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Study 1 Citation: Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, Monaghan E, Li D, Weinshenker B for the EVIDENCE* Study Group and the University of British Columbia MS/MRI Research Group Randomized, comparative study of interferon ß-1a treatment regimens in MS: The EVIDENCE Trial Neurology. 2002;59:1496-1506 *EVidence of Interferon Dose-response: European North American Comparative Efficacy |
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Abstract:
This study was conducted to compare the safety and efficacy of two IFNß
products using different dosing regimens. 677 patients were enrolled in
this multicenter, randomized, and controlled trial. The regimens included
Rebif given subcutaneously at three doses of 44 mcg weekly and Avonex given
in a single weekly intramuscular dose of 30 mcg weekly for a total of 24
weeks. MRI evaluation of active lesions per scan was the primary endpoint.
Results suggested that patients receiving the Rebif regimen had fewer
relapses than those using the Avonex regimen. The Rebif regimen also
included more injection site reactions and some mild rises in liver enzymes
and leukocyte counts.
interferon ß-1a, Rebif, Avonex, intramuscular injection, subcutaneous injection, relapsing-remitting MS, RRMS, relapses
Discussion:
Previous studies suggested that there might be a dose-dependent response for IFNß regimens and that the administration routes may influence results. The results of these studies have been equivocal. Subcutaneous administration of Rebif has been studied in the past with improved MRI results using a 44 mcg dose when compared to a 22 mcg dose three times weekly.6 Avonex was studied using weekly 30 mcg and 60 mcg doses with no significant differences in MRI and other measures.7
This study enrolled 677 patients in 56 centers with RRMS who had no previous experience with interferons. To achieve the desired results at a 95% level of confidence to detect a 30% increase in the primary endpoint (relapse rate), the study required 280 patients per treatment arm for a total of 560 complete records. Randomization resulted in 339 patients in the Rebif treatment arm and 338 in the Avonex arm. 95% of Rebif patients completed week 24 of the study and 93% completed through week 48. 96% of the Avonex patients completed week 24 and 94% completed the full 48 weeks. The Rebif group was considered higher dose with approximately four times the amount of drug administered over the treatment period of the study compared with the Avonex group.
The physicians who were assigned to assess the patients were blinded to the treatment (the patients were instructed to cover injection sites and to not reveal treatment regimens to the evaluating physicians). Patients were monitored every four weeks for the duration of the treatment arm. Full Functional System (FS) and Expanded Disability Status Scale (EDSS) tests and scoring were conducted at baseline and weeks 12, 24, 36, and 48. MRIs were performed at baseline and every four weeks. Blood measures for general hematologic and biochemical effects, thyroid function tests, and the presence of neutralizing antibodies (NAb) were conducted. In addition, phone follow-ups were conducted between visits to monitor for relapses.
Relapses were defined with an objective measure by the blinded assessor along with the worsening or new appearance of a symptom that lasted for at least 24 hours without fever. The severity of the relapse considered changes in FS and EDSS scores as shown here:
| Severity | FS change | EDSS change |
| Mild | 1 point change in 1-3 FS | Increase of ½ point |
| Moderate | 2 point change in 1-2 FS | Increase of 1-2 points |
| Severe | >2 point change in 1-2 FS | >2 point increase |
The randomized groups were not statistically different in demographics, EDSS scores, and MRI findings at baseline. More than 90% of the participants were Caucasian and three-quarters were women. During the 24-week treatment arm relapses were seen in 25% of the Rebif group and 37% of the Avonex group. The odds ratio adjusted for study center was 1.9 (95% confidence interval, range 1.3-2.6, p=0.0005) for the higher dose (Rebif group) suggesting a 90% likelihood that patients would be relapse-free during the treatment phase. Several other statistical analyses supported the better results in the higher dose group. In addition to a lower relapse rate, the higher dose group showed a prolonged time to their first relapse episode and a very strong trend toward fewer numbers of relapses compared to the other group (p=0.003 and p=0.022 respectively). After the 24-week treatment period there were 20 patients in the Rebif group and 28 patients in the Avonex group that showed disease progression. On MRI the Rebif group showed fewer combined unique active lesions than the Avonex group (p<0.0001) with the peak effect occurring within two-three months of treatment initiation. No new MRI lesions were seen in 48% of the Rebif group compared to 33% of the Avonex group.
