Abstract
Objective: To compare efficacy of interferon β-1a, 22 μg or 44 μg weekly, with placebo in relapsing MS.
Background: Uncertainty exists concerning the optimal dose regimen for interferon β in relapsing-remitting MS. Many patients and physicians prefer the convenience and lesser side effects of an injection given once weekly (qw) as opposed to three times weekly. Pharmacokinetic data and information on biologic markers suggest that this frequency may be suboptimal.
Methods: Randomized, double-blind study of interferon β-1a 22 μg, 44 μg, or placebo administered by weekly subcutaneous injection for 48 weeks. Proton density (PD)/T2-weighted and T1-weighted–gadolinium MRI scans during 24 weeks of therapy were analyzed for the number of combined unique (CU) lesions (primary outcome). Biannual PD/T2 scans were analyzed for T2 activity and burden of disease (BOD).
Results: CU lesions at 24 weeks had a median of 0.71/scan with placebo, 0.5/scan with 22 μg (not significant), and 0.33/scan with 44 μg (p = 0.002). T2 new lesion count/scan (mean/median) at 48 weeks was 3.2/1.5 for placebo, 2.4/1.0 for 22 μg (p = 0.03), and 1.5/1.0 for 44 μg (p = 0.0005). BOD at 48 weeks showed a median increase of 5.9% for placebo compared with a decrease of 1.4% in the 44 μg group (p = 0.0058) and 2% in the 22 μg group (p = 0.0018). No clinical variable, apart from steroid use in the 44 μg qw group (p = 0.014), showed significance.
Conclusions: These data confirm an MRI benefit of interferon β-1a at low dose in MS, but highlight the limited clinical effect. Taken together with other studies, the data demonstrate a dose–effect relationship for both clinical and MRI variables.
Although interferon β (IFNβ) is efficacious in the treatment of MS,1-7 the optimal dose, route of administration, injection frequency, and duration of therapy have not been clearly established. Both total dose and dose frequency affect the magnitude and duration of the biologic response.8,9 Even using the same total weekly dose of IFN, a greater response is seen with three times weekly (tiw) dosing than with once weekly (qw) dosing.10,11 These data are supported in both animal studies of experimental autoimmune encephalitis (EAE)12 and in human clinical trials.1,7,13,14 Studies using more than one dose of IFNβ consistently demonstrate that a higher dose is more effective.1,2,7 Moreover, serum levels of IFNβ drop rapidly to baseline within 24 hours of administration.15
Many MS patients are currently treated with once weekly administration of IFN based on the advantages of less frequent injections and side events. Although these more user-friendly factors may improve compliance, mounting evidence of an IFNβ dose response raises the question of whether efficacy is being sacrificed for convenience.
The current study was initiated to investigate whether low doses of IFNβ-1a are effective in MS. This study (Once Weekly Interferon for MS [OWIMS]) using once weekly IFNβ-1a ran almost concurrently with the Prevention of Relapses and disability by Interferon β-1a Subcutaneously in MS (PRISMS) study.7 The PRISMS study was a 2-year double-blind, placebo-controlled study testing doses of 22 μg tiw (66 μg total weekly dose) and 44 μg tiw (132 μg total weekly dose) of IFNβ-1a (Rebif; Ares-Serono, Geneva, Switzerland) given subcutaneously in relapsing-remitting MS (RRMS) patients with Expanded Disability Status Scale (EDSS) scores of 0 to 5.0. The Multiple Sclerosis Collaborative Research Group (MSCRG) study was a 2-year double-blind, placebo-controlled study in RRMS patients with EDSS of 1 to 3.5 using once weekly IM IFNβ-1a (Avonex; Biogen, Cambridge, MA) at a total weekly dose of 30 μg.4 The current study included patients similar to those of PRISMS and MSCRG and therefore provided an opportunity to investigate the effects of a wide range of IFNβ-1a doses in patients with active RRMS and to clarify the relationship between dose and clinical effect.
