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Moving toward earlier treatment of multiple sclerosis: Findings from a decade of clinical trials and implications for clinical practice

Open AccessPublished:August 02, 2013DOI:https://doi.org/10.1016/j.msard.2013.07.001

      Highlights

      • Trials of interferon beta and glatiramer acetate in patients with a first clinical event suggestive of multiple sclerosis.
      • Implications on timing of treatment initiation.
      • Early treatment in light of the evolution of the McDonald diagnostic criteria.

      Abstract

      The first clinical presentation of multiple sclerosis (MS) is usually a single episode of typical symptoms and signs and is designated a “first clinical demyelinating event” (FCDE) or a “clinically isolated syndrome”. Patients with an FCDE who show ‘silent’ magnetic resonance imaging lesions are at high risk of further clinical events and therefore of meeting the criteria for the diagnosis of clinically definite MS (CDMS). Here we review five Phase III trials, in which treatment with the following disease-modifying drugs (DMDs) was initiated at this early stage: interferon beta (ETOMS, CHAMPS, BENEFIT, and REFLEX) and glatiramer acetate (PreCISe). Differences in the design of the trials and their patient inclusion criteria limit comparisons. However, the proportion of placebo-treated patients who developed CDMS within 2 years was 38–45% across studies, and this rate was significantly reduced by DMD treatment. Conversion to McDonald MS was reported by only two of the trials: BENEFIT (2001 criteria) and REFLEX (2005 criteria). Around 85% of placebo-treated patients developed McDonald MS by 2 years in each, and again a beneficial effect of DMD treatment was seen. Overall, these studies support early use of DMDs to treat patients with an FCDE who are at high risk of conversion to CDMS.

      Abbreviations:

      CDMS (clinically definite multiple sclerosis), CI (confidence interval), CNS (central nervous system), DMD (disease-modifying drug), FCDE (first clinical demyelinating event), GA (glatiramer acetate), Gd (gadolinium), HR (hazard ratio), IFNβ (interferon beta), MRI (magnetic resonance imaging), MS (multiple sclerosis), q.w. (once weekly), s.c. (subcutaneous(ly)), t.i.w. (three times weekly)

