Exercise-Induced Serum Enzyme Elevations Confounding the Evaluation of Investigational Drug Toxicity: Report of Two Cases in a Vaccine Trial

Abstract

Two subjects developed marked elevations in creatine kinase and other serum enzymesassociated with mild myalgia during a randomized, double-blind, controlled Phase 1 clinical trial ofan investigational live, attenuated vaccine against West Nile virus (ChimeriVax™-WN02). Onesubject had received ChimeriVax™-WN02 while the other subject was enrolled in an activecontrol group and received licensed yellow fever 17D vaccine (YF-VAX®). Subsequently, theclinical trial was interrupted, and an investigation was begun to evaluate the enzymeabnormalities. As daily serum samples were collected for determination of quantitative viremia, itwas possible to define the enzyme elevations with precision, and to relate these elevations tophysical activity of the subjects, symptoms, and virological and serological measurements.Evaluation of both subjects clearly showed that skeletal muscle injury, and not cardiac or hepaticdysfunction, was responsible for the biochemical abnormalities. This investigation also implicatedstrenuous exercise as the cause of the apparent muscle injury rather than the study vaccines. Asa result of this experience, subjects engaged in future early-stage trials of these live, attenuatedviral vaccines will be advised not to engage in contact sports or new or enhanced exerciseregimens for which they are not trained or conditioned. The inclusion of placebo control arm (inlieu of or addition to an active vaccine control) will also be useful in differentiating causally relatedserum enzyme elevations.