Issues related to bioequivalence can cause problems with interpretation of study data. IFNβ-1a (Rebif) is given at doses of 6 MIU or 12 MIU, which equates to 22 μg or 44 μg on a mass basis. Avonex (another IFNβ-1a) is given at a dose of 6 MIU or 30 μg. The different MIU/μg suggests apparent product differences, but when the two products are tested using the same cell line, same virus system, and equal mass units, Avonex and Rebif have the same biologic activity.16 The apparent difference in MIU/μg designation is therefore the result of using different assay systems. Based on current dosing recommendations, Avonex employs the lowest weekly dose at 30 μg, followed by Rebif at 66 μg per week, with the highest dose being Rebif at 132 μg per week. The doses used in the current study, of 22 and 44 μg of Rebif given once a week, bracket the approved Avonex dose.
Methods.
Study design.
OWIMS was a multicenter, randomized, double-blind, placebo-controlled study that began enrollment in March 1995. Enrollment was completed in November 1995 and the last study visit for the 1-year time point occurred in November 1996. A total of 293 patients, age 18 to 50 years, from 11 centers in five countries participated. All patients had clinically definite or laboratory supported definite RRMS17 of at least 1 year’s duration and Kurtzke EDSS scores of 0 to 5.0.18 Patients had experienced at least one relapse in the prior 24 months but not in the 8 weeks before entry. At least three lesions consistent with MS were required on a screening MRI. Prior IFN, cyclophosphamide, or lymphoid irradiation treatment led to exclusion, as did the use of any immunosuppressive or experimental therapies in the preceding 12 months. Corticosteroids could not be used within 8 weeks of study start. Pregnancy, lactation, and severe medical or psychiatric illness were also exclusion criteria. All patients gave written informed consent.
Treatment assignment was determined by a computer-generated randomization list produced by the Corporate Biometrics Department of Ares-Serono. The randomization code for each patient was delivered to the investigator in sealed envelopes to be opened only in emergency situations requiring knowledge of treatment assignment. Envelopes were returned at the end of treatment. Patients were randomized in a 1:1:1 ratio, stratified by study center, to receive IFNβ-1a (Rebif) 22 or 44 μg or placebo (human serum albumin and mannitol), administered subcutaneously qw for an initial period of 24 weeks. If desired, patients could remain on blinded study medication for another 24 weeks with an additional proton density/T2-weighted (PD/T2) scan performed at week 48. After 48 weeks, patients receiving placebo were rerandomized in a 1:1 ratio to receive IFNβ-1a 22 or 44 μg subcutaneously qw, for those who wished to remain on therapy. Only data from the 48-week placebo-controlled phase are included in this report.
Both active treatment and placebo were administered as ready-to-use solutions in a volume of 0.5 mL. Dose adjustments were allowed for management of symptomatic or laboratory-identified adverse events.
Two physicians at each center assessed all patients. The treating physician supervised drug administration, recorded and treated adverse events, and monitored safety assessments. The evaluating physician was responsible for neurologic assessments, both at scheduled visits and during exacerbations. Throughout the study, the evaluating physician remained unaware of adverse event profiles and any changes in safety assessments. To preserve blinding, patients were instructed to cover injection sites and to refrain from discussing any symptoms that might be in any way related to treatment when visiting the evaluating physician.
MRI scanning and analysis.
PD/T2 scans and postgadolinium T1-weighted (T1-Gd) scans were performed on all patients at prestudy screening (21 to 35 days before study entry), on study day 1, and at the end of study weeks 4, 8, 12, 16, 20, and 24. In addition, further PD/T2 scans were carried out at the end of week 48. All scans were performed according to a detailed protocol designed to standardize procedures among sites and were analyzed at a central site (MRI Analysis Group at the University of British Columbia, Vancouver, Canada).
Outcome measures.