      Keywords

      1. Introduction

      Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) that is characterized by demyelination and axonal injury and loss. The clinical presentation of this chronic disorder is usually a single acute first clinical demyelinating event (FCDE), also known as clinically isolated syndrome. This is a neurologic episode lasting >24 h that is consistent with demyelination within the CNS, and typically involves the optic nerve, brainstem, subcortical white matter, or spinal cord (
      • Miller D.
      • Barkhof F.
      • Montalban X.
      • Thompson A.
      • Filippi M.
      Clinically isolated syndromes suggestive of multiple sclerosis, part 1: natural history, pathogenesis, diagnosis, and prognosis.
      ). Many patients who experience an FCDE often have further attacks separated by periods of clinical stability, a pattern characterizing the relapsing–remitting form of MS. If clinically ‘silent’ brain or spinal cord lesions are seen on a magnetic resonance imaging (MRI) scan performed at the time of the FCDE, the patient is at particularly high risk of further attacks. About 5–10% of patients go on to experience steady progression of disease without further attacks, also known as primary progressive MS.
      In the early stages of MS, inflammatory activity leads to demyelination, which is thought to contribute to the axonal damage and neuronal loss that usually manifests later in the disease course (
      • Bruck W.
      The pathology of multiple sclerosis is the result of focal inflammatory demyelination with axonal damage.
      ). Typically, demyelination and axonal loss are seen mostly within MS plaques, but axonal damage can also be found in normal appearing white matter (
      • Bjartmar C.
      • Trapp B.D.
      Axonal degeneration and progressive neurologic disability in multiple sclerosis.
      ). Less frequently in early MS, lesions may also be seen in gray matter, and diffuse structural changes have been described in normal appearing gray matter (
      • Hulst H.E.
      • Geurts J.J.
      Gray matter imaging in multiple sclerosis: what have we learned?.
      ). Demyelination and subsequent axonal loss are associated with clinical relapses and cumulative functional disability, respectively (
      • Bruck W.
      The pathology of multiple sclerosis is the result of focal inflammatory demyelination with axonal damage.
      ,
      • De Stefano N.
      • Narayanan S.
      • Francis G.S.
      • Arnaoutelis R.
      • Tartaglia M.C.
      • Antel J.P.
      • et al.
      Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability.
      ).
      According to the diagnostic criteria first developed in 1983 by
      • Poser C.M.
      • Paty D.W.
      • Scheinberg L.
      • McDonald W.I.
      • Davis F.A.
      • Ebers G.C.
      • et al.
      New diagnostic criteria for multiple sclerosis: guidelines for research protocols.
      , a diagnosis of clinically definite MS (CDMS) requires a patient to experience an FCDE, followed by a second clinical attack, at least a month later (showing dissemination of disease activity in time) and involving different areas of the CNS (showing dissemination in space). However, new diagnostic criteria were developed in 2001 by
      • McDonald W.I.
      • Compston A.
      • Edan G.
      • Goodkin D.
      • Hartung H.P.
      • Lublin F.D.
      • et al.
      Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis.
      , which acknowledge the utility of MRI techniques in demonstrating dissemination in time and space using subclinical disease activity. The McDonald criteria integrate clinical and paraclinical diagnostic methods, in particular MRI findings, to allow an earlier diagnosis of MS than the Poser criteria that only use clinical parameters. In 2005, the McDonald criteria were updated to allow dissemination in time to be demonstrated by the appearance of a new T2 lesion on a scan, compared to a baseline or reference scan performed at least 30 days before (
      • Polman C.H.
      • Reingold S.C.
      • Edan G.
      • Filippi M.
      • Hartung H.P.
      • Kappos L.
      • et al.
      Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”.
      ). In 2010, the McDonald criteria were revised again, and now dissemination in time could be demonstrated by the presence of a new T2 and/or gadolinium (Gd)-enhancing lesion on follow-up MRI performed at any time following the reference scan, or by the simultaneous presence of asymptomatic Gd-enhancing and non-enhancing lesions in the first scan (
      • Polman C.H.
      • Reingold S.C.
      • Banwell B.
      • Clanet M.
      • Cohen J.A.
      • Filippi M.
      • et al.
      Diagnostic criteria for multiple sclerosis: 2010 revisions to the “McDonald criteria”.
      ). This revision to the McDonald criteria enables MS to be diagnosed even earlier in the disease course than does the previous 2005 version, as long as the criteria for dissemination in space are also fulfilled. The 2010 criteria are still being validated but initial reports support their utility (
      • Gomez-Moreno M.
      • Diaz-Sanchez M.
      • Ramos-Gonzalez A.
      Application of the 2010 McDonald criteria for the diagnosis of multiple sclerosis in a Spanish cohort of patients with clinically isolated syndromes.
      ,
      • Sedani S.
      • Lim M.
      • Hemingway C.
      • Wassmer E.
      • Absoud M.
      Paediatric multiple sclerosis: examining utility of the McDonald 2010 criteria.
      ).
      Multiple sclerosis can be treated with disease-modifying drugs (DMDs), such as interferon beta (IFNβ) and glatiramer acetate (GA), which aim to reduce the frequency and severity of clinical attacks and delay the progression of disability. The effects of DMDs on clinical disease activity are usually paralleled by reductions in counts of active MRI lesions and in lesion burden (
      • Comi G.
      • Filippi M.
      • Wolinsky J.S.
      European/Canadian Glatiramer Acetate Study Group. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis.
      ,
      • Jacobs L.D.
      • Cookfair D.L.
      • Rudick R.A.
      • Herndon R.M.
      • Richert J.R.
      • Salazar A.M.
      • et al.
      Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis.
      ,
      • Paty D.W.
      • Li D.K.
      Interferon beta-1b is effective in relapsing–remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group.
      ,
      • PRISMS Study Group
      Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis.
      ). MS pathology is known to start before the clinical signs of the disease appear, and evidence suggests that the anti-inflammatory effects of DMDs are most effective during the early, inflammatory stages of the disease, and less effective in the progressive stages (
      • Kieseier B.C.
      The mechanism of action of interferon-beta in relapsing multiple sclerosis.
      ,
      • Wolinsky J.S.
      • Narayana P.A.
      • O′Connor P.
      • Coyle P.K.
      • Ford C.
      • Johnson K.
      • et al.
      Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial.
      ). Therefore, treating at the earliest possible opportunity—the FCDE—may be the most effective strategy to manage disease progression.
      The currently available preparations of IFNβ and GA have been investigated in clinical trials assessing whether treatment initiation at the FCDE delays the diagnosis of MS. This review paper aims to explore the results from the randomized phases of these studies and to discuss the implications of these findings for future clinical practice.

      2. Methods

      The source material was obtained from the primary publications from all manufacturer-sponsored trials comparing IFNβ or GA with placebo in patients with an FCDE who had not received prior treatment with immunosuppressant or immunomodulatory agents. Secondary publications were only considered if they provided clarification or correction of information in the primary papers.
      The MEDLINE and EMBASE databases were searched from 1995 to 1 June 2012. Searches were limited to studies in humans and papers published in English. A total of 799 articles were identified, within which there were five primary publications describing five manufacturer-sponsored trials of IFNβ or GA in patients with an FCDE.
      • CHAMPS (Controlled High-risk Avonex Multiple Sclerosis; IFNβ-1a, 30 μg intramuscularly once weekly [q.w.]); patients enrolled 1996–1998 (
        • Jacobs L.D.
        • Beck R.W.
        • Simon J.H.
        • Kinkel R.P.
        • Brownscheidle C.M.
        • Murray T.J.
        • et al.
        Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group.
        )
      • ETOMS (Early Treatment Of MS; IFNβ-1a, 22 μg subcutaneously [s.c.] q.w.); patients enrolled 1995–1997 (
        • Comi G.
        • Filippi M.
        • Barkhof F.
        • Durelli L.
        • Edan G.
        • Fernández O.
        • et al.
        Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study.
        )
      • BENEFIT (Betaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment; IFNβ-1b, 250 μg s.c. every other day); patients enrolled 2002–2003 (
        • Kappos L.
        • Polman C.H.
        • Freedman M.S.
        • Edan G.
        • Hartung H.P.
        • Miller D.H.
        • et al.
        Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes.
        )
      • PreCISe (early glatiramer acetate treatment in delaying conversion to clinically definite MS in subjects Presenting with a Clinically Isolated Syndrome; GA, 20 mg s.c. daily); patients enrolled 2004–2006 (
        • Comi G.
        • Martinelli V.
        • Rodegher M.
        • Moiola L.
        • Bajenaru O.
        • Carra A.
        • et al.
        Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial.
        )
      • REFLEX (REbif FLEXible dosing in early MS; IFNβ-1a, 44 μg s.c. three times weekly [t.i.w.] or q.w.), study conducted 2006–2010 (
        • Comi G.
        • De Stefano N.
        • Freedman M.S.
        • Barkhof F.
        • Polman C.H.
        • Uitdehaag B.M.
        • et al.
        Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial.
        ).

