Quantitative liver function tests as surrogate markers for end-points in controlled clinical trials: A retrospective feasibility study

✍ Scribed by E Lotterer; J Hogel; W Gaus; W E Fleig; J Bircher

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 215 KB
• Volume: 26
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510260609

✦ Synopsis

and nonabstinent patients with alcoholic liver disease investigated in this study, such numbers could serve for the planning Quantitative liver function tests such as the determination of controlled clinical trials, in which the control group is likely to deteriorate and the treated group is expected to of galactose elimination capacity (GEC) or the aminopyrine breath test (ABT) may have the potential to serve as refined improve. Trials based on GEC or ABT would require only 37 or 30 patient years of observation compared with a median entry criteria and surrogate markers for end-points in controlled clinical trials. The magnitude of a statistically detect-of 444 patient years (range, 50-2,100 patient years) reported for various published controlled clinical trials using survival able difference in test results and the period of observation required to document such a difference must be known to analysis. (HEPATOLOGY 1997;26:1426-1433.) properly design such trials. Therefore, we explored retrospectively the time course of changes in GEC and ABT and their

Controlled clinical trials for patients with liver disease reproducibility from a cohort of patients with alcoholic cirrhohave been difficult to design, cumbersome to perform, and sis followed for 12 to 42 months, with a median of 34 months.

have often failed or given conflicting results. 1 This situation In 15 patients who stopped drinking, GEC improved signifigenerally is unsatisfactory and discourages therapeutic recantly by 0.64 mg/min/kg within 1 year (mean; 95% confisearch. Several reasons may explain these problems: dence interval [CI]: 0.42; 0.86). In contrast, it deteriorated 1. Disease severity at the onset of the trial generally is by 0.53 mg/min/kg within 1 year (95% CI: 0.32; 0.74) in not adequately defined. The Child-Pugh classification reflects another 17 patients who continued to drink (P õ .01). The late disease only, 2,3 and early disease is overlooked. 4,5 The residual standard deviation of the changes in GEC with reresult is a heterogenous study population and consequent spect to the patients' initial values was 0.43 mg/min/kg (95% noise that can be overcome only by very dramatic therapeutic CI: 0.32; 0.52). In addition, ABT improved significantly by effects or extremely large sample sizes. With better stratifica-0.14% doserkg/mmol CO 2 (95% CI: 0.09; 0.18) in the abstition of patients included in a trial, smaller therapeutic effects nent group, and deteriorated by 0.09% doserkg/mmol CO 2 might be evident. (95% CI: 0.06; 0.13) in the nonabstinent group (P õ .01).

2. Death is often the end-point in clinical trials. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] The residual standard deviation in the above sense for ABT Although this is an important and objective measure of outwas 0.08% doserkg/mmol CO 2 (95% CI: 0.06; 0.10). These come, it can occur for varying reasons, e.g., upper gastroindata indicate that clinical trials with a sample size of n Å 20 testinal hemorrhage, renal failure, portal systemic encephain each group must achieve absolute differences (ADs) in GEC lopathy, septicemia, hepatocellular carcinoma, and can be of 0.6 mg/min/kg and of 0.7 mg/min/kg to reach statistical unrelated to the liver. It probably is quite inefficient to lump significance at the 5% and 1% level, respectively. In the presthese differing events together and relate them to a single ent study, a period of 11 and 12 months was necessary to therapeutic intervention. observe such differences. The corresponding results for the 3. Progression of many liver diseases is slow and variable, ABT are 0.11% doserkg/mmol CO 2 (9 months of follow-up;

often requiring years or decades to evolve to a final stage. 1 5% level) and 0.13% doserkg/mmol CO 2 (11 months of ob-Thus, it is necessary to investigate a large number of patients servation; 1% level), respectively. Provided that patients with for a long period of time to detect treatment-related effects with death as the end-point, a procedure that is often difficult Abbreviations: GEC, galactose elimination capacity; ABT, aminopyrine breath test;

or impossible and, at the least, expensive. The time period SCl, sorbitol clearance; AD, absolute difference; RD, relative difference; CI, confidence can be reduced by studying only the late stage of a disease, interval.