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Immunomodulators, biologics not associated with AE-related withdrawal from UC trials
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Immunomodulators or biologics were not found to be associated with significant patient withdrawal from ulcerative colitis clinical trials due to adverse events compared with placebo in a recent systematic review and meta-analysis. However, azathioprine did not appear to have a favorable ratio of efficacy to adverse event-related study withdrawal for maintenance therapy of moderate-to-severe UC.
“The aim of this meta-analysis was to evaluate UC placebo-controlled clinical trial data to determine the relative [adverse events]-associated tolerability of biologics and immunomodulators in the induction and maintenance of disease-free remission, based on study withdrawal due to [adverse events],” Corey A. Siegel, MD, from Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, and colleagues wrote. “These findings were then correlated with a traditional measure of therapeutic efficacy to compare [adverse event]-related tolerability and efficacy in a single metric.”
Corey A. Siegel
The research team evaluated randomized, double-blind, placebo-controlled trials of induction, maintenance, or combined induction/maintenance single-agent therapy for moderate-to-severe UC with at least 50 participants, published up to May 2015. Studies of biologics included two trials of Remicade (infliximab, Janssen), three trials of Humira (adalimumab, AbbVie), two trials of Simponi (golimumab, Janssen), and three trials of Entyvio (vedolizumab, Takeda). Studies of immunomodulators included two trials of tacrolimus and two trials of azathioprine.
Tolerability based on relative risk calculated using the number of study withdrawals due to adverse events on therapy vs. placebo served as the primary endpoint. Number needed to treat (NNT) and number needed to stop (NNS) were also determined, “with a higher [NNS/NNT] ratio representing a higher proportion of patients experiencing drug benefit compared with withdrawal from a trial due to an [adverse event].”
The research team found that induction therapy with either immunomodulators or biologics did not result in in excess study withdrawal, so NNS/NNT ratio could not be assessed. Moreover, neither maintenance nor combined induction-and-maintenance trials of biologics resulted in excess study withdrawal.
Two trials of maintenance therapy with azathioprine resulted in an NNS of 13.8 (RR = 2.8; 95% CI, 0.7-10.5) and an NNS/NNT ratio of 2.4. “In other words, for every 2.4 patients on [azathioprine] benefiting from therapy, one person withdrew from the study due to an [adverse event],” the researchers wrote.
“In this study, we did not find evidence that immunomodulators and biologics are associated with significant study withdrawal due to [adverse events] in clinical trials. However, the efficacy of maintenance therapy with immunomodulators appears attenuated by the frequency of [adverse event] study withdrawals based on the resulting NNS/NNT ratio, whereas maintenance therapy with biologics is not associated with excess study withdrawal in clinical trials.
“In [summary], biologic agents appear to have a favorable ratio of efficacy to [adverse event]-related study withdrawal for maintenance therapy of moderate-to-severe UC, whereas [azathioprine] did not,” they concluded. – by Adam Leitenberger
Disclosure: Siegel reports he has served as a consultant and on the advisory board for AbbVie, Given Imaging, Janssen, Prometheus and Takeda; has delivered CME talks for AbbVie and Janssen; and has received grant support from AbbVie, Janssen, Salix, UCB and Warner-Chilcott.
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