      3. Results

      3.1 Study designs

      While all five studies examined the effects of DMD treatment in patients who had experienced an FCDE, there were differences in the study designs, which are summarized in Table 1.
      Table 1Summary of study designs.
      StudyRandomization groupsEntry requirementsTime of primary analysisPrimary endpointDefinition of CDMS
      Time from FCDE to study startPresentationMRIAge (years)
      CHAMPS (
      • Jacobs L.D.
      • Beck R.W.
      • Simon J.H.
      • Kinkel R.P.
      • Brownscheidle C.M.
      • Murray T.J.
      • et al.
      Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group.
      )
      IFNβ-1a, 30 µg i.m. q.w. (n=193)Placebo (n=190)≤27 daysMonofocal
      Post hoc analysis found that some patients were multifocal.
      ≥2 clinically ‘silent’ T2 lesions ≥3 mm diameter; ≥1 periventricular, or ovoid18–50Stopped after 18-month interim analysisCumulative probability of CDMSSecond clinical neurologic event (lasting >48 h that could be attributed to a different part of the central nervous system to that underlying the initial event); or an increase of ≥1.5 EDSS score from Month 1
      ETOMS (
      • Comi G.
      • Filippi M.
      • Barkhof F.
      • Durelli L.
      • Edan G.
      • Fernández O.
      • et al.
      Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study.
      )
      IFNβ-1a, 22 µg s.c. q.w. (n=154)Placebo (n=155)≤3 monthsMonosymp-tomatic/polysymp-tomatic≥4 white-matter lesions on T2-weighted scans; ≥3 white-matter lesions, if ≥1 infratentorial or Gd+18–402 yearsProportion of patients reaching CDMSSecond exacerbation (appearance of a new symptom or worsening of a present symptom shown by change in EDSS or functional system score, lasting ≥24 h, preceded by ≥30 days’ clinical stability)
      BENEFIT (
      • Kappos L.
      • Polman C.H.
      • Freedman M.S.
      • Edan G.
      • Hartung H.P.
      • Miller D.H.
      • et al.
      Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes.
      )
      IFNβ-1b 250 µg s.c. e.o.d.(n=292)Placebo (n=176)≤60 daysMonofocal/multifocal≥2 clinically ‘silent’ T2 lesions ≥3 mm diameter; ≥1 periventricular, ovoid or infratentorial18–452 yearsProportion of patients reaching CDMS/McDonald MS (2001 criteria)Second exacerbation (appearance of a new symptom or worsening of a present symptom lasting ≥24 h, preceded by ≥30 days’ clinical stability)
      PreCISe (
      • Comi G.
      • Martinelli V.
      • Rodegher M.
      • Moiola L.
      • Bajenaru O.
      • Carra A.
      • et al.
      Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial.
      )
      GA, 20 mg s.c. daily (n=243)Placebo (n=238)≤90 daysMonofocal≥2 T2 lesions ≥6 mm diameter18–453 yearsTime to CDMSSecond exacerbation (appearance of a new symptom or worsening of a present symptom, with increase in EDSS score or functional system score, lasting ≥48 h, preceded by ≥30 days’ clinical stability)
      REFLEX (
      • Comi G.
      • De Stefano N.
      • Freedman M.S.
      • Barkhof F.
      • Polman C.H.
      • Uitdehaag B.M.
      • et al.
      Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial.
      )
      IFNβ-1a, 44 µg s.c. t.i.w. (n=171)IFNβ-1a, 44 µg s.c. q.w. (n=175)Placebo (n=171)≤60 daysMonofocal/multifocal≥2 clinically ‘silent’ T2 lesions ≥3 mm diameter; ≥1 periventricular, ovoid or infratentorial18–502 yearsTime to McDonald MSSecond event affecting a different functional system from the first event and lasting ≥24 h, preceded by ≥30 days’ clinical stability or a sustained ≥1.5 point increase in EDSS score
      CDMS, clinically definite multiple sclerosis; EDSS, Expanded Disability Status Scale; e.o.d., every other day; FCDE, first clinical demyelinating event; GA, glatiramer acetate; Gd+, gadolinium-enhancing; IFNβ, interferon beta; i.m., intramuscularly; MRI, magnetic resonance imaging; MS, multiple sclerosis; q.w., once weekly; s.c., subcutaneously; t.i.w., three times weekly.
      a Post hoc analysis found that some patients were multifocal.
      Inclusion and exclusion criteria were broadly similar across studies, although the PreCISe study design specified that patients had to have monofocal presentation only, that is, symptoms and signs that could be explained by one brain lesion. In contrast, BENEFIT and REFLEX permitted monofocal or multifocal presentation. The CHAMPS study design specified that only patients with monosymptomatic presentation were eligible, although a post hoc analysis discovered evidence that 30% of patients had multifocal findings at baseline (
      • O′Connor P.
      • Kinkel R.P.
      • Kremenchutzky M.
      Efficacy of intramuscular interferon beta-1a in patients with clinically isolated syndrome: analysis of subgroups based on new risk criteria.
      ). ETOMS grouped patients as being monosymptomatic or polysymptomatic, but these terms cannot be equated to monofocal or multifocal presentation.
      All the trials examined the drug regimens licensed in patients with relapsing forms of MS, except ETOMS, which used a lower dose and frequency of IFNβ-1a (22 µg s.c. q.w.) than is currently licensed. In addition to the licensed regimen for IFNβ-1a (44 µg s.c. t.i.w.), REFLEX also investigated a 44 µg q.w. regimen.
      “Clinically definite” multiple sclerosis was the primary endpoint in all of the studies, except REFLEX, in which it was the main secondary endpoint; the primary endpoint in REFLEX was McDonald MS (2005 criteria) (
      • Comi G.
      • De Stefano N.
      • Freedman M.S.
      • Barkhof F.
      • Polman C.H.
      • Uitdehaag B.M.
      • et al.
      Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial.
      ). The BENEFIT study had the co-primary endpoint of McDonald MS (2001 criteria) (
      • McDonald W.I.
      • Compston A.
      • Edan G.
      • Goodkin D.
      • Hartung H.P.
