Allison Gandey

September 14, 2009

September 14, 2009 (Düsseldorf, Germany) — The trial that grabbed international headlines when first launched has come to an unsuccessful conclusion. Despite high hopes for a role for statins in multiple sclerosis, investigators presenting during the weekend here at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) described a failed atorvastatin trial.

The 18-month study known as STAYCIS was a randomized, double-blind, placebo-controlled trial. It explored the effect of 80 mg atorvastatin (Lipitor, Pfizer) in delaying or decreasing clinical and magnetic resonance imaging disease activity.

Investigators focused on patients with clinically isolated syndrome and magnetic resonance findings suggestive of multiple sclerosis. The trial design called for 152 patients but only recruited 82.

"We were underpowered to detect the planned effect," senior investigator Scott Zamvil, MD, from the University of California–San Francisco, told Medscape Neurology. "We had a lack of enrollment, and in hindsight, it was highly unlikely that we were ever going to make our primary endpoint with this design," Dr. Zamvil said. "A phase 2 study like this probably should have had a separate magnetic resonance imaging endpoint."

Dr. Scott Zamvil

The primary endpoint included the proportion of patients developing 3 new T2-bright brain foci or a new clinical exacerbation during the first 12 months.

During an interview, Henry McFarland, MD, acting chief of the cellular immunology section of the National Institutes of Health, said he agrees, "This trial definitely should have had a clinical endpoint or an imaging one." Attaining both was highly improbable, he noted.

Design issues aside, Dr. McFarland said the real problem was the lack of power. "If you start a study, you have an ethical obligation to see it through and do everything possible to ensure there is a sufficient cohort."

STAYCIS Trial Underpowered

Investigators had hoped that treatment with atorvastatin, known for having a good safety track record, would result in immunological tolerance. The trial was unsuccessful, however, which means that despite the work of investigators from the 14 centers involved and the efforts of the 82 patients recruited, the study question has no answer.

"This is very tragic," said session cochair Gavin Giovannoni, MBBCh, PhD, from the Institute of Cell and Molecular Science at Barts and the London School of Medicine and Dentistry, United Kingdom. "This is an ethical issue and really highlights how important it is to consider logistics and think things through," Dr. Giovannoni said.

This is very tragic.

Presenting during the late-breaking news session at the meeting, lead investigator Emmanuelle Waubant, MD, from the University of California–San Francisco, described a trial crippled by slow enrollment and recruitment problems.

When the trial was first launched in 2005, it was still common not to treat patients right away with disease-modifying therapy, she said. "This tended to delay the start of enrollment."

The success of other agents such as interferon also left clinicians questioning whether they should encourage patients to enter a statin trial — especially one with a placebo group. "Some institutions felt less comfortable enrolling patients to the study," Dr. Waubant added.

The 18-month trial was also a tough sell for patients who were scheduled to receive atorvastatin or placebo for 12 months and then no treatment for the remaining 6 months of the study. "Many patients decided not to participate in the trial for this reason," Dr. Zamvil said to Medscape Neurology.

"Still," he noted, "we saw a positive effect with therapy." Patients in the atorvastatin group were more likely to remain T2-lesion free compared with placebo (odds ratio, 3.93; P = .012 on 2-stage regression).

Proportion of Patients Free of New T2 Lesions*

T2 Lesions Atorvastatin (n = 49) Placebo (n = 32)
Free of lesions 55.3% 27.6%

*Up to 12 months or before starting interferon.

Patients in the atorvastatin group were also more likely to remain gadolinium-positive free (odds ratio, 2.70; P = .078).

"The effect was moderate, and there is still a lot we don't know," Dr. Zamvil said. "More work must be done."

This study was supported by the National Institute of Allergy and Infectious Diseases. It was managed by the Immune Tolerance Network and received partial support from Pfizer and Biogen-Idec.

25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis: Abstract 132. Presented September 12, 2009.

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