [6,8]. Evidence that glatiramer acetate treatment can lead to Correspondence: Dr Marc Debouverie, Service de Neurologie, Hoˆ pital Central, 29, Avenue du Mare chal de Lattre de Tassigny, Nancy Cedex, France (tel.: ; fax: ; m.debouverie@chu-nancy.fr). a sustained slowing down of disease progression in MS has recently become available from the 10-year followup data from the US pivotal randomized, controlled, phase III trial [9]. In treatment-naı ve patients with relapsing remitting disease, open-label, observational studies comparing glatiramer acetate to b-interferons have shown that the treatment benefit associated with glatiramer acetate is at least equivalent to that of the b-interferons [10 12]. As it has a mechanism of action and side-effect profile different from that of b-interferons, glatiramer acetate may be of interest in the treatment of patients who have failed b-interferon therapy or to whom b-interferons cannot be prescribed. Three recent studies [13 15] demonstrated that for patients to whom b-interferon therapy is not effective, switching to glatiramer acetate leads to a reduction in relapse rate of a magnitude similar to that seen in treatment-naı ve patients, whereas in patients switching from b-interferons because of unacceptable side-effects, treatment efficacy is maintained. Before glatiramer acetate was licensed in France, the drug was made available on a named-patient basis to patients with relapsing remitting MS. As b-interferons were already available in France at this time, this programme was restricted to two groups of patients: (i) those in whom b-interferon treatment was contraindicated and who could thus initiate glatiramer acetate as 1266 Journal compilation Ó 2007 EFNS

2 Treating RRMS patients with glatiramer acetate 1267 a first-line treatment and (ii) those previously treated with a b-interferon who developed intolerance necessitating discontinuation of the b-interferon, in whom glatiramer acetate was offered as a second-line treatment [16]. On the other hand, patients in whom b- interferon treatment was considered inadequately efficacious or who were poorly adherent were not eligible for glatiramer acetate treatment. The programme ran from December 1997 to June 2002, when glatiramer acetate became generally available in France. Patients were followed up quarterly. The data obtained demonstrated a reduction in relapse rate compared with the period before the switch, a stable level of disability during treatment and an acceptable side-effect profile of glatiramer acetate [16]. In September 2002, a long-term extension to the early access programme was implemented and participating neurologists were offered the possibility to include their patients in the extension and thus continue to contribute to the study database. The objective of this study was to collect long-term data on the efficacy and tolerability of glatiramer acetate in patients with RRMS. We now present data from this long-term extension analysed 8 years after the start of the early access programme. Methods Study design This was a phase IIIb/IV, open-label, observational study including an initial treatment phase and a longterm extension. The initial treatment phase was conducted within the framework of a Temporary Use Licence procedure [autorisation temporaire d utilisation (ATU)] for glatiramer acetate granted in September 1997 by the French Agency for the Safety of Healthcare Products [Agence Française de Se curité Sanitaire des Produits de Sante (AFSSAPS)]. The scheme was open to all neurologists treating patients with MS in France. Individual applications could be made by a neurologist to the AFSSAPS for treatment licenses for any patient with RRMS who presented a contraindication or lack of tolerance to b-interferons. Glatiramer acetate could then be prescribed to all patients whose application was approved by the AF- SSAPS. The first patient was included in December 1997 and the programme continued until the marketing of glatiramer acetate in France in June The patient could change the neurologist he consulted during the study, and in such a case the investigator was replaced in the database. The last follow-up visit in the framework of the ATU took place in September The total possible theoretical follow-up period during the ATU phase ranged from 4 to 58 months. After the end of the ATU phase, a long-term extension (ATU-LT) programme was decided in September 2002 for which all patients completing the ATU phase were eligible. Formal inclusion in the ATU-LT phase started in May 2003, the last inclusion was in March 2004 and patients were followed up until December 2005, a duration of 2 years and 9 months. Recruitment into the ATU-LT phase continued until December The total possible follow-up period in the two phases combined for participants in the ATU-LT ranged from to 8 years. Subjects Patients with RRMS, aged between 18 and 70 years, who were either intolerant to b-interferon treatment or in whom such a treatment was contraindicated were eligible for the ATU phase. Subjects with a known hypersensitivity to glatiramer acetate and mannitol, and those whose cognitive function did not permit them to understand the objectives or consequences of the study were excluded. Women of childbearing age were expected to use an accepted form of contraception. Written, informed consent was obtained from all participants. All subjects included in the ATU phase and who had made a documented follow-up visit in the 12 months before the formal start (March 2003) of the ATU-LT phase and who consulted during the recruitment period were eligible for the ATU-LT phase. Patients who had discontinued glatiramer acetate for any reason or whose disease had converted to a secondary progressive course were excluded. Study procedures At the inclusion visit, demographic data and disease history details were documented, inclusion and exclusion criteria verified and baseline EDSS scores measured. Glatiramer acetate treatment was initiated at 20 mg/day s.c. Subjects subsequently visited their study centre every 3 months, when data were collected on efficacy and tolerability. Efficacy measures included relapses ascertained by a neurologist since the previous follow-up visit and determination of disability with the Expanded Disability Status Scale (EDSS) [17]. No explicit criteria were specified in the protocol for definition of a relapse, which was left to the investigator s discretion and standard practice. Progression of disability was defined as an increase of EDSS score by at least one point confirmed after 6 months. Tolerability was evaluated by spontaneous adverse event reporting.

