Patients with an apparent first demyelinating event who are treated early with subcutaneous interferon beta-1a experience a significantly longer time until progression to multiple sclerosis, compared with those whose treatment is initiated after diagnosis with clinically definite MS, according to 3-year results from the ongoing phase III, double-blind REFLEX extension trial.
The best results from the REFLEXION trial occurred in those treated early with a 44-mcg dose given three times weekly.
The findings provide additional evidence that treating early makes a difference in the long run, lead investigator Dr. Mark Freedman said in an interview. Dr. Freedman will present the results April 25 at the annual meeting of the American Academy of Neurology.
"What we saw at 2 years [in the REFLEXION trial] is definitely still there at 3 years. Treating early is the best opportunity for getting control of the disease," he said.
Not only do the findings show that early treatment matters, they show that the dose matters – even at the start of treatment, said Dr. Freedman, director of the multiple sclerosis research unit at the Ottawa (Ont.) Hospital and professor of neurology at the University of Ottawa. "The one question that remained after all the other interferon trials was the question about the dose," and now the answer is 44 mcg three times weekly.
In the REFLEX trial, 517 patients with a first demyelinating event were randomized to receive placebo; 44-mcg of interferon beta-1a three times weekly; or an off-label, 44-mcg dose of interferon beta-1a once weekly. They received treatment for 24 months or until they were diagnosed with clinically definite multiple sclerosis (CDMS), at which time they were switched to the three-times-weekly interferon dose. Both doses of interferon, when given early, significantly delayed CDMS and MS based on the more MRI-dependent McDonald criteria, compared with placebo. For MS diagnosed with the McDonald criteria, the three-times-weekly interferon dose was associated with significantly greater delay than the once-weekly dose.
All patients from the REFLEX trial were eligible for REFLEXION; 402 (78%) participated. All those originally on placebo who did not reach CDMS were switched to interferon three times weekly, and those in the initial interferon once- or three-times-weekly groups who did not reach CDMS remained in their original treatment group.
Integrated data from the two trials, analyzed by original group, showed that the 36-month cumulative probability of CDMS was 41.3% for the placebo/delayed-treatment group, 27.6% for the once-weekly interferon group, and 27.1% for the three-times-weekly interferon group. The 36-month probability of McDonald-criteria MS was 87% for placebo/delayed treatment, 79% for the once-weekly interferon group, and 67% for the three times weekly interferon group.
As in the REFLEX trial, the difference in time to progression was statistically significant for both interferon groups compared with placebo based on both clinical and MRI-based criteria, and for the three-times-weekly interferon group compared with the once-weekly interferon group based on McDonald criteria, Dr. Freedman said.
The REFLEX and REFLEXION trials were conducted using a human serum albumin-free formulation of interferon beta-1a that is available in numerous countries worldwide but not in the United States. Participants had a first clinical episode suggestive of a demyelinating event, including symptoms such as tingling, numbness, muscle weakness, or balance problems. They also had at least two clinically silent brain lesions detected on MRI.
CDMS was diagnosed in those experiencing a second clinical attack or a sustained increase of more than 1.5 in the Expanded Disability Status Scale score. Those who initially received placebo but who did not develop CDMS – and who therefore switched to interferon only after entering the REFLEXION trial – started interferon treatment an average of 58 days following their initial symptoms.
An added benefit of starting with this higher dose is that, compared with the lower dose, it was associated with a reduction in the persistent flulike symptoms known to be associated with interferon beta-1a, Dr. Freedman said.
The REFLEXION trial, which is sponsored by Merck Serono S.A., will continue for a total of 5 years, he said.
Dr. Freedman had no other disclosures to report.