More MS news articles for May 2001

Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study

http://www.thelancet.com/journal/vol357/iss9268/full/llan.357.9268.original_research.16313.1

19 May 2001
Volume 357, Number 9268

Giancarlo Comi, Massimo Filippi, Frederik Barkhof, Luca Durelli, Gilles Edan, Oscar Fernández, Hans-Peter Hartung, Pierrette Seeldrayers, Per Soelberg Sørensen, Marco Rovaris, Vittorio Martinelli, Otto R Hommes, and the Early Treatment of Multiple Sclerosis Study Group*

*Other members listed at end of paper Multiple Sclerosis Centre, Department of Neuroscience, IRCCS San Raffaele, Milan, Italy (G Comi MD, M Filippi MD, M Rovaris MD, V Martinelli MD); Multiple Sclerosis-Magnetic Resonance Centre, Department of Radiology, Vrije Universiteit Medical Centre, Amsterdam, Netherlands (F Barkhof MD); Department of Neurosciences, University of Turin, Turin, Italy (L Durelli MD); Clinique Neurologique, Université de Rennes, Rennes, France (G Edan MD); Servicio de Neurología, Hospital Carlos Haya, Málaga, Spain (O Fernández MD); Department of Neurology, Karl-Franzens Universität, Graz, Austria (H-P Hartung MD); Department of Neurology, CHU de Charleroi, Charleroi, and Hôpital Erasme, Brussels, Belgium (P Seeldrayers MD); Department of Neurology, Rigshospitalet, Copenhagen, Denmark (P Soelberg Sørensen MD); and European Charcot Foundation, Nijmegen, Netherlands (O R Hommes MD) Correspondence to: Prof Giancarlo Comi, Department of Neuroscience, IRCCS Ospedale S Raffaele, via Olgettina 60, 20132 Milano, Italy (e-mail:g.comi@hsr.it)

Summary

Background

Interferon beta reduces activity in multiple sclerosis as measured clinically and by magnetic resonance imaging (MRI). We assessed the effect of interferon beta-1a on the occurrence of relapses in patients after first presentation with neurological events, who are at high risk of conversion to clinically definite multiple sclerosis.

Methods

Eligible patients had had a first episode of neurological dysfunction suggesting multiple sclerosis within the previous 3 months and had strongly suggestive brain MRI findings. Patients were randomly assigned interferon beta-1a 22 µg or placebo subcutaneously once weekly for 2 years. Neurological and clinical assessments were done every 6 months and brain MRI every 12 months. Analyses excluded one patient assigned placebo who received no study injections.

Findings

241 (78%) of 308 randomised patients received study treatment for 2 years; 278 (90%) remained in the study until termination. 57 (85%) of 67 who stopped therapy did so after conversion to clinically definite multiple sclerosis. Fewer patients developed clinically definite multiple sclerosis in the interferon group than in the placebo group (52/154 [34%] vs 69/154 [45%]; p=0·047). The time at which 30% of patients had converted to clinically definite multiple sclerosis was 569 days in the interferon group and 252 in the placebo group (p=0·034). The annual relapse rates were 0·33 and 0·43 (p=0·045). The number of new T2-weighted MRI lesions and the increase in lesion burden were significantly lower with active treatment.

Interpretation Interferon beta-1a treatment at an early stage of multiple sclerosis had significant positive effects on clinical and MRI outcomes.

Lancet 2001; 357: 1576-82

See Commentary

Introduction

Multiple sclerosis is a severe disorder of the central nervous system. In about 85% of patients, the disease begins with a relapsing stage; the relapses are associated with perivenular foci of inflammation in the white matter. In the initial phase, relapses are generally followed by complete or almost complete clinical recovery. After this relapsing-remitting phase, most patients enter a secondary progressive phase and accumulate irreversible neurological deficits.1,2

Treatment of patients in the early phases of the disease may be advisable for two reasons. First, studies by pathology and magnetic resonance imaging (MRI) suggest that axonal damage is an early event in multiple-sclerosis lesions and normal-appearing white matter.3-6 Second, a large proportion of patients presenting with clinically isolated syndromes suggestive of demyelinating events develop new neurological symptoms leading to a diagnosis of clinically definite multiple sclerosis. In these cases, the burden of brain lesions visible on T2-weighted MRI scans is a strong predictor of conversion.7-10 Interferon beta is known to reduce greatly the extent of active MRI lesions and, as a consequence, the accumulation of the MRI-measured lesion burden.11-14 This treatment given early in the course of multiple sclerosis might therefore affect the subsequent course of the disease, by decreasing the amount of inflammation.15

Phase III clinical trials have shown that various formulations of interferon beta can significantly reduce clinically assessed and MRI-measured disease activity in patients with relapsing-remitting multiple sclerosis.11-14 In two of these trials, the progression of disability was also decreased, albeit to a lesser extent. These studies also suggested that the beneficial effect of interferon beta in multiple sclerosis increases with drug dose and varies according to disease duration.

