Guest guest Posted April 16, 2004 Report Share Posted April 16, 2004 Yes, you are right. LDN has not been compared, I assume that LDN works. I did some detailed reading of the Cochrane data base, as to why they think copa does not work. It seems that they have excluded from analysis MANY studies, which SUPPORT the efficacy of copa on the grounds that they do not meet certain strict epidemiological criteria. In my opinion, while strict scientific criteria may not have been met, it does not mean that those studies are irrelevant, as they are published in acclaimed medical journals. In any case the details are below, if someone has the patience. Its a long document, so you may want to print. Yash Therapy with glatiramer acetate for multiple sclerosis [Review] Munari, L; Lovati, R; Boiko, A Date of Most Recent Update: 27-November-2003 New Abstract Background: Some clinical data have shown that glatiramer acetate (Copaxone ®), a synthetic amino acid polymer empirically found to suppress experimental allergic encephalomyelitis (EAE), an animal model of MS, might help improve the outcome of patients with multiple sclerosis (MS). Objectives: We performed a Cochrane review of all randomised, placebo- controlled trials of glatiramer acetate in MS, whatever the disease course. Search strategy: We searched the Cochrane MS Group trials register (June 2003), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2003), MEDLINE (PubMed) (January 1966 to June 2003), EMBASE (January 1988 to June 2003) and hand searching of symposia reports (1990-2002) from the neurological Associations and MS Societies in both Europe and America. Selection criteria: All randomised controlled trials (RCTs) comparing glatiramer acetate and placebo in patients with definite MS, whatever the administration schedule and disease course, were eligible for this review. Data collection and analysis: Both patients with relapsing-remitting (RR) and chronic progressive (CP) MS were analysed. Study protocols were comparable across trials as to patient entry criteria and outcome definition. No major flaws were found in methodological quality. However, efficacy of blinding should be balanced against well-known side effects, including injection-site reactions in glatiramer acetate-treated patients. Main results: A total of 646 patients contributed to this review, as it is summarised in Table 01. Glatiramer acetate did not show any significant effect on disease progression, measured as a sustained worsening in the Expanded Disability Status Scale (EDSS). On the other hand, a slight decrease in the mean EDSS score, driven by a major study, should be considered in the light of the limited validity of this outcome measure. No benefit was shown in CP MS patients (progression at two years: RR = 0.69, 95% CI [0.33 to 1.46]). The frequency of reported adverse events does not support any major toxicity associated with glatiramer acetate administration. The most common systemic adverse event was a transient and self-limiting patterned reaction of flushing, chest tightness, sweating, palpitations, anxiety (relative risk = 3.40 (95% CI [2.22 to 5.21], p <0.00001]). Local injection-site reactions were observed in up to a half of patients treated with glatiramer acetate, thus making a blind assessment of outcomes questionable. Conclusions: Glatiramer acetate did not show any beneficial effect on the main outcome measures in MS, i.e. disease progression, and it does not substantially affect the risk of clinical relapses. Therefore its routine use in clinical practice is not currently supported. More investigations are needed. Further research should also develop more reliable measures of patient disability over time and include quality of life among primary outcomes. ---------------------------------------------------------------------- ---------- Issue protocol first published 2001 Issue 3 Date new studies sought but none found 08 June, 2003 Date new studies found but not yet included or excluded 10 September, 2002 Date new studies found and included or excluded 10 September, 2002 Issue next stage Issue 1, 2005 Issue review first published 2004 Issue 1 Background Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with either relapsing/remitting or progressive course. The pathology is characterized by random foci of demyelination and axonal loss throughout the CNS. Despite a better knowledge of these pathologic findings in the last decade, little is known about their underlying etiology. Based on experimental data, an autoimmune damage of the myelin sheath has been postulated as a mechanism of CNS inflammation. Susceptible animals inoculated with myelin components are known to develop experimental allergic encephalomyelitis (EAE), which is considered a laboratory model of MS (Wisniewski 1977). Glatiramer acetate (Copaxone ®) is a synthetic amino acid polymer empirically found to suppress EAE. In animal models, the development of EAE can be prevented by glatiramer acetate administration (Teitelbaum 1997), possibly due to a displacement of immune cells targeted at native myelin components. Clinical results consistent with this rationale have also been shown in humans, leading to regulatory authorization. Although glatiramer acetate has been recently made available for treatment of MS patients, concerns exist about the potential risk of altering natural immune response. Given the expectations raised by this agent, we believe that a systematic review of all randomised controlled trials (RCTs) evaluating glatiramer acetate should be undertaken in order to provide both clinicians and consumers with the most comprehensive information. Objectives This review is aimed at determining efficacy and safety of the administration of glatiramer acetate in patients with MS. The main outcomes of interest were: (1) Clinical progression of disease in terms of sustained disability (2) Frequency of clinical relapses (3) Incidence of any adverse events (4) Patient's quality of life Secondary questions to be answered concern: (5) Number of patients treated with steroids and number of steroid courses administered during acute relapses or active disease progression (6) Impact of treatment on hospital admissions and length of stay, in order to detect potential savings both in terms of healthcare resources and patient's time Criteria for considering studies for this review Types of participants Patients of any age and either gender with definite MS according to Poser criteria (Poser 1983), whatever disease severity, were eligible for the review. Any patterns of MS course (relapsing/remitting, relapsing/progressive, secondary progressive or primary progressive) have been considered. MS patients receiving cytostatics, immunomodulators or immunosuppressants in the 6 months prior to study enrolment were excluded from the analysis. Therefore, information on patient treatment regimens before entering the trial has been sought. Types of intervention All therapeutic schedules involving glatiramer acetate administration, whatever the administration route, dosage, treatment duration and the interval between symptom onset and randomisation were considered as test treatment. Courses of steroids were permitted, provided they were administered without any restriction in both arms. Types of outcome measures We sought for the following measures in either treatment group at 12 and 24 months and at the end of the scheduled follow-up period: (1) Patients who progressed. Whenever unspecified, progression has been defined as a persistent worsening of at least one point in EDSS (Kurtzke 1983), recorded out of relapse and confirmed by a follow-up assessment at six months. However, other definitions of progression given in the original paper could be accepted, including a persistent half-point increase starting from EDSS score = 5.5, as it is often reported in the literature. (2) Mean disability score EDSS and its standard deviation. (3) Patients experiencing at least one exacerbation, which is defined as the acute or subacute appearance/reappearance of neurological signs and symptoms for at least 24 hours, in the absence of fever, infection or concurrent steroid withdrawal. (4) Relapse-free survival, if available. (5) Changes in quality of life scores, where available. Safety outcomes were assessed among primary endpoints by unique measures cumulating all events occurred throughout the trial: (6) Number of both local and systemic side effects. (7) Number of patients with severe side effects. If not otherwise specified, side effects have been defined as severe when leading to one of the following: death, hospitalisation, treatment discontinuation. The following data have also been analysed as secondary endpoints, where available: (8) Number of patients treated with steroids. (9) Number of steroid courses administered in each group. (10) Number of hospitalisations and total days in hospital. Types of studies All randomised or quasi-randomised controlled trials (RCTs) comparing glatiramer acetate and placebo in patients with definite MS were eligible for the review. Uncontrolled trials and studies where glatiramer acetate has been compared with interventions other than placebo were not included. Both double-blind and single-blind studies were eligible. Search strategy for identification of studies 1) We searched the Cochrane MS Group trials register (searched June 2003), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2003), MEDLINE (PubMed) (January 1966 to June 2003) and EMBASE (January 1988 to June 2003) (2) hand searching of the references quoted in the identified trials (3) hand searching of symposia reports (1990-2002) from the most important neurological associations and MS Societies in Europe and America; (4) contact with researchers who were participating in trials on glatiramer acetate. Contacts with the owner pharmaceutical company (Teva Pharmaceutical, Ltd.) were attempted without reply. So, we established reliable contacts with researchers involved in glatiramer acetate development. Reference search was carried out using the following terms: glatiramer acetate, copolymer-1, Cop-1, CPX, copaxone Methods of the review DATA EXTRACTION Selection of eligible studies and data extraction have been carried out independently by two reviewers (LM, RL). When relevant data were unavailable, decision about trial inclusion was resolved by the two reviewers. Results were then compared in order to rule out any misunderstandings, mistakes or biases possibly arising from data evaluation. Details on treatment administration schedule, patient enrolment criteria, diagnostic criteria, randomisation methods, blinding, outcome analysis, follow-up length, dropouts, side effects were also recorded for each study, in order to evaluate quality profiles (see Methodological quality). All data were registered in a collection form. Disagreements were resolved by discussion between the two reviewers. Trialists involved were asked to provide further details on study results where they seemed unclear from the article. TRIAL QUALITY ASSESSMENT All studies were given a quality score ranging from 0 to 5 (Jadad 1996), based on the following criteria: randomisation, allocation concealment, blinding, decisions about dropouts and withdrawals. Relevant information was collected using a convenient form developed by the Multiple Sclerosis Cochrane Review Group. Randomisation has been defined as either telephone calls to a randomisation centre, reference to computer-generated random lists or tables of random numbers. Quasi-randomised trials without properly concealed allocation (e.g.: patient alternation, open random list, date of birth, day of the week or hospital admission number) have been included in the review. Allocation concealment has been scored as: A = adequate, B = unclear, C =inadequate, D = not used, according to the scale reported in RevMan 4.1. Relevant disagreements have been resolved by discussion in order to achieve a unique score for each considered item. In case of significant differences between treatment and placebo, the effect of blinding could be tested in sensitivity analysis, since knowledge of treatment allocation may affect the assessment of study endpoints. Trial quality scores are listed in the summary table along with other characteristics of included studies. STATISTICAL ANALYSIS Data have been analysed according to an intention-to-treat approach. Relative risks, risk difference and their 95% confidence intervals (CI) have been calculated for binary outcomes. Continuous outcomes have been evaluated as weighted mean differences in treatment effects and their standard deviation (SD). The weighted treatment effect was calculated across trials for each outcome. Combined results were expressed as weighted estimates of relative risks with their 95% CI when binary variables were considered. Continuous outcomes were combined using weighted mean differences and their 95% CI. Basically, data were analysed in a fixed-effect model (Yusuf 1985). Homogeneity across trials have been tested in a chi square test with alpha = 0.10. When significant heterogeneity was found, results were checked in a random-effects model (Brocke 1996). Characteristics of both included and excluded trials (along with their exclusion criteria) have been listed in a summary table. All results have been organised and processed by the RevMan 4.1 (RevMan) developed by the Cochrane Collaboration. The effects of potential sources of heterogeneity have been explored by subgroup analysis where appropriate (see results). Sensitivity analysis on trial quality and missing data was not needed. Description of the studies Out of 103 references identified by the search strategy, 41 abstracts were provisionally selected to be read as full published papers. A further 24 were then excluded based on the following criteria: eight were uncontrolled open-label studies (Abramsky 1977; Bornstein 1982; Baumhefner 1988; Kott 1997; Meiner 1997; De Seze 2000; Duda 2000; Flechter 2002b), six reported on experimental investigations where only laboratory endpoints have been assessed (lymphocyte activity, cytokine outburst, uric acid increase) (Constantinescu 2000; Qin 2000; Brenner 2001; Chen 2001; Farina 2001; Karandikar 2002), four restricted the analysis to MRI parameters (Cohen 1995; Mancardi 1998; Wolinsky 2001; Sormani 2002), three were comparing glatiramer acetate and beta-interferons without any placebo group (Fusco 2001; Khan 2001; Flechter 2002a), one study considered pretreatment data a control for the treatment effect without randomising patient allocation as it is required in cross-over design ( 1998), one was a re-analysis of the US phase III study where neuropsychological test performance has been measured as the only clinical endpoint (Weinstein 1999) and the last one re-analysed the US phase III core trial introducing a peculiar summary measure of the total in-trial morbidity (Liu 2000). (See table of excluded studies). The remaining 17 papers were related to four RCTs contributing to this review and published between 1987 and 2001 (Bornstein 1987;; Bornstein 1991; 1995; Comi 2001). In all, these studies account for a total of 646 patients, 320 of whom allocated to glatiramer acetate and 326 to placebo. Three studies enrolled patients with relapsing-remitting (RR) disease (Bornstein 1987; 1995; Comi 2001), while another trial investigated the effect of glatiramer acetate in chronic-progressive (CP) MS (Bornstein 1991). Therapeutic schedules were homogeneous within MS patterns. Therefore, the following treatments have been compared with placebo: * glatiramer acetate: 20 mg subcutaneously, self-administered daily in RR MS * glatiramer acetate: 30 mg subcutaneously, self-administered twice daily in CP MS Treatment has been given for 9 (Comi 2001), 24 (Bornstein 1987; Bornstein 1991) or 35 months ( 1995). All trials on RR MS enrolled patients with definite disease (Poser 1983). Bornstein et al. (Bornstein 1987) randomised patients within an age range of 20 to 35 years, with at least two exacerbations in the two years before admission, provided they were not severely disabled (EDSS score below 6) and/or emotionally unstable. Fifty- eight percent of study population were female and 64% of initially screened patients were excluded due to any of the following: age, low frequency of exacerbations, lack of documentation, impaired psychological profile, transition to CP MS, distance from the clinic or pregnancy. The US phase III pivotal trial ( 1995) was a multicentre study involving 11 centres in the US. Eligible patients had an EDSS = 5 and at least two documented relapses in the two years prior to entry, the last one occurring at least one year before randomisation; they should also be neurologically stable and free from corticosteroid therapy for at least 30 days prior to entry. Patients could be enrolled within a larger age range (18 to 45) and the final proportion of female subjects was 73%.Only 12% of candidate participants were excluded based on the following criteria: treatment with glatiramer acetate or previous immunosuppression with cytotoxic therapy or lymphoid irradiation, pregnancy or lactation, diabetes mellitus, positive HIV/HTLV-1 serology, Lyme disease, need of aspirin or chronic non-steroidal anti-inflammatory drugs throughout the trial, unwillingness to undergo adequate contraception. Only EDSS modifying attacks confirmed by current neurological examination were accepted as relapses. Out of 215 patients who completed the first 24- month follow-up, 203 entered an additional 11-month treatment schedule ( 1998), reproducing the same trial design. The investigators also carried out a further open-label follow-up up to six years from randomisation in 208 patients from the original cohort of 251 ( 2000), not included in this review. The European-Canadian MRI study (Comi 2001) applied the following inclusion criteria: patients aged 18 to 50 with an EDSS = 5 with MS from at least one year. One documented relapse in the preceding two years was deemed sufficient to enter the study, but at least 1 enhancing lesion was essential in the screening brain MRI. Moreover, all randomised patients were clinically relapse-free and steroids- free in the 30 days before entry. A total of 29 centres participated in the study and 51% of screened patients were excluded due to any of the following: previous use of glatiramer acetate or oral myelin, prior lymphoid irradiation, use of immunosuppressant or cytotoxic agents in the past two years, use of azathioprine and/or other immunosuppressant including steroids during the previous six months, concomitant therapy with an experimental drug for either MS or another disease, serious intercurrent systemic or psychiatric illnesses; unwillingness to practice reliable contraception during study and known hypersensitivity to gadolinium, unavailability to repeat MRI