The primary outcome measure in the study was the number of combined unique (CU) active lesions at 24 weeks detected by MRI scanning; i.e., those showing PD/T2 or T1-Gd activity. Secondary MRI outcome measures included: the proportion of scans showing combined active lesions; the percentage change in burden of disease (BOD) (defined as the total area in mm2 of lesions identified in PD/T2 scans based on the difference in BOD on scans at baseline and week 48); T2 lesion activity at 24 weeks based on monthly scans up to week 24; and T2 lesion activity based on scans at baseline, week 24, and week 48. Clinical outcome measures included: exacerbation count per patient; exacerbation severity; time to first exacerbation; proportion of patients remaining exacerbation-free; need for steroid therapy; and hospitalizations related to MS. An exacerbation was defined as the appearance of a new symptom or worsening of an old symptom, attributable to MS, accompanied by an appropriate new neurologic abnormality or focal neurologic dysfunction lasting at least 24 hours in the absence of fever and preceded by stability or improvement for at least 30 days.19
Disease activity was assessed by counting the number of active lesions appearing on PD/T2 and T1-Gd scans. Active lesions appearing on PD/T2 scans were identified as new, enlarging, or recurrent according to established methodology.20 Enhancing lesions appearing on T1-Gd scans were identified as new or persistent. Combined active lesions were individual lesions showing PD/T2 activity, T1-Gd activity, or both, adjusted to avoid double counting. BOD was determined by calculating the total area of lesions appearing on PD/T2 scans. Lesion area was summed slice by slice, and the total area per scanning sequence was recorded in mm2.
Patients underwent neurologic assessment, including scoring on the EDSS and the Scripps Neurological Rating Scale (SNRS),21 at prestudy screening, on study day 1, and at the end of weeks 4, 12, 24, 36, 48, 72, and 96. Patients were also instructed to contact the center if they felt they were experiencing a relapse to be seen and examined within 7 days of the onset of each exacerbation. Routine hematology, biochemistry, thyroid function, and urinalysis testing was performed. Serum samples were tested for anti–IFNβ binding antibodies at 6-month intervals by SCL Bioscience Services Ltd., Cambridge, UK. Positive samples were tested for IFNβ neutralizing antibody (NAb) activity by RBM, Ivrea, Italy. A NAb titer of ≥20 neutralizing unit/mL was considered positive.
Patients experiencing an exacerbation during the study could be given IV methylprednisolone at a dose of 1.0 g/day for 3 consecutive days at the treating physician’s discretion. Acetaminophen was recommended for prophylactic use and to ameliorate constitutional symptoms as required throughout the study.
Statistical methods.
In keeping with an intention-to-treat analysis, all patients were analyzed as randomized with inclusion of all outcome data. The data from the few patients who withdrew early from the study were retained in the statistical analyses through the use of a censoring mechanism and their time on study accounted for by different means, depending on which statistical method was used.
The study was powered at 80% to detect a 50% reduction in the number of combined active lesions at week 24 between the 44 μg dose and placebo. Using an effect size of 0.46, a two-sample two-sided t-test, and a significance level of 0.05, a sample size of 75 evaluable patients per group was determined. A 10% dropout rate was assumed.
An analysis of variance on the ranks was used to assess the number of combined active lesions at week 24 (the primary endpoint). For each endpoint analyzed, a global model was fitted, which included factors for center, baseline number of combined active lesions, BOD, and treatment. No center effect was found. A generalized linear model with a log link and variance proportional to the mean was used to analyze relapse count. Other statistical methods used were Cox proportional hazards models for “time to” endpoints, logistic regression models for binary outcomes, and Pearson χ2 tests for counts of patients experiencing particular categories of adverse events. Analysis of variance on the ranks was used to analyze most continuous endpoints, including the MRI activity endpoints. All statistical tests were two-sided. The primary analysis was based on comparison of 44 μg to placebo and no adjustments for multiple comparisons were performed.
Results.