In a 2-year follow-up study of patients with isolated optic neuritis, treatment with high-dose intravenous methylprednisolone reduced the early risk of conversion to clinically definite multiple sclerosis.16 Although this beneficial effect seemed to be lost after 4 years,17 the findings suggest that early initiation of treatment might be important among patients presenting with clinically isolated syndromes suggestive of multiple sclerosis.

This double-blind placebo-controlled randomised study aimed to assess the effects of low-dose interferon beta-1a (Rebif, Serono, Geneva, Switzerland) on the risk of conversion to clinically definite multiple sclerosis.

Methods

Patients

Eligible patients had clinical syndromes indicating unifocal or multifocal involvement of the central nervous system, were aged 18-40 years, had presented with a first neurological episode suggesting multiple sclerosis in the previous 3 months, had one or more abnormalities evident during the neurological examination, and had a positive brain MRI scan. An MRI scan was judged positive when one of the following criteria was met: presence of at least four white-matter lesions on the T2-weighted scans; presence of at least three white-matter lesions, if at least one was infratentorial or enhancing after injection of gadolinium-diethylenetriaminepenta-acetic acid (Gd-DTPA). Steroid treatment of the initial attack was allowed only for moderate or severe exacerbations. An exacerbation was defined as moderate or severe if associated with a score of 3 or more in at least one functional system18 (with the exception of the visual system, for which a score of 3 was taken to indicate moderate or severe relapses), or if associated with a score of 2 in at least three functional systems. Reasons for exclusion were any previous immunosuppressive or immunomodulatory treatment; participation in any experimental procedure during the year before the study; other serious intercurrent systemic illnesses or psychiatric disorders; pregnancy; and unwillingness to use reliable methods of contraception during the study. The ethics committees of all participating centres approved the study, and patients gave written informed consent before joining the study.

Design

57 centres in 14 European countries took part in this double-blind, placebo-controlled, randomised trial (study reference GF 7480). Patients were enrolled between August, 1995, and July, 1997. The treatment was assigned according to a computer-generated randomisation list stratified by centre. Owing to the small numbers of patients per centre, data from centres were pooled by country. Eligible patients underwent complete physical and neurological examinations. Their disability was rated on the expanded disability status scale (EDSS),18 the ambulation index, and the Scripp's neurological rating scale (SNRS).19 To exclude other possible neurological disorders, eligible patients went through a series of medical tests according to the type of presentation: erythrocyte sedimentation rate, complement, Lyme serology, antinuclear antibodies, anticardiolipin antibodies, Treponema pallidum haemagglutination assay, and HIV testing. Spinal-cord MRI or myelography and examinations of cerebrospinal fluid were done for purely spinal-cord presentations, and complete ophthalmological examinations for optic-neuritis presentations. The process of enrolment was under the supervision of the coordinating centre in Milan. An eligibility form for each patient was sent to two members of the steering committee and, in case of disagreement, the final decision was taken by one of two prespecified members of the committee (GC or VM). All brain MRI scans were assessed for eligibility by two other members of the steering committee (MF and FB). If all the inclusion and exclusion criteria were met, the coordinating centre gave approval for the patient to be enrolled.

Patients were randomly assigned either 22 µg interferon beta-1a (Rebif, Serono) or placebo by subcutaneous injection once weekly for 2 years. At each study site, a treating physician was responsible for the overall management of the patient, including safety monitoring. An evaluating physician was responsible for all scheduled neurological examinations and exacerbation follow-up visits. Neurological and safety assessments, including vital signs, haematology, and biochemical tests, were done at the end of months 1, 6, 12, 18, and 24. Brain MRI was done as part of prestudy screening and at the end of months 12 and 24.

The primary outcome measure was the conversion to clinically definite multiple sclerosis as defined by the occurrence of a second exacerbation.20 In this study, an exacerbation was defined as the appearance of a new symptom or worsening of a pre-existing symptom, accompanied by a corresponding new neurological sign or focal neurological dysfunction lasting at least 24 h, in the absence of fever, and preceded by stability or improvement for at least 30 days. Patients were instructed to inform the referring centre immediately in the case of a possible exacerbation, and a visit was arranged within 1 week. An event was counted as an exacerbation only when the evaluating physician was able to detect an objective change at the neurological examination shown by a change of the EDSS score or the functional system scores. A change in bowel, bladder, or cognitive function alone was not accepted. Two members of the steering committee (GC and VM) reviewed the documentation of all exacerbations and, by consensus, classified them as confirmed (if satisfying the above criteria) or unconfirmed (if the criteria were not met).

