title: Dose titration of intramuscular interferon beta-1a reduces the severity and incidence of flu-like symptoms during treatment initiation.
abstract: OBJECTIVE
  Flu-like symptoms (FLS) are common side effects of interferon beta (IFNβ) therapy and can negatively affect the willingness of patients with multiple sclerosis to initiate therapy. Although dose titration is commonly used to reduce the severity and incidence of IFNβ-related FLS during treatment initiation, these benefits have not been confirmed in a well controlled study. The objective of this randomized, dose-blinded, parallel-group study was to assess the effect of dose titration on the severity and incidence of FLS during the initial 8 weeks of once-weekly intramuscular (IM) IFNβ-1a administration.
  
  
  METHODS
  Healthy volunteers were randomized 1:1:1 to one of three IM IFNβ-1a regimens: 3-week titration (weekly quarter-dose increments over 3 weeks to full dose [30 µg]); 6-week titration (biweekly quarter-dose increments over 6 weeks to full dose); or no titration (full dose over 8 weeks). At weekly clinic visits, the severity of each FLS was rated 1 hour pre-injection and 4-6 hours and 12-15 hours post-injection. Study endpoints included post-injection change in FLS severity and post-injection FLS incidence (percentage of subjects with a ≥2-point increase in total FLS severity score) at each time point.
  
  
  BACKGROUND
  Clinicaltrials.gov identifier: NCT01119677.
  
  
  RESULTS
  Of 234 subjects enrolled, 194 (83%) completed the study. At 8 weeks, FLS severity was significantly reduced at both post-injection time points with 3-week titration (76% reduction at 4-6 hours, p < 0.001; 37% reduction at 12-15 hours; p < 0.001) and 6-week titration (50% reduction at 4-6 hours, p < 0.001; 32% reduction at 12-15 hours; p = 0.002) compared with no titration. The incidence of FLS was also significantly reduced at both time points with both titration regimens. Safety profiles for both titration regimens were consistent with the current IM IFNβ-1a label. Study limitations included that there is currently no validated assessment tool for evaluating the severity of FLS, that the study enrolled healthy volunteers, that different proportions of females were randomized to the 3-week-titration group than to the 6-week and no-titration groups, and that evaluation of the potential impact of titration on symptoms occurring substantially later after injection was not part of the study protocol.
  
  
  CONCLUSIONS
  Dose titration during initiation of IM IFNβ-1a reduces FLS severity and incidence in healthy volunteers compared with no titration.
authors: PRISM Research, Inc, St. Paul, MN, USA.
authors: Mark A
authors: MA
authors: Matson
authors: Thomas R
authors: TR
authors: Zimmerman
authors: Dianne
authors: D
authors: Tuccillo
authors: Yongqiang
authors: Y
authors: Tang
authors: Aaron
authors: A
authors: Deykin
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D015994:Incidence; D007251:Influenza, Human / Q000139:chemically induced* / Q000517:prevention & control*; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D016899:Interferon-beta; D000068556:Interferon beta-1a