3 1268 M. Debouverie et al. Adverse events were classified into local injection-site reactions and systemic reactions. Statistical analysis Four study populations were investigated in this report. The ATU Safety Set consists of all patients originally included in the ATU phase of the study. The ATU-LT Safety Set comprises those members of the ATU Safety Set who continued treatment into the ATU-LT phase. The ATU Efficacy Set and the ATU-LT Efficacy Set correspond to those members of the ATU and ATU-LT Safety Sets, respectively, who provided at least one efficacy data set following initial inclusion into the ATU phase. Inter-group comparisons were performed with Fisher s exact test for categorical variables and with Wilcoxon test for quantitative variables. Two-tailed tests were used throughout and inter-group differences were considered significant at a probability threshold of All data were analysed centrally using software from SAS (version 8.2; Cary, NC, USA). Ethics The study was conducted according to the Declaration of Helsinki (Hong Kong Amendment), Good Clinical Practices (European Guidelines), and pertinent French legal and regulatory requirements. Written informed consent was obtained from each subject. Subjects were free to withdraw from the study at any time for any reason, without effect on their medical care. Treatment licenses under the global ATU were granted individually to participating neurologists by the AFSSAPS. As patient care was not otherwise altered by inclusion in the study, ethics committee approval was not necessary. With respect to data confidentiality, the study was declared to the ÔCommission Nationale d Informatique et Liberte sõ. Results Participating physicians During the ATU phase of the study, 232 neurologists received treatment licenses from the AFSSAPS. At the end of the ATU phase, 82 neurologists (35.3%) accepted to continue collecting data on their patients in the ATU-LT phase. However, because of the possibility of patient migration between centres, the neurologist including the patient in the ATU-LT was not necessarily the same as the one who applied for the treatment license. Six additional neurologists who did not apply for the original treatment license entered patients coming from another centre into the ATU-LT phase. In addition, 25 patients had switched from non-participating neurologists to one of five new centres who included them in the ATU-LT phase. Thus, 82 neurologists followed up patients through both phases of the study and 11 neurologists followed up the patients in the ATU-LT only. Study sample Patient disposition over the two phases of the study is presented in Fig. 1. Overall, 637 patients were treated during the ATU phase of the study, and these constitute the ATU Safety Set. Of these, 512 provided at least one post-inclusion efficacy measure and thus constitute the ATU Efficacy Set (80.4%). The total number of patients who entered the ATU- LT phase was 205, representing 32.2% of the original ATU population. These constitute the ATU-LT Safety Set. Of the remaining 432 patients, 277 (43.5% of the original ATU population) were followed up by neurologists who declined to participate in the ATU-LT phase, 40 (11.1%) discontinued during the ATU phase, principally due to an adverse event, and 115 (31.9%) were lost to follow-up either during the ATU phase or between the two phases of the study. At least one post-inclusion efficacy measure was available for 199 (97.1%) of these patients, who constitute the ATU-LT Efficacy Set. In the ATU-LT Safety Set, 126 patients (61.5%) provided follow-up data until the end of the study in December 2005, whereas 35 (17.1%) were documented as having discontinued glatiramer acetate and 44 were lost to follow-up (21.5%). Ten subjects (4.9%) discontinued treatment because of an adverse event and in five (2.5%) subjects disease had converted to a secondary progressive course. The characteristics of patients at the time of original inclusion into the ATU in all four study populations are presented in Table 1. No significant differences were observed for any of these variables between the ATU and ATU-LT group and patients from the ATU who did not participate in the long-term extension. The mean age of the study population was approximately 38 years and around three-quarters of subjects were women. Approximately one-quarter of patients were included because they presented a contraindication to b-interferons and three-quarters because of intolerance. In the ATU Efficacy Set (Table 2), no significant differences were observed between treatment-naı ve patients and those discontinuing b-interferon treatment because of side-effects in either relapse activity prior to inclusion (P ¼ 0.181; chi-squared test) or EDSS score at inclusion (P ¼ 0.247; Wilcoxon test).