      • Lublin F.D.
      • et al.
      Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis.
      ). The definition of CDMS differed among studies, but all required a second clinical event or deterioration of present symptoms or disability for a diagnosis of CDMS (Table 1).
      The primary analyses of BENEFIT and ETOMS took place after 2 years, as did the event-driven analysis of REFLEX. The primary analysis was planned after 3 years in both CHAMPS and PreCISe; however, CHAMPS was stopped after an 18-month interim analysis showed a benefit of active treatment compared with placebo. For the same reason, the double-blind, placebo-controlled phase of PreCISe was stopped and the data analyzed when patients had a mean treatment exposure of 2.3 years.
      In BENEFIT, REFLEX, and PreCISe, all patients who experienced a second attack and converted to CDMS were switched to open-label active treatment. In contrast, in ETOMS, further treatment was at the discretion of the treating physician; only 22/155 (14%) of the patients randomized to placebo switched to open-label s.c. IFNβ-1a treatment upon conversion to CDMS. In addition, the design of CHAMPS was such that patients who converted to CDMS left the study, rather than switched to open-label active treatment.
      The five studies varied in the patient baseline characteristics they reported (Table 2). As with time from the FCDE to study entry, the median time between the FCDE and starting treatment differed among studies and was shortest in CHAMPS and longest in ETOMS. The time from the FCDE to initiation of treatment was not reported in BENEFIT. All the studies included patients who had received prior steroid treatment. In CHAMPS, all patients received steroid treatment at baseline; in fact some patients may have received ≥1 steroid treatment if it was felt that any pre-study steroid therapy was suboptimal. In comparison, 70% to 71% of patients in ETOMS, BENEFIT, and REFLEX and 64% of patients in PreCISe had received prior steroid treatment. The ratio of male to female patients and their mean age were similar among studies.
      Table 2Summary of baseline patient characteristics.
      TrialMonofocal (%)Steroid treatment (%)T1 Gd+ lesions
      Gd+ lesions indicate the number of active MRI lesions with ongoing inflammatory processes.
      T2 lesions
      T2 lesions indicate the total number of MRI lesions (active and inactive).
      Male (%)Age (years)Time from event to treatment (days)
      CHAMPS (
      • Jacobs L.D.
      • Beck R.W.
      • Simon J.H.
      • Kinkel R.P.
      • Brownscheidle C.M.
      • Murray T.J.
      • et al.
      Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group.
      )
      100
      Following re-analysis by O′Connor et al. (2009), 30% were found to be multifocal with monofocal presentation, 100% were classified as monofocal on original inclusion criteria.
      100
      Some patients received >1 course of steroid treatment.
      0
      Median.
      50% with >4; 29% with >72533
      Mean.
      19
      Median.
      ETOMS (
      • Comi G.
      • Filippi M.
      • Barkhof F.
      • Durelli L.
      • Edan G.
      • Fernández O.
      • et al.
      Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study.
      )
      617059% with ≥1
      Data supplied on request (Merck Serono S.A. --- Switzerland).
      91% with >8
      Data supplied on request (Merck Serono S.A. --- Switzerland).
      36
      Data supplied on request (Merck Serono S.A. --- Switzerland).
      28
      Median.
      ,
      Data supplied on request (Merck Serono S.A. --- Switzerland).
      ; 28.4
      Mean.
      ,
      Data supplied on request (Merck Serono S.A. --- Switzerland).
      84
      Data supplied on request (Merck Serono S.A. --- Switzerland).
      ,
      Median to randomization.
      ; 78.6
      Data supplied on request (Merck Serono S.A. --- Switzerland).
      ,
      Mean to randomization.
      BENEFIT (
      • Kappos L.
      • Polman C.H.
      • Freedman M.S.
      • Edan G.
      • Hartung H.P.
      • Miller D.H.
      • et al.
      Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes.
      )
      53710
      Median.
      18
      Median.
      2930
      Median.
      Unknown
      PreCISE (Comi et al., 2009)100641.5
      Mean.
      ; 0
      Median.
      32
      Mean.
      ; 22
      Median.
      3331.2
      Mean.
      74
      Median.
      REFLEX (
      • Comi G.
      • De Stefano N.
      • Freedman M.S.
      • Barkhof F.
      • Polman C.H.
      • Uitdehaag B.M.
      • et al.
      Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial.
      )
      53.670.61.3
      Mean.
      ; 0
      Median.
      22.3
      Mean.
      ; 17
      Median.
      ; 72.9% with ≥9
      35.830.7
      Mean.
      57.6
      Mean.
      Gd+, gadolinium-enhancing; MRI, magnetic resonance imaging.
      a Gd+ lesions indicate the number of active MRI lesions with ongoing inflammatory processes.
      b T2 lesions indicate the total number of MRI lesions (active and inactive).
      c Following re-analysis by
      • O′Connor P.
      • Kinkel R.P.
      • Kremenchutzky M.
      Efficacy of intramuscular interferon beta-1a in patients with clinically isolated syndrome: analysis of subgroups based on new risk criteria.
      , 30% were found to be multifocal with monofocal presentation, 100% were classified as monofocal on original inclusion criteria.
      d Some patients received >1 course of steroid treatment.
      e Median.
      f Mean.
      g Data supplied on request (Merck Serono S.A. --- Switzerland).
      h Median to randomization.
      i Mean to randomization.
      In summary, while the study designs and patient populations were broadly similar, there were also important differences that preclude direct comparison of trial results.