After the occurrence of the second exacerbation, as stipulated in the protocol, the investigator discussed with the patient the possibility of starting open-label treatment with interferon beta-1a once weekly until the completion of the trial. However, masking of the study preparation given during the double-blind phase was maintained for both patients and physicians. Moderate or severe relapses during the study were treated with a standard dose of 1·0 g intravenous methylprednisolone for 3 consecutive days.

Secondary outcome measures included change in the SNRS score, time to second exacerbation, and several MRI measures (number of T2 active lesions [new and enlarging T2 lesions], number of enhancing T1 lesions, number of patients without MRI activity [ie, no active T2 lesions or enhancing lesions throughout the study], and yearly changes of hyperintense T2 lesion volume).

All the MRI scanners operated at field strengths of 0·5-1·5 T. On each occasion, the following scans were done: T1-weighted axial, coronal, and sagittal scouts, which were used to locate internal anatomical landmarks to prescribe a precise imaging plane for each patient at pre-enrolment and at all follow-up imaging sessions; dual-echo conventional spin-echo (repetition time [TR] 2000-2500 ms, echo time [TE] 30-60/70-120 ms, number of acquisitions 1); precontrast T1-weighted conventional spin-echo (TR <800 ms, TE <25 ms, number of acquisitions 2 or more); post-contrast T1-weighted scans, with the same acquisition parameters and slice locations as precontrast scans, 5-7 min after the injection of Gd-DTPA. All injections of Gd-DTPA were bolus infusions of 0·2 mmol/kg. For all scans, 24 contiguous interleaved axial slices were acquired with 5 mm slice thickness, 192 to 256x256 raw data matrix and 220-250 mm square field-of-view. For follow-up scans, the scan planes were carefully repositioned according to published guidelines.21

All scans were sent to the Neuroimaging Research Unit in Milan and reviewed centrally. Unsatisfactory images were rejected and repeated. On all scans, lesions were first identified by agreement of two experienced observers (MF and FB, who were unaware of treatment allocation) on the hard copies of the first echo of the dual-echo scans, and on the T1 scans; the second echo of the dual-echo scans was always used to increase confidence in lesion identification. Gadolinium-enhancing lesions were identified according to published guidelines.22 On follow-up scans, the number of new or enlarging T2 hyperintense lesions and the numbers of total and new gadolinium-enhancing T1 lesions were assessed by the same observers. New lesions were defined as those not visible on the corresponding images obtained a year earlier. Enlarging lesions were defined as those that had increased in size by at least 50% compared with the corresponding images obtained a year earlier. Hyperintense T2 and enhancing T1 lesion volumes were measured by trained technicians unaware of the patient's identity and the order of scan acquisition. A semiautomated segmentation technique based on local thresholding was used for lesion segmentation,23 with the marked hard copies as a reference.

Statistical methods

The sample size was calculated on the basis of previous epidemiological studies,2,7,24 which indicated that 40% of patients in the placebo group would convert to clinically definite multiple sclerosis within 2 years. The sample size was based on the assumption of 20% conversion in treated patients, 90% power, and a two-tailed test of significance at the 0·029 level, with allowance for an interim analysis (not done) but preservation of the overall type I error probability of 0·05. With the assumption of a 20% dropout rate, we calculated by standard methods for sample sizes for the comparison of two proportions, that 155 patients per group were necessary. Analyses were done on all patients who received at least one injection (308 of 309 randomised patients). Odds ratios comparing the occurrence of clinically definite multiple sclerosis between groups were derived from a logistic regression analysis with adjustment for country and factors found to be significant predictors of conversion to clinically definite multiple sclerosis. These factors included time since first attack and T2 lesion number at screening and multisymptomatic onset. Patients who withdrew from the study before reaching the primary endpoint were classified as exacerbation-free. Time to clinically definite multiple sclerosis was compared between treatment groups by the log-rank test and a Cox proportional-hazards model with adjustment for country and factors found to be significant predictors of clinically definite multiple sclerosis. A baseline-adjusted ANCOVA on ranks with treatment and country in the model was used for the MRI variables. The Steering Committee was responsible for all issues relating to the conduct of the study. The Clinical Trials and Neuroimaging Research Units, Department of Neuroscience, Scientific Institute San Raffaele coordinated all study activities.

