Interferon beta-1b for clinically isolated syndrome (multiple sclerosis)

06 Jun 2007 Interferon beta-1b for clinically isolated syndrome (multiple sclerosis)

Background information of the condition:

Multiple sclerosis: is a degenerative white-matter disease and may present with acute symptoms of neurological impairment (known herein as clinically isolated syndrome – CIS).  CIS is the clinical stage of relevance to this systematic review.
Based on several cohort studies, the estimated risk to develop multiple sclerosis (MS) after CIS is about 45% in 3 years, 41-65% in 5 years, 42% in 7 years, and 59% to 68% in 10 years.^{1,2,3,4,5,6,7}  The median duration of remission between the first and second episode range from 10 months to more than 2 years^1,8.
No specific MS test exists and hence the diagnosis is made by a neurologist combining clinical signs and symptoms, history and laboratory work-up to exclude other diseases and to support the MS diagnosis.  Diagnosis can use two criteria: a clinical diagnosis based on Poser criteria (clinically defined MS CDMS15) and a laboratory diagnosis using McDonald criteria^1,6, which incorporates MRI findings.

Drug

Category: Interferon beta-1b is categorized as an immunomodulator.

Mechanism of action: Interferon beta-1b has been shown to possess both antiviral and immunomodulatory activities, although the mechanisms are not clearly understood.

Dose: The recommended dose for both relapsing-remitting and secondary progressive MS patients is 0.25 mg (8 MIU) injected subcutaneously every other day.  However, the recommended dose for the new indication in CIS has not been provided in the product monograph.  In the only study using the medication in patients with single demyelinating event, the researchers used titration doses.

Duration of treatment:  has not been specified.

Methodology of Systematic review

Research question: In double blind randomized controlled trials (DBRCTs) does interferon beta-1b provide a significant therapeutic advantage compared to placebo or other approved treatments in adult patients with a CIS accompanied by at least two clinically silent lesions typical of multiple sclerosis on magnetic resonance imaging?

Assessment principles: DB RCTs comparing interferon beta-1b to interferon beta-1a. glatiramer acetate, intra venous immunoglobulins, corticosteroids or placebo will be critically appraised according to the following hierarchy of health outcome measures – mortality, non-fatal serious adverse events, slowing in the progression of physical disability, quality of life, recurrences of demyelinating events, surrogate outcomes like MRI findings, withdrawals due to adverse events, other adverse events and neutralizing antibodies.

Search strategy: The search includes submissions from the manufacturer and electronic databases [Medline, Embase, Cochrane database from 1966 until December 2006].

Search findings: No randomized clinical trials (RCTs) compared interferon beta-1b with other standard drugs used in the treatment of adult patients with CIS.  One DBRCT was identified comparing interferon beta-1b to placebo and was critically appraised.¹²

Results: Kappos et al 2006¹², compared treatment with interferon beta-1b (dose titration) to placebo for a DB treatment period of 2 years followed by an open label period of 5 years in 487 adult patients with CIS and ≥ 7 T2 weighted MRI lesions at baseline.  Participants were centrally randomized in a 5:3 ratio to receive interferon beta-1b (N = 305) or placebo (N = 182).
Imbalance between treatment groups was minimized for (selected) factors with potential impact on the risk of developing definite MS such as steroid use during the first clinical event; investigator’s classification of the first event as mono- or polysymptomatic (symptoms indicative of a single lesion, or more than one lesion); number of T2 lesions on the screening MRI; and CSF result.
Efforts to maintain blinding included identical appearance, packaging and labeling, covering the injection sites during examination by neurologist, evaluation by a physician who was not involved in the care of the patient and assessment of blinding questionnaire at end of the study.
There was no difference in mortality, non-fatal serious adverse events and quality of life between interferon bata-1b group and placebo groups.  There was a significant decrease in the risk to develop clinical defined MS by both Poser and McDonald criteria (absolute risk increase [ARI]=16%, number need to treat [NNT]=6) and delay in diagnosis of MS by Poser criteria (618 vs. 255 days) in the interferon beta 1b as compared to placebo group.  There was a significant difference in the percentage of patients diagnosed as having clinically defined MS according to Poser criteria (26% in interferon group and 44% in placebo group) as compared to those diagnosed with McDonald criteria (65% in interferon group and 81% in placebo group).
The interferon beta 1b group showed a significant increase in withdrawal due to adverse events (ARI=8%, NNT=13); injection site reaction (ARI=40%, NNH=3); flu-like symptoms (ARI=26, NNT=4); headache (ARI=10%; NNT=10); leukopenia (ARI=13%, NNT=8); fever (ARI=9%, NNT=12); rash (ARI=8%, NNT=12) and elevated liver enzyme ALT five times the baseline value (ARI=13%, NNT=8).  Neutralizing antibodies were detected in 30% of treated patients, 20% of these patients convert to negative status later.  Due to significant increase in adverse events blinding was affected. Treating physicians and the patients identified more frequently the actual treatment (for interferon beta-1b: 49% and 67% and for placebo: 51% and 52%, for physicians and patients, respectively). That is, 2/3 of patients receiving interferon knew that they were on interferon.