studies. We excluded from the review the 9-month open- label extension phase of this trial. Average disease duration was uneven across trials: 5.5 (Bornstein 1987), 6.9 ( 1995) and 8.1 years (Comi 2001). Therefore, patients enrolled in the European-Canadian MRI study may represent a less severe subset, since they were eligible after a single relapse in the two previous years. Patients enrolled had to be free of any steroid treatment for at least 30 days (Bornstein 1987; 1995; Comi 2001) and clinically stable for at least 30 days ( 1995; Comi 2001). Minimum time elapsed from the last relapse was not specified in one study (Bornstein 1987). The study (Bornstein 1991) randomised CP patients between the age of 20 and 60, with a chronic-progressive course for at least 18 months, less than two exacerbations in the previous 24 months, disability 2- 6.5 on EDSS, emotional stability and a favourable psychosocial profile. These criteria were assessed in a pre-trial observation period lasting no more than 15 months and led to exclude 47% of candidate participants. CLINICAL OUTCOMES Three studies reported a clinical endpoint as the primary outcome measure: proportion of relapse-free patients at the end of follow-up (Bornstein 1987), mean number of relapses ( 1995) and time to reach a confirmed progression in the CP study (Bornstein 1991). Studies on RR MS also evaluated the following secondary (and tertiary) endpoints: time to progression (Bornstein 1987), relapse rate (Bornstein 1987; Comi 2001), change in EDSS scores from baseline (Bornstein 1987; 1995), number of relapses (Comi 2001), proportion of relapse-free patients ( 1995; Comi 2001), time to first relapse after randomisation, proportion of patients with sustained disease progression ( 1995). Secondary outcomes in the CP study (Bornstein 1991) were: time to unconfirmed progression, time to progression when defined as a half- unit change in EDSS lasting three months, change in the EDSS score from baseline, overall evaluation of neurologic status. In order to provide a consistent profile across different clinical endpoints, treatment effect has been estimated on negative outcomes. Therefore, patients with at least one exacerbation were calculated as differences from relapse-free counts. Relapse was defined in two studies as the appearance or reappearance of one or more neurologic symptoms, with signs persisting for at least 48 hours and immediately preceded by a relatively stable or improving neurologic state of at least 30 days ( 1995; Comi 2001). Another trial protocol required that patient symptoms were associated with changes in the neurologic exam involving an increase of at least 1 point in any of the 8 Kurtzke functional groups. Sensory symptoms alone were not considered (Bornstein 1987). Progression was defined in all studies as an increase of at least 1 point EDSS maintained for at least three months (Bornstein 1987; Bornstein 1991; 1995). It is noteworthy that the review protocol was more conservative, requiring at least six months of sustained 1-point EDSS worsening to be classified as progression, even if other definitions could be accepted. In one trial the 1 point cut-off was restricted to patients with a baseline EDSS = 5.0, while patients with a baseline EDSS < 5.0 should exhibit at least a 1.5 point increase to indicate a progression (Bornstein 1991). As a separate endpoint from progression, three trials analysed the proportion of patients worsened by at least 1 point in disability score at the end of follow-up as compared to baseline (Bornstein 1987; Bornstein 1991; 1995). It assumed that this endpoint does not take into account if a sustained increase in EDSS score has occurred, and it is open to misinterpretations as to the final patient outcome. Therefore, we have chosen not to analyse clinical worsening as reported by these studies in order to avoid misleading results when inconsistent with those obtained in disease progression (see Discussion). Consistently, clinical improvement based on a =1 point decrease in EDSS score versus baseline was not analysed. SIDE EFFECTS AND ADVERSE EVENTS The number of patients experiencing side effects of treatment have been counted, by event, in all studies. However, information on how many patients reported at least one adverse event whatsoever was unavailable, so that the overall incidence of side effects could not be calculated. The number of patients who dropped out because of adverse effects could be extracted from three studies (Bornstein 1987; 1995; Comi 2001). SECONDARY ENDPOINTS Two studies have compared the number of hospitalisations observed at the end of follow-up between glatiramer acetate and placebo arms ( 1995; Comi 2001). Data on the number of steroid courses administered were also available from two studies (Bornstein 1991; Comi 2001). MRI PARAMETERS One study (Comi 2001) evaluated the total number of enhancing lesions on MRI as the primary endpoint, clinical outcomes being analysed as tertiary endpoints. Secondary outcomes of this trial were: total volume of enhancing lesions, number of new enhancing lesions, number of new lesions on T2-weighted images, %change of lesion volume on T2- weighted images, change in the volume of hypointense lesions on T1- weighted images. MRI parameters were also analysed in secondary reports from the US phase III pivotal study, both for a small subset of the main trial (Ge 2000) and the open-label extension phase (Wolinsky 2001). CONCOMITANT MEDICATION In two studies, standard steroid treatment could be administered during relapses, without restrictions (Bornstein 1987; 1995). Moreover, symptomatic medications (Bornstein 1987) or conventional therapy received at the time of randomisation ( 1995) could be maintained throughout the study. A standard treatment schedule for relapses was specified in one trial protocol as 1.0 g i.v. methylprednisolone for three consecutive days (Comi 2001). Limitations to the use of steroids were introduced in the CP study (Bornstein 1991), where the maximum dose should not exceed 100 mg prednisone or 80 UI ACTH daily during exacerbations, lasting no more than four weeks. (See table of included studies). Methodological qualities of included studies RANDOMISATION Allocation concealment was adequate in three studies (Bornstein 1991; 1995; Comi 2001). In another study (Bornstein 1987) patients were randomised within matched pairs, but the method to obtain treatment allocation was not clearly specified. Allocation concealment was therefore defined as " unclear " for this report. BLINDING All trials were double-blind in design. However, the occurrence of peculiar side effects of glatiramer acetate (e.g.: injection site and skin reactions) casts doubts on the possibility to ensure a reliable masking. In the attempt to reduce this flaw, all study protocols introduced a separate evaluation by two independent physicians: an examining neurologist was responsible for the scheduled monitoring of clinical endpoints, while a treating physician was in charge of managing side effects and concomitant therapy. The latter physician could be either aware (Bornstein 1987; Bornstein 1991) or unaware ( 1995) of patient allocation. In another study, blinding of physicians was not formally assessed because clinical endpoints were only considered as tertiary outcomes (Comi 2001). Independently of investigators' accuracy, it can be assumed that all trials failed to carry out a fully blind assessment. In one study claimed to be double blind (Bornstein 1987), both patients and physicians correctly identified 70 to 80% of treatment allocations. Surprisingly, however, investigators stated that " the ability to guess treatment correctly was influenced by the effect of treatment rather than by side effects " . WITHDRAWALS AND LOST TO FOLLOW-UP Bornstein et al. (Bornstein 1987) report that two patients out of 25 allocated to placebo discontinued the study and were excluded from the analysis because of unreliable data due to an altered psychological profile. This was considered as a violation of the intention-to-treat analysis. Therefore, we had to count 23 participants in the placebo arm when data were extracted from either percentages or means in the original paper. Data from other five patients who dropped out were analysed, two in the placebo arm and three allocated to glatiramer acetate. One exacerbation and two adverse events were counted in this group. The European/Canadian trial (Comi 2001) had 14 dropouts, equally balanced between treatment and placebo. All of them where included in the analysis. The US pivotal trial ( 1995) counted 19 withdrawals in glatiramer acetate-treated patients and 17 among those taking placebo. Causes of discontinuation were not reported in 10 glatiramer acetate-allocated patients and 14 controls, representing 9.6% of the randomised sample altogether. Out of 215 patients who completed the first 24-month follow-up, 12 refused to enter the 11-month extension having opted to receive the newly emerging beta-interferon therapy. The two-year clinical profiles exhibited by these patients and those enrolled in the extension trial were comparable. A further nine subjects dropped out at the end of the 35-month follow-up (three in the treatment arm, seven allocated to placebo). All data related to this group were included in the analysis, although causes of dropout are not reported in detail. The CP MS study also reported a balanced withdrawal