Results

375 patients were screened for the study (figure 1). 73 patients were found not to be eligible: MRI criteria were not satisfied in 21, inclusion or exclusion criteria were not satisfied in 41, eight withdrew consent, treatment could not be started in time for two, and one patient withdrew between recruitment and randomisation.

Figure 1: Trial profile

CDMS=clinically definite multiple sclerosis. One placebo-group patient who withdrew before conversion was not receiving medication.

Of the 309 patients randomised, 278 (90%) completed the study. One patient in the placebo group did not receive study medication and is not included in outcome analyses. 13 (8%) of 154 patients in the interferon beta-1a group and 18 (12%) of 154 in the placebo group withdrew from the study. Reasons for discontinuation were protocol violations (two), adverse events (three), pregnancy (two), other unspecified reasons (four), and the decision of the investigator and the patient to start active treatment after conversion to clinically definite multiple sclerosis. Only four patients from each group withdrew before developing clinically definite multiple sclerosis (including the placebo-group patient who never received the allocated preparation). The distribution of duration of follow-up was similar in the two groups. There were 154 patients in each group at baseline, 150 in the placebo group and 152 in the interferon group at 6 months, 145 and 152 at 12 months, 136 and 143 at 18 months, and 137 and 141 at 24 months. 241 (78%) patients received study treatment until the end of the study. 57 (85%) of the 67 who stopped study therapy did so after conversion to clinically definite multiple sclerosis, as allowed by the protocol.

At baseline, the two randomised groups were similar in terms of demographic, clinical, and MRI characteristics (table 1). 63 (41%) of 154 patients in the interferon beta-1a group and 58 (37%) of 155 in the placebo group had clinical evidence of two or more separate lesions in the central nervous system (ie, a total of 39% of patients had a multifocal presentation). On the basis of clinical findings, lesions were located as reported in table 2. Examination of cerebrospinal fluid showed intrathecal synthesis of IgG (abnormal IgG index and/or presence of oligoclonal bands) in 176 patients; no abnormalities were detected in 41 patients, and lumbar puncture was not done for 92. The cerebrospinal fluid was positive in 85 (79%) of 107 patients in the interferon group and 91 (83%) of 110 in the placebo group. The initial attack was treated with steroids in 104 (68%) of 154 of the interferon group and 112 (73%) of 154 in the placebo group.



 
Characteristic Interferon Placebo
beta-1a (n=154) (n=155)
Demography
Mean (SD) age in years 28·9 (6·0) 28·0 (6·1)
Number M/F 60/94 52/103
EDSS score*
Mean (SD) 1·17 (1·2) 1·17 (1·2)
Median 1·0 1·0
SNRS score
Mean (SD) 96·4 (5·0) 95·9 (5·7)
Clinical features
Number of first attacks treated with steroids 105 (68%) 112 (72%)
Number with positive CSF/total examined 85/117 (79%) 91/110 (83%)
Median (IQR) number of T2 lesions 26 (16-44) 22 (15-40)
Median (IQR) number of enhancing lesions 1 (0-3) 1 (0-3)
Number of patients with enhancing lesions 89 (58%) 91 (59%)
Median (IQR) T2 lesion volume (mm3)‡ 5542 4964 
(3143-10 719) (2680-10 556)
*Data available for 149 patients in interferon beta-1a group and 146 in placebo group. Mean scores at baseline do not reflect the severity of the attack because baseline assessments may have been up to 3 months after the onset of the attack. †Data available for 147 patients in each group. ‡Data available for 132 patients in interferon beta-1a group and 131 in placebo group.
Table 1: Baseline clinical and MRI characteristics of patients



 
Site Number of patients
Inferferon beta-1a (n=154) Placebo (n=155)
Spinal cord 43 (28%) 43 (28%)
Brainstem 60 (39%) 56 (36%)
Cerebrum 36 (23%) 47 (30%)
Cerebellum 24 (16%) 20 (19%)
Optic nerve 54 (35%) 44 (28%)
Other 3 (2%) 3 (2%)
Attribution of the clinical findings of the initial attack. The total exceeds 100% because patients with multifocal presentations are included in each relevant category.
Table 2: Site of involvement in central nervous system during first attack


52 (34%) of 154 patients in the interferon beta-1a group and 69 (45%) of 154 in the placebo group group converted to clinically definite multiple sclerosis during the 2-year study (p=0·047, table 3). The odds ratio for conversion was 0·61 (95% CI 0·37-0·99; p=0·045 by logistic regression with adjustment for country, onset type, baseline T2 lesion count [eight or fewer versus nine or more], and time from first attack to randomisation [60 days or >60 days]). There were no statistically significant centre or treatment by centre effects.



