QUANTITATIVE LIVER-FUNCTION TESTS AS SURROGATE MARKERS FOR END-POINTSIN CONTROLLED CLINICAL-TRIALS - A RETROSPECTIVE FEASIBILITY STUDY

Quantitative liver function tests such as the determination of galacto se elimination capacity (GEC) or the aminopyrine breath test (ABT) may have the potential to serve as refined entry criteria and surrogate m arkers for end-points in controlled clinical trials, The magnitude of a statistically detectable difference in test results and the period o f observation required to document such a difference. must be known to properly design such trials. Therefore, we explored retrospectively t he time course of changes in GEC and ABT and their reproducibility fro m a cohort of patients with alcoholic cirrhosis followed for 12 to 42 months, with a median of 34 months. In 15 patients who stopped drinkin g, GEC improved significantly by 0.64 mg/min/kg within 1 year (mean; 9 5% confidence interval [CI]: 0.42; 0.86). In contrast, it deteriorated by 0.53 mg/min/kg within 1 year (95% CI: 0.32; 0.74) in another 17 pa tients who continued to drink (P < .01). The residual standard deviati on of the changes in GEC with respect to the patients' initial values was 0.43 mg/min/kg (95% CI: 0.32; 0.52). In addition, ABT improved sig nificantly by 0.14% dose.kg/mmol CO2 (95% CI: 0.09; 0.18) in the absti nent group, and deteriorated by 0.09% dose.kg/mmol CO2 (95% CI: 0.06; 0.13) in the nonabstinent group (P < .01). The residual standard devia tion in the above sense for ABT was 0.08% dose.kg/mmol CO2 (95% CI: 0. 06; 0.10). These data indicate that clinical trials with a sample size of n = 20 in each group must achieve absolute differences (ADs) in GE C of 0.6 mg/min/kg and of 0.7 mg/min/kg to reach statistical significa nce at the 5% and 1% level, respectively. In the present study, a peri od of 11 and 12 months was necessary to observe such differences. The corresponding results for the ABT are 0.11% dose.kg/mmol CO2 (9 months of follow-up; 5% level) and 0.13% dose.kg/mmol CO2 (11 months of obse rvation; 1% level), respectively. Provided that patients with liver di seases treated with drugs are similar to the abstinent and nonabstinen t patients with alcoholic liver disease investigated in this study, su ch numbers could serve for the planning of controlled clinical trials, in which the control group is likely to deteriorate and the treated g roup is expected to improve. Trials based on GEC or ABT would require only 37 or 30 patient years of observation compared with a median of 4 44 patient years (range, 50-2,100 patient years) reported for various published controlled clinical trials using survival analysis.