      3.2 CDMS

      The proportions of placebo-treated patients who converted to CDMS over 2 years ranged from 38% to 45% (Table 3). Each of the studies reported a significantly lower risk of developing CDMS in the active treatment arms at either 2 years (ETOMS, BENEFIT, PreCISe, REFLEX) or 3 years (CHAMPS) (Table 4). The risk reductions for CDMS were similar in BENEFIT, PreCISe, and REFLEX, as demonstrated by the hazard ratios (HRs) that ranged from 0.48 to 0.55. In REFLEX there was no significant difference in treatment effect between the s.c. IFNβ-1a t.i.w. and q.w. treatment regimens.
      Table 3Patients with CDMS at 2 years in the ‘early treatment’ studies.
      StudyTherapyPatients who had CDMS at 2 years (%)p-Value
      Active treatmentPlacebo
      CHAMPS (
      • Jacobs L.D.
      • Beck R.W.
      • Simon J.H.
      • Kinkel R.P.
      • Brownscheidle C.M.
      • Murray T.J.
      • et al.
      Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group.
      )
      IFNβ-1a 30 μg i.m. q.w.2038<0.001
      ETOMS (
      • Comi G.
      • Filippi M.
      • Barkhof F.
      • Durelli L.
      • Edan G.
      • Fernández O.
      • et al.
      Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study.
      )
      IFNβ-1a 22 μg s.c. q.w.34450.047
      BENEFIT (
      • Kappos L.
      • Polman C.H.
      • Freedman M.S.
      • Edan G.
      • Hartung H.P.
      • Miller D.H.
      • et al.
      Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes.
      )
      IFNβ-1b 250 μg s.c. e.o.d.2845<0.001
      PreCISe (
      • Comi G.
      • Martinelli V.
      • Rodegher M.
      • Moiola L.
      • Bajenaru O.
      • Carra A.
      • et al.
      Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial.
      )
      GA 20 mg s.c. q.d.2543<0.001
      REFLEX (
      • Comi G.
      • De Stefano N.
      • Freedman M.S.
      • Barkhof F.
      • Polman C.H.
      • Uitdehaag B.M.
      • et al.
      Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial.
      )
      IFNβ-1a 44 μg s.c. t.i.w.2138<0.001
      IFNβ-1a 44 μg s.c. q.w.220.002
      CDMS, clinically definite multiple sclerosis; GA, glatiramer acetate; IFN, interferon; i.m., intramuscularly; q.d., once daily; e.o.d., every other day; q.w., once weekly; s.c., subcutaneously; t.i.w., three times weekly.
      Table 4Risk reductions for CDMS at 2 years.
      StudyTherapyMeasureRatio95% CIp-Value
      CHAMPS (
      • Jacobs L.D.
      • Beck R.W.
      • Simon J.H.
      • Kinkel R.P.
      • Brownscheidle C.M.
      • Murray T.J.
      • et al.
      Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group.
      )
      IFNβ-1a 30 μg i.m. q.w.Rate ratio0.560.38–0.810.002
      Adjusted rate ratio0.490.33–0.73<0.001
      ETOMS (
      • Comi G.
      • Filippi M.
      • Barkhof F.
      • Durelli L.
      • Edan G.
      • Fernández O.
      • et al.
      Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study.
      )
      IFNβ-1a 22 μg s.c. q.w.Odds ratio0.610.37–0.990.045
      BENEFIT (
      • Kappos L.
      • Polman C.H.
      • Freedman M.S.
      • Edan G.
      • Hartung H.P.
      • Miller D.H.
      • et al.
      Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes.
      )
      IFNβ-1b 250 μg s.c. e.o.d.Adjusted HR0.500.36–0.70<0.0001
      PreCISe (
      • Comi G.
      • Martinelli V.
      • Rodegher M.
      • Moiola L.
      • Bajenaru O.
      • Carra A.
      • et al.
      Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial.
      )
      GA 20 mg s.c. q.d.HR0.550.40–0.770.0005
      REFLEX (
      • Comi G.
      • De Stefano N.
      • Freedman M.S.
      • Barkhof F.
      • Polman C.H.
      • Uitdehaag B.M.
      • et al.
      Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial.
      )
      IFNβ-1a 44 μg s.c. t.i.w. vs. placeboAdjusted HR0.480.31–0.73<0.001
      IFNβ-1a 44 μg s.c. q.w. vs. placeboAdjusted HR0.530.35–0.790.002
      IFNβ-1a 44 μg s.c. t.i.w. vs. q.w.Adjusted HR0.900.56–1.430.774
      CDMS, clinically definite multiple sclerosis; CI, confidence interval; e.o.d., every other day; GA, glatiramer acetate; HR, hazard ratio; IFNβ, interferon beta; i.m., intramuscularly; q.d., once daily; q.w., once weekly; s.c., subcutaneously; t.i.w., three times weekly.
      Median time to CDMS was not reported in any of the studies because fewer than 50% of patients in each study had reached CDMS within the 2-year follow-up period. ETOMS reported the time taken for 30% of patients to develop CDMS (569 days in patients receiving IFNβ-1a 22 µg s.c. q.w. and 252 days in those receiving placebo). PreCISe reported the time taken for 25% of patients to reach CDMS as 722 days with GA, compared with 366 days with placebo.
      Overall, all of the trials reported similar rates of conversion to CDMS in patients who received placebo, and this rate of conversion was reduced by DMD treatment in all five trials. BENEFIT, REFLEX, and PreCISe all reported treatment effects of a similar size, with the caveat of the differences in study design discussed above.

