麻豆传媒

NEW ORLEANS -- Among patients with relapsing-remitting multiple sclerosis (MS), little clinical benefit was seen for combining glatiramer acetate (Copaxone) with interferon beta-1a (Avonex) versus either drug alone in a large randomized trial.

Annualized relapse rates during the 3-year study, using a rigorous definition of exacerbation, were 0.12 in the so-called CombiRx trial with a combination of glatiramer acetate and interferon, compared with 0.11 for glatiramer acetate alone (P=0.27) and 0.16 for interferon alone (P=0.02), Fred Lublin, MD, of Mount Sinai Medical School in New York City reported here.

Proportions of patients relapsing during the 3-year study were as follows:

• Combination: 23.1%
• Glatiramer acetate alone: 20.5% (P=0.21 versus the combination)
• Interferon alone: 26.0% (P=0.19 versus the combination)

Lublin reported the results Friday at the American Academy of Neurology's annual meeting. Unlike nearly every other study presented here, no outcomes data were included in the abstract released prior to the meeting.

The combination also failed to outperform the individual drugs in most other outcomes, including rates of disability progression and time to first relapse.

A report from the CombiRx trial earlier in the week focusing on MRI results was largely negative. The combination was better than either drug as monotherapy on a few measures of brain lesion counts and volumes, but for most there was no advantage over the best-performing monotherapy.

Glatiramer acetate and interferon-beta have been the mainstays of multiple sclerosis treatment for many years. Although most patients eventually relapse or progress while taking one of these agents, they usually switch treatments rather than add the other one.

Robert Fox, MD, of the Cleveland Clinic, told 麻豆传媒 that combination treatment is uncommon in routine practice -- because, for one thing, the drugs are expensive and insurance seldom pays for both at once.

With little experience, clinicians have not really known whether combining the two drugs would even be helpful, Fox said.

The CombiRx trial, funded by the National Institutes of Health, started in 2005. A total of 1,008 patients were enrolled through April 2009, with 3-year data finally locked earlier this month.

Patients were randomized to three study arms in a 2:1:1 ratio -- the combination or to one drug or the other as monotherapy, with a placebo-controlled, double-dummy, and double-blinded design.

Mean patient age was about 38, with an average disease duration of 4.3 years and just over a year after diagnosis when they enrolled in the study.

In addition to the strict definition of relapse used in the primary outcome measures, Lublin and colleagues also examined outcomes with a looser definition under which symptoms could be counted as a relapse when disability was not formally assessed within a week of onset.

Relapse rates with this definition naturally were higher -- about double those seen in the primary outcome. But the pattern was the same, with the combination and glatiramer monotherapy having nearly the same rates, and somewhat higher rates with interferon monotherapy.

In fact, Lublin said, glatiramer acetate was the clear winner between the two monotherapies in the primary outcome, annualized relapse rate. There were trends toward better outcomes with glatiramer on some other measures but they did not reach significance.

There was one outcome in which the combination did outperform the individual drugs: in the proportion of patients rated as free of disease activity, defined as absence of relapse, disability progression, and combined unique activity (CUA) lesions on MRI scans.

This outcome was met by 33.3% of patients in the combination arm versus 21.2% of the interferon group and 19.4% of those assigned to glatiramer acetate (both P<0.001 versus the combination).

Lublin said this outcome was driven by the MRI results. Although most MRI measures showed no advantage for the combination, there were significantly fewer CUA lesions in the combination group.

Serious adverse events were seen in 136 patients, with a total of 190 such events. However, there was no difference in rates among the three treatment arms, Lublin said.

He said more analyses would be conducted, as patients will continue to be followed for 7 years. He and his colleagues want to evaluate predictors of response and also whether the CUA lesion reduction in the combination group will eventually lead to better clinical results later on.

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