4 Treating RRMS patients with glatiramer acetate 1269 ATU safety set n = 637 ATU efficacy set n = 512 Followed by NP n = 277 Lost to follow-up n = 115 Discontinued GA n = 40 Adverse events: 25 Aggravation of MS: 9 Other: 16 ATU- LT safety set n = 205 ATU- LT efficacy set n = 199 Lost to follow-up n = 44 Completing ATU- LT n = 126 Discontinued GA n = 35 Adverse events: 10 Aggravation of MS: 5 Other: 23 Figure 1 Patient flow through the ATU and ATU-LT phases of the study. ATU, autorisation temporaire d utilisation; ATU-LT, autorisation temporaire d utilisation-long term extension programme; GA, glatiramer acetate; MS, multiple sclerosis; NP, non-participating neurologist (in the ATU-LT phase). Note that reasons for discontinuation are not mutually exclusive, and more than one reason may be documented for an individual patient. Patients who were followed up by neurologists not participating in the ATU-LT phase and who were lost to follow-up or discontinued treatment during the ATU phase are not represented on this flow diagram. Table 1 Patient characteristics at inclusion into the ATU phase for the ATU and ATU-LT Safety and Efficacy Sets ATU ATU-LT Safety Set (n ¼ 637) Efficacy Set (n ¼ 512) Safety Set (n ¼ 205) Efficacy Set (n ¼ 199) Age (years) 38.3 ± ± ± ± 9.4 Gender Men 146 (23.0) 116 (22.7) 48 (23.4) 44 (22.1) Women 489 (77.0) 396 (77.3) 157 (76.6) 155 (77.9) Time since diagnosis (years) 8.6 ± ± ± ± 6.7 EDSS score 3.4 ± ± ± ± 1.6 Relapses in previous 2 years (46.5) 246 (48.5) 99 (48.5) 97 (48.7) >3 329 (53.5) 261 (51.5) 104 (51.2) 102 (51.3) Reason for inclusion into ATU Contraindication to IFN-b 145 (23.3) 123 (24.1) 47 (23.2) 47 (23.6) Intolerance to IFN-b 478 (76.7) 388 (75.9) 156 (76.8) 152 (76.4) Exposure to IFN-b a n ¼ 478 n ¼ 388 n ¼ 156 n ¼ 152 IFN-b1a i.m. (Biogen Idec) 299 (62.6) 248 (63.9) 99 (63.5) 96 (63.2) IFN-b1b s.c. (Merck Serono) 189 (39.5) 153 (39.4) 55 (35.3) 53 (34.9) IFN-b1a s.c. (Bayer Schering Pharma) 128 (26.8) 98 (25.3) 47 (30.1) 47 (30.9) Treatment duration (months) 15.5 ± ± ± ± 13.4 Data are presented as mean ± SD for quantitative variables and n (%) for categorical variables. ATU, autorisation temporaire d utilisation; ATU-LT, autorisation temporaire d utilisation-long term extension programme; EDSS, Expanded Disability Status Scale; IFN, interferon. a Patients may have received more than one b-interferon preparation. In the great majority of cases (94.8% of the ATU Safety Set and 96.2% of the ATU-LT Safety Set), appearance of systemic side effects were reported as the reason for intolerance. In addition, 34.8% of subjects in the ATU Safety Set and 21.8% of the ATU-LT Safety Set reported that local injection site reactions contributed to intolerance. This was the only variable that differed significantly between the ATU and ATU-LT

5 1270 M. Debouverie et al. Table 2 Relapse rates and EDSS scores in treatment-naïve patients and in patients switched from a b-interferon in the ATU Efficacy Set at baseline and after 2 years of treatment with glatiramer acetate Baseline Year 2 Treatment duration >3 relapses in previous 2 years EDSS score (mean ± SD) Mean annualized relapse rate EDSS score Treatment-naı ve patients n ¼ 123 n ¼ 123 n ¼ 57 n ¼ (46.3) 3.6 ± ± ± 1.9 Patients switched from IFN n ¼ 383 n ¼ 388 n ¼ 170 n ¼ (53.3) 3.4 ± ± ± 2.0 Data are presented as mean values ± SD, except for relapses at baseline which are given as number of patients (%). ATU, autorisation temporaire d utilisation; EDSS, Expanded Disability Status Scale; IFN, interferon. Sets (P < 0.001; Fisher s exact test). In addition, inadequate efficacy of b-interferons was reported in 82 patients (12.7%) in the ATU Safety Set and 27 patients (13.2%) in the ATU-LT Safety Set. In the ATU Safety Set, the proportion of patients presenting more than three relapses in the 2 years prior to inclusion was 68.3% for the patients considered as non-responders by the investigators and 41.4% for those considered as responders. The most widely prescribed b-interferon prior to inclusion was interferon-b 1a i.m., used by approximately two-thirds of the study population. However, many patients had been exposed to more than one b-interferon preparation. This was the case for 127 patients in the ATU Safety Set (26.6%), of whom 61 (12.9%) had been treated with interferon-b 1a i.m. and interferon-b 1b s.c., 43 (9.1%) with interferon-b 1a i.m. and interferon-b 1a s.c., 8 (1.7%) with interferon-b 1b s.c. and interferon-b 1a s.c. and 15 (3.2%) with all three preparations. The mean treatment exposure to any b-interferon in the ATU Safety Set was 