 
Endpoint Inferferon beta-1a (n=154)  Placebo (n=154) p
Number of patients converting to CDMS 52 (34%) 69 (45%) 0·047*
Days (95% CI) to conversion to CDMS (30th percentile) 569 (317 to (infinity)) 252 (173 to 413) 0·034†
Annual relapse rate 0·33 0·43 0·045‡
Median (IQR) change in EDSS score from baseline to year 2§ 0 (-1 to 0) 0 (-1 to 0) 0·521||
Median (IQR) change in SNRS score from baseline to year 2 0 (-1 to 2) 0 (-1 to 2) 0·747||
CDMS=clinically definite multiple sclerosis. *chi2 test. †Log-rank test. ‡Poisson regression with treatment in the model. §Data available for 135 patients in interferon beta-1a group and 129 in placebo group. ||ANOVA. ¶Data available for 133 and 129 patients.
Table 3: Clinical endpoints


The time to the occurrence of the second relapse in 30% of patients (30th centile used rather than median because this was the last quantile reached by both groups), determining the conversion to clinically definite multiple sclerosis, was 569 days in the interferon beta-1a group and 252 days in the placebo group (figure 2; hazard ratio 0·65 [0·45-0·94], p=0·023 by Cox's proportional hazards with onset type, baseline T2 lesion count, and time from first attack to randomisation). The annualised relapse rate was 0·33 in the interferon beta-1a group and 0·43 in the placebo group (incidence density ratio 0·77 [0·59-1·00], p=0·054). As expected, owing to the early phase of the disease and the inclusion in an active phase, the median EDSS and SNRS scores were unchanged in both groups during the study. 15% of the interferon beta-1a group and 20% of the placebo group had confirmed worsening on the EDSS of at least 1 point at the final evaluation; the proportions of patients with 2-point worsening were 4% and 6%. The only baseline clinical and MRI variables that were significantly predictive of outcome were multifocal onset (odds ratio 1·99 [1·14-3·46], p=0·015) and T2 lesion number more than eight (3·64 [1·30-10·2; p=0·014).



 
Endpoint Inferferon beta-1a Placebo (n=144) p
(n=146)
Median (IQR) number of 
lesions per patient per scan
T2 active lesions 2·0 (0·5 to 4·5) 3·0 (1·5 to 6·25) <0·001
Enhancing lesions 0·5 (0 to 1) 0 (0 to 1) 0·809
T2 lesion volume†
Median (IQR) absolute  -487 (-1789 to 802) -299 (-932 to 2020) 0·002
change at year 2 (mm3)
Median (IQR) percentage  -13·0 (-26 to 17) 8·8 (-20 to 36) 0·002
change from baseline to year 2
*ANCOVA on ranks. Not all patients had scan data that could be used for volume determination. †Data available for 114 patients in interferon beta-1a group and 109 in placebo group.
Table 4: MRI endpoints


Figure 2: Kaplan-Meier survival curve of probability of no conversion to clinically definite multiple sclerosis (CDMS) over 2 years

The results of the MRI analyses are given in table 4. There were significantly fewer new T2 lesions in the interferon beta-1a group than in the placebo group (p<0·001; figure 3). The vast majority of the patients in both groups had evidence of MRI conversion defined by the appearance of at least one new MRI lesion of diameter more than 10 mm or three new lesions of diameter less than 10 mm. However, the proportion of patients without MRI activity during the study was significantly higher in the interferon beta-1a group than in the placebo group (23 of 146 [16%] vs eight of 133 [6%], p=0·005). No difference between the study groups was observed for T1 active lesions. The difference between the groups in MRI activity was probably underestimated, because 26 (17%) patients in the placebo group, having developed clinically definite multiple sclerosis, received open-label treatment with interferon beta-1a. The effect of interferon beta on suppressing new enhancing lesion formation is very rapid,25 and a scan taken even a few days after the treatment will show a reduction in the number of enhancing lesions; the number of new T2 lesions, however, will be only marginally influenced because the new T2 lesions have accumulated before onset of the open-label treatment.

Figure 3: Median number of active T2 lesions per patient per scan by treatment group

Data given for active lesions during year 1, year 2, and overall. Differences between groups assessed by ANCOVA on ranks.

