Dose titration of intramuscular interferon beta-1a reduces the severity and incidence of flu-like symptoms during treatment initiation

Abstract

Background/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.

Clinical trial registration:

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.

Conclusion:

Dose titration during initiation of IM IFNβ-1a reduces FLS severity and incidence in healthy volunteers compared with no titration.

Key words::

• Flu-like symptoms
• intramuscular interferon beta-1a
• Multiple sclerosis
• Safety
• Titration
• Treatment initiation

Transparency

Declaration of funding

This study was supported by Biogen Idec Inc.

Declaration of financial/other relationships

M.A.M. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article. T.R.Z., D.T., Y.T., and A.D. are employees of Biogen Idec.

Acknowledgements

Medical writing assistance was provided by Tracy Wetter, PhD, and Matthew Jacobson of Infusion Communications and was funded by Biogen Idec Inc.

Data were previously presented in poster format at the Consortium of Multiple Sclerosis Centers 2011 Annual Meeting held on 1–4 June in Montreal, Canada. They were also be presented in poster format at the European Federation of Neurological Societies 2011 Annual Meeting on 10–13 September in Budapest, Hungary, and at the European Committee for Treatment and Research in Multiple Sclerosis 2011 Annual Meeting on 19–22 October in Amsterdam, The Netherlands.

Notes

†Avonex is a registered trade name of Biogen Idec Inc., Weston, MA, USA.