      3.3 McDonald MS

      When ETOMS and CHAMPS were initiated, the McDonald diagnostic criteria had not yet been developed. BENEFIT and REFLEX were the only studies to report conversion to McDonald MS. The proportion of placebo-treated patients who went on to develop McDonald MS was high and similar between the two studies: 85% in BENEFIT and 86% in REFLEX after 2 years.
      Both BENEFIT and REFLEX reported a reduction in the proportion of patients developing McDonald MS in the treatment arms compared with placebo. In BENEFIT, 69% of patients receiving s.c. IFNβ-1b reached McDonald MS (2001 criteria) over 2 years (HR: 0.54; 95% confidence interval [CI]: 0.43–0.67; p<0.001). In REFLEX, the proportions of patients with McDonald MS (2005 criteria) at 2 years were 62% and 76% for the t.i.w. and q.w. treatment groups, respectively. Risk reductions were, for t.i.w. vs. placebo, adjusted HR: 0.49 (95% CI: 0.38–0.64; p<0.001); for q.w. vs. placebo, adjusted HR: 0.69 (95% CI: 0.54–0.87; p=0.008); and for t.i.w. vs. q.w., adjusted HR: 0.71 (95% CI: 0.54–0.91; p=0.009). Furthermore, both dosing frequencies of s.c. IFNβ-1a delayed McDonald 2005 MS. The median time from initiation of treatment to McDonald MS (2005 criteria) was 97 days for placebo, 182 days for s.c. IFNβ-1a q.w., and 310 days for s.c. IFNβ-1a t.i.w.

      3.4 MRI

      The advent of the McDonald criteria placed further importance on assessment of MRI parameters for assessing potential MS disease activity in patients with an FCDE. However, each of the five studies assessed different MRI measures, which precludes comparison among the studies. Nonetheless, all of the studies demonstrated significant reductions in some measures of MRI disease activity when treatment was compared with placebo. All studies allowed patients in the placebo arm to switch to active treatment if they developed CDMS within 2 years, which means that the MRI data are biased, either by the inclusion of partially treated placebo groups (if all 2-year scans are included), or by censoring data when patients converted to CDMS.