15.5 years (Table 1). Treatment exposure The length of time that the patients were treated with glatiramer acetate during the study is presented in Fig. 2. For the 637 patients included in the ATU Safety Set, 46.6% were treated for <1 year. In the ATU-LT Safety Set, 55.1% of 205 subjects were treated for at least 4 years. Beyond 5 years, the ATU and ATU-LT populations were identical. Less than 50 patients were treated for >6 years. Efficacy data After 1 year of treatment with glatiramer acetate, the mean annualized relapse rate during this period was 0.4 ± 0.8 in the ATU Efficacy Set and 0.5 ± 0.8 in the ATU-LT Efficacy Set. The mean annualized relapse rate remained relatively constant throughout Number of subjects Number of subjects < Study duration (years) < Study duration (years) Figure 2 Treatment duration in the ATU (left panel) and ATU- LT (right panel) phases of the study. The line graphs represent the number of subjects remaining in the study at each time horizon. The histograms represent the number of subjects with the indicated duration of treatment. Open symbols and columns: Safety Sets; filled symbols and columns: Efficacy Sets. the 7-year maximum possible treatment period (Table 3). After 1 year of treatment, the mean EDSS score was 3.3 ± 1.8 in the ATU Efficacy Set and 3.1 ± 1.7 in the ATU-LT Efficacy Set. Mean EDSS scores were 3.3 ± 2.1 after 5 years of treatment (median treatment 7 7

6 Treating RRMS patients with glatiramer acetate 1271 Table 3 Relapse rates in the ATU and ATU-LT Efficacy Sets over the 7-year maximal treatment period ATU Efficacy Set ATU-LT Efficacy Set Evaluation period n Mean annualized relapse rate Subjects with 3 relapses/2 years (%) n Mean annualized relapse rate Subjects with 3 relapses/2 years (%) Year ± ± 0.8 Year ± (8.4) ± (8.3) Year ± (13.7) ± (12.8) Year ± (9.1) ± (9.5) Year ± (8.3) ± (8.3) Year ± (8.3) ± (8.3) Year ± (14.3) ± (14.3) ATU, autorisation temporaire d utilisation; ATU-LT, autorisation temporaire d utilisation-long term extension programme. EDSS score Treatment duration (years) Table 5 Efficacy outcome measures in the ATU Efficacy Set in patients treated for 1, 5 and 7 years Treatment duration Mean annualized relapse rate EDSS score EDSS progression >1 step 1 2 years 0.3 ± 0.8 (n ¼ 63) 3.6 ± 1.8 (n ¼ 55) 0/53 (0.0) 4 5 years 0.7 ± 1.1 (n ¼ 63) 3.4 ± 2.1 (n ¼ 47) 1/46 (2.2) 7 years or more 0.2 ± 0.4 (n ¼ 7) 3.1 ± 0.7 (n ¼ 6) 1/6 (16.7) ATU, autorisation temporaire d utilisation; EDSS, Expanded Disability Status Scale. Figure 3 Mean EDSS disability scores at different time points across the study. Data represent mean values ± standard deviation. Filled symbols: ATU Efficacy Set; open symbols: ATU-LT Efficacy Set. From 5 years onward, both Efficacy Sets are identical. The numbers above the error bars represent the number of patients at each evaluation. duration in the ATU-LT population) and 3.1 ± 1.5 after 7 years of treatment. No evolution of mean EDSS scores was thus observed over the treatment period (Fig. 3). After 5 years, 5.7% of subjects had progressed by at least one point on the EDSS disability scale (Table 4). Table 4 Number of patients (%) progressing by at least one step on the EDSS disability scale in the ATU and ATU-LT Efficacy Sets over the 7-year maximal treatment period Evaluation period ATU Efficacy Set (%) ATU-LT Efficacy Set (%) Year 1 3/234 (1.3) 3/138 (2.2) Year 2 8/189 (4.2) 7/149 (4.7) Year 3 9/144 (6.3) 9/131 (6.9) Year 4 9/84 (10.7) 9/81 (11.1) Year 5 2/35 (5.7) 2/35 (5.7) Year 6 1/19 (5.3) 1/19 (5.3) Year 7 1/6 (16.7) 1/6 (16.7) ATU, autorisation temporaire d utilisation; ATU-LT, autorisation temporaire d utilisation-long term extension programme. After 2 years of treatment with glatiramer acetate, no differences were observed in outcome in terms of either relapse rate or EDSS score between treatment-naı ve patients and those discontinuing a b-interferon treatment because of poor tolerability (Table 2). In order to identify possible early drop out of patients who responded poorly to glatiramer acetate, efficacy outcome measures after 1 year of treatment were compared in the ATU Efficacy Set between patients who were treated for 1 year only (median follow-up duration in the ATU Efficacy Set) and for those treated for 5 (median follow-up duration in the ATU-LT Efficacy Set) and 7 years (maximum followup duration). No obvious differences were seen between subgroups (Table 5). Safety Adverse events were reported in 87.3% of the ATU-LT Safety Set. These represented local injection site reactions (discomfort, erythema or induration), reported in 81.0% subjects, and systemic reactions (immediate post-injection reactions, consisting of flushing, chest tightness and shortness of breath, palpitation, and anxiety), reported in 49.3% subjects (Table 6). However, treatment discontinuation because of an adverse event was rare (4.9% of the ATU-LT Safety Set).

