Annals of Internal Medicine: Multiple Sclerosis Topic Collection

Oral fingolimod was more effective than intramuscular interferon for relapsing–remitting multiple sclerosis

Hughes J. — Tue, 18 May 2010 00:00:00 GMT

Question

In patients with relapsing–remitting multiple sclerosis (MS), what are the relative efficacy and safety of oral fingolimod compared with intramuscular interferon β-1a?

Methods

Design

Randomized controlled trial (Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis [TRANSFORMS]). ClinicalTrials.gov NCT00340834.

Allocation

Concealed.*

Blinding

Blinded (patients, clinicians, study personnel, outcome assessors, steering-committee members, and study statistician).*

Follow-up period

12 months.

Setting

172 centers in 18 countries.

Patients

1292 patients 18 to 55 years of age (mean age 36 y, 67% women) who had been diagnosed with MS that met the revised McDonald criteria and had a relapsing–remitting course, had had ≥ 1 documented relapse in the previous year or ≥ 2 documented relapses in the previous 2 years, and scored 0 to 5.5 on the Expanded Disability Status Scale (range 0 to 10, worst). Exclusion criteria were documented relapse or corticosteroid treatment in ≤ 30 days, active infection, macular edema, immunosuppression, and clinically important comorbidity.

Intervention

Oral fingolimod, 1.25 mg/d (n = 426) or 0.5 mg/d (n = 431), or intramuscular interferon β-1a, 30 µg/wk (n = 435), for 12 months.

Outcomes

Annualized relapse rate (number of confirmed relapses during a 12-mo period), number of new or enlarged hyperintense lesions on T₂-weighted magnetic resonance imaging scans, confirmed disability progression, and adverse events.

Patient follow-up

89% (intention-to-treat analysis).

Main results

Compared with the interferon group, both fingolimod groups had lower relapse rates (with no difference between fingolimod doses), larger proportions of patients without relapse, longer time to first relapse, and fewer new or enlarged lesions (Table). Groups did not differ for proportion of patients without confirmed disability progression (Table). Serious adverse events were reported for 11% of the 1.25-mg fingolimod group (including 2 deaths related to herpesvirus infection), 7.0% of the 0.5-mg fingolimod group, and 5.8% of the interferon group, with the most frequent events being bradycardia, atrioventricular block, infection, and cancer.

Conclusion

In patients with relapsing–remitting multiple sclerosis, both doses of oral fingolimod were more effective than interferon β-1a but the higher dose was associated with more serious adverse events.Fingolimod vs interferon β-1a for relapsing–remitting multiple sclerosis†OutcomesAt 12 moFingolimod, 1.25 mgFingolimod, 0.5 mgInterferon β-1aAnnualized relapse rate (95% CI)0.20 (0.16 to 0.26)0.16 (0.12 to 0.21)0.33 (0.26 to 0.42)No relapse80%83%69%No disability progression93%94%92%Mean number of new or enlarged lesions on T₂-weighted images (SD)1.5 (2.7)1.7 (3.9)2.6 (5.8)†SD = standard deviation; CI defined in Glossary. P < 0.001 for all comparisons between fingolimod and interferon, except for No disability progression (not significant).

Oral fingolimod was more effective than placebo for relapsing–remitting multiple sclerosis

Hughes J. — Tue, 18 May 2010 00:00:00 GMT

Question

In patients with relapsing–remitting multiple sclerosis (MS), what are the relative efficacy and safety of oral fingolimod compared with placebo?

Methods

Design

Randomized placebo-controlled trial (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis [FREEDOMS]). ClinicalTrials.gov NCT00289978.

Allocation

Concealed.*

Blinding

Blinded {patients, clinicians, data collectors, outcome assessors, data analysts, and safety committee}†.*

Follow-up period

24 months.

Setting

138 centers in 22 countries.

Patients

1272 patients 18 to 55 years of age (mean age 37 y, 70% women) who had been diagnosed with MS that met the revised McDonald criteria and had a relapsing–remitting course, had had ≥ 1 documented relapse in the previous year or ≥ 2 documented relapses in the previous 2 years, and scored 0 to 5.5 on the Expanded Disability Status Scale (range 0 to 10, worst). Exclusion criteria were documented relapse or corticosteroid treatment in ≤ 30 days, active infection, macular edema, immunosuppression, and clinically important comorbidity.

Intervention

Oral fingolimod, 1.25 mg/d (n = 429) or 0.5 mg/d (n = 425), or placebo (n = 418) for 24 months.

Outcomes

Annualized relapse rate (number of confirmed relapses per y), number of new or enlarged lesions on T₂-weighted magnetic resonance imaging scans, confirmed disability progression, and adverse events.