pattern (Bornstein 1991), with 10 glatiramer acetate treated patients and 10 controls discontinuing medication. Early withdrawals were all included in the analysis: 17 were censored at the time of discontinuation, the other three (glatiramer acetate = 2, placebo = 1) being counted as confirmed progression. VALIDITY SCORE The Jadad score was calculated as a measure of internal validity. Only one study achieved the full score, ( 1995) two trials scored 4 due to unclear effectiveness of masking at outcomes assessment (Bornstein 1991; Comi 2001), one study was given three because of unclear allocation concealment and insufficient details on withdrawn patients (Bornstein 1987). Results PRIMARY OUTCOMES PATIENTS WHO PROGRESSED AT 2 YEARS Information about progression was available from three trials and 407 patients (Bornstein 1987; Bornstein 1991; 1995). Although no significant heterogeneity was found (chi-square = 1.70, p = 0.43), the analysis was stratified by disease course. Pooled relative risk of progression was 0.77 (95% CI [051 to 1.14], p = 0.19) in RR MS and 0.69 (95% CI [0.33 to 1.46], p = 0.3) in CP MS. Overall treatment effect calculated in all 407 patients failed to reach statistical significance: 0.75 (95% CI [0.53 to 1.07], p = 0.11). CHANGE IN DISABILITY SCORE AT THE END OF FOLLOW-UP Mean changes in EDSS disability score were calculated in two trials (Bornstein 1987; 1995). As different follow-up durations are available from the US phase III trial, both 24- and 35-month data are shown although results are not pooled. A slight decrease in EDSS score favouring glatiramer acetate is observed at two years (WMD= - 0.33, 95% CI [-0.58 to -0.08], p = 0.01) and at 35 months (WMD= - 0.45, 95% [-0.74 to -0.16], p = 0.002) in RR MS patients. PATIENTS WITH AT LEAST ONE EXACERBATION Patients with at least one exacerbation were calculated from relapse- free patients. This information was available in three studies and 540 subjects with RR MS, evaluated at different follow-up lengths (Bornstein 1987; 1995; Comi 2001). Results have been split into three time windows: within one year (which includes the 9-month assessment reported in the European/Canadian study), at two years and at 35 months. Relative risks of experiencing at least 1 exacerbation were, respectively: 0.77 (95% CI [0.61 to 0.99], p= 0.04) within one year of treatment, 0.87 (95% CI [0.74 to 1.02], p= 0.08) at two years, and 0.89 (95% CI [0.74 to 1.06], p= 0.19) at 35 months. Since the same study appears in more than one stratum ( 1995), no pooled analysis is provided for this outcome. Significant heterogeneity was found between Bornstein's pilot trial and the European/Canadian study (chi-square 4.10, p = 0.043), possibly related to different trial duration. Then we tested pooled relative risk of relapse within one year of randomisation in a random-effect model, without any significant difference between glatiramer acetate and placebo: relative risk = 0.64 (95% CI [0.31 to 1.34], p= 0.2). RELAPSE-FREE SURVIVAL Median time to first relapse was analysed in one study ( 1995), with a median time of 287 days in patients treated with glatiramer acetate and 198 days in controls (Weibull regression model, p =0.097). Our elaboration on individual patient data extracted from the pilot trial paper (Bornstein 1987) point to a median of 5 months (95% CI [2 to 8]) in the placebo arm, while the median of glatiramer acetate-treated group could not be calculated as more than 50% of those subjects were censored without relapse at 24 months (log-rank chi-square = 6.68, p = 0.0098). These results could not be combined. CHANGES IN QUALITY OF LIFE SCORES No study planned to analyse patient quality of life as an outcome measure. ADVERSE EFFECTS All trials evaluated adverse events, accounting for 407 to 646 patients. Two studies ( 1995; Comi 2001) mainly focussed on injection-site changes and patterned transient systemic reactions, while the other two (Bornstein 1987; Bornstein 1991) reported a more analytical list of all observed side effects. Patterned reactions were most commonly reported, consisting of a transient self-limiting combination of: flushing, chest tightness, sweating, palpitations, anxiety. These symptoms unpredictably occurred within minutes of injection and spontaneously resolved before 30 minutes. Patterned reactions were more often observed in glatiramer acetate treated patients, with a relative risk of 3.40 (95% CI [2.22 to 5.21], p <0.00001]). Other systemic side effects significantly related to glatiramer acetate administration were: dizziness (relative risk =1.96 95% CI [1.38 to 2.78], p =0.0002]), palpitations (relative risk =2.23 95% CI [1.16 to 4.28], p =0.02]). The incidence of headache, dyspnoea, anxiety, faintness, drowsiness, rash, cramps, joint pain, appetite loss, constipation, abdominal discomfort, nausea and vomiting was not significantly different between groups. Local injection-site reactions included any of the following: itching (relative risk =5.17 95% CI [3.31 to 8.08], p <0.00001]), swelling (relative risk =3.69 95% CI [2.56 to 5.32], p <0.00001]), redness or erythema (relative risk =3.02 95% CI [2.30 to 3.97], p <0.0002]) and pain (relative risk =1.87 95% CI [1.54 to 2.27], p <0.00001]). No adverse events leading to patient's death or major toxicity were reported. One study (Comi 2001) mentioned the occurrence of " serious adverse experiences " in 10 glatiramer acetate treated and six placebo patients, respectively, but these unspecified events were classified as unrelated to treatment. Side effects causing treatment discontinuation were observed in three trials (Bornstein 1987, 1995, Comi 2001), but their relation with glatiramer acetate is not definitely established (relative risk =2.97, 95% CI [0.90 to 9.87], p = 0.08]). SECONDARY OUTCOMES HOSPITALISATIONS AT THE END OF FOLLOW-UP Data from hospital admission rates at nine or 35 months were extracted from two studies and 449 patients ( 1995; Comi 2001). Hospitalisations were significantly decreased in the glatiramer acetate group: relative risk = 0.60 (95% CI [0.40 to 0.91, p = 0.02]). STEROID COURSES AT THE END OF FOLLOW-UP Two studies evaluated the number of administered steroid cycles on a total of 345 patients (Bornstein 1991; Comi 2001) at nine or 24 months, respectively. This was significantly lower in the glatiramer acetate arm: relative risk = 0.69 (95% CI [0.55 to 0.87, p = 0.001]). ADDITIONAL OUTCOMES MEAN NUMBER OF RELAPSES Although it was not planned in the review protocol, this outcome was included in the analysis because it was available from three studies and 538 patients (Bornstein 1987; 1995; Comi 2001). Again, results have been stratified by length of follow-up. Significant heterogeneity has been found across studies, both at one year (chi- square = 9.29, p = 0.0023) and at two years (chi-square = 9.51, p = 0.002). Weighted mean differences of treatment effect have been tested in a random effects model, showing no significant decrease of relapses observed at one year (-0.81, 95% CI [-0.95 to 0.34], p= 0.17) and two years (-1.16, 95% CI [-2.84 to 0.52], p= 0.17). Data at three years reproduce the results from the extension of a single trial ( 1998) supporting a statistically significant decrease in the average relapse counts: -0.64 (95% CI [-1.04 to -0.24], p= 0.002). Discussion We have undertaken this systematic review to explore the amount of evidence currently supporting the use of glatiramer acetate in the management of MS. Our pragmatic approach to include all MS candidates for the administration of this agent, whatever the disease pattern, was aimed at collecting and reviewing all available data on this compound. Unfortunately, we should remark that 16 years after the first randomised pilot trial (Bornstein 1987) information on efficacy of glatiramer acetate did not move so far ahead from the original phase III database. On the other hand, the few completed, company- supported RCTs available are rather homogeneous in their protocols and treatment schedules. The primary endpoint considered in this review, i.e. disease progression, seems unaffected by daily glatiramer acetate administration up to two years. It should be noted that all studies required only three months of sustained EDSS worsening to classify patient outcome as a progression, instead of six months as it was established in the review protocol. Even if we had to accept this definition given in the original papers, we cannot exclude that some patients classified as developing progression may actually have experienced a prolonged relapse. Indeed, progression is an irreversible state by definition. However, only 23 glatiramer acetate- treated patients have been reported as " worsened " versus baseline at 35 months in the pivotal trial ( 1995), although 27 were deemed " progressed " at two years. These findings support our choice to exclude from the analysis data on clinical worsening versus baseline. Actually, it seems unlikely that glatiramer acetate can prevent patient deterioration over time without affecting the risk of progression as defined by the same disability scale (EDSS). When average EDSS changes versus baseline are analysed, a slight decrease in EDSS score has been shown at two years, and a half-point improvement at about three years in RR MS. Some remarks, however, should be taken into account. Firstly, disease progression based on a sustained worsening in patient's disability is expected to