度洛西汀的疗效：八项临床试验中MMRM和LOCF_ANCOVA结果的综合总结。
The efficacy of duloxetine: a comprehensive summary of results from MMRM and LOCF_ANCOVA in eight clinical trials.
作者信息
Mallinckrodt Craig H, Raskin Joel, Wohlreich Madelaine M, Watkin John G, Detke Michael J
机构信息
Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN, USA.
出版信息
BMC Psychiatry. 2004 Sep 8;4:26. doi: 10.1186/1471-244X-4-26.
BACKGROUND
A mixed-effects model repeated measures approach (MMRM) was specified as the primary analysis in the Phase III clinical trials of duloxetine for the treatment of major depressive disorder (MDD). Analysis of covariance using the last observation carried forward approach to impute missing values (LOCF_ANCOVA) was specified as a secondary analysis. Previous research has shown that MMRM and LOCF_ANCOVA yield identical endpoint results when no data are missing, while MMRM is more robust to biases from missing data and thereby provides superior control of Type I and Type II error compared with LOCF_ANCOVA. We compared results from MMRM and LOCF_ANCOVA analyses across eight clinical trials of duloxetine in order to investigate how the choice of primary analysis may influence interpretations of efficacy.
METHODS
Results were obtained from the eight acute-phase clinical trials that formed the basis of duloxetine's New Drug Application for the treatment of MDD. All 202 mean change analyses from the 20 rating scale total scores and subscales specified a priori in the various protocols were included in the comparisons.
RESULTS
In 166/202 comparisons (82.2%), MMRM and LOCF_ANCOVA agreed with regard to the statistical significance of the differences between duloxetine and placebo. In 25/202 cases (12.4%), MMRM yielded a significant difference when LOCF_ANCOVA did not, while in 11/202 cases (5.4%), LOCF_ANCOVA produced a significant difference when MMRM did not. In 110/202 comparisons (54.4%) the p-value from MMRM was lower than that from LOCF_ANCOVA, while in 69/202 comparisons (34.2%), the p-value from LOCF_ANCOVA was lower than that from MMRM. In the remaining 23 comparisons (11.4%), the p-values from LOCF_ANCOVA and MMRM were equal when rounded to the 3rd decimal place (usually as a result of both p-values being <.001). For the HAMD17 total score, the primary outcome in all studies, MMRM yielded 9/12 (75%) significant contrasts, compared with 6/12 (50%) for LOCF_ANCOVA. The expected success rate was 80%.
CONCLUSIONS
Important differences exist between MMRM and LOCF_ANCOVA. Empirical research has clearly demonstrated the theoretical advantages of MMRM over LOCF_ANCOVA. However, interpretations regarding the efficacy of duloxetine in MDD were unaffected by the choice of analytical technique.
背景
在度洛西汀治疗重度抑郁症（MDD）的III期临床试验中，指定混合效应模型重复测量法（MMRM）作为主要分析方法。使用末次观察结转法（LOCF）进行缺失值插补的协方差分析（LOCF_ANCOVA）被指定为次要分析方法。先前的研究表明，当无数据缺失时，MMRM和LOCF_ANCOVA得出的终点结果相同，而MMRM对缺失数据导致的偏差更具稳健性，因此与LOCF_ANCOVA相比，能更好地控制I型和II型错误。我们比较了度洛西汀八项临床试验中MMRM和LOCF_ANCOVA分析的结果，以研究主要分析方法的选择如何影响疗效的解读。
方法
结果来自构成度洛西汀治疗MDD新药申请基础的八项急性期临床试验。纳入比较的是各方案中事先指定的20个评分量表总分及分量表的所有202次平均变化分析。
结果
在202次比较中的166次（82.2%），度洛西汀与安慰剂之间差异的统计学显著性在MMRM和LOCF_ANCOVA分析中是一致的。在202例中的25例（12.4%），MMRM得出显著差异而LOCF_ANCOVA未得出，而在202例中的11例（5.4%），LOCF_ANCOVA得出显著差异而MMRM未得出。在202次比较中的110次（54.4%），MMRM的p值低于LOCF_ANCOVA的p值，而在202次比较中的69次（34.2%），LOCF_ANCOVA的p值低于MMRM的p值。在其余23次比较（11.4%）中，LOCF_ANCOVA和MMRM的p值四舍五入到小数点后第三位时相等（通常是因为两个p值均<.001）。对于所有研究中的主要结局指标汉密尔顿抑郁量表17项总分（HAMD17），MMRM得出9/12（75%）的显著对比，而LOCF_ANCOVA为6/12（50%）。预期成功率为80%。
结论
MMRM和LOCF_ANCOVA之间存在重要差异。实证研究已清楚证明MMRM相对于LOCF_ANCOVA的理论优势。然而，关于度洛西汀治疗MDD疗效的解读不受分析技术选择的影响。
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