Lotterer E, Högel J, Gaus W, Fleig W E, Bircher J
First Department of Medicine, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
Hepatology. 1997 Dec;26(6):1426-33. doi: 10.1002/hep.510260609.
Quantitative liver function tests such as the determination of galactose elimination capacity (GEC) or the aminopyrine breath test (ABT) may have the potential to serve as refined entry criteria and surrogate markers for end-points in controlled clinical trials. The magnitude of a statistically detectable difference in test results and the period of observation required to document such a difference must be known to properly design such trials. Therefore, we explored retrospectively the time course of changes in GEC and ABT and their reproducibility from a cohort of patients with alcoholic cirrhosis followed for 12 to 42 months, with a median of 34 months. In 15 patients who stopped drinking, GEC improved significantly by 0.64 mg/min/kg within 1 year (mean; 95% 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 patients who continued to drink (P < .01). The residual standard deviation 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 significantly by 0.14% dose x kg/mmol CO2 (95% CI: 0.09; 0.18) in the abstinent group, and deteriorated by 0.09% dose x kg/mmol CO2 (95% CI: 0.06; 0.13) in the nonabstinent group (P < .01). The residual standard deviation in the above sense for ABT was 0.08% dose x 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 GEC of 0.6 mg/min/kg and of 0.7 mg/min/kg to reach statistical significance at the 5% and 1% level, respectively. In the present study, a period of 11 and 12 months was necessary to observe such differences. The corresponding results for the ABT are 0.11% dose x kg/mmol CO2 (9 months of follow-up; 5% level) and 0.13% dose x kg/mmol CO2 (11 months of observation; 1% level), respectively. Provided that patients with liver diseases treated with drugs are similar to the abstinent and nonabstinent patients with alcoholic liver disease investigated in this study, such numbers could serve for the planning of controlled clinical trials, in which the control group is likely to deteriorate and the treated group 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 444 patient years (range, 50-2,100 patient years) reported for various published controlled clinical trials using survival analysis.
定量肝功能测试，如半乳糖清除能力（GEC）测定或氨基比林呼气试验（ABT），有可能作为精细的纳入标准和替代指标，用于对照临床试验的终点评估。为了合理设计此类试验，必须了解测试结果中具有统计学显著性差异的幅度以及记录这种差异所需的观察期。因此，我们回顾性地研究了一组酒精性肝硬化患者在12至42个月（中位数为34个月）内GEC和ABT的变化时间过程及其可重复性。在15名戒酒的患者中，1年内GEC显著改善了0.64 mg/min/kg（平均值；95%置信区间[CI]：0.42；0.86）。相比之下，在另外17名继续饮酒的患者中，1年内GEC恶化了0.53 mg/min/kg（95%CI：0.32；0.74）（P <.01）。GEC相对于患者初始值变化的残余标准差为0.43 mg/min/kg（95%CI：0.32；0.52）。此外，戒酒组的ABT显著改善了0.14%剂量x kg/mmol CO2（95%CI：0.09；0.18），非戒酒组恶化了0.09%剂量x kg/mmol CO2（95%CI：0.06；0.13）（P <.01）。上述意义上ABT的残余标准差为0.08%剂量x kg/mmol CO2（95%CI：0.06；0.10）。这些数据表明，每组样本量为n = 20的临床试验，GEC的绝对差异（ADs）分别达到0.6 mg/min/kg和0.7 mg/min/kg时，才能在5%和1%的水平达到统计学显著性。在本研究中，观察到这些差异分别需要11个月和12个月。ABT的相应结果分别为0.11%剂量x kg/mmol CO2（随访9个月；5%水平）和0.13%剂量x kg/mmol CO2（观察11个月；1%水平）。假设接受药物治疗的肝病患者与本研究中调查的戒酒和未戒酒酒精性肝病患者相似，这些数字可用于对照临床试验的规划，其中对照组可能恶化，治疗组预期改善。基于GEC或ABT的试验与使用生存分析的各种已发表对照临床试验报告的中位数444患者年（范围50 - 2100患者年）相比，仅需要37或30患者年的观察期。
