INCOMIN and EVIDENCE

INCOMIN trial Avonex v. Betaseron 188 patients with RRMS , two years study, single blinding (patients were not blinded) 51 % of Betaseron patients were relapse free, v. 36 % of Avonex patients; 55 v. 26 % were free from new T2 lesions (favoring betaseron patients).

EVIDENCE-- Avonex v.Rebif-- 677 patients, outcome at 24 weeks, followed for 48 weeks, single blinded (like INCOMIN). The percentage of relapse free was 74.9 % for Rebif, 63 % for Avonex. There were more NABS in Rebif group and they did worse than the Rebif patients without NABS but better than the Avonex patients.

Copolymer (copaxone) pivotal trial

Studied patients with RRMS, 18-45, EDSS 0-5, 2 exacerbations or more in 2 years, stable for thirty days. 251 patients (73 percent female) with endpoint relapse rate. Exacerbation rate decreased significantly, disability not robust data. Confirmed progression of not close to significance but EDSS was marginally significant.

The followup study with MRI European/Canadian confirmed a 33 % reduction in exacerbations, and a 35 % reduction in enhancing lesions.

Rebif pivotal trial

560 patients RRMS 18-50 >= 2 exacerbations over 2 years, EDSS 0-5, no exacerbations for two months prior to study entry, 3 arms, placebo, 22 and 44 ug three times a week, two year followup. All four outcome measures, exacerbation rate, percentage of exacerbation free patients, MRI attack rate, and confirmed progression of disability were helped (confirmed progression was marginal). Higher dose suggestedmore efficacy but the data was not significantly robust on that point.

Avonex pivotal trial

301 patients with rrms 18-55, >2 exacerbations over three years, EDSS 0-3.5, none within two months, placebo v. 1 treatment dose, followed for two years. Result was a decreased exacerbation rate, slightly less than betaseron, decreased progression and attack rate, but burden of disease on MRI was not significant. Barry Arnason called these results "marginal." However, he stated it was the first independent confirmation of the betaseron trial.

Betaseron trials-- four main ones

Pivotal trial-- placebo 123, .05 mcg B 125, .25 mg 125. Primary endpoints were exacerbation rate and % of exacerbation free patients. 72/372 failed to complete their assigned treatment (19%). Exacerbation rates was 1.31, 1.14, and 0.9 respectively in the three groups favoring .25 dose. The % exacerbation free was 16, 18, and 25 respectively.

Two secondary progressive trials, European and North American. In European trial the primary outcome variable was disability, a one point increase on EDSS or 0.5 increase if the EDSS was greater than 6. Patients with CDMS or SPMS were enrolled, 360 patients with MS and 358 with placebo. Patients needed to sustain EDSS for six months prior to study entry. One dose of Betaseron was used. The time to increased EDSS was greater in patients receiving Betaseron. There was less MRI activity in the betaseron group. The relapse rate was .42 in the betaseron group, .63 in the placebo group. These results were highly significant the trial was stopped in the middle and led to approval of Betaseron for SPMS.

In the North American trial for MS, there was no significant difference between the groups.

Natalizumab v. interferons with cost measure

NEW YORK (Reuters Health) May 11 - Natalizumab is comparable to interferon beta-1a in the net health benefits it provides for relapsing multiple sclerosis, an analysis of published data suggests. Previous reports have shown natalizumab to be effective in preventing relapsing and slowing disease progression, but the drug has also been linked to an increased risk of progressive multifocal leukoencephalopathy (PML), which often proves fatal. Whether the benefits of natalizumab provides offsets this risk is unclear. In the current study, Dr. Ray Dorsey, from the University of Rochester Medical Center in New York, and colleagues analyzed published data to assess the quality-adjusted life years (QALYs) gained with natalizumab. A comparison was then made with interferon beta-1a. Data for the natalizumab analysis was drawn from the Natalizumab Safety and Efficacy in Relapsing Multiple Sclerosis (AFFIRM) trial, while the interferon data came from the Prevention of Relapses and Disability by Interferon Beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study. Each study lasted roughly 2 years. The investigators report their findings in the May 1st issue of Neurology. The authors found that in terms of the effect on QALYs, natalizumab was minimally more effective than interferon at reducing disease relapses. The agents were comparable in their ability to slow disease progression. Because natalizumab did carry a slight risk of PML, the final net health effect of the drugs was nearly identical - 0.033 QALYs gained. 'Over the first 2 years of therapy, the health effect of natalizumab for the treatment of relapsing multiple sclerosis is much greater than the expected harm from PML,' the authors conclude. Still, they write, long-term observational studies are needed to fully characterize the risk of PML with this drug. Neurology 2007;68:1524-1528. Multiple Sclerosis (MS) Reuters Health Information 2007. 2007 Reuters Ltd.