Patient follow-up

81% (intention-to-treat analysis).

Main results

Compared with the placebo group, both fingolimod groups had lower relapse rates (with no difference between fingolimod doses), larger proportions of patients without relapse or confirmed disability progression, longer time to first relapse or disability progression, and fewer new or enlarged lesions (Table). Serious adverse events were reported for 12% of the 1.25-mg fingolimod group, 10% of the 0.5-mg fingolimod group, and 13% of the placebo group, with the most frequent events being bradycardia and basal-cell carcinoma.

Conclusion

In patients with relapsing–remitting multiple sclerosis, both doses of oral fingolimod were more effective than placebo, and rates of serious adverse events were similar.Fingolimod vs placebo for relapsing–remitting multiple sclerosis‡OutcomesAt 24 moFingolimod, 1.25 mgFingolimod, 0.5 mgPlaceboAnnualized relapse rate (95% CI)0.16 (0.13 to 0.19)0.18 (0.15 to 0.22)0.40 (0.34 to 0.47)No relapse75%70%46%No disability progression83%82%76%Mean number of new or enlarged lesions on T₂-weighted images (SD)2.5 (5.5)2.5 (7.2)9.8 (13.2)‡SD = standard deviation; CI defined in Glossary. P < 0.001 for all comparisons between fingolimod and placebo, except for No disability progression (P = 0.01, fingolimod 1.25 mg vs placebo; P = 0.03, fingolimod 0.5 mg vs placebo).

Oral cladribine was more effective than placebo for relapsing–remitting multiple sclerosis

Hughes J. — Tue, 18 May 2010 00:00:00 GMT

Question

In patients with relapsing–remitting multiple sclerosis (MS), what are the relative efficacy and safety of oral cladribine compared with placebo?

Methods

Design

Randomized placebo-controlled trial (Cladribine Tablets Treating Multiple Sclerosis Orally [CLARITY]). ClinicalTrials.gov NCT00213135.

Allocation

Concealed.*

Blinding

Blinded {patients, clinicians, data collectors, outcome assessors, data analysts, and safety committee}†.*

Follow-up period

96 weeks.

Setting

155 centers in 32 countries.

Patients

1326 patients (mean age 39 y, 68% women) who had been diagnosed with MS that met the McDonald criteria and had a relapsing–remitting course, had lesions consistent with MS on magnetic resonance imaging, had had ≥ 1 relapse in the previous year, and scored ≤ 5.5 on the Expanded Disability Status Scale (range 0 to 10, worst). Exclusion criteria included relapse in ≤ 28 days, failure of ≥ 2 previous disease-modifying therapies, previous use of immunosuppressive therapy, and abnormal results on hematologic testing in ≤ 28 days.

Intervention

Oral cladribine, 5.25 mg/kg of body weight cumulative dose (n = 456) or 3.5 mg/kg cumulative dose (n = 433), or placebo (n = 437) over 52 weeks. Short courses (one or two 10-mg tablets daily for 4 or 5 d) were given at weeks 1, 5, 9, 13, 48, and 52 (the 3.5-mg/kg group received placebo at 9 and 13 wk).

Outcomes

Annualized relapse rate (number of confirmed relapses per y), number of active T₂-weighted lesions on magnetic resonance imaging scans, confirmed disability progression, and adverse events.

Patient follow-up

89% (intention-to-treat analysis).

Main results

Compared with the placebo group, both cladribine groups had lower relapse rates (with no difference between cladribine doses), larger proportions of patients without relapse or disability progression, longer time to first relapse or disability progression, and fewer active lesions (Table). Serious adverse events were reported for 9.0% of the 5.25-mg/kg cladribine group, 8.4% of the 3.5-mg/kg cladribine group, and 6.4% of the placebo group, with the most frequent events being lymphocytopenia, infections and infestations, and neoplasia.

Conclusion

In patients with relapsing–remitting multiple sclerosis, both doses of oral cladribine were more effective than placebo but were associated with more adverse events.Cladribine vs placebo for relapsing–remitting multiple sclerosis‡OutcomesAt 96 wkCladribine, 5.25 mg/kgCladribine, 3.5 mg/kgPlaceboAnnualized relapse rate (95% CI)0.15 (0.12 to 0.17)0.14 (0.12 to 0.17)0.33 (0.29 to 0.38)No relapse79%80%61%No disability progression85%86%79%Mean number of active lesions on T₂-weighted images0.330.381.43‡CI defined in Glossary. P < 0.001 for all comparisons between cladribine and placebo, except for No disability progression (P = 0.03, cladribine 5.25 mg/kg vs placebo; P = 0.02, cladribine 3.5 mg/kg vs placebo).