The baseline patient characteristics (table 1) show no differences among groups and are similar to those from other recently completed MS treatment trials.1,3,7 Baseline characteristics of patients in the PRISMS and MSCRG studies are presented for purposes of comparison. OWIMS enrolled 293 patients in total (figure 1), with 100 in the placebo group, 95 in the low-dose (22 μg qw) group, and 98 in the high-dose (44 μg qw) group. Ninety-eight percent of patients completed the 24-week monthly MRI phase whereas 92% completed 48 weeks on protocol. There were 6 dropouts by 24 weeks (all but one returned for the week 24 visit) and 24 dropouts by 48 weeks (6 due to adverse events). Ninety-six percent of total planned injections were taken during the study. The baseline MRI characteristics are shown in table 2, demonstrating that the low-dose treatment group had a somewhat higher mean CU lesion score than the high-dose group (2.9 versus 2.1, respectively) as well as a greater BOD. The increased lesion score for the 22 μg qw group is the result of a single patient who had 75 new active lesions between screening and study day 1 despite the absence of new clinical activity. Eliminating this one individual results in a mean value of 2.1, virtually identical to those of the other two groups. Lesion activity and BOD at baseline were considered as covariates in the respective analyses of in-study MRI activity measures and change in BOD.
Comparative demographic characteristics of patients enrolled in the OWIMS study
Figure 1. Enrollment and retention of patients (48 weeks). IFN = interferon; AE = adverse event.
MRI baseline values
The primary outcome for the study was the count of combined T1-Gd and PD/T2 unique new and newly active lesions at 24 weeks, whereas secondary MRI outcomes included new/active PD/T2 lesions and the percentage change in PD/T2 BOD at 48 weeks. Of the 2,328 T1-Gd scans performed, only eight were rejected. A total of 2,853 PD/T2 scans were performed during the 48-week placebo-controlled period, of which 28 were rejected for noncompliance with the scanning protocol: 17 of these were replaced.
Primary outcome results are presented in figure 2, showing a reduction in the median number of combined active lesions of 29% for low-dose (p = 0.08) and 53% for high-dose (p = 0.002) Rebif. There was no statistical difference between low- and high-dose therapy (p = 0.2). Figure 2 also shows the results for T2 active lesions alone and T1-Gd enhancing lesions alone, demonstrating an effect on both types of individual activity; again, only the reduction for the higher dose was statistically significant. The proportion of active scans, a secondary outcome measure, showed similar results, with 50% active scans for placebo, 45% for 22 μg qw (not significant), and 33% for 44 μg qw (p = 0.02). PD/T2 lesion activity at 24 weeks was reduced in both treated groups but only the reduction for the 44 μg qw dose achieved statistical significance (p = 0.004). Differences between doses were not significant (p = 0.10 and p = 0.13, respectively).
Figure 2. MRI lesion activity over 24 weeks based on scans performed every 4 weeks. The mean active lesion rate/patient/scan was determined throughout the study and then expressed as the median for each group. Combined active lesions are adjusted to avoid double counting. PD = proton density.
Data at 48 weeks show median values for total PD/T2 activity (new and enlarging lesions) of 1.5 for placebo, 1.0 for 44 μg (p = 0.0005), and 1.0 for 22 μg (p = 0.03). Percentage change in PD/T2-determined BOD demonstrated a significant effect for both doses of Rebif (table 3).
Percentage change in burden of disease at 48 weeks
Table 4 lists the results for relapse-related measures showing a consistent trend favoring the high dose of Rebif compared with both placebo and low-dose Rebif. The differences were not statistically significant apart from the mean number of steroid courses used per patient.
