ARTICLE IN BRIEF
After 21 years, those randomized to take 250 mcg interferon early on in a clinical trial (in 1988) showed a significant reduction in all-cause mortality compared to the placebo group. And the risk of death for that group was 47 percent less than the placebo group, who went without active treatment for 3.8 years.
SAN DIEGO—In a follow-up study with almost complete capture of the original 372 multiple sclerosis patients (MS) who were randomized in a trial in 1988, researchers have found that survival rates for those treated with 250 microgram (mcg) of interferon beta early on were significantly better than those who did not get treatment during the early years.
After 21 years, those randomized to the 250 mcg interferon group showed a significant reduction in all-cause mortality compared to the placebo group (p=.0173). And the risk of death for that group was 47 percent less than the placebo group, who went without active treatment for 3.8 years.
“Data from the… study show a large and clinically important survival benefit for initial IFNB-1b treatment versus placebo in this cohort of patients, with the preponderance of mortality in the placebo arm adjudicated to be MS-related,” researchers said in the Bayer HealthCare Pharmaceuticals-funded study presented here at the annual meeting of the American Neurological Association.
Douglas Goodin, MD, medical director of the University of California, San Francisco Multiple Sclerosis Center, who led the study, said the findings might encourage patients to start medication sooner.
Because pivotal trials tend to focus on short-term outcomes, and because of logistical challenges, long-term results of drugs are often hard to come by. And that has been the case with interferon's effects on MS.
This study helps answer that question, said John Corboy, MD, professor of neurology at the University of Colorado, Denver School of Medicine, who was not involved with the research.
“The study's major importance is that it has been difficult to identify long-term benefits of early use of the MS drugs, and less death definitely would count as a benefit,” he said.
The pivotal trial included treatment-naïve patients with relapsing-remitting MS between ages 18 and 50, with an Expanded Disability Status Scale (EDSS) score of 5.5 or lower; they also had had two more clinical exacerbations in the previous two years.
In 1988, they were randomized to receive either 250 mcg of interferon beta, 50 mcg of interferon beta, or a placebo.
Patients took their assigned therapies for a median of 3.8 years, after which they all began to receive some kind of active treatment, as determined together with their doctors.
From October 2009 to December 2010, investigators searched vital records, public records, and the National Death Index to find out whether the patients were still alive.
They determined the status of 98 percent (366) of the patients; 81 (22 percent) had died. There were 37 deaths (31 percent) in the placebo group tracked down after 21 years —this compared with 22 deaths (18 percent) in the 250 mcg treatment group and 22 deaths (18 percent) in the 50 mcg treatment group. Twenty-six of the deaths in the placebo group were determined to be MS-related, compared with 16 in the 250 mcg group and 12 in the 50 mcg group.
Independent assessors determined whether a death was MS-related, Dr. Goodin said, based on an algorithm that was defined in advance. Causes of death were categorized into one of seven categories, including cardiovascular, cancer, pulmonary infection, sepsis and others, he said.
For example, if a person died of a pulmonary cause and was debilitated, that would have been considered an MS-related death, as would someone who'd had an EDSS score of above 7, Dr. Goodin said.
The hazard ratio for death in the 250 mcg group was 0.532 compared with placebo — a 47 percent reduction in death risk. The results were similar for the 50 mcg group, Dr. Goodin said, but those results weren't presented in detail.
Researchers also found that baseline factors proved to be independent of the effects of the treatment.
Dr. Goodin acknowledged that the results of the study donPt address whether taking interferon earlier affects the amount of disability patients will suffer — though a study now in press, with 70 percent capture of this same cohort after 16 years, shows some benefit in limiting disability.
“One of the things you'd like to be able to tell them — and I think there's less high-quality evidence for this — is that if you start early, at 20 years down the line, you're going to be less disabled,” Dr. Goodin said. “This doesn't address this. These could all be deaths of people that are already at EDSS of 8 or 9. But there is independent evidence at least from this cohort that it looks like you are prolonging the time (to) wheelchair, prolonging the time to secondary progressive stage of MS,” in which disability starts advancing much more quickly.
Dr. Corboy said the results speak for themselves. “I think the data are what it is, so it is believable in that sense,” he said. But he added that the findings are somewhat perplexing, since there was not much information reported on how the patients were doing over the course of the 21 years, and the benefits during those first three years were relatively small.
“How did the relatively modest difference in the first three years translate to less death at 21 years?” he asked. “Still, it is interesting and provocative.”
The findings may not lead to much change in the clinic, though, Dr. Corboy said. “I don't think this will change much practice in the US, as the standard has been for almost ten years to treat very early,” he said. “There are still some hold-outs elsewhere, perhaps even in the US, and financially the cost has gotten excruciatingly high. I have not seen the cost inflation resulting in a change in doctors (and) patients behavior as yet, so long as co-pays stay low.”