For technical reasons, MRI data were not available in an electronic format for lesion volume to be assessed in all patients. In the placebo group, there was an increase in T2 lesion volume (8·8%) at year 2 compared with the baseline value; in the interferon beta-1a group, a median decrease of 13·0% at year 2 was observed (p=0·002). The absolute change in T2 lesion volume was also significantly lower in the interferon beta-1a group than in the placebo group (p=0·002).

Adverse events were reported more frequently in patients assigned interferon beta-1a than in those assigned placebo. These events included injection-site inflammation (60% vs 12%), fever (28% vs 12%), myalgia (17% vs 9%), and chills (11% vs 5%). Serious adverse events (defined according to the guidelines of the International Conference on Harmonisation) were reported in five patients in the placebo group and six in the interferon beta-1a group.

Discussion

Pathology3,4 and MRI studies5,6,26 suggest that axonal damage is an early event in the evolution of multiple sclerosis. Evidence is accumulating that, in the early phases of the disease, axonal damage depends primarily on inflammatory processes.27,28 The mechanism of action of interferon beta in multiple sclerosis is predominantly anti-inflammatory.14 Therefore, better results would be expected with early than with later treatment of multiple sclerosis, consistent with the observed greater benefit from interferon beta treatment in relapsing-remitting than in secondary progressive multiple sclerosis.29-31

The goal of this study was to assess the effect of interferon beta-1a in the earliest clinically detectable phase of multiple sclerosis. Treatment with a low dose of interferon beta-1a significantly lowered the proportion of patients who converted to clinically definite multiple sclerosis and reduced the frequency of relapses overall. Treatment was also effective in decreasing the number of new T2 lesions and the accumulation of MRI-measured lesion burden. However, only 16% of the patients assigned active therapy and 6% of those assigned placebo were free of temporal dissemination of MRI lesions in the 2 years after the clinical onset of the disease. Thus, interferon beta-1a did not stop the disease activity in the vast majority. Moreover, the very high rate of MRI conversion indicates that the entry criteria of this study reliably identify patients at high risk of further disease activity.

No effect of interferon beta treatment on disability was observed, but this absence of effect is not surprising given the very early phase of multiple sclerosis and the short study duration. An interesting observation is that 20% of the placebo group and 15% of the interferon beta-1a group had confirmed progression of 1 point on the EDSS, confirming some irreversible nervous damage in this early phase of the disease. Longer follow-up is needed to show whether the lowered disease activity with early treatment will result in long-term benefit in terms of disability.

These results are consistent with those of the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS), which was stopped after a positive preplanned interim analysis.32 In that study, the cumulative probability of conversion to clinically definite multiple sclerosis was 35% in the interferon beta-1a group and 50% in the placebo group, although this value is projected because less than 16% of patients reached the 3-year timepoint. Comparison on total relapse rate is not possible because patients in CHAMPS were not followed up after they had converted to clinically definite multiple sclerosis. Furthermore, the hazard ratio for conversion to clinically definite multiple sclerosis was 0·56 (95% CI 0·38-0·81) for CHAMPS and 0·65 (0·45-0·94) for our study. Although the treatment effect was slightly greater in CHAMPS than in our study, this difference may be related to differences in the dose administered, the population of patients, or the study design and conduct. Interferon beta-1a was used in both studies, but we used a dose of 22 µg and CHAMPS a dose of 30 µg; available data suggest that dose may have an effect on outcome.11,13

Furthermore, the patients studied differed in that CHAMPS included only those with an acute unifocal demyelinating event, whereas our study allowed both unifocal and multifocal clinical presentations. The risk of conversion was about two times higher for multifocal than for unifocal presentations, and about 40% of patients in our study had multifocal onset. The higher MRI lesion number also suggests a more severe group in our study than in CHAMPS. The dose of interferon beta-1a we used is ineffective in established relapsing-remitting multiple sclerosis, therefore more severe multiple sclerosis may be less sensitive to the effect of interferon. Patients in CHAMPS were treated with high-dose intravenous steroids at onset, whereas in our study the proportion of steroid-treated patients was 70%, with a variable dose and route. Although high-dose intravenous steroids affect early conversion to clinically definite multiple sclerosis in acute optic neuritis,16,17 the influence of this difference in steroid treatment for all clinically isolated syndromes is unknown. Patients in CHAMPS were enrolled within 2 weeks of the clinical presentation of disease compared with 3 months in our study; this difference could lead to subtly different populations. Finally, the MRI selection criteria we used were more stringent than those used in CHAMPS, with resultant higher lesion numbers and burdens of disease consistent with more severe disease.