Results for clinical outcome measures
Adverse events associated with IFN therapy are reported in table 5. Importantly, depression was not increased with therapy, and no injection site necrosis was seen. Thirteen patients experienced 14 serious adverse events: 3 in the placebo group (hernia, vomiting/dehydration, thrombophlebitis), 5 in the low-dose group (cholelithiasis, depression, flu, lymphopenia, trigeminal neuralgia), and 6 in the high-dose group (cholelithiasis [two cases], ovarian mass, pyelonephritis, gastroenteritis, depression with suicide attempt). There were six adverse events (five in the 44 μg qw group and one in the 22 μg qw group) leading to withdrawal of therapy, including depression in two patients (noted previously) and systemic or local side effects of therapy in four patients, all in the 44 μg group. Eighteen patients withdrew for other reasons, including pregnancy, desire to use newly approved MS therapies, or patient preference.
Percentage of patients ever reporting adverse events during the study
NAbs were detected in 5.3% of patients in the low-dose group and 16.3% of those in the high-dose group. Antibodies appeared earlier in the high-dose than the low-dose group, and persisted during the period of observation. There is no indication of any difference in MRI activity for patients who had developed NAbs by week 48, but the numbers developing NAbs are small and the duration of the study may be too short to detect any such impact.
Discussion.
The convenience and fewer side effects of administering a low dose of IFNβ-1a once a week attracts patients and improves compliance. Both patient and animal data, however, suggest that lower IFN-β doses may compromise efficacy when compared with higher dose regimens.1,7-13 Data showing that IFN-induced biologic markers are less influenced by once-a-week rather than three times a week dosing,9 and showing that blood levels of IFNβ-1a fall rapidly within 24 hours of administration,15 highlight the importance of dose frequency. All recent studies of IFN therapy in MS1,2,7,13,14 but one4 have demonstrated the greatest impact on MRI measures, with lesser effects on clinical measures such as relapse rate and disability. The current study shows that even low doses of IFN can have significant effects on the number of active lesions and the accumulation of BOD, despite demonstrating only nonsignificant trends for clinical outcomes. MRI, as the most sensitive outcome measure, detected dose differences at all weekly doses tested (i.e., 22, 44, 66, 132 μg). For all MRI measures in this study, the 44 μg qw dose was statistically better than placebo, whereas the 22 μg qw dose showed statistical differences on only two of the MRI indices. On all MRI measures except change in BOD, the higher dose showed a nonsignificant trend to improvement compared to the lower 22 μg qw dose. In PRISMS, both doses were superior to placebo and 132 μg weekly was statistically better at reducing T2 activity than 66 μg weekly. Although not significant, the clinical results also show stronger trends for high versus low dose in OWIMS and in PRISMS, where additionally, the higher dose had a significantly more positive impact on Ambulation Index and the need for MS-related hospitalizations compared with low dose.
Together with other trials of IFNβ-1a in RRMS, this study provides definitive data to support the concept of a dose effect for IFNβ-1a on both MRI and clinical outcome measures in MS. The low doses of IFNβ-1a—i.e., 22, 30, and 44 μg per week—demonstrate a trend to reduced relapses compared with corresponding placebo groups of 0%, 10%, and 19%, respectively, none of which is statistically significant. The studies, however, were not powered to detect significant differences in this endpoint at 1 year. The MRI impact of these same low doses is greater, and on several measures reaches statistical significance more often, with 44 μg than with 22 μg weekly. As doses of IFNβ-1a increase from 22 or 44 μg per week to 66 or 132 μg per week, meta-analysis shows that the impact on both clinical and MRI outcomes increases and is highly significant (p < 0.001).22 Of the outcome measures used in MS trials, clinical variables are less sensitive to IFN therapy than MRI. To date, successful disease-modifying treatments have only been able to reduce relapse rate by about 30%, even with the highest dose of IFNβ of 132 μg.7 MRI response rates approach 80 to 90% with the highest doses. The lack of a statistically significant treatment difference between doses in either OWIMS or PRISMS individually may reflect an underpowering of each study for the outcome measure, insufficient change in the variable to be detected, or insufficient difference in total dose within each study. Nevertheless, taken together, the data from PRISMS, OWIMS, and MSCRG suggest an increasing clinical response with increasing dose frequency exposure to IFN, an effect that appears to be independent of differences in either biologic activity or route of administration.22,23 The concept that a dose–response relationship exists in MS is not surprising given similar dose-dependent results obtained from other studies of IFN in MS, in EAE, and for IFN use in other indications.1,7,13,14 In these studies, the higher the dose of IFN, the greater the impact.