be a more robust endpoint than a decrease in EDSS score assessed in a single scheduled visit. Moreover, we should balance these findings against the reliability of blinding when evaluating glatiramer acetate- treated patients, given a two to five fold increase in injection-site reactions. The more sensitive the endpoint, the more exposed to insufficient masking would be the results. Again, EDSS score is an ordinal scale and it would be more appropriate to analyse it as a threshold to detect disease progression rather than calculating a mean difference. Finally, combined results on clinical improvement are driven by a single largest trial ( 1995), accounting itself for up to 87% of data. In summary, the above findings do not support a beneficial role of glatiramer acetate on the clinical status of RR MS patients over time. Benefit of glatiramer acetate on clinical relapses also remains questionable. Results on the risk of having at least 1 exacerbation point to a possible relative risk reduction by 20% in the first year of treatment. These results are driven by a small pilot study (Bornstein 1987), supporting a significant heterogeneity among included trials. When the average number of relapses is considered, results are no better after correcting for heterogeneity. This heterogeneity might reflect differences in patient selection, since risk estimates in controls (basal risks) appear uneven across studies. Using a random effects model, no significant decrease in the average relapse counts can be observed at one year and two years, while a single study suggests that the frequency of relapses experienced at three years could be slightly reduced by less than one, on average, in glatiramer acetate-treated patients. In this respect, it should be noted that the weighted mean difference may not be an appropriate measure to analyse relapse counts. Actually, this variable seems to follow a positive asymmetric distribution (standard deviations tend to increase with increasing mean values across studies) rather than approximating the normal function, as it is assumed by the weighted mean difference analysis. As regards adverse events, no major toxicity was observed. Reactions are predominantly localised to the injection site or self-limiting. The most common side effect is a combination of flushing, chest tightness, sweating, palpitations, anxiety, referred to as " patterned reaction " and it cannot be considered a harmful event. We have found a little higher incidence (24% of glatiramer acetate-treated patients and 7% of those taking placebo) than reported in the literature (15% and 5%). Rare side effects, however, cannot be explored in phase III trial settings and deserve a careful post-marketing surveillance (Mancardi 2000). Secondary endpoint analysis supports a decrease in hospital admission rates and steroid courses related to glatiramer acetate treatment. Despite increasing speculation on process endpoints in pharmacoeconomic models, it should be noted that * they are strictly related to the local healthcare financing system; * they reflect healthcare policies rather than needs; * they ultimately depend on physician's choices. For instance, treating neurologists may tend to manage more aggressively patients that were not given a presumably beneficial therapy. Therefore, both hospitalisation and virtually costless steroids are actually of little help in estimating the economic profile of glatiramer acetate. It has been recently suggested that the evaluation of MRI parameters in trials of MS may introduce an objective measure of treatment effect (Sormani 2002). MRI parameters are still surrogates of therapeutic efficacy and cannot represent a therapeutic goal themselves. Moreover, according to Prentice's validity criteria (Prentice 1989), surrogate endpoints should fully capture the net effect of treatment on clinical outcomes, and this cannot be shown in the absence of a significant clinical benefit. Conclusions Implications for practice In conclusion, glatiramer acetate seems to have no beneficial effect on the main outcome measures in this disease, i.e. disease progression, and it does not substantially affect the risk of clinical relapses over time. Therefore, there is at present insufficient evidence to support its routine use in clinical practice and more data from randomised clinical trials are needed. Two major RCTs on glatiramer acetate are currently under way. A large study to assess benefit of oral glatiramer acetate in RR MS (CORAL) has recruited more than 1600 patients and is expected to be completed by October, 2002 (Markowitz 2000b). An interim analysis, however, did not show any benefit from either high (50 mg) or low (5 mg) daily doses of oral glatiramer acetate compared with inactive placebo (Teva 2002). Another trial (PROMISE) was planned to compare daily glatiramer acetate 20 mg given subcutaneously with placebo in primary progressive MS patients (Markowitz 2000a) but it was stopped for futility. Implications for research Looking forward to the results of ongoing trials, future studies on glatiramer acetate should deal with the following problems: * undertake a really blind assessment of patients treated with subcutaneous glatiramer acetate * develop a sensitive, comprehensive and reliable measure of patient disability over time * establish a unique and reliable clinical definition of patient progression * include patient's quality of life among primary endpoints * make definitely clear the relationship between MRI parameters and clinical outcomes fully accomplishing Prentice criteria (Prentice 1989). Internal sources of support to the review * External sources of support to the review * Potential conflict of interest L. Munari, Neurologist and Statistician, is the Chief Medical Officer of the Azienda Ospedaliera Niguarda Ca' Granda, Milan, Italy. He does not have any conflicts of interest with pharmaceutical companies. R. Lovati is an independent practicing physician participating in the activities of the Neuroepidemiology Unit and MS Cochrane Review Group at the Ist. Nazionale Neurologico C. Besta, Milan, Italy. A. Boiko is Professor in the Department of Neurology and Neurosurgery of the Russian State Medical Universtity, without any liaison or competition within the pharmaceutical market Acknowledgements Reviewers wish to thank Prof. Rice (Dept. of Clinical Neurological Sciences, University of Western Ontario, London, Ontario), Dr. Graziella Filippini (Neuroepidemiology Unit and MS Cochrane Review Group, Ist. Nazionale Neurologico C. Besta, Milan, Italy) and Prof. Giancarlo Comi (Dept. of Neuroscience, Scientific Institute San Raffaele, Milan, Italy) for their support in collecting data and appreciated remarks. Contribution of Reviewer(s) AB gave the idea of the review and wrote a first draft version of the protocol. RL and LM carried out double-checked data extraction. LM wrote the final protocol and final text of the review, integrating AB and RL comments and remarks. Synopsis Currently available data do not provide definite evidence that glatiramer acetate (Copaxone ®) can prevent relapses or slow progression of the disease, and more research is needed. Multiple sclerosis (MS) is a chronic disease of the nervous system which affects young and middle-aged adults and can lead to permanent disability. MS damages several parts of the nerves, including the myelin sheath. Glatiramer acetate (Copaxone ®) is a synthetic amino acid polymer empirically found to suppress experimental allergic encephalomyelitis (EAE), an animal model of MS. Available data do not support a beneficial effect of Glatiramer acetate in preventing both disease progression, measured as a sustained worsening in disability, and clinical relapses. As regards adverse events, no major toxicity was observed. Local injection-site reactions were observed in up to a half of treated patients. More research is needed. Table of comparisons Fig 01 COP1 versus placebo: primary outcomes [Help with image viewing] ---------------------------------------------------------------------- ---------- Patients who progressed at 2 years ---------------------------------------------------------------------- ---------- [Help with image viewing] ---------------------------------------------------------------------- ---------- Change in disability score at the end of follow-up ---------------------------------------------------------------------- ---------- [Help with image viewing] ---------------------------------------------------------------------- ---------- Patients with at least 1 exacerbation ---------------------------------------------------------------------- ---------- [Help with image viewing] ---------------------------------------------------------------------- ---------- Mean number of relapses ---------------------------------------------------------------------- ---------- Table of comparisons Fig 02 COP1 versus placebo: secondary outcomes [Help with image viewing] ---------------------------------------------------------------------- ---------- Number of hospitalisations at the end of follow-up ---------------------------------------------------------------------- ---------- [Help with image viewing] ---------------------------------------------------------------------- ---------- Number of steroid courses at the end of follow-up ---------------------------------------------------------------------- ---------- Table of comparisons Fig 03 