There has been some concern that the production of neutralizing antibodies (NAb) for IFNß-1a due to chronic administration may reduce the long-term effectiveness of treatment. In this study 25% of the Rebif group and 2% of the Avonex group developed NAb at a level of greater than 20 units (level set to be considered positive for NAb). The authors note that though the development of NAb was clearly higher in the higher dose group, there was no apparent reduction in clinical efficacy of either treatment for the duration of the 48 weeks of treatment and monitoring. Interestingly, both patients who were NAb+ and NAb- remained similar in rate of relapses. There was no information that appeared to predict the development of NAb because there were no apparent baseline differences between those who did or did not develop NAb.
Adverse effects that were more common in the higher dose (Rebif) group included injection site problems (83% of the Rebif group compared to 28% of the Avonex group). Four patients on the Rebif regimen and one patient on the Avonex regimen cited this effect as one of the reasons for discontinuing their participation in the study. However, most of the events were considered mild. A flu-like syndrome occurred in similar numbers of patients between the two groups (42% in the Rebif group and 49% of the Avonex group). Mildly elevated liver function tests were seen in 18% of the Rebif arm compared to 9% of the Avonex arm (p=0.002) and were considered severe in 3 patients in each arm. Three patients discontinued participation based on elevated liver tests (2 in Rebif arm and 1 in Avonex). More Rebif patients showed leukocyte increases than seen in the Avonex group (11% versus 5%; p=0.002) with lymphopenia reported as severe in 3 Rebif patients and 1 Avonex patient. The total number of adverse events was 21 in the Rebif group and 18 in the Avonex group with nine of the events considered to be drug related. Discontinuation of treatment occurred in 16 Rebif participants and 14 Avonex participants.
Summary of Study 1
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Higher dosing of IFNß-1a was more effective in reducing relapse rate in patients with RRMS in this 48-week trial (24 weeks treatment followed by 24 weeks monitoring). The authors note that while the Rebif group (subcutaneous injections of 44 mcg three times weekly) appeared to fare better according to the primary MRI-based outcomes than the Avonex group (30 mcg weekly intramuscular injection), there were no separate conclusions based on the total weekly dose, administration route, or frequency of injections. Previous studies have been equivocal in dose-related findings. The authors of the work reported here suggest that a lack of divided doses and more frequent dosing may be a factor in the varying outcomes of previous studies. In addition, this study used different methods of administration. The authors note that no consensus currently exists on which mode may be more effective. The study was designed to provide a Class I level of evidence according to criteria set by the American Academy of Neurology (see Journal Club introduction for details about the AAN criteria). Limitations of the study include the lack of double-blinded design, which was not considered feasible because of the obvious differences between the modes of administration. Treating and assessment physicians were separate to maintain a blinding of the assessors. At week 48 of the study a survey taken by the assessors showed that they could correctly guess the treatment arm of the participants 52% of the time (57% of the Rebif group and 47% of the Avonex group). Because the effectiveness of both drugs has been previously established, this study was conducted to compare the results between the treatments. Due to the short duration of the trial MRI-based evaluation was most likely to show any differences and was chosen as the primary endpoint. Authors also acknowledge the short duration of the study but suggest that the results were more significant than expected. Further evaluation of disability progression would likely require continuation of the study for at least two years. Therefore, any conclusions on differences in progression remain purely speculative. The authors did extrapolate natural history studies to anticipate a beneficial effect of therapies on disease progression could be realized if patients are treated during early inflammatory phases of MS. Significantly more patients in the higher dose arm showed a presence of NAb. This study did not show a reduction in clinical effectiveness of therapy in patients who developed NAb compared to those who did not. However, the authors suggested that further follow-up beyond the period of the study may be required to make a clear determination either way. Adverse effects did not seem to affect patient adherence to therapy by those who continued to participate for the duration of the trial. Increases in liver function tests were all reversed either spontaneously or with dose reduction. Injection site reactions were more common in the subcutaneous injection group with one patient showing necrosis at the site. Overall, the authors concluded that different regimens can show different levels of effectiveness. However, they could not clearly identify the level of the effect by individual factors of treatment administration route, total weekly dose level, or frequency as parts of the regimen differences. The findings of this and other studies may help to clarify treatment and regimen options in order to optimize therapies for MS. |