7 1272 M. Debouverie et al. Table 6 Adverse events reported in the ATU-LT Safety Set (n ¼ 205) No. patients (%) Discussion Description No. patients (%) Any adverse event 179 (87.3) Local injection-site 166 (81.0) reactions Systemic reactions 101 (49.3) Discontinuations for adverse events 10 (4.9) Local injection-site 6 (2.9) reactions Systemic reactions 8 (3.9) ATU-LT, autorisation temporaire d utilisation-long term extension programme. The objective of the LT-ATU study was to study the effectiveness and tolerability of glatiramer acetate over an 8-year period in patients with RRMS in whom b-interferons were contraindicated or poorly tolerated. Approximately half of the ATU-LT study sample were treated for at least 5 years. In the ATU-LT Efficacy Set, mean annualized relapse rates following initiation of glatiramer acetate treatment fell to 0.5 relapses per year and remained stable over the entire observation period. EDSS disability scores also remained stable during the study period. The efficacy of glatiramer acetate in these patients was indicated by a decreased relapse rate and a high proportion of patients without disease progression measured with the EDSS. Relapse rates after 1 year of treatment were similar to those reported in a metaanalysis of randomized clinical trials of glatiramer acetate [18]. In the long-term follow-up data from the pivotal phase III study of glatiramer acetate [9], relapse rates continued to fall after the first year, reaching a plateau of around 0.25 after 4 years. We did not observe such a progressive fall, and relapse rates remained stable at around 0.5 throughout the follow-up. This difference may be attributed to the fact that the patients included in this study presented more severe disease at inclusion than those included in the placebo-controlled, clinical trials. The relapse rates observed in the present study also fall within the range of those reported in three other observational studies of patients switched from b-interferons (0.53, 0.91 and 0.34) [13 15]. Concerning changes in disability, our observation of stability in EDSS scores over the study period and no deterioration of disability in around 85% of patients is also consistent with the data from the long-term followup data from the randomised clinical trial. However, it should be recognized that the possibility of patient migration between neurologists during the study raises the possibility of inter-rater differences in scoring disability in the same patient, which may introduce bias. However, such bias is likely to be minor as only 25 patients (12%) actually changed neurologists during the study. Natural history studies have indicated that disability would be expected to evolve in untreated patients by around 0.1 EDSS points a year [19], a rate of deterioration that was not reached in this study. As magnetic resonance imaging (MRI) is not used systematically in the follow-up of patients with MS in France, lesions visible on MRI were not evaluated as an outcome measure in this study and information on this important marker of disease activity was not collected. Information on MRI outcomes in patients switched between disease-modifying treatments would be interesting to collect in future studies. An important potential source of bias in long-term studies of disease-modifying treatment is selective dropout of subjects responding poorly to treatment, leading to progressive enrichment of good responders in the study and consequent overestimation of the effectiveness of treatment. We attempted to control for this bias in two ways. First, we compared the treatment response in the ATU-LT population with those in the source ATU population. Relapse rates and EDSS scores evolved in a similar fashion in the two groups, and no relevant differences in efficacy were observed. Secondly, we compared initial response in patients dropping out of the study after 1 year with those remaining in the study for 5 years. Again, initial responses were comparable. For these reasons, bias introduced into the study because of selective loss of poor responders appears to be limited. The observational study enabled effectiveness and safety data to be collected in a naturalistic treatment setting. The study evaluated a specific