      4. Discussion

      Five Phase III clinical trials, all with broadly similar patient populations, have investigated the effects of DMD treatment in patients with an FCDE. While there were differences in study designs that preclude direct efficacy comparisons between the studies, all five showed that treatment with IFNβ or GA significantly delayed the onset of MS, whether defined as CDMS or McDonald MS. The rates of conversion to CDMS in the placebo arms were similar among all the studies, as was the rate of conversion to McDonald MS in BENEFIT and REFLEX. Taken together, the results of these studies show that, if untreated, 38% to 45% of patients with an FCDE and ≥2 T2 lesions convert to CDMS, and approximately 85% reach McDonald MS, within 2 years of the first event. In the REFLEX trial, although both t.i.w. and q.w. treatment delayed the occurrence of clinical relapses, the t.i.w. regimen had a more pronounced effect on the subclinical MRI activity that leads to the diagnosis of McDonald MS in patients who had not yet developed CDMS (
      • Comi G.
      • De Stefano N.
      • Freedman M.S.
      • Barkhof F.
      • Polman C.H.
      • Uitdehaag B.M.
      • et al.
      Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial.
      ).
      The McDonald criteria were developed to both increase the accuracy of diagnosis and shorten the time it takes to diagnose MS by including evidence from MRI scans that may provide evidence of dissemination in space and time in the absence of a second clinical attack. It is of interest that a dose effect of s.c. IFNβ-1a was observed on time to McDonald 2005 MS but not on time to CDMS in the REFLEX study. This could be explained by the greater sensitivity of MRI outcomes compared with clinical outcomes, but how this translates to clinical outcomes in the longer term remains unclear.
      The McDonald diagnostic criteria were revised in 2010 (
      • Polman C.H.
      • Reingold S.C.
      • Banwell B.
      • Clanet M.
      • Cohen J.A.
      • Filippi M.
      • et al.
      Diagnostic criteria for multiple sclerosis: 2010 revisions to the “McDonald criteria”.
      ): proof of dissemination in space changed from requiring ≥9 T2 lesions to ≥1 T2 lesion in ≥2 of the 4 locations characteristic for MS (juxtacortical, periventricular, infratentorial, and spinal cord). Proof of dissemination in time can now be shown by the simultaneous presence of asymptomatic Gd-enhancing and non-enhancing lesions at any time or a new T2 and/or Gd-enhancing lesion on a follow-up MRI. The high specificity of the McDonald 2010 criteria is supported by a post hoc analysis of REFLEX that showed that patients retrospectively diagnosed with McDonald 2010 MS at baseline were at a higher risk of developing McDonald 2005 MS during the study (
      • Freedman M.S.
      • Comi G.
      • De Stefano N.
      • Kappos L.
      • Barkhof F.
      • Polman C.H.
      • et al.
      Efficacy of subcutaneous interferon-beta-1a in patients with a first clinical demyelinating event: the REbif FLEXible dosing in early multiple sclerosis (REFLEX) study—outcomes in patients stratified by the 2010 McDonald criteria.
      ). The use of the 2010 criteria in future clinical practice means that the proportion of patients with an FCDE who are not diagnosed with MS is therefore likely to decrease. It will be important to determine whether this putative new ‘clinically isolated syndrome’ population of patients would still benefit from treatment with a DMD, although the post hoc analysis of the REFLEX study found robust treatment effects in patient subgroups both with and without retrospective McDonald MS 2010 diagnosis (
      • Freedman M.S.
      • Comi G.
      • De Stefano N.
      • Kappos L.
      • Barkhof F.
      • Polman C.H.
      • et al.
      Efficacy of subcutaneous interferon-beta-1a in patients with a first clinical demyelinating event: the REbif FLEXible dosing in early multiple sclerosis (REFLEX) study—outcomes in patients stratified by the 2010 McDonald criteria.
      ), suggesting that patients in this more narrowly defined population do indeed benefit from early treatment.
      Post hoc analyses of data from the BENEFIT and ETOMS studies demonstrate that MRI findings at the time of the FCDE might predict future disease activity. In the BENEFIT study, conversion to CDMS by 3 years was significantly more frequent in patients with ≥9 T2 lesions and those with ≥1 Gd-enhancing lesion on baseline MRI (
      • Barkhof F.
      • Rocca M.
      • Francis G.
      • Van Waesberghe J.H.
      • Uitdehaag B.M.
      • Hommes O.R.
      • et al.
      Validation of diagnostic magnetic resonance imaging criteria for multiple sclerosis and response to interferon beta1a.
      ). Similarly in ETOMS, the odds of developing CDMS over 2 years were significantly greater in patients with ≥9 T2 lesions at baseline. The presence of at least one Gd-enhancing lesion at baseline also appeared to be predictive of CDMS but did not reach significance (
      • Moraal B.
      • Pohl C.
      • Uitdehaag B.M.
      • Polman C.H.
      • Edan G.
      • Freedman M.S.
      • et al.
      Magnetic resonance imaging predictors of conversion to multiple sclerosis in the BENEFIT study.
      ). Caution should be exercised when interpreting the results of such post hoc analyses.
      Extension studies were conducted for BENEFIT, CHAMPS, and PreCISe; the REFLEX extension (REFLEXION) is ongoing. While a full review of these extension studies is outside of the scope of this paper, the reported data show long-term benefit of early treatment with DMDs. In pre-planned extensions, the beneficial effects of early IFNβ-1b and GA treatment on the risk of developing CDMS were confirmed 5 years after randomization in the BENEFIT and PreCISe studies, respectively (
      • Kappos L.
      • Freedman M.S.
      • Polman C.H.
      • Edan G.
      • Hartung H.P.
      • Miller D.H.
      • et al.
      Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial.
      ,
      • Comi G.
      • Martinelli V.
      • Rodegher M.
      • Moiola L.
      • Bajenaru O.
      • Carra A.
      • et al.
      Benefit of early treatment with glatiramer acetate (COPAXONE): results from the 5-year prospectively planned follow up in patients with clinically isolated syndrome from the PreCISe study.
      ). An investigator-initiated, post-planned extension to CHAMPS—CHAMPIONS—also confirmed the long-term benefit of early intramuscular IFNβ-1a treatment on the risk of developing CDMS (
      • Comi G.
      • Martinelli V.
      • Rodegher M.
      • Moiola L.
      • Bajenaru O.
      • Carra A.
      • et al.
      Benefit of early treatment with glatiramer acetate (COPAXONE): results from the 5-year prospectively planned follow up in patients with clinically isolated syndrome from the PreCISe study.
      ,
      • Kinkel R.P.
      • Kollman C.
      • O′Connor P.
      • Murray T.J.
      • Simon J.
      • Arnold D.
      • et al.
      IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event.
      ). In REFLEXION, the primary endpoint of time to CDMS at 36 months after randomization into REFLEX has been reported, and both dose frequencies of s.c. IFNβ-1a were found to significantly delay conversion to CDMS compared with delayed treatment (
      • Freedman M.S.
      • Comi G.
      • De Stefano N.
      • Barkhof F.
      • Polman C.H.
      • Uitdehaag B.M.J.
      • et al.
      Efficacy of two dosing frequencies of subcutaneous interferon beta-1a on the risk of conversion from a first demyelinating event to multiple sclerosis and on MRI measures of disease: 3-year results of Phase III, double-blind, multicentre trials (REFLEX and REFLEXION).
      ). The pre-planned extension to year 5 is ongoing. As with the post hoc analyses, the data from these extension studies should be interpreted with caution.
      The results from these five studies have shown that most untreated patients rapidly convert to MS following an FCDE, and that early DMD treatment can significantly reduce the risk of developing MS. The benefit of early treatment was maintained during long-term follow-up. These findings have already led to a shift toward earlier treatment (
      • Comi G.
      Shifting the paradigm toward earlier treatment of multiple sclerosis with interferon beta.
      ). Of note, not all patients presenting with an FCDE have a second clinical event establishing CDMS (
      • Fisniku L.K.
      • Brex P.A.
      • Altmann D.R.
      • Miszkiel K.A.
      • Benton C.E.
      • Lanyon R.
      • et al.
      Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis.
      ). It remains to be seen whether these short-term benefits translate into long-term improvements such as reduced disability in clinical practice. Although BENEFIT found an advantage of early treatment on disability progression at 3 years′ follow-up (
      • Kappos L.
      • Freedman M.S.
      • Polman C.H.
      • Edan G.
      • Hartung H.P.
      • Miller D.H.
      • et al.
      Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study.
      ), the difference between the groups did not remain significant at 5 years′ follow-up (
      • Kappos L.
      • Freedman M.S.
      • Polman C.H.
      • Edan G.
      • Hartung H.P.
      • Miller D.H.
      • et al.
      Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial.
      ). However, crossover from placebo to active treatment may have masked some treatment effects. Similarly the 5-year evaluation of the CHAMPS cohort found no benefit of treatment on disability outcomes, with the additional caveat of a low patient retention rate (
      • Kinkel R.P.
      • Kollman C.
      • O′Connor P.
      • Murray T.J.
      • Simon J.
      • Arnold D.
      • et al.
      IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event.
      ). REFLEXION has yet to report disability outcomes. However, long-term follow-up from trials of DMDs in patients with relapsing MS suggest that early advantages are maintained over time with continued treatment (
      • Kappos L.
      • Traboulsee A.
      • Constantinescu C.
      • Erälinna J.P.
      • Forrestal F.
      • Jongen P.
      • et al.
      Long-term subcutaneous interferon beta-1a therapy in patients with relapsing–remitting MS.
      ,
      • Bermel R.A.
      • Weinstock-Guttman B.
      • Bourdette D.
      • Foulds P.
      • You X.
      • Rudick R.A.
      Intramuscular interferon beta-1a therapy in patients with relapsing–remitting multiple sclerosis: a 15-year follow-up study.
      ,
      • Ebers G.C.
      • Traboulsee A.
      • Li D.
      • Langdon D.
      • Reder A.T.
      • Goodin D.S.
      • et al.
      Analysis of clinical outcomes according to original treatment groups 16 years after the pivotal IFNB-1b trial.
      ,
      • Ford C.
      • Goodman A.D.
      • Johnson K.
      • Kachuck N.
      • Lindsey J.W.
      • Lisak R.
      • et al.
      Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate.
      ). Although the evidence from the aforementioned trials supports treating with DMDs at the time of the first FCDE as an effective strategy to manage disease progression, several other factors must be considered when making the decision to treat early, including—but not limited to—tolerability issues, local licensing laws and treatment cost.