COP1 versus placebo: adverse effects [Help with image viewing] ---------------------------------------------------------------------- ---------- Localised to the injection site ---------------------------------------------------------------------- ---------- [Help with image viewing] ---------------------------------------------------------------------- ---------- Systemic adverse effects ---------------------------------------------------------------------- ---------- [Help with image viewing] ---------------------------------------------------------------------- ---------- Adverse effects causing treatment withdrawal ---------------------------------------------------------------------- ---------- Characteristics of included studies Study: Bornstein 1987 Methods: Randomised controlled trial. Patients have been enrolled in matched pairs with random assignment of either patient. Randomisation method not clearly specified. Intention-to-treat analysis. Double-blind, but patient's self-evaluation of either side effects or changes in neurologic status were reported to an unblinded clinical assistant. Treatment period: 24 months. Follow-up period: 24 months. Withdrawn criteria: unusable data (2 placebo) Withdrawals: placebo = 2 (dropouts for psychological reasons) Dropouts = 7: placebo = 4 (2 psychological reasons; 2 unstated), COP1 = 3 (1 exacerbation; 2 unstated). Participants: 50 patients: COP1 25, placebo 25. Israel 1 centre. Sex: both. Age: 20-35 Included (36%): definite MS with RR course, >= 2 exacerbations in the 2 years before admission, Kurtzke <= 6, emotionally stable. Patients enrolled when " clinically stable " and out of steroid treatment. Excluded (64%): age (23), low frequency of exacerbations (21), lack of documentation (19), psychologic profile (15), transition to chronic (8), distance from the clinic (3), pregnancy (1). Baseline characteristics: 58% female mean age: COP1 30.0 yrs, placebo 31.1 yrs mean EDSS: COP1 2.9, placebo 3.2 disease duration: COP1 4.9 yrs, placebo 6.1 yrs. Interventions: Rx: COP1* 20 mg. Placebo: bacteriostatic saline. Subcutaneous COP1 or placebo self-administered daily. Co-interventions: unspecified steroid treatment during exacerbations; symptomatic medications (e.g.: cholinergic and spasmolytic drugs). Outcomes: Primary outcome: proportion of relapse-free patients at the end of follow-up. Secondary outcomes: frequency of relapses, change in EDSS scores from baseline, time to progression. Relapse defined as: patient symptoms accompanied by observed objective changes on the neurologic exam involving an increase of at least 1 point in the score for 1 of the 8 functional group of Kurtzke scale. Sensory symptoms alone not considered Progression defined as: increase of at least 1 point EDSS maintained for at least 3 months Notes: Jadad score = 3. Two different preparations of Copolymer-1 have been used in the study, but patients treated with either preparation cannot be itentified throughout the trial. Assumptions: 2 withdrawn in placebo group Allocation concealment: B Study: Bornstein 1991 Methods: Randomised controlled trial. Randomised block design with 2 EDSS strata (<5.0 and >=5.0) Central allocation at trial office Intention-to-treat analysis. Double-blind, but patient's self-evaluation of either side effects or changes in neurologic status were reported to an unblinded clinical assistant. Statisticians were also aware of patient allocation Treatment period: 24 months. Follow-up period: 24 months. Withdrawals: COP1 = 10, placebo = 10. Details of whatever groups: 6 unwilling to continue, 5 side effects, 3 confirmed progression (2 COP1 and 1 placebo), 6 unspecificed reasons. Participants: 106 patients: COP1 51, placebo 55. Israel and USA, 2 centres. Sex: both. Age: 20-60 Included (63%):Definite diagnosis of MS with CP course, evidence of a chronic-progressive course for at least 18 months, <=2 exacerbations in the previous 24 months, disability 2-6.5 on EDSS, emotional stability and capability of participating in a double-blind clinical trial as determined by psychosocial evaluation. These criteria were assessed in a pre-trial observation period lasting <=15 months Excluded (47%): second exacerbation (2); EDSS >=7 (8), patient's treatment choice (10), insufficient progression (31), other reasons (12) Baseline characteristics: 55% female mean age: COP1 41.6, placebo 42.3. mean EDSS: COP1 5.7 placebo 5.5 disease duration: not available Interventions: Rx: COP1* 30 mg. Placebo: bacteriostatic saline. Subcutaneous COP1 or placebo self-administered twice daily. Co-interventions: " limited use of steroids " up to 100 mg prednisone or 80 UI ACTH daily during exacerbations, not exceeding 4 weeks. Outcomes: Primary outcome: time to reach a confirmed progression Secondary outcomes: time to unconfirmed progression, time to progression to 0.5 EDSS units, change in the EDSS score from baseline, overall evaluation of neurologic status Progression defined as: increase of at least 1 point EDSS for patients with a baseline EDSS >= 5.0 (or a worsening of 1.5 EDSS units for those with a baseline <5.0) maintained for at least 3 months Notes: Jadad score = 4. Assumptions: 8 COP1 and 9 placebo censored without events. Allocation concealment: A Study: Comi 2001 Methods: Randomised controlled trial. Randomisation stratified by centers with a pre-assigned computer- generated list. Intention-to-treat analysis. Although supposed unaware of treatment allocation, patient and physician blinding was not formally assessed as outcome measures focussed on MRI parameters. Treatment period: 9 months. Follow-up period: 9 months. Drop-outs: COP1 = 7 (3 adverse events, 1 moved away from study center, 1 severe exacerbation, 4 withdrew consent; more than one causes are counted for the same patient), placebo = 7 (2 adverse events, 1 treatment believed ineffective, 1 poor compliance, 1 lost to follow-up, 2 refused to continue MRI monitoring) Participants: 239 patients: COP1 119, placebo 120. Europe and Canada 29 centres Sex: both. Age: 18-50 Included (49%): definite MS with RR course, a diagnosis of MS for at least 1 year, age 18-50 inclusive, EDSS of 0 to 5, at least 1 documented relapse in the preceding 2 years, at least 1 enhancing lesion in their screening brain MRI, clinically relapse-free and steroids-free in the 30 days before entry Excluded (51%): previous use of COP1 or oral myelin, prior lymphoid irradiation, use of immunosuppressant or cytotoxic agents in the past 2 years, use of azathioprine, cyclosporine, interferons, deoxyspergualine, chronic corticosteroids during the previous 6 months. Concomitant therapy with an experimental drug for MS or for another disease. Serious intercurrent systemic or psychiatric illnesses; unwilling to practice reliable contraception during study; known hypersensitivity to Gadolinium-DTPA or unavailable to undergo repeat MRI studies. Currently on relapse or steroid treatment (13); unspecified requirement unmet (233) Baseline characteristics: Unspecified gender distribution mean age: COP1 34.1, placebo 34.0. mean EDSS: COP1 2.3 placebo 2.4 disease duration: COP1 7.9 years, placebo 8.3 years Interventions: Rx: COP1** 20 mg. Placebo: unspecified preparation Subcutaneous COP1 or placebo self-administered daily. Co-interventions: relapses could be treated by a standard dose of 1.0 g i.v. metilprednisolone for 3 consecutive days Outcomes: Primary outcome: total number of enhancing lesions on MRI. Secondary outcomes: total volume of enhancing lesions, number of new enhancing lesions, number of new lesions on T2-weighted images, % change of lesion volume on T2-weighted images, change in the volume of hypointense lesions on T1-weighted images. Tertiary outcomes: relapse rate, number of relapses, proportion of relapse-free patients Relapse defined as: appearance or reappearance of one or more neurologic symptoms, accompanied by abnormalities persisting for at least 48 hours and immediately preceded by a relatively stable or improving neurologic state of at least 30 days. A relapse was confirmed when patient's symptoms were accompanied by objective changes in neurologic examination consistent with at least 0.5 EDSS increase, 1 grade in the score of two or more functional systems, or 2 grades in one functional system. Transient neurologic deterioration associated with fever or infection in MS patients was not considered as relapse, nor was a change in nbowel, bladder or cognitive function alone. Notes: Jadad score = 4. The Authors state that physician blinding was not formally assessed because primary and secondary outcome measures were MRI patterns Allocation concealment: A Study: 1995 Methods: Randomised controlled trial. Central allocation at trial office Intention-to-treat analysis. Double-blind. Treatment period: 24 months (+ 11 in the extension phase). Follow-up period: 24 months (+ 11 in the extension phase). Withdrawals: COP1 = 19 (3 pregnancy, 1 progression, 2 serious adverse event, 3 transient self-limited systemic reactions, 10 not specified) placebo = 17 (2 poor protocol compliance, 1transient self-limited reaction, 14 not specified). Nine additional patients (COP1= 2, placebo= 7) dropped out during the extension study. Participants: 251 patients: COP1 125, placebo 126. USA 11 centres Sex: both. Age: 18-45 Included (88%): criteria clinically definite MS or laboratory- supported definite with RR course, ambulatory, with an EDSS of 0.0 to 5.0, a history of at least 2 clearly defined