title: 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 enzymes associated with mild myalgia during a randomized, double-blind, controlled Phase 1 clinical trial of an investigational live, attenuated vaccine against West Nile virus (ChimeriVax-WN02). One subject had received ChimeriVax-WN02 while the other subject was enrolled in an active control group and received licensed yellow fever 17D vaccine (YF-VAX). Subsequently, the clinical trial was interrupted, and an investigation was begun to evaluate the enzyme abnormalities. As daily serum samples were collected for determination of quantitative viremia, it was possible to define the enzyme elevations with precision and to relate these elevations to physical activity of the subjects, symptoms, and virological and serological measurements. Evaluation of both subjects clearly showed that skeletal muscle injury, and not cardiac or hepatic dysfunction, was responsible for the biochemical abnormalities. This investigation also implicated strenuous exercise as the cause of the apparent muscle injury rather than the study vaccines. As a result of this experience, subjects engaged in future early-stage trials of these live, attenuated viral vaccines will be advised not to engage in contact sports or new or enhanced exercise regimens for which they are not trained or conditioned. The inclusion of placebo control arm (in lieu of or addition to an active vaccine control) will also be useful in differentiating causally related serum enzyme elevations.
authors.affiliation: Pharmaceutical Research Associates Inc, Lenexa, Kansas, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Johnson
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Monath
authors.forename: Niranjan
authors.initials: N
authors.lastname: Kanesa-Thasan
authors.forename: Danell
authors.initials: D
authors.lastname: Mathis
authors.forename: Chuck
authors.initials: C
authors.lastname: Miller
authors.forename: Seth
authors.initials: S
authors.lastname: Shapiro
authors.forename: Richard
authors.initials: R
authors.lastname: Nichols
authors.forename: Karen
authors.initials: K
authors.lastname: McCarthy
authors.forename: Alison
authors.initials: A
authors.lastname: Deary
authors.forename: Philip
authors.initials: P
authors.lastname: Bedford
mesh_terms: D000328:Adult; D004311:Double-Blind Method; D004798:Enzymes / Q000097:blood*; D015444:Exercise / Q000502:physiology*; D006334:Heart Function Tests; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D018482:Muscle, Skeletal / Q000293:injuries; D014612:Vaccines / Q000009:adverse effects*; D014765:Viral Vaccines / Q000009:adverse effects / Q000276:immunology; D014766:Viremia / Q000097:blood / Q000821:virology; D014779:Virus Replication; D014902:West Nile virus / Q000276:immunology; D022341:Yellow Fever Vaccine / Q000009:adverse effects / Q000276:immunology
chemical_list: D004798:Enzymes; D014612:Vaccines; D014765:Viral Vaccines; D022341:Yellow Fever Vaccine