A short 2 week dose titration regimen reduces the severity of flu-like symptoms with initial interferon gamma-1b treatment

Abstract

Objectives:

Flu-like symptoms (FLS) are commonly experienced by patients receiving interferon gamma-1b which may cause discontinuation or disruption of dosing during initial therapy or on re-initiation following a break in therapy. In contrast to Type I interferons, the impact of dose-titration on FLS has not been reported and is not a practice described or included in the approved prescribing information for interferon gamma-1b.The objective of this study was to assess the effect of a 2 week titration regimen on the severity of FLS during the initial 3 weeks of therapy with three times weekly subcutaneous injections of interferon gamma-1b.

Methods:

Healthy men and women were randomized into a double-blind, two-period, crossover study. Each study period was 3 weeks in duration and there was a minimum 15 day washout between treatment periods. Two treatment regimens were compared: No Titration dosing (full 50 mcg/m² subcutaneously [SC] three times weekly for 3 weeks) and Titration (15 mcg/m² SC three times weekly during week 1, 30 mcg/m² SC three times weekly during week 2 followed by the full dose of 50 mcg/m² SC three times weekly during week 3). Subjects remained in the clinic for at least 12 hours following each injection. FLS was based on a composite score for fever, chills, tiredness and muscle aches assessed at baseline and 4, 8 and 12 hours following each injection. Acetaminophen was allowed at the discretion of the PI. The primary endpoint was the change from baseline in FLS severity at 8 hours averaged over the 3 weeks of treatment. Additional endpoints included FLS at 4 and 12 hours, individual flu-like symptoms, rates of discontinuation, incidence of FLS and acetaminophen use.

Clinical trials registration:

NCT 01929382.

Results:

Of the 40 subjects randomized, there were 15 (37.5%) discontinuations. Titration resulted in a significant reduction in FLS severity at 8 hours (p = 0.023) averaged over the 3 week treatment period. The difference in 3 week FLS severity reflects differences during week 1 treatment, indicating an early peak in FLS severity during the No Titration treatment and subsequent development of tolerance. In contrast, titration results in near baseline severity scores throughout the treatment period. Similar trends were seen for 4 and 12 hour FLS severity scores. Of the individual FLS, difference in fever severity was most marked. Safety profiles for both regimens were consistent with the approved prescribing information for interferon gamma-1b. Study limitations included the use of healthy subjects rather than disease subjects, the lack of a validated assessment tool for evaluating FLS and the relatively high discontinuation rate.

Conclusion:

A short 2 week, dose-titration regimen reduces FLS severity following interferon gamma-1b treatment initiation in normal subjects.

Keywords::

• Dose titration
• Fever
• Flu-like symptoms
• Interferon gamma-1b
• Tolerance

Transparency

Declaration of funding

This study was supported by Vidara Therapeutics Research Ltd.

Declaration of financial/other relationships

J.G.D. and M.L.M. have disclosed that they are employees and shareholders of Vidara Therapeutics Research Ltd. M.A.M. has disclosed that he is an employee of Prism Research Inc., a contract research organization contracted to conduct this study. He has no other significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewers on this manuscript received an honorarium from CMRO for their review work, but have no relevant financial or other relationships to disclose.

Acknowledgments

The study was project managed and monitored by IND2Results and statistical analysis was provided by Applied Statistics and Consulting.

Previous presentation: A preliminary presentation of data was submitted in abstract form to the Clinical Immunology Society (CIS) and was accepted for poster presentation at the 2014 Annual Meeting in Baltimore, MD, 10–13 April 2014.

Notes

*Actimmune is a registered trademark of Vidara Therapeutics International Ltd.