Sleep Disturbance and fatigue in Multiple Sclerosis

Attarian HP et al. Arch Neurol 2004;61:525-528. (Wash U). Authors uued a case control format to compare 15 patients with MS anf fatigue, 15 MS patients without fatigue and 15 age/sex matched healthy controls. Tools were Fatigue Descriptive Scale, Epworth Sleepiness Scale. The MS patients with fatigue included 2 with delayed sleep phase, 10 with disrupted sleep, and 3 with normal sleep. 12/15 MS patients had normal sleep. The healthy controls had normal sleep.

laquimod at AAN

The oral immunomodulatory agent laquinimod significantly reduces MRI-measured disease activity in relapsing–remitting multiple sclerosis (RRMS) patients, according to results from a phase IIb study in humans. Laquinimod appears to act by modulating the Th1/Th2 balance and inducing the Th3 cytokine transforming growth factor (TGF)-ß. The efficacy of this agent at a dose of 0.3 mg/d was previously established in a 24-week phase II trial in RRMS patients. To assess the effects of 2 different doses of this agent on MRI-monitored disease activity, Giancarlo Comi, University Hospital San Raffaele, Milan, Italy, and colleagues randomized 306 RRMS patients to daily placebo (n=102) or daily doses of laquinimod 0.3 mg/d (n=98) or 0.6 mg/d (n=106) over a period of 36 weeks. All patients were required to have had 1 or more relapses in the year prior to study entry and at least 1 enhancing lesion at screening. Baseline demographic, clinical, and MRI characteristics were comparable for all patient groups. No significant treatment differences were seen for the 0.3 mg dose, reported Dr. Comi. However, significant differences in favor of the 0.6 mg dose over placebo were found for the cumulative number of enhancing lesions/scan in the last 4 scans (2.6±5.3 vs 4.2±9.2; P=0.0048) and for most secondary and exploratory MRI-based outcome measures. In addition, trends in favor of the 0.6 mg dose over placebo were demonstrated for annual relapse rate (0.52±0.92 vs 0.77±1.25; P=0.21), relapse-free patients (70.8% vs 62.7%; P=0.33), and time to first relapse ( P=0.14). Both doses of laquinimod were well tolerated, with only some transient and dose-dependent increases in liver enzymes. Overall, these results support the continued study of the 0.6 mg dose of laquinimod for the treatment of RRMS, concluded Dr. Comi.

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Daclizumab in multiple sclerosis

The monoclonal antibody daclizumab, which is currently used to prevent rejection in organ transplantion recipients, also shows efficacy in the treatment of multiple sclerosis (MS) patients, reported Eman Ali, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, and colleagues. Almost two-thirds of patients who received this agent in a recent clinical trial experienced an improvement or stabilization in Expanded Disability Status Scale (EDSS) scores. Daclizumab is a humanized monoclonal antibody directed against the interleukin (IL)-2 receptor a subunit that is expressed on activated T cells. According to Dr. Ali, daclizumab may be efficacious in MS because of its ability to block this receptor subunit, thereby inhibiting IL-2 signaling, limiting T-cell expansion, and reducing brain inflammation. Dr. Ali and colleagues conducted a retrospective study of this agent in 40 relapsing–remitting MS (RRMS) patients and 15 secondary–progressive MS (SPMS) patients for a mean period of 13 months, most of whom were also receiving ß-interferon treatment. The investigators found that EDSS scores improved in 20% of patients, stabilized in 40%, and worsened in 40%. Treatment effects were more favorable in RRMS patients, with about 63% showing improvement or stabilization. In SPMS patients, improvement or stabilization was seen in about 53% of patients. In a subgroup of 28 patients, the tolerability of the drug was evaluated by a 0–10 visual analogue scale (0=very well tolerated, 10=not tolerated), and the average score was shown to be 1.87. Fatigue and nausea were the most common side effects followed by skin rash.

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AAN 2007 BENEFIT STUDY

Three-year data from the BENEFIT study suggest that, in patients with clinically isolated syndrome (CIS), immediate treatment with interferon (IFN) ß-1b significantly delays progression to clinically definite multiple sclerosis (CDMS). These findings provide further evidence that early treatment, even when administered at the first event suggestive of MS, provides long-term benefits for patients. In the BENEFIT study, 468 CIS patients with MRI findings suggestive of MS were treated with subcutaneous IFN ß-1b (250 µg; n=292) or placebo (n=176) every other day until either a diagnosis of CDMS was attained or they reached 2 years of evaluation. Patients were then eligible to receive open-label IFN ß-1b for up to 5 years after start of double-blind treatment. According to Mark Freedman, University of Ottawa, Ottawa, Canada, this is the first prospectively planned, controlled, multicenter trial to address the impact of randomly assigned immediate vs later initiation of IFN ß-1b (250 µg) therapy at the time of CIS on the further evolution to MS. A total of 418 patients have enrolled in the open-label phase of the study, 261 of whom were previously treated with IFN ß-1b (96%); 157 of whom were previously treated with placebo. Three years after the start of the double-blind study, 37% of those who had received IFN ß-1b from the start and 51% of those who originally received placebo had fulfilled the criteria for CDMS, reported Dr. Freedman. In addition, confirmed Expanded Disability Status Scale (EDSS) progression was seen in 16% of early treatment patients, compared with 24% of delayed treatment patients; this corresponded to a 40% risk reduction after 3 years ( P=0.0218). Differences in EDSS scores did not appear to be affected by changes in relapse rates between the 2 groups.

Comment-- this study has the same pitfalll as the other extension studies in multiple sclerosis with a biased sample for inclusion in the extension trial. Biases include selection bias and others.   

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