Effects of dose relative to body weight in the national cooperative gallstone study: A fixed-dose trial

Abstract

Most clinical trials of a drug employ total fixed doses (mg/day) but the results are also often analyzed according to doses relative to body weight (mg/kg/day). The latter corresponds to a subgroup analysis stratified by body weight. This paper describes the difficulty in interpreting such results as illustrated by the National Cooperative Gallstone Study (NCGS). The NCGS evaluated the efficacy and safety of chenodiol for the dissolution of gallstones using fixed dosage groups (750, 375, and 0 mg/day). Analyses are presented comparing those patients who received high vs. low relative doses by virtue of a low (≦62.5 kg) vs. high (>62.5 kg) body weight. Although a significantly higher proportion of those with a low body weight achieved partial (50% reduction in volume) or complete dissolution of gallstones, these subgroups also differed significantly in a variety of characteristics (sex, age, percent ideal body weight; and floating gallstones) which have been shown to be prognostic of dissolution with a fixed dose of chenodiol. Similarly, although the body weight subgroups differed in the proportions of patients experiencing clinically significant diarrhea, they also differed in the characteristic (sex) associated with diarrhea. After adjustment for these characteristics, the differences for dissolution and diarrhea between the high and low relative dose subgroups were not significant. Thus, an analysis by relative (mg/kg) doses of the results of a fixed dose clinical trial should be used only with caution to determine whether a high relative dose (mg/kg) of an agent would be more efficacious or less safe when applied to the general population.