David Ladkani

Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial

To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis.

A prospective open-label study of glatiramer acetate: Over a decade of continuous use in multiple sclerosis patients

A decade of continuous glatiramer acetate (GA) use by relapsing remitting multiple sclerosis (RRMS) patients was evaluated in this ongoing, prospective study, and the neurological status of ‘Withdrawn’ patients was assessed at a 10-year long-term follow-up (LTFU) visit. Modified intention-to-treat (mITT, n=232) patients received ≥ 1 GA dose since 1991; ‘Ongoing’ patients (n=108) continued in November 2003. Of 124 patients, 50 Withdrawn patients returned for LTFU. Patients were evaluated every six months (EDSS). Mean GA exposure was 6.99, 10.1 and 4.26 years for mITT, Ongoing, and Withdrawn/LTFU patients, respectively. While on GA, mITT relapse rates declined from 1.18/year prestudy to ∼1 relapse/5 years; median time to ≥ 1 EDSS point increase was 8.8 years; mean EDSS change was 0.739±1.66 points; 58% had stable/improved EDSS scores; and 24, 11 and 3% reached EDSS 4, 6 and 8, respectively. For Ongoing patients, EDSS increased 0.509±1.65; 62% were stable/improved; and 24, 8 and 1% reached EDSS 4, 6 and 8, respectively. For Withdrawn patients at 10-year LTFU, EDSS increased 2.249±1.86; 28% were stable/improved; and 68, 50 and 10% reached EDSS 4, 6 and 8, respectively. While on GA nearly all patients (mean disease duration 15 years) remained ambulatory. At LTFU, Withdrawn patients had greater disability than Ongoing patients.

Effects of glatiramer acetate on relapse rate and accumulated disability in multiple sclerosis: meta-analysis of three double-blind, randomized, placebo-controlled clinical trials

Three randomized, double-blind, placebo-controlled trials have shown that glatiramer acetate (GA) is effective in reducing relapse rate in patients with relapsing-remitting (RR) multiple sclerosis (MS). Using raw data pooled from 540 patients, we performed a meta-analysis of these three trials, to investigate whether the extent of G A efficacy varies according to disease-related variables at study entry. Three regression models were developed to assess the efficacy of G A on the annualized relapse rate (primary outcome measure), on the total number of on-trial relapses and on the time to first relapse. We also explored the efficacy of G A on accumulated disability and the potential role of baseline clinical variables as predicto rs of relapse-rate variables and treatment efficacy. The mean adjusted annualized relapse rate on study was 1.14 in the pooled placebo -treated subjects and 0.82 in the pooled GA group (P =0.004), indicating an average reductio n in annualized relapse rate of 28%. A bout a one third reductio n of the total number of on-trial relapses was also observed in patients receiving GA (P B-0.0001), who had a median time to the first relapse of 322 days versus a median time to the first relapse of 219 days seen in those receiving placebo (P =0.01). A beneficial effect on accumulated disability was also found (risk ratio of 0.6; 95%; C I =0.4-0.9; P =0.02). The drug assignment (P =0.004), baseline EDSS score (P =0.02) and number of relapses during the two years prior to study entry (P =0.002) were significant predicto rs of on-trial annualized relapse rate. No other demographic or clinical variable at baseline significantly influenced the treatment effect. This meta-analysis reaffirms the effectiveness of G A in reducing relapse rate and disability accumulatio n in RRMS, at a magnitude comparable to that of other available immunomodulating treatments. It also suggests that G A efficacy is not significantly influenced by the patients’ clinical characteristics at the time of treatment initiation.

Randomized, double-blind, dose-comparison study of glatiramer acetate in relapsing–remitting MS

Objective: To evaluate the safety, tolerability, and efficacy of glatiramer acetate (GA) 40 mg daily vs the approved 20-mg formulation in relapsing–remitting multiple sclerosis. Methods: Eligibility criteria included clinically definite multiple sclerosis, Expanded Disability Status Scale score 0 to 5.0, no previous use of GA, at least one relapse in the previous year, and 1 to 15 gadolinium-enhancing (GdE) lesions on a screening MRI. MRI was repeated at months 3, 7, 8, and 9, and neurologic examinations were performed at baseline and months 3, 6, and 9. Results: Of 229 subjects screened, 90 were randomly assigned to GA 20 mg (n = 44) or 40 mg (n = 46). The groups were well matched at baseline for demographic, clinical, and MRI characteristics. The primary efficacy endpoint, total number of GdE lesions at months 7, 8, and 9, showed a trend favoring the 40-mg group (38% relative reduction, p = 0.0898). A difference between the two dose groups emerged as early as month 3 (52% reduction; p = 0.0051). There was a trend favoring the 40-mg group for relapse rate with benefit on proportion of relapse-free subjects (p = 0.0183) and time to first relapse (p = 0.0367). GA 40 mg was well tolerated, with an overall safety profile similar to that of 20 mg. Some features of injection site reactions and immediate postinjection reactions were more common and severe with the higher dose. Conclusions: Glatiramer acetate (GA) 40 mg was safe and well tolerated. The overall efficacy results suggested that a 40-mg dose of GA may be more effective than the currently approved 20-mg daily dose in reducing MRI activity and clinical relapses.