and documented relapses in the 2 years prior to entry, onset of the first relapse at least 1 year before randomisation, neurologically stable and free from corticosteroid therapy for at least 30 days prior to entry Excluded (12%): treatment with COP1 or previous immunosuppression with cytotoxic therapy or lymphoid irradiation; pregnancy or lactation, IDDM, positive HIV/HTLV-1 serology, Lyme disease, required use of aspirin or chronic NSAID during trial; unwilling to undergo adequate contraception. Baseline characteristics: 73% female mean age: COP1 34.6 yrs, placebo 34.3 yrs mean EDSS: COP1 2.8, placebo 2.4 disease duration: COP1 7.3 yrs, placebo 6.6 yrs. Interventions: Rx: COP1** 20 mg. Placebo: not specified. Subcutaneous COP1 or placebo self-administered daily. Co-interventions: standard steroid protocol during exacerbations; conventional medication received at the time of randomisation Outcomes: Primary outcome: mean number of relapses. Secondary endpoints: proportion of relapse-free patients, time to first relapse after randomisation, proportion of patients with sustained disease progression and mean change in EDSS score. Relapse defined as: appearance or reappearance of one or more neurologic abnormalities persisting for at least 48 hours and immediately preceded by a relatively stable or improving neurologic state of at least 30 days. A relapse was confirmed when patient's symptoms were accompanied by objective changes in neurologic examination consistent with at least 0.5 EDSS increase, 2 points on one of the seven functional systems, or 1 point on two or more of the functional systems Progression defined as: increase of at least 1 point EDSS maintained for at least 3 months Notes: Jadad score = 5. Authors carried out both an intention-to treat and an on-treatment analyses, caliming that results are comparable. This study has been extended for an additional 11 months until all 203 remaining patients (i.e.: excluding 36 already withdrawn and 12 who refused to participate in the extension trial), have received 24 months of treatment. Clinical status of these 12 withdrawn between the early and the extension phase are no different from the remaining cohort. Extension study was carried out double blind. Allocation concealment: A *COP1 prepared and supplied by Weinzmann Institute of Science and Bio- Yeda Co. (Rehovot, Israel); **COP1 prepared and supplied by TEVA Pharmaceutical Industries, Ltd., Petah Tiqva, Israel) Characteristics of excluded studies Study: Abramsky 1977 Reason for exclusion: Uncontrolled open-label study. Study: Baumhefner 1988 Reason for exclusion: Uncontrolled open-label study. Study: Bornstein 1982 Reason for exclusion: Uncontrolled open-label study. Study: Brenner 2001 Reason for exclusion: Experimental series. Only laboratory measures of treatment effect are reported. Study: Chen 2001 Reason for exclusion: Experimental series from subset of the the US copaxone phase III core study. Only laboratory measures of treatment effect are reported. Study: Cohen 1995 Reason for exclusion: Report from a subset of the US copaxone phase III core study where only MRI parameters are reported. Study: Constantinescu 2000 Reason for exclusion: Open-label controlled trial. Only laboratory measures of treatment effect are reported. Study: De Seze 2000 Reason for exclusion: Report from a phase I uncontrolled trial of oral copaxone. Study: Duda 2000 Reason for exclusion: Uncontrolled study. Study: Farina 2001 Reason for exclusion: Non-randomised open-label controlled trial. Only laboratory measures of treatment effect are reported. Study: Flechter 2002a Reason for exclusion: Open label trial comparing two Copaxone administration schedules and interferon-beta1b. Study: Flechter 2002b Reason for exclusion: Report from an open-label uncontrolled trial. Study: Fusco 2001 Reason for exclusion: Non-randomised study comparing copaxone and interferon-beta1a in relapsing-remitting MS. Study: Karandikar 2002 Reason for exclusion: Experimental series. Only laboratory measures of treatment effect are reported. Study: Khan 2001 Reason for exclusion: Non-randomised, open-label study comparing interferon-beta1a, interferon-beta1b and copaxone. Study: Kott 1997 Reason for exclusion: Open-label uncontrolled study of copaxone in MS patients with or without optic neuritis. Study: Liu 2000 Reason for exclusion: Re-analysis of the US copaxone phase III core study evaluating the 'area under the disability/time curve' (AUC) as a summary measure of the total in-trial morbidity experienced by patients. Study: Mancardi 1998 Reason for exclusion: Report from an open study on copaxone where pretreatment data served as controls of treatment effect. Only MRI parameters are reported. Study: Meiner 1997 Reason for exclusion: Phase III uncontrolled open-label trial. Study: 1998 Reason for exclusion: Report from a non-randomised open study on copaxone where pretreatment data served as controls of treatment effect. Study: Qin 2000 Reason for exclusion: Experimental series comparing the effect of copaxone on MS patients and healthy volunteers on laboratory measures of treatment effect. Study: Sormani 2002 Reason for exclusion: Re-analysis of the European-Canadian MRI study aimed at validating MRI endpoints as surrogates of clinical outcomes in MS patients. Study: Weinstein 1999 Reason for exclusion: Re-analysis of the of the US copaxone phase III core study evaluating neuropsychologic parameters. Baseline test performance was normal and improved over time in both treatmemt groups. Study: Wolinsky 2001 Reason for exclusion: Re-analysis of the of the US copaxone phase III core study evaluating MRI parameters. Table 01 Patient characteristics Disease course: RR Copaxone: 269 EDSS at baseline: 2.3 +/- 2.9 Placebo: 271 EDSS at baseline: 2.4 +/- 3.2 Total: 540 Disease course: CP Copaxone: 51 EDSS at baseline: 5.7 Placebo: 55 EDSS at baseline: 5.5 Total: 106 Disease course: Total Copaxone: 320 EDSS at baseline: Placebo: 326 EDSS at baseline: Total: 646 Disease course: Copaxone: EDSS at baseline: Placebo: EDSS at baseline: Total: References to studies included in this review Bornstein 1987 Bornstein MB, A, Slagle S, Weitzman M, Crystal H, Drexler E et al. A pilot trial of Cop 1 in exacerbationg-remitting multiple sclerosis. New England Journal of Medicine 1987;317(7):408-14. [Context Link] Bornstein 1991 Bornstein MB, A, Slagle S, Weitzman M, Drexler E, Keilson M et al. A placebo-controlled, double-blind, randomized, two-center, pilot trial of Cop 1 in chronic progressive multiple sclerosis. Neurology 1991;41(4):533-9. [Context Link] Comi 2001 Comi G, Filippi M for The Copaxone MRI study Group, Milan Italy. The effect of glatiramer acetate (Copaxone) on disease activity as measured by cerebral MRI in patients with relapsing-remitting multiple sclerosis (RRMS): a multi-center, randomized, double-blind, placebo-controlled study extended by open-label treatment. Neurology 1999;52(Suppl 2):A289. [Context Link] Comi G, Filippi M, Wolinsky J. The extension phase of the European- Canadian MRI study demonstrates a sustained effect of glatiramer acetate in relapsing-remitting multiple sclerosis. JNS 2001;187 (Suppl. 1). Comi G, Filippi M, Wolinsky JS and the European/Canadian Glatiramer Acetate Study Group. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of Glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing-remitting multiple sclerosis. ls of Neurology 2001;149(3):290-7. Filippi M, Rovaris M, Rocca MA, Sormani MP, Wolinsky JS, Comi G. Glatiramer acetate reduces the proportion of new MS lesions evolving into " black holes " . Neurology 2001;57(4):731-3. Rovaris M, Comi G, Wolinsky JS, Filippi M. The effect of glatiramer acetate on brain volume changes in patients with relapsing-remitting multiple sclerosis. JNS 2001;187(Suppl.1). 1995 Ge Y, Grossman RI, Udupa JK, Fulton J, Constantinescu CS, - Scarano F, et al. Glatiramer acetate (Copaxone) treatment in relapsing-remitting MS: quantitative MR assessment. Neurology 2000;54 (4):813-817. [Context Link] Greenstein JI. Extended use of glatiramer acetate (Copaxone) for MS [Letter]. Neurology 1999;52(4):897-898. KP. Management of relapsing/remitting multiple sclerosis with copolymer 1 (Copaxone). Multiple Sclerosis 1996;1(6):325-326. KP. The U.S.Phase III Copolymer 1 Study Group. Antibodies to Copolymer 1 do not interfere with the clinical effect. ls of Neurology 1995;38:973 (Abstract). KP. Experimental therapy of relapsing-remitting multiple sclerosis with copolymer-1. ls Neurology 1994;36 Suppl:S115-117. KP, BR, Cohen JA, Ford CC, Goldstein J, k RP et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double.