      5. Conclusion

      Early treatment with DMDs benefits patients with an FCDE who are at high risk of conversion to MS by reducing the risk of conversion to MS (defined by either the Poser or McDonald criteria) and delaying the occurrence of a second attack. Although the long-term benefits of early intervention with DMDs, particularly on overall disease progression, remain to be demonstrated, results from long-term follow-up studies in patients with relapsing MS suggest that treatment with DMDs will improve outcomes for these patients. Despite the differences between the five FCDE trials in terms of study design, endpoint definition, and recruitment environment, the findings all support initiating treatment with DMDs at the time of the FCDE.

      Conflicts of interest

      Mark Freedman (or his professional corporation) has received compensation from Actelion, Bayer HealthCare, Biogen Idec, Celgene, EMD Serono (Canada), Genzyme, Glycominds, Novartis, Sanofi-Aventis, and Teva Canada Innovation.
      Giancarlo Comi has received honoraria and consultation fees from Serono Symposia International Foundation, Merck Serono, Novartis, Teva, Sanofi-Aventis, Bayer Schering, and Biogen Dompè.
      Nicola De Stefano has received honoraria from Schering, Biogen Idec, Teva, and Merck Serono for consulting services, speaking, and travel support; and serves on advisory boards for Merck Serono.
      Frederik Barkhof has received honoraria or consultation fees from Merck Serono, UCB, Novartis, Roche, Sanofi-Aventis and Serono Symposia International Foundation.
      Chris Polman has received honoraria, consultation fees, or research support from Actelion, Biogen Idec, Bayer Schering, GlaxoSmithKline, Merck Serono, Novartis, Teva, UCB, and Roche.
      Bernard Uitdehaag has received consultation fees from Novartis, Merck Serono, Biogen Idec, Synthon, and Danone Research.
      Lorenz Lehr was an employee of Merck Serono S.A.—Switzerland at the time of manuscript preparation.
      Bettina Stubinski was an employee of Merck Serono S.A.—Switzerland at the time of manuscript preparation.
      Ludwig Kappos has received institutional research support from Acorda, Actelion, Advancell, Allozyne, Barofold, Bayer, Bayhill, Biogen Idec, BioMarin, Boehringer Ingelheim, CSL Behring, Eli Lilly, Geneuro, Genmab, GlaxoSmithKline, Glenmark, Merck Serono, MediciNova, Novartis, Sanofi-Aventis, Santhera, Shire, Roche, Teva, UCB, and Wyeth.

      Role of funding

      The development of this manuscript was made possible by Merck Serono S.A.—Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany.

      Acknowledgments

      The authors thank Veronica Porkess, Steve Smith, and Joanne Tang of Caudex Medical, Oxford, UK (supported by Merck Serono S.A.—Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany), for assistance with the preparation of the initial draft of this review and for collating input from all authors (VP and SS), and for editing the text and assistance with preparation for submission (JT).

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