By Chris Berrie
PRAGUE, CZECH REPUBLIC -- October 16, 2007 -- Interferon beta-1a (IFNbeta-1a) has no significant efficacy benefits or safety issues over the polypeptide glatiramer acetate for patients with relapsing-remitting multiple sclerosis (RRMS), according to results from a multicentre, randomised, comparative, assessor-blinded, open-label trial.
Principal investigator Dan D. Mikol, MD, PhD, Associate Professor of Neurology, Department of Neurology, University of Michigan, Michigan, United States, presented the findings here on October 14 at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
This was the first head-to-head study of IFNbeta-1a and glatiramer acetate.
"The planned sample size was 736 patients, and included in the expectations was that there would be an 80% power to detect a 30% difference between these two agents in the primary outcome, which was time to first relapse."
Dr. Mikol and colleagues enrolled 764 patients aged 18 to 60 years and diagnosed with relapsing-remitting MS by McDonald criteria, had experienced one or more attacks within the prior 12 months, and were clinically stable or had improving neurological state in the prior 4 weeks. They also had magnetic resonance imaging (MRI) evidence of brain lesions and an expanded disability status scale (EDSS) of 0 to 5.5.
Following prestudy evaluation, 386 patients were randomised to 44 mcg of subcutaneous IFNbeta-1a three times weekly and 378 patients to 20 mg of subcutaneous glatiramer acetate once daily, both for 96 weeks.
Key baseline clinical characteristics in the two treatment groups were similar for time since first relapse (5.93 years, 6.55 years, respectively), number of T1 Gd-enhancing lesions (1.47, 1.65), T1 Gd-enhanced lesion volume (254.81, 241.99 mm3), and T2 lesion volume (7915.61, 7560.38 mm3).
However, 60% of patients in the interferon arm had more than one relapse in the previous 24 months compared with 71% in the glatiramer acetate arm, Dr. Mikol noted.
The primary endpoint was time to first relapse; the predefined secondary endpoints were mean number of T2 active (new or enlarging) lesions per patient per scan, and mean number of T1 Gd-enhancing lesions per patient per scan.
Tertiary endpoints were: mean number of combined unique active (CUA) lesions per patient per scan, and proportion of scans per patient with CUA lesions; clinical assessment of relapse rate, and proportion of patients free of relapses.
For the primary, secondary and some of the tertiary analyses, results were also stratified by prespecified subgroups.
At 96 weeks, the researchers found no significant differences between the IFNbeta-1a and glatiramer acetate treatment arms in terms of the primary outcome (hazard ratio [HR], 0.943; 95% confidence interval [CI], 0.74-1.21; P =.643). Dr. Mikol noted that these two patient groups experienced 45% fewer relapses than expected.
Due to this slow relapse rate, the researchers included a series of prespecified subgroup analyses relating to baseline T1 Gd-enhancing lesions (0 vs >=1), relapses 2 years prior to baseline (1 vs >=2), geographic region (non-Russia vs Russia), EDSS at baseline (<=median 2.0 vs >median 2.0), baseline T2 lesion volume (<=median 3707.5 vs >median 3707.5 mm3), and MS therapy in the prior 6 months (e.g. steroids; no vs yes).
The only subgroup where the researchers found a significant difference at the 96-week evaluation was EDSS at baseline in favor of IFNbeta-1a (n = 207) over glatiramer acetate (n = 211) in the group with EDSS scores below the median (HR, 0.648; 95% CI, 0.45-0.94; P =.022)
Although the researchers observed no significant difference between IFNbeta-1a and glatiramer in the number of T2 active lesions per patient per scan (0.7 vs 0.8; P =.178), within the prespecified subgroup analyses, they found significantly fewer T2 active lesions in patients treated with IFNbeta-1a both in the subgroup of patients with EDSS scores lower than the median (P =.035) and in non-Russian patients versus Russian patients (P =.043).
Significant benefit in favor of IFNbeta-1a versus glatiramer was seen for the secondary endpoint of T1 Gd-enhancing lesions (0.2 vs 0.4; P <.001) and for mean CUA lesions per patient per scan (0.9 vs 1.2; P =.010). Within the subgroups, IFNbeta-1a was better than glatiramer in patients who were non-Russian (P <.001), had baseline scores that were lower than the median on the EDSS (P <.001), with baseline lesion volume greater than the median (P <.001) and had prior MS therapy (P <.001).
For the tertiary endpoints of mean number of CUA lesions/patient/scan, and proportion of scans/patient with CUA lesions, these both indicated significant benefit for IFNbeta-1a, with mean treatment differences of -0.31 (P =.010) and -5.9 (P =.009), respectively.
Finally, for the annualized relapse rates for IFNbeta-1a and glatiramer acetate, there were no significant differences between these two treatment groups (0.30 vs 0.29; P =.828). "What is intriguing and certainly stands out in this trial is the fact that the relapse rate on-study was so low, 0.3, which is certainly much lower than was anticipated and is different to what has been seen in previous clinical trials," added Dr. Mikol.
Thus Dr. Mikol summarized, "There were no significant difference in primary endpoint of time to first relapse; the safety outcomes were consistent with the known profiles of both treatments; and there was significant difference in favor of IFNbeta-1a for T1 Gd-enhancing lesions and for some of the additional pre-specified subgroup analyses.
Funding for this study was provided by Merck Serono International S.A. and Pfizer Inc.
[Presentation title: The REGARD Trial: A Randomised Assessor-Blinded Trial Comparing Interferon Beta-1a and Glatiramer Acetate in Relapsing-Remitting Multiple Sclerosis. Abstract 119]
