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.

Phase I Dose-Escalation Study of a Monovalent Heat Shock Protein 70-Herpes Simplex Virus Type 2 (HSV-2) Peptide-Based Vaccine Designed To Prime or Boost CD8 T-Cell Responses in HSV-Naïve and HSV-2-Infected Subjects

“…Each elevation of CK was associated with an unusual or marked physical activity or intercurrent illness and returned to normal. Elevations of CK detected in a recent clinical trial of flavivirus vaccines were also ascribed to physical exertion, leading to an adjustment in study design in which contact sports or new exercise regimens were discouraged among study participants (17). It is not known why we failed to observe vaccine immunogenicity.…”

A live, attenuated recombinant West Nile virus vaccine

“…Only one subject (ChimeriVax-WN02 3.0 log group) had a mild elevation in body temperature (38.2°C) as an AE (on day 6). Two subjects with high elevations of creatine phosphokinase, one in the ChimeriVax-WN02 5.0 log and one in the YF-VAX group, were the subject of an intensive investigation concluding that the enzyme elevations were likely due to muscle injury from strenuous physical exercise rather than to the study vaccines (9). CV-WN, ChimeriVax-WN02; YF, yellow fever 17D; Pos, number monkeys positive by PCR; Eq͞ml, plaque-forming equivalents per ml; inoc, inoculation site; contra, contralateral arm; mandib, mandibular; mesen, mesenteric; skel, skeletal.…”

Concomitant or sequential administration of live attenuated Japanese encephalitis chimeric virus vaccine and yellow fever 17D vaccine

“…13 The study participants were predominately physically active adults and there was no requirement for participants to reduce levels of exercise prior to immunization or follow-up blood sampling. These abnormal CPK values were detected at screening, were transient and self-limiting, and were not associated with any particular treatment group or local AE.…”