-blind, placebo-controlled trial. Neurology 1995;45(7):1268-1276. KP, BR, Cohen JA, Ford CC, Goldstein J, k RP et al. Extended use of glatiramer acetate (copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology 1998;50(3):701-708. KP, BR, Ford CC, Goodman A, Guarnaccia J, k RP, et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Copolymer 1 Multiple Sclerosis Study Group. Multiple Sclerosis 2000;6(4):255-66. KP, Copolymer Multiple Sclerosis Treatment Group. Effects of copolymer on neurologic disability in patients with relapsing- remitting multiple sclerosis: results of a phase III trial. Journal of Neurology 1995;242:S38 (Abstract). Schiffer RB, KP, BR, et al. Copolymer-1 reduces the relapse rate and positively influences disability in relapsing- remitting multiple sclerosis: results of a phase III multi-center double-blind, placebo- controlled trial. European Journal of Neurology 1995;2:103 (Abstract). References to studies excluded in this review Abramsky 1977 Abramsky O, Teitelbaum D, Arnon R. Effect of a synthetic polypeptide (COP 1) on patients with multiple sclerosis and with acute disseminated encephalomeylitis. Preliminary report. Journal of Neurolological Sciences 1977;31(3):433-8. [Context Link] Baumhefner 1988 Baumhefner RW, Tourtellotte WW, Syndulko K, Shapshak P, Osborne M, Rubinshtein G. Copolymer 1 as therapy for multiple sclerosis: the cons. Neurology 1988;38(7 Suppl 2):69-72. [Context Link] Bornstein 1982 Bornstein MB, AI, Teitelbaum D, Arnon R, Sela M. Multiple sclerosis: trial of a synthetic polypeptide. ls of Neurology 1982;11(3):317-9. [Context Link] Brenner 2001 Brenner T, Arnon R, Sela M, Abramsky O, Meiner Z, Riven Kreitman R, et al. Humoral and cellular immune responses to Copolymer 1 in multiple sclerosis patients treated with Copaxone. Journal of Neuroimmunology 2001;115(1-2):152-160. [Context Link] Chen 2001 Chen M, Gran B, Costello K, K, R, Dhib-Jalbut S. Glatiramer acetate induces a Th2-biased response and crossreactivity with myelin basic protein in patients with MS. Multiple Sclerosis 2001;7(4):209-19. [Context Link] Cohen 1995 Cohen JA, Grossman RI, Udupa JK, Smatasekera S, Miki Y, Polansky M, et al. Assessment of the efficacy of Copolymer-1 in the Treatment of Multiple Sclerosis by Quantitative MRI. Neurology 1995;45(Suppl 4). [Context Link] Constantinescu 2000 Constantinescu CS, Freitag P, Kappos L. Increase in serum levels of uric acid, an endogenous antioxidant, under treatment with glatiramer acetate for multiple sclerosis. Multiple Sclerosis 2000;6(6):378-81. [Context Link] De Seze 2000 De Seze J, Edan G, Labalette M, Dessaint JP, Vermersch P. Effect of glatiramer acetate (Copaxone) given orally in human patients: interleukin-10 production during a phase 1 trial. ls of Neurology 2000;47(5):686. [Context Link] Duda 2000 Duda PW, Schmied MC, Cook SL, Krieger JI, Hafler DA. Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. Journal of Clinical Investigation 2000;105(7):967-76. [Context Link] Farina 2001 Farina C, Bergh FT, Albrecht H, Meinl E, Yassouridis A, Neuhaus O, Hohlfeld R. Elispot assay detects COP-induced interleukin-4 and interferon-gamma response in blood cells. Brain 2001;124(4):705-719. [Context Link] Flechter 2002a Flechter S, Kott E, Steiner-Birmanns B, Nisipeanu P, Korczyn AD. Copolymer 1 (glatiramer acetate) in relapsing forms of multiple sclerosis: open multicenter study of alternate-day administration. Clinical Neuropharmacology 2002;25(1):11-5. [Context Link] Flechter 2002b Flechter S, Vardi J, Pollak L, Rabey JM. Comparison of glatiramer acetate (Copaxone) and interferon beta-1b (Betaferon) in multiple sclerosis patients: an open-label 2-year follow-up. Journal of Neurological Sciences 2002;197(1-2):51-55. [Context Link] Fusco 2001 Fusco C, Andreone V, Coppola G, Luongo V, Guerini F, Pace E, et al. HLA-DRB1*1501 and response to copolymer-1 therapy in relapsing- remitting multiple sclerosis. Neurology 2001;57(11):1976-79. [Context Link] Karandikar 2002 Karandikar NJ, Crawford MP, Yan X, Ratts RB, Brenchley JM, Ambrozak DR, et al. Glatiramer acetate (Copaxone) therapy induces CD8+ T cella response in patients with multiple sclerosis. Journal of Clinical Investigation 2002;109(5):641-9. [Context Link] Khan 2001 Khan OA, Tselis AC, Kamholz JA, Garbern JY, RA, k RP. A prospective, open-label treatment trial to compare the effect of IFNbeta-1a (Avonex), IFNbeta-1b (Betaseron), and glatiramer acetate (Copaxone) on the relapse rate in relapsing-remitting multiple sclerosis: results after 18 months of therapy. Multiple Sclerosis 2001;7(6):349-53. [Context Link] Kott 1997 Kott, Kessler. Optic Neuritis in Multiple Sclerosis Patients Treated with Copaxone. Journal of Neurology 1997;244:S23-24. [Context Link] Liu 2000 Liu C, Blumhardt LD. Benefits of glatiramer acetate on disability in relapsing-remitting multiple sclerosis. An analysis by area under disability/time curves. The Copolymer 1 Multiple Sclerosis Study Group. Journal of Neurological Sciences 2000;181(1-2):33-7. [Context Link] Mancardi 1998 Mancardi GL, Sardanelli F, Parodi RC, Melani E, Capello E, et al. Effect of copolymer-1 on serial gadolinium-enhanced MRI in relapsing remitting multiple sclerosis. Neurology 1998;50(4):1127-33. [Context Link] Meiner 1997 Meiner Z, Kott E, Schechter D, et al. Frontiers in Multiple Sclerosis: Clinical Research and Therapy 1997; Dunitz, London, 213-21Abramsky O, Ovadia H. [Context Link] 1998 A, Shapiro S, Gershtein R, Kinarty A, Rawashdeh H, Honigman S, et al. Treatment of multiple sclerosis with copolymer-1 (Copaxone): implicating mechanisms of Th1 to Th2/Th3 immune-deviation. Journal of Neuroimmunology 1998;92(1-2):113-21. [Context Link] Qin 2000 Qin Y, Zhang DQ, Prat A, Pouly S, Antel J. Characterization of T cell lines derived from glatiramer-acetate-treated multiple sclerosis patients. Journal of Neuroimmunology 2000;108(1-2):201-6. [Context Link] Sormani 2002 Sormani MP, Bruzzi P, Comi G, Filippi M. MRI metrics as surrogate markers for clinical relapse rate in relapsing-remitting MS patients. Neurology 2002;58(3):417-21. [Context Link] Weinstein 1999 Weinstein A, Schwid SI, Schiffer RB, McDermott MP, Giang DW, Goodman AD. Neuropsychologic status in multiple sclerosis after treatment with glatiramer. Archives of Neurology 1999;56(3):319-24. [Context Link] Wolinsky 2001 Wolinsky JS, Narayana PA, KP. MRI and clinical correlates. Multiple Sclerosis Study Group and the MRI Analysis Center. Multiple Sclerosis 2001;7(1):33-41. [Context Link] References to ongoing studies Markowitz 2000a Study contact information not provided. Contact reviewer for more information. Ongoing study Starting date of trial not provided. Contact reviewer for more information. [Context Link] Markowitz C. A multinational, multicenter, double-blind, placebo- controlled study to evaluate the efficacy, tolerability and safety of glatiramer acetate for injection in primary progressive multiple sclerosis patients. http://www.uphs.upenn.edu/neuro/clintrial/MS- Promise-Markowitz.htm 2000. Markowitz 2000b Study contact information not provided. Contact reviewer for more information. Ongoing study Starting date of trial not provided. Contact reviewer for more information. [Context Link] Markowitz C. A multinational, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, tolerability and safety of 2 doses of glatiramer acetate orally administered in relapsing remitting multiple sclerosis patients. http://www.uphs.upenn.edu/neuro/clintrial/MS-Coral-Markowitz.htm 2000. Teva 2002 Study contact information not provided. Contact reviewer for more information. Ongoing study Starting date of trial not provided. Contact reviewer for more information. [Context Link] Teva Pharmaceutical Industries Ltd. Teva reports results from oral copaxone study. http://www.copaxone.com . Additional references Brocke 1996 Brocke S, Gijbels K, Allegretta M, Ferber I, Piercy C, Blankenstein T, et al. Treatment of experimental encephalomyelitis with a peptide analogue of myelin basic protein. Nature 1996;379(6563):343-46. [Context Link] Ge 2000 Ge Y, Grossman RI, Udupa JK, Fulton J, Constantinescu CS, - Scarono F et al. Glatiramer acetate (Copaxone) treatment in relapsing- remitting MS: quantitative MR assessment. Neurology 2000;54(4):813- 17. [Context Link] Jadad 1996 Jadad A, A, Carroll D. Assessing the quality of randomised trials: is blinding necessary?. Controlled clinical trials 1996;17 (1):1-12. [Context Link] Kurtzke 1983 Kurtzke JF. Rating neurological impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33(11):1444- 52. [Context Link] Mancardi 2000 Mancardi GL, Murialdo A, Drago F, Brusati C, Croce R, Inglese M, et al. Localized lipoatrophy after prolonged treatment with copolymer 1. Journal of Neurology 2000;247(3):220-1. [Context Link] Moulin 1988 Moulin DE, Foley KM, Ebers GC. Pain syndromes in multiple sclerosis. Neurology 1988;38(12):1830-34. Poser 1983 Poser CM, Paty DW, Scheinberg L, Mc WI, FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. ls of Neurology 1983;13(3):227-31. [Context Link] Prentice 1989 Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med 1989;8(4):431-440. [Context Link] Teitelbaum 1997 Teitelbaum D, Arnon R, Sela M. Coplymer 1: from basic research to clinical application. Cellular and Molecular Life Sciences: CMLS 1997;53(1):24-28. [Context Link] Tourtellotte 1983 Tourtellotte WW et al. Multiple Sclerosis 1983; and Wilkins, Baltimore, 513-578Hallpike JF et al. Whitehead 1994 Whitehead A, NM. A meta-analysis of clinical trials involving different classifications of response into ordered categories. Statistics in Medicine 1994;13(23-24):2503-15. Wisniewski 1977 Wisniewski HM, AB. Chronic relapsing experimental allergic encephalomyelitis: an experimental model of multiple sclerosis. ls of Neurology 1977;1(2):144-8. [Context Link] Yusuf 1985 Yusuf S, Peto R, J, R, Sleight P. Beta-blockade during and after myocardial infarction: an overview of the randomised trials. Progress in Cardiovascular Diseases 1985;27(5):335-71. [Context Link] -- In low dose naltrexone , noclue915@a... wrote: > I do not believe LDN is included in these stats.These were for CRABS only. Quote Link to comment Share on other sites More sharing options...
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