Although the patient inclusion criteria were not identical in MSCRG, OWIMS, and PRISMS, the mean age, relapse rate prior to entry, and EDSS scores are very similar. Debate exists in the literature about product differences,24 but data indicate that the two forms of IFNβ-1a, Avonex and Rebif, have identical physicochemical features, including amino acid structure and glycosylation,25 and when tested on an identical mass basis, have equal pharmacokinetic profiles and pharmacodynamic effects regardless of the route of administration.8
The relapse data presented here for Rebif are 1-year results, as placebo was discontinued in the OWIMS study at the 1-year timepoint. Comparative relapse data are presented in figure 3 including all reported phase III studies of IFNβ-1a in RRMS. The relapse data for the MSCRG study show a 1-year reduction in relapses of 9.6%,26 which falls between the reduction for 22 μg qw and 44 μg qw and is considerably less than the 1-year relapse rate reduction of 33% or 37% using 22 μg tiw or 44 μg tiw, respectively, found in PRISMS.7 For disability and other relapse-related outcome measures, such as the proportion of patients relapse free and the time to first exacerbation, the lower doses used by MSCRG and OWIMS failed to show the statistical benefit seen with the two higher doses used in the PRISMS study. This suggests that although low doses of IFN have some clinical effect, this benefit is small and may be delayed, only becoming manifest a year or more after initiation of therapy26,27; however, this may simply be a matter of insufficient dose initially. The effect of high dose is greater and is seen within the first 3 months of therapy on clinical and MRI variables.
Figure 3. Comparative relapse rate reduction using interferon β-1a, 1 year after initiating therapy combining. Data from Once Weekly Interferon for MS (OWIMS), Prevention of Relapses and disability by Interferon β-1a Subcutaneously in MS (PRISMS), and the Multiple Sclerosis Collaborative Research Group studies.
The development of NAbs also showed a dose effect. Rising weekly doses of 22, 44, 66, and 132 μg resulted in NAb formation in 5%, 16%, 24%, and 12% of patients, respectively. This produces a typical antibody curve generated when one measures antibody formation in the presence of increasing antigen concentrations, with high zone tolerance as a possible explanation for the diminution of NAbs at the highest dose. There was no indication in either PRISMS or OWIMS that NAbs had a deleterious clinical impact in contrast to what has been reported with Betaseron.3,28 However, trends to reduced MRI benefit have been noted with NAbs in PRISMS (data on file; Ares-Serono, Geneva, Switzerland) as has been reported with Avonex.29
In this study, Rebif was shown to be safe, with side effects of similar type and rate as other types of IFN. Although injection site reactions occurred, they were generally mild and no injection site necrosis was seen among the 8,779 injections of drug. Systemic IFN side effects are seen with both the IM and the subcutaneous routes of administration and are comparable in severity and duration regardless of injection frequency.9
Depression, which emerged as a concern with IFN therapy in the original IFNβ-1b study, was found at a rate similar to placebo, a finding in agreement with three other recently completed studies of IFNβ-1a and -1b in MS.4,7,28
A remaining question is whether the dose of IFN β-1a can be further increased to achieve additional benefit. The slope of perceived benefit on relapse rate begins to flatten between 66 μg and 132 μg/week. However, there is still additional MRI benefit with the higher dose. Because tolerability for the two doses was similar, the higher dose is justified based on greater benefit. Whether there is a limit to IFN dose remains unresolved. Factors such as receptor saturation and tolerance may limit the maximal dose of IFN that can be used. Whether more frequent administration of smaller doses or slow release forms of IFN would increase benefit needs to be explored. Newer strategies to enhance IFN benefit without increasing dose are needed. Consideration is also being given to combination therapy with IFN and other drugs to enhance efficacy. The data from the current study, combined with those from prior IFN studies, confirm that the benefit of IFN therapy in MS is dependent on the total dose used and is more sustained with increased injection frequency. This leads to the conclusion that the once weekly dose of IFNβ-1a currently in use may be insufficient. A maximal clinical and MRI response in MS at least requires the equivalent of IFNβ-1a 22 μg tiw (66 μg/week).