Copaxone’s effect on MRI-monitored disease in relapsing MS is reproducible and sustained

All but 6% of the subjects with relapsing remitting MS who were randomly assigned to receive glatiramer acetate or placebo for the 9-month controlled phase of the European/Canadian MRI trial entered an open-label extension with quarterly clinical and MRI evaluations for another 9 months. There was a 54% reduction in the mean number of enhanced lesions for those converted from placebo to glatiramer acetate and an additional 24.6% reduction for those always on glatiramer acetate. Over the entire study the accumulated T2 disease burden was 34.2% less for those always on glatiramer acetate.

Long-term follow-up of patients treated with glatiramer acetate: a multicentre, multinational extension of the European/Canadian double-blind, placebo-controlled, MRI-monitored trial

Glatiramer acetate (GA) is effective in reducing clinical and magnetic resonance imaging (MRI) activity in relapsing-remitting multiple sclerosis (RRMS). Serial long-term MRI data are lacking for large cohorts of GA-treated patients. The European/Canadian GA study consisted of two consecutive phases, each lasting nine months. The first treatment phase was randomized, double-blind and placebo-controlled. The second was an open-label, active treatment phase with daily administration of 20 mg GA subcutaneously for all patients. For the long-term follow-up (LTFU), dual echo, pre- and postgadolinium T1-weighted brain MRI scans were obtained with the same acquisition scheme as for the original trial and a neurological assessment was performed. Lesion volumes, normalized brain volumes and percentage brain volume changes (PBVC) were measured. One hundred and forty-two (63.4%) of the 224 patients who completed the two phases of the European/Canadian study underwent the LTFU after a mean period of 5.8 years (range: 5.3-6.4); 73 were treated with GA from study initiation. MRI measures at LTFU did not significantly differ between patients originally assigned to placebo and those who were always treated with GA, but the proportion of patients who did not require walking aids at LTFU was lower in the latter group (P=0.034). PBVC between baseline and LTFU was significantly correlated with lesion load at study entry. An earlier initiation of GA treatment in patients with active RRMS might, at least partially, have a favourable impact on long-term disease evolution. Multiple Sclerosis 2007; 13: 502-508. http://msj.sagepub.com

Effect of Alfacalcidol on multiple sclerosis-related fatigue: A randomized, double-blind placebo-controlled study

Context: Fatigue is one of the most common and disabling symptoms of multiple sclerosis (MS); however, there is no medication that has been approved specifically to treat MS-related fatigue. Objective: We aimed to evaluate the effect of vitamin D analogue, Alfacalcidol, on MS-related fatigue. Design, settings, participants: This was a randomized, double-blind, parallel group, placebo-controlled trial in patients with clinically definite MS by McDonald criteria conducted in a single university-affiliated medical center in Israel. Randomly selected patients from the Sheba MS Registry computerized database (N=600) were assessed using the self-report Fatigue Severity Scale (FSS). Patients with clinically meaningful fatigue (N=259) were further assessed for trial eligibility, and MS patients with significant fatigue (N=158; 61%, 118 females, mean age 41.1 ± 9.2 years and mean disease duration of 6.2 ± 5.5 years) were included in the study and randomized to receive treatment or placebo. Intervention: Alfacalcidol (1 mcg/d, N=80) or placebo (N=78) was administered for six consecutive months. Main outcome measure: The primary endpoint of the study was the change between Alfacalcidol and placebo-treated patients in the Fatigue Impact Scale (FIS) score; the cut-off point for improvement was defined as 30% decrease. All analyses followed the intention-to-treat principle and were performed for all participants based on the group they were randomly allocated regardless of whether or not they dropped out. Results: Alfacalcidol decreased the mean relative FIS score as compared with placebo (–41.6% vs. –27.4%, p=0.007, respectively). This advantage was further emphasized when the modified FIS (MFIS) relative change was calculated. Quality of Life (QoL) improved in Alfacalcidol-treated patients as compared with placebo in the RAYS psychological (p=0.033) and social (p=0.043) sub-scales. The Alfacalcidol-treated group had reduced number of relapses (p=0.006) and higher proportion of relapse-free patients (p=0.007). Reduction of relapses by Alfacalcidol became significant at 4 months of treatment, was sustained at 6 months and decayed 2 months after drug discontinuation. Alfacalcidol treatment was safe and no serious adverse events were recorded. Conclusion: Alfacalcidol is a safe and effective treatment strategy to decrease fatigue and improve QoL in patients with MS.