In terms of study design and conduct, patients, by definition, could not convert to clinically definite multiple sclerosis in the first month of treatment in CHAMPS, but they could in our study. On the assumption that therapy may take some weeks to manifest its effects fully, this design could bias against active therapy in our study. The major difference in study conduct relates to follow-up. Although planned for 3 years, CHAMPS terminated early. Of 383 patients entered, 44 were lost to follow-up in the first 2 years, before conversion, and for 77 patients, the study ended before 2 years of therapy. Therefore, only 262 (68%) of 383 of patients in CHAMPS were followed up to an endpoint or 2 years compared with 298 (97%) of 308 in our study, a factor that could have a substantial impact on 2-year outcome.

Because the observed effects are quite small, whether a low dose of interferon beta-1a, such as that used in our study, should be recommended for the early treatment of multiple sclerosis is debatable. Nevertheless, the benefit observed in this study on relapse rate exceeds that observed in another study that tested the same product and dose14 in patients with established relapsing-remitting multiple sclerosis. Although not proven, this finding suggests that early multiple sclerosis is more sensitive to the therapeutic effect of interferon beta-1a than more advanced disease. The therapeutic benefit on relapses is supported by the MRI findings, in which both lesion activity and the accumulation of lesion burden were reduced compared with placebo. Among the various effects on MRI, we observed that interferon beta-1a also resulted in a significant increase in the proportion of patients with absence of any MRI activity over 2 years.

The safety profile of interferon beta-1a in this study was similar to that reported in other trials13,14 albeit with a lower rate of adverse events and withdrawals due to the use of a lower dose. Injection-site reactions were common, but they were mostly mild, and injection-site necrosis was not observed. Good tolerability contributed to good compliance in the trial.
Early Treatment of Multiple Sclerosis Study Group

