High-dose simvastatin (Zocor) significantly reduced brain atrophy and slowed advancement of disability for 2 years in patients with secondary progressive multiple sclerosis, researchers said here.

In a 140-patient randomized trial, patients receiving 80 mg/day of simvastatin had an annualized rate of brain volume loss of just 0.298% compared with 0.589% among those given placebo (P=0.003), reported Jeremy Chataway, MA, PhD, of University College London in England.

Significant reductions in disability progression, as measured by EDSS and MS Impact Score (MSIS), were also seen with simvastatin in the trial, he told attendees at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis.

On the other hand, differences between the treatment groups in specific functional outcomes, such as walking ability and hand dexterity, did not reach statistical significance.

But, Chataway noted, despite the high dose of simvastatin, adverse effects were similar between groups and there were no cases of serious muscle toxicity. "Treatment was generally very well tolerated," he said.

With the advent of several effective drugs to prevent MS relapses, the major unmet clinical need in the disease is treatment for progressive forms. Most patients with relapsing-remittingMS eventually develop the secondary progressive form, in which disability continues to increase even though acute attacks have stopped.

Because statin drugs have a range of anti-inflammatory effects, apart from their cholesterol-lowering activity, they have attracted attention as a possible therapy for MS.

A 2004 trial in patients with relapsing-remitting MS showed reductions in brain lesions as seen in MRI scans, suggesting an effect on the underlying disease process. Other trials were conducted in this form of the disease, which ultimately pointed to a lack of clinical benefit.

But researchers now believe that the disease changes its basic nature when converting from relapsing-remitting to progressive, such that statins might have more benefit at the later stage.

That prompted the current trial, in which patients with established secondary progressive MS were randomized to high-dose simvastatin or placebo for 2 years.

The investigators chose brain atrophy as the trial's primary endpoint because, Chataway told MedPage Today, they wanted to mainly evaluate effects on the underlying disease process at this stage of development. He said that a phase III trial would ideally use clinical outcomes as primary endpoints.

Brain MRI scans were performed 2 weeks before starting treatment, after 1 year, and after 2 years, with the final scan taken 30 days after the last drug dose. Ten patients had missing or inadequate MRIs, leaving 130 in the efficacy analysis.

Mean participant age was about 51, with an average duration of progressive MS of 7 years. About two-thirds of the sample were women. Some 14% had experienced a relapse within the past year and 18% had had one within the previous 2 years, with a higher rate of such relapses in patients randomized to placebo.

Median EDSS score at baseline was 6, with a mean of 5.8. Mean MSIS score was 70.

Patients assigned to simvastatin received 40 mg/day for the first month, with the dosage then increased to 80 mg/day for the remainder of the study. Compliance was good, with 70% to 90% of patients taking the full protocol dose at any given point.

For the primary outcome of annualized reduction in total brain volume, the difference between the simvastatin and placebo groups came to 0.254 percentage points favoring the statin group (95% CI 0.085 to 0.423).

The following secondary outcomes, expressed as the difference in change from baseline with simvastatin versus placebo, also showed a significant advantage for active treatment:

EDSS score: -0.254 (95% CI -0.464 to -0.069)
MSIS total score: -4.78 (95% CI -9.39 to -0.02)
MSIS physical subscore: -3.73 (95% CI -7.18 to -0.28)

Chataway noted that about 10% of patients in the simvastatin group showed an actual improvement of at least 0.5 points relative to baseline in EDSS scores, compared with no one in the placebo group.

All other secondary clinical outcome measures also favored simvastatin but failed to reach statistical significance. These included the MSIS psychological subscore and functional abilities evaluated with the MS Functional Composite index, both overall and for individual types of activity.

No differences between treatment groups were seen in the number or rate of new and enlarging T2 lesions or in relapses, but Chataway told MedPage Today that such results would be expected in the secondary progressive population.

About 20% of patients in both groups had adverse events judged by the blinded investigators as treatment-related. Chataway said the group was on alert for muscle-related complaints because of the high statin dose used, but the concerns were not borne out.

He told MedPage Today that not only was a phase III trial warranted in secondary progressive MS, but also a phase II study in primary progressive MS.

At a press conference held after Chataway's report, leaders of ECTRIMS said the findings were encouraging but that it was too soon to say that simvastatin is effective against secondary progressive MS.

Michel Clanet, MD, the group's president, pointed out that brain atrophy was a surrogate outcome. Before clinicians should consider prescribing statins in this population, there will need to be conclusive proof of disability prevention, he suggested.

ECTRIMS Secretary Xavier Montalban, MD, echoed the comment. "We need that bridge"between surrogate and clinically relevant outcomes, he said.

The chair of the 2012 meeting, Christian Confavreux, MD, added that the data on brain atrophy were incomplete. Although the study demonstrated a reduction in loss of total brain volume, he noted that it remained unclear, for example, whether that reflected preservation of actual brain tissue or merely the prevention of water loss.

The study was supported by the Moulton Charitable Foundation, Berkeley Group, the Multiple Sclerosis Trials Collaboration, and the U.K. National Institute of Health Research.

All study authors declared they had no relevant financial interests.

Clanet reported consulting/speaking fees from Genzyme, Biogen Idec, and Bayer Schering and research grants from Bayer Schering, Biogen Idec, Merck Serono, Novartis, sanofi aventis and Teva Pharma.

Confavreux reported consulting fees from Biogen Idec, Genzyme, Novartis, Merck Serono, sanofi aventis, Teva Pharma, and UCB Pharma; lecture fees from Bayer-Schering, Biogen Idec, Genzyme, LFB, Merck Serono, sanofi aventis and Teva Pharma; and research support from Bayer-Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, sanofi aventis and Teva Pharma.

Montalban reported relationships with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG.

Primary source: European Committee for Treatment and Research in Multiple Sclerosis
Source reference:
Chataway J, et al "The MS-STAT trial: High dose simvastatin demonstrates neuroprotection without immune-modulation in secondary progressive multiple sclerosis (SPMS) – a phase II trial" ECTRIMS 2012; Abstract 38a.

Source: MedPage Today © 2012 MedPage Today, LLC (10/10/12)