Glatiramer acetate treatment in PPMS: Why males appear to respond favorably

In a large multicenter randomized, and double blind placebo controlled trial of glatiramer acetate (GA) in primary progressive multiple sclerosis (PPMS), an originally unplanned post hoc analysis suggested that males assigned to GA therapy experienced less progression of disability than their counterparts assigned to placebo; no similar potential treatment differences were seen among the females in this study. In this report we further explore the data from that trial in an attempt to determine if this outcome could have been the expression of a gender dependant treatment effect. The analyses conducted do not support a treatment by gender interaction for GA in either PPMS or relapsing forms of MS. Nor could we find consistent precedence in the literature for important effects of gender on outcome, recognizing that such effects have not always been carefully sought. It remains reasonable to consider that there exist differences in the rates of clinical disease progression between men and women with MS that should be better studied.

Effects of seasons on magnetic resonance imaging-measured disease activity in patients with multiple sclerosis.

The number of gadolinium (Gd)-enhancing lesions on monthly magnetic resonance imaging (MRI) scans of the brain is widely used to monitor multiple sclerosis (MS) clinical trials. In relapsing-remitting (RR) MS, serial monthly Gd-enhanced MRI scans are five to ten times more sensitive than clinical measures in detecting disease activity and, therefore, allow treatment effects to be investigated by studying fewer patients for shorter follow-up periods than when using clinically-based end points. In addition, counting the numbers of enhancing lesions is a very reproducible process in experienced hands, and it also allows the observers to be unaware of the treatment regimen of individual patients, thus avoiding bias due to unblinding. A retrospective study by Auer et al recently reported that the frequency and extent of Gd-enhancing lesions on serial MRI scans from MS patients is influenced by seasonal fluctuations, being significantly higher in the first than in the second half of the year. This study was, however, based on relatively small samples of patients and scans (202 scans were obtained from 53 patients, ie, an average number of less than four scans per patient) and the frequency of scanning was highly variable. Therefore, its results might have been heavily influenced by MRI findings from individual patients. Because the MRI activity at a given timepoint is significantly correlated with that seen during the previous and the subsequent months, a cluster of few scans with very high numbers of Gd-enhancing lesions could have artificially increased the average activity during certain periods. The month-to-month fluctuations of the number of enhancing lesions might, therefore, be a chance effect depending on the variable timing of patient sampling and on the high interpatient variability of MRI activity. Because Auer et al concluded that such a marked seasonal variation of Gd-enhancing lesions in MS patients may prevent us from reaching reliable conclusions from MRImonitored trials, we re-addressed this issue by studying the seasonal fluctuations of the number of Gd-enhancing lesions as seen on 11 consecutive brain MRI scans obtained every 4 weeks over a 10-month period from 120 RRMS patients, who were part of the untreated arm of a previous multi-center, randomized, double-blind, placebo-controlled trial. All the scans were collected between February 1997 and August 1998, using a standardized imaging protocol across the participating centers. The only treatment allowed during the study period was steroid for acute relapses. Enhancing lesions were counted by two experienced observers by consensus. The average number of enhancing lesions per scan was 4.1 (SD 5 7.1). The Figure shows the month-to-month variation of the mean number of enhancing lesions, which is higher in March [mean number of enhancing lesions (SD) 5 5.7 (9.5)] and lower in December [mean number of enhancing lesions (SD) 5 3.3 (5.0)]. To avoid interpretation bias due to the interpatient variability of MRI activity, we made a statistical analysis of the pairwise comparisons between the numbers of enhancing lesions during the four seasons in 92 patients who had at least one scan for each of the seasons (Friedman test for nonparametric data). The mean numbers of enhancing lesions (SD) were 4.4 (6.6), 5.1 (8.5), 4.5 (6.7), and 4.5 (7.6) for winter, spring, summer, and autumn, respectively. No significant difference of MRI activity between seasons was found. These results demonstrate that, although MRI activity in RRMS patients varies in the different seasons, this fluctuation is not significant. Our data were obtained from a large sample of patients with heterogeneous geographical origins, who were recruited from different European and Canadian centers. In addition, baseline MRI scans were collected over a period covering all the four seasons. For these reasons, our results should not be biased by other factors that are known to influence MS activity. In conclusion, the seasonal fluctuations of subclinical activity in patients with RRMS should not affect the interpretation of the results from MRImonitored clinical trials a great deal.

Once-daily glatiramer acetate decreases magnetic resonance imaging disease activity in Japanese patients with relapsing–remitting multiple sclerosis

Multiple sclerosis (MS) prevalence, clinical patterns, and treatment responses vary between races and geographical latitudes. Glatiramer acetate (GA; Copaxone) has provided a safe, effective treatment option for relapsing–remitting MS patients in the USA, European nations, and other countries for decades. The objective of the present study was to assess the safety and efficacy of GA in reducing magnetic resonance imaging disease activity in Japanese patients with active relapsing–remitting MS.