Steering Committee--G Comi (Chair), M Filippi, F Barkhof, L Durelli, G Edan, O Fernández, H-P Hartung, P Seeldrayers, P Soelberg Sørensen, M Rovaris, F Martinelli, O R Hommes. Writing Committee--G Comi (Chair), M Filippi, F Barkhof, L Durelli, G Edan, O Fernández, H-P Hartung, P Seeldrayers, P Soelberg Sørensen, M Rovaris, F Martinelli, O R Hommes, G Francis. Other investigators Austria--Graz, Karl Franzens University (S Strasser-Fuchs, P Kapeller, A Lechner); Innsbruck, Universitätsklinik für Neurologie (W Poewe, T Berger, F Deisenhammer); Vienna, Donauspital Neurologie (W Kristoferitsch, J Lassmann). Belgium--Charleroi, Hôpital Civil de Chaleroi (P Seeldrayers, T Piette); Fraiture, Centre Neurologique de Fraiture (D Guillaume); Overpelt, MS Kliniek and Revalidatie Centrum (L Vande Gaer). Denmark--Copenhagen, Rigshospitalet Copenhagen (P Soelberg Sorensen, A Oturai, B Wanscher); Glostrup, KAS Glostrup (J Frederiksen, J Jensen, F Sellebjerg). Finland--Oulu, University of Oulu (M Reunanen, J Pyhtinen, M Reunanen). France--Besancon, Hôpital Jean Minjoz (L Rumbach, E Berger, L Tatu); Bordeaux, Service de Neurologie, Hopital Pellegrin (B Brochet, B Barroso, A Gayou, I Ghorayeb, C Quelmeneur); Creteil, Hôpital Henri Mondor (P Cesaro, A Créange); Limoges, Centre Hospitalier Universitaire Dupuytren (J M Vallat, P Couratier, J Y Salle); Lomme, Centre Hospitalier Saint Phillibert (P Hautecoeur); Marseille, Centre Hospitalier Universitaire Timone (J Pelletier, A Dalecky); Rennes, Centre Hospitalier Universitaire de Pontchaillou (G Edan, S Belliard, I Brunet, V De Burghgraeve, O De Marco, V Cahagne); Toulouse, Centre Hospitalier Universitaire Toulouse, Hôpital de Purpan (M Clanet, I Berry, D Brassat. Germany--Berlin, Universitätsklinikum Benjamin Franklin (P Marx, F Klostermann, H C Schumacher, M Stangel); Bochum, Knappschaftskrankenhaus Bochum-Langendreer (W Gehlen, M Haupts); Bochum, Sauerlandklinik Hachen (D Pöhlau, J Federlein, V Hoffman, T Postert, S Schimrigk); Erfurt, Neurologische Klinik und Poliklinik der Universität (H W Kölmel, A Thieme); Hamburg, Universitätskrankenhaus Eppendorf (C Heesen, J Gbadamosi, B Hadji); Hannover, Medizinische Hochschule (F Heidenreich, S Marckmann, C Trebst, A Windhagen); Heidelberg, Universitätsklinikum Neurologische Klinik (B Storch-Hagenlocher, R Runkel, M E Vogt-Schaden); Münster, Klinik und Poliklinik für Neurologie der Universität (E B Ringelstein, F Bethke, A Frese, R Lüttman); Würzburg, Klinik und Poliklinik der Universität (H P Hartung, P Rieckmann, A Chan, M Mäurer). Italy--Bari, Istituto di Clinica delle Malattie Nervose e Mentali (P Livrea); Brescia, Università degli Studi di Brescia (L A Vignolo, R Capra, M Codella, S Galluzzi); Fidenza, Divisione di Neurologia Ospedale Civile (E Montanari, C Grassa); Gallarate, Centro Studi Sclerosi Multipla (A Zibetti, A Ghezzi, M Zaffaroni); Genova, Dipartimento di Scienze Neurologiche e della Visione, Università di Genova (G L Mancardi, F Sardanelli, A Uccelli); Milano, Istituto Neurologico Carlo Besta (C Milanese, L la Mantia); Milano, Ospedale San Raffaele (G Comi, M Filippi, F Martinelli, V Martinelli, L Moiola, M Rocca, M Rodegher, M Rovaris); Milano, Istituto Don Gnocchi (D Caputo, I Mini, L Mendozzi); Pavia, Istituto Neurologico C Mondino, Dipartimento di Scienze Neurologiche (V Cosi, R Bergamaschi, A Citterio); Roma, Università di Roma La Sapienza (C Fieschi, M Frontoni, E Giugni, S Bastianello); Torino, Ospedale Giovanni Bosco (I Sacerdote). Netherlands--Amsterdam, A Z Vrje Universiteit (B Uitdehaag, K Nasseri, J Killestein); Nijmegen, Stichting Multiple Sclerose Centrum (O Hommes, P J H Jongen); Rotterdam, Academisch Ziekenhuis Dijkzigt (P A van Doorn, J W B Moll, H Pieterman). Norway--Nordbyhagen, Sentralsykehuset i Akersus (A Beiske, A Gunnar Solberg); Oslo, Rikshospitalet (D Jensen, C Lund). Poland--Lodz, Medical Academy of Lodz (K W Selmaj, A Mochecka). Spain--Avilés, Servicio de Neurologia Hospital San Agustín de Avilés (D F Uría, D Ferreiro); Barcelona, Hospital de Bellvitge (T Arbizu- Urdiain, A Martinez-Yélamos, J J Hermández Regadera, G M Ozaeta); Barcelona, Hospital Val d'Hebron (X Montalban, C Nos, M Tintoré, A Rovira, J Rio); Bilbao, Hospital de Cruces (A Antigüedad); Madrid, Clinico San Carlos (E Varela de Seijas); Madrid, Doce de Octubre (J Esteban); Madrid, Hospital General Universitario Gregorio Marañón (S Giménez-Roldán, C De Andrés, A Guillem); Madrid, Hospital Puerta de Hierro (A Garcia-Merino, M R Blasco); Madrid, University Hospital La Paz (P Barreiro Tella, E Diez Tejedor, B Fuentes); Malaga, Hospital Carlos Haya (O Fernández, M Bravo Utrera); Oviedo, Hospital General de Asturias (C Hernández-Lahoz, A Tunón-Alvarez); Sevilla, Unidad de Esclerosis Múltiple (G Izquierdo, J M Garcia-Moreno). Sweden--Stockholm, Karolinska Hospital (T Olsson, M Andersson). Switzerland--Lausanne, Centre Hospitalier Universitaire Vaudois, Service de neurologie (M Schluep, G Bogovsslavsky); St Gallen, Neurologische Klinik nd Poliklinik (C Vouga, H P Ludin, G Rilling);Valens, Neurologie Rehabilitationszentrum (S Beer, J Kesselring); Zürich, Neurologische Klinik und Poliklinik (C Vouga, H P Ludin, G Rilling). UK--Nottingham, University Hospital, Queen's Medical Centre (L Blumhardt, C Liu, V Orpe).
Acknowledgments

In addition to the patients who took part, we thank M Rocca and J H T M van Waesberghe for MRI analysis, H Kamsteeg (CRO), C O'Donovan (data management), S Margrie (statistician), D Piani and N Ammoury (Serono Medical Affairs), C Deakin (Caudex), and C Abraham (help with the report), and Serono study monitors in each country. The European Charcot Foundation promoted the study. Sponsorship was provided by Serono International SA (Geneva, Switzerland).

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