The efficacy of duloxetine: a comprehensive summary of results from MMRM and LOCF_ANCOVA in eight clinical trials.
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.
Mallinckrodt
Craig H
CH
Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN, USA. cmallinc@lilly.com
Raskin
Joel
J
Wohlreich
Madelaine M
MM
Watkin
John G
JG
Detke
Michael J
MJ
D000704:Analysis of Variance; D000928:Antidepressive Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data; D003627:Data Interpretation, Statistical; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000523:psychology; D017277:Drug Approval / Q000379:methods; D000068736:Duloxetine Hydrochloride; D023381:Endpoint Determination / Q000706:statistics & numerical data; D006801:Humans; D008137:Longitudinal Studies; D015233:Models, Statistical; D010147:Pain Measurement / Q000706:statistics & numerical data; D010919:Placebos; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D013876:Thiophenes / Q000627:therapeutic use*; D016896:Treatment Outcome
D000928:Antidepressive Agents; D010919:Placebos; D013876:Thiophenes; D000068736:Duloxetine Hydrochloride