population of patients who could not be treated with b-interferons who had not been investigated systematically in the randomized pivotal clinical trial programme. These patients presented with a longer disease duration and higher EDSS scores at inclusion than in previous clinical trials, reflecting a patient population that for the most part had already tried and failed one or more b-interferon treatment. Apart from the criterion of b-interferon failure, the entry criteria to this study were less restrictive than those applied to the placebocontrolled clinical trials of either glatiramer acetate or b-interferons, increasing the representativity of the study with respect to everyday care of patients with MS in France. Compared with previous observational studies of glatiramer acetate in patients switched from b-interferons, the present study allowed data to be collected out to 8 years. The longest follow-up period reported previously was 42 months [13]. An important

8 Treating RRMS patients with glatiramer acetate 1273 group of patients who were not assessed specifically in this study are those who discontinue b-interferon treatment because of inadequate efficacy or poor adherence, although inadequate efficacy was reported in some patients included for intolerability to b-interferons. Such patients were not permitted to receive glatiramer acetate during the named-patient early access programme. Nonetheless, other studies have shown that patients discontinuing b-interferons due to inadequate efficacy can achieve satisfactory disease control when switched to glatiramer acetate [13]. Retention in the study over the total possible treatment period of 8 years was acceptable given the observational nature of the study. However, over half the neurologists including patients into the ATU phase declined to participate in the long-term extension. This could be explained by the fact that, after glatiramer acetate was made available in France and the ATU scheme stopped, neurologists were free to prescribe the drug to their patients without the constraints of completing and returning case report forms, which was not previously possible. The proportion of patients lost to follow-up during the ATU-LT phase (21.6%) is relatively high, but to be expected in an observational study with relatively unstructured follow-up. Although the majority of subjects in the study had discontinued b-interferon treatment because of the occurrence of side-effects, the tolerability of glatiramer acetate in these same subjects appeared acceptable, as only 10% patients of the ATU Safety Set discontinued treatment because of an adverse event. Treatment discontinuation was likely to occur early, and occurred in <5% of subjects followed up in the long-term extension. Adverse events reported were local injection-site reactions and post-injection reactions, which occurred early after initiation of treatment. The physician has the choice of four different immunomodulatory treatment options for the management of RRMS. Although the efficacy of these treatments is similar [20], they are not equivalent, and individual subjects may tolerate or respond to one better than another. In particular, there are important differences in the mechanism of action and side-effect profile between glatiramer acetate on the one hand and the b-interferons on the other. Moreover, development of neutralizing antibodies to b-interferons, which may occur in up to 40% of patients, can lead to treatment failure and current consensus guidelines recommend that treatment be switched in patients in whom such antibodies are detected [21]. The results of the present study are consistent with those of published short-term switching studies [13 15], showing that switching from b-interferons to glatiramer acetate is both effective and well tolerated. Moreover, our findings extend these previous observations to show that the treatment benefit is preserved over longer follow-up periods. In conclusion, the results of this open-label study indicate that switching patients with RRMS who are failing b-interferon to glatiramer acetate treatment is a relatively safe and effective strategy to control disease progression. Conflicts of interest The authors have no conflicts of interest to declare. References 1. Simpson D, Noble S, Perry C. Glatiramer acetate: a review of its use in relapsing-remitting multiple sclerosis. CNS Drugs 2002; 16: Neuhaus O, Farina C, Wekerle H, Hohlfeld R. Mechanisms of action of glatiramer acetate in multiple sclerosis. 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