Critical appraisal issues:

1. The primary outcome, clinically defined MS was defined as either relapse or sustained progression. However, the number of patients with relapse or sustained progression has not been reported separately. Sustained progression is far more significant to patient outcome, while relapses could be mild or severe, with and without residual neurological dysfunction.
2. Information regarding the severity of the second demylenating event is needed in addition to simply reporting frequency of events.  A statistically significant decrease in the number of patients diagnosed with clinically defined MS in the interferon beta-1b group over duration of 2 years, may not reflect a change in the burden of disease in the population if disease is significantly worsened in the betaseron population, albeit for fewer individuals.
3. Delaying the second demylenating event or having fewer MRI lesions over the two-year period has not been shown to translate into an improvement in quality of life or delay in progression of disability.
4. This study examined a patient subgroup with a minimal number of T2-weighted brain lesions per patient of 7 or more (7 in the treatment group and 7.5 in the placebo group).  The effect of treatment in patients with fewer baseline MRI lesions is not known.  In this population, 50% of patients in the placebo group did not develop a second clinical event at the end of 2 years.
5. The authors fail to report how many people had MS according to both criteria and how many had MS only based on one of the criteria.  The higher sensitivity for McDonald’s criteria in diagnosing MS may or may not be desirable feature for patients faced with the long-term implications of a MS diagnosis.  In particular, a diagnosis of MS after the first clinically suggestive episode is incorrect for half of the people in this study. Nevertheless, they will have to live with strong anticipation of a second episode, lifelong.
6. MRI is a poor surrogate outcome measure, as it has not been correlated with patient outcome.

Conclusions:

1. No DBRCTs were identified comparing interferon beta-1b to other standard therapies in adult patients with CIS.  Therefore, there is insufficient evidence that interferon beta-1b provides a therapeutic advantage over other standard therapies.
2. Based on one DBRCT (Kappos et al, 2006) comparing treatment with interferon beta-1b to placebo in 487 adult patients with CIS and 7 or more T2 weighted MRI lesions, there is sufficient evidence that treatment with interferon beta 1b has an advantage over placebo in delaying the diagnosis of MS according to modified Poser (CDMS) as well as McDonald criteria, during a two-year period.  However, in order to interpret this benefit, additional information is needed regarding the severity of the second demylenating event. Interferon beta-1b did not result in a benefit in terms of mortality, serious adverse events, quality of life or disability.  Interferon beta-1b treatment resulted in significant increase in several adverse events and withdrawal due to adverse events.
3. The clinical impact of exposing 50% of the CIS population, who do not develop MS, to interferon is unknown. Adoption of treatment strategies that exposes this patient population to years of interferon therapy must include long term studies of MS negative patients, not only patients who are ultimately labeled with this diagnosis.

References

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2. Eriksson M, Andersen O and Runmarker B: Long-term follow up of patients with clinically isolated syndromes, relapsing¡/remitting and secondar y progressive multiple sclerosis. Multiple Sclerosis 2003; 9:260-274.
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10. McDonald WI, Compston A, Edan G, Goodkin D et al: Recommended Diagnostic Criteria for Multiple Sclerosis: Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol 2001; 50: 121–127.
11. Betaseron product monograph, Berlex Canada, January 2007
12. Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Bauer L, Jakobs P, Pohl C, Sandbrink R for the BENEFIT study group: Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006 Oct 10; 67(7):1242-1249.