Appendix
The OWIMS Study Group comprises the following participating institutions, listed by enrollment, with principal investigators (bold), radiologists (bold italics), coinvestigators (italics), and study coordinators. All MRI interpretation was carried out at the Vancouver center.
University Hospital, London, Canada—G. Ebers, D. Lee, G. Rice, J. Lesaux, K. Kennedy. Ignatius Hospital, Breda, the Netherlands—E.A.C.M. Sanders, R.J. Versteylen, J. de Rijk van Andel, J.P. Story, M. de Milliano. St. Michael Hospital, Toronto, Canada—P. O’Connor, G. Cheung, P. Houston, J. Hall. Ospe-dale San Raffaele, Milan, Italy—G. Comi, M. Filippi, V. Martinelli, G. Santuccio, A. Poggi, M. Gironi, L. Moiola. Höpital Notre-Dame, Montréal, Canada—P. Duquette, P. Bourgouin, G. Pepin, J. Poirer, G. Bernier, R. Dubois. Foothills Hospital, Calgary, Canada—L. Metz, R.T. Diamond, R. Bell, D. McGowan, A. Demchuk, E. Harris, M. Yeung, A. Murphy. Queen Elizabeth II Health Sciences Centre, Halifax, Canada—T.J. Murray, R. Vandorpe, V. Bhan, C. Maxner, P. Weldon, L. Armstrong. Höpital de l’Enfant Jésus, Québec City, Canada—J.-P. Bouchard, P. Grondin, F. Gosselin, M. Thibaut, L. Kirouac, A. Morin. Hadassah Medical Centre, Jerusalem, Israel—O. Abramsky, J.M. Gomori, D. Karussis, A. Karni, M. Mor. The Ottawa Hospital–General Campus, Ottawa, Canada—M.S. Freedman, L. Avruch, R. Nelson, S. Christie, H. Rabinovitch, C. Freedman, M. Benavente. Centre Hospitalier Universitaire de Marseille, France—J. Pelletier, O. Levrier, P. Bensa, A. Dalesky. Vancouver Hospital, Canada, UBC MS MRI Group—D. Paty, D. Li, B. Rhodes, A. Riddehough, G. Zhao, X. Wang, Y. Chang. Ares-Serono International SA, Geneva, Switzerland—A. Abdul-Ahad, N. Ammoury, F. Dupont, G. Francis, R. Furcha, A. Galazka, R. Hyde, M. Olson, M.-O. Pernin, S. Shah. Writing committee—M. Freedman (chair), G. Ebers, J. Murray, P. O’Connor, D. Paty, G. Rice, G. Francis.
Acknowledgments
Acknowledgment
Jean-Pierre Malkowski was instrumental in completion of the manuscript.
Footnotes
↵*See the Appendix on page 685 for a listing of members of the OWIMS Study Group.
Funded by Ares-Serono International SA (Geneva, Switzerland) and monitored by Clinical Research Associates from Ares-Serono (L. Liganor, H. Harris-Harper, J. Archer, V. Bociek, P. Duijzings, G. Ursicino, S. Rotem, M. Sauvage).
Presented in part at the 123rd annual meeting of the American Neurological Association; Montreal, Canada; October 21, 1998.
- Received February 25, 1999.
- Accepted in final form July 20, 1999.
References
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