title: Tolerability and safety profile of 12- to 28-week treatment with interferon beta-1b 250 and 500 microg QOD in patients with relapsing-remitting multiple sclerosis: a multicenter, randomized, double-blind, parallel-group pilot study.
abstract: BACKGROUND
  It is not known whether the currently available treatment regimen of interferon beta-1b (IFNbeta-1b) 250 microg provides the maximum benefit possible in the treatment of relapsing-remitting multiple sclerosis (RRMS), or whether higher doses of IFNbeta-1b will prove to be more beneficial.
  
  
  OBJECTIVE
  The objective of the present study was to evaluate the tolerability and safety profile of IFNbeta-1b 500 microg compared with the currently approved 250-microg dose.
  
  
  METHODS
  A multicenter, randomized, double-blind, parallel-group pilot study was carried out to compare IFNbeta-1b 250 microg with IFNbeta-1b 500 microg, both self-administered SC QOD for >or=12 weeks in patients with RRMS. Patients in both groups started with 25% (0.25 mL) of their final dose and were scheduled to increase the dose by 0.25 mL every 2 weeks, so that the full dose (1.0 mL, 250 microg or 500 microg) would be reached by week 7. The primary outcome measure was the percentage of patients experiencing each of the following adverse events (AEs): influenza-like symptoms (general term used to code the presence of >1 symptom typical of influenza), fever, myalgia, asthenia, headache, injection-site reactions, injection-site pain, or liver or hematologic abnormalities. All patients underwent a priori magnetic resonance imaging (MRI) with 0.1 mmol/kg gadolinium (Gd)-diethylenetriaminepentaacetic acid as contrast medium at screening and at week 12. MRI evaluation was included as a safety measure to monitor for excessive new disease not visible through clinical symptoms.
  
  
  RESULTS
  Seventy-seven patients were assessed for inclusion in the study. Of these, 6 patients were screening failures and the remaining 71 were randomized to treatment (38-250 and 33-500 microg IFNbeta-1b). The uneven numbers in the groups were a consequence of the randomization process. Two patients in the 250-microg group (withdrawal of consent) and 1 in the 500-microg group (not completing follow-up visit) prematurely discontinued medication. The demographic characteristics were not significantly different between the 250-microg (n=38; mean [SD] age, 37.9 [8.3] years; weight, 83.5 [19.0] kg; height, 168.4 [9.3] cm) and 500-microg (n=33; mean [SD] age, 37.8 [7.7] years; weight, 82.3 [19.5] kg; height, 169.9 [10.5] cm) treatment groups. The patients in both groups were mostly white (87% and 73%, respectively). Baseline Expanded Disability Status Scale scores also were not significantly different between the 2 groups (mean [SD] score, 2.8 [1.4] vs 2.0 [1.4], respectively). In the IFN(2)-1b 250-microg group, 97% of the patients titrated to the full dose at some point during the course of the study, compared with 91% of the 500-microg group (P=NS). A dose-response effect was observed in some of the more frequent AEs (no. [%]) that included influenza-like syndrome (250-microg group, 13 [34] vs 500-microg group, 16 [48]), asthenia (13 [34] vs 16 [48], respectively), headache (12 [32] vs 12 [36]), myalgia (10 [26] vs 13 [39]), hypesthesia (10 [26] vs 11 [33]), nausea (6 [16] vs 8 [24]), paresthesia (6 [16] vs 8 [24]), myasthenia (4 [11] vs 8 [24]), chills (3 [8] vs 6 [18]), depression (3 [8] vs 5 [15]), back pain (2 [5] vs 5 [15]), increased liver enzymes (4 [11] vs 6 [18]), lymphopenia (4 [11] vs 3 [9]), fever (2 [5] vs 4 [12]), and pain in extremities (1 [3] vs 4 [12]). The between-group incidence of injection-site reactions was not significantly different. No new or unexpected AEs were recorded. Changes in MRI parameters between screening and 12 weeks were not significantly different between dose groups; these included median T2 lesion volume, median Gd-enhanced lesion volume, median Gd-enhanced lesion number, and mean number of newly active lesions.
  
  
  CONCLUSIONS
  IFNbeta-1b 500 microg administered SC QOD was generally well tolerated in these patients with RRMS. Large, randomized controlled studies are needed to determine if there are significant differences in MRI end points between the 250- and 500-microg doses.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. hurwi003@mc.duke.edu
authors.forename: Barrie J
authors.initials: BJ
authors.lastname: Hurwitz
authors.forename: Douglas
authors.initials: D
authors.lastname: Jeffery
authors.forename: Barry
authors.initials: B
authors.lastname: Arnason
authors.forename: Kim
authors.initials: K
authors.lastname: Bigley
authors.forename: Patricia
authors.initials: P
authors.lastname: Coyle
authors.forename: Douglas
authors.initials: D
authors.lastname: Goodin
authors.forename: Samer
authors.initials: S
authors.lastname: Kaba
authors.forename: Stephen
authors.initials: S
authors.lastname: Kirzinger
authors.forename: Sharon
authors.initials: S
authors.lastname: Lynch
authors.forename: Raul
authors.initials: R
authors.lastname: Mandler
authors.forename: Daniel
authors.initials: D
authors.lastname: Mikol
authors.forename: Kottil
authors.initials: K
authors.lastname: Rammohan
authors.forename: Richard
authors.initials: R
authors.lastname: Sater
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Sriram
authors.forename: Ben
authors.initials: B
authors.lastname: Thrower
authors.forename: Francis
authors.initials: F
authors.lastname: Boateng
authors.forename: Peter
authors.initials: P
authors.lastname: Jakobs
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Wash
authors.forename: Timon
authors.initials: T
authors.lastname: Bogumil
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000328:Adult; D004185:Disability Evaluation; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis / Q000188:drug therapy* / Q000534:rehabilitation; D010865:Pilot Projects; D011994:Recombinant Proteins; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D011994:Recombinant Proteins; D000068576:Interferon beta-1b; D016899:Interferon-beta