Biomedical subjects
Lisa M LaVange
Publications and source records attributed to Lisa M LaVange.
Randomization-based nonparametric methods for the analysis of multicentre trials.
Multicentre trials offer several advantages over single centre trials in clinical research, including the ability to recruit patients at a faster rate over the course of the study, increased generalizability through the use of a broader patient population, and the ability to shed light on the replication of findings at multiple centres in a single study. A nonparametric approach to the analysis of multicentre trial data provides a convenient way for addressing the role of centres as well as baseline covariables during data analysis. With the use of randomization-based nonparametric methods, the strategy for evaluating the null hypothesis of no treatment effect can be prespecified during study planning without requiring a specific structure for the relationship of response criteria (or endpoints) to centres, covariables, or potential interaction terms. Further, the basis of inference for the application of these methods is the randomization mechanism, and the population to which inference can be directly made is the study population itself. No assumptions about underlying distributions, data structures, likelihood functions, or samples from super populations of inference are required. A three-step approach is proposed for handling centres via randomization-based nonparametric methods. In Step 1, a test of overall treatment effect is carried out using data from all centres simultaneously, without any assumption about treatment by centre interaction. In Step 2, the question of treatment by centre interaction is addressed, usually through the use of parametric multiple regression methods. In cases with suggestion of such interaction, Step 3 is conducted to evaluate different weighting schemes in forming pairwise treatment comparisons averaged across centres to assess the robustness of treatment effects observed in Step 1. An attractive inferential feature of this three-step approach is that the Type I error for the test of treatment effect is controlled by requiring statistical significance at each step to proceed to the next step. Extended Mantel-Haenszel methods with stratification adjustment for centre can be used to provide a nonparametric assessment of treatment effect. When adjustment for other covariates, such as baseline values, is desired, the more recent nonparametric analysis of covariance methods are available. Both methods are easy to use, require no assumptions beyond that of a valid randomization mechanism, and can be applied in a similar manner to dichotomous, ordinal, failure time, or continuous response criteria (endpoints). The methods are illustrated using data from a confirmatory clinical trial of a therapeutic agent for the treatment of dry eye disease.
Statistical approaches to effectiveness measurement and outcome-driven re-randomizations in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) studies.
The design of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia and Alzheimer's disease studies pose several statistical challenges, including issues related to performing multiple comparisons, defining effectiveness outcomes, and collecting and analyzing data from a design with multiple outcome-driven re-randomizations. We discuss the CATIE strategy for addressing many hypotheses within the context of one clinical trial while controlling the overall type I error rate. We provide motivation for the use of two effectiveness outcomes: time to all-cause discontinuation and composite endpoints that combine outcomes from multiple domains, such as efficacy, safety, cost-effectiveness, and quality of life. Methods for statistical analysis of an outcome-driven re-randomization trial are compared and evaluated. We describe analysis within each phase, analysis based on the first randomization or treatment algorithms, and repeated measures modeling. Finally, strategies are described for designing an electronic data collection system for trials with repeated outcome-driven re-randomizations.
Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistant chronic depression.
BACKGROUND: Although various strategies have been proposed to treat antidepressant nonresponders, little controlled research has been published that examines prospectively the use of switching to an alternate antidepressant. METHODS: This was a multisite study in which outpatients with chronic major depression (with or without concurrent dysthymia), who failed to respond to 12 weeks of double-blind treatment with either sertraline hydrochloride (n = 117) or imipramine hydrochloride (n = 51), were crossed over or switched to 12 additional weeks of double-blind treatment with the alternate medication. Outcome measures included the 24-item Hamilton Rating Scale for Depression and the Clinical Global Impressions--Severity and Improvement scales. RESULTS: The switch from sertraline to imipramine (mean dosage, 221 mg/d) and from imipramine to sertraline (mean dosage, 163 mg/d) resulted in clinically and statistically significant improvements. The switch to sertraline treatment was associated with fewer adverse effect complaints and significantly less attrition owing to adverse effects. Although sertraline treatment also resulted in significantly higher response rates in the intent-to-treat samples (60% in the sertraline group and 44% in the imipramine group), neither the intent-to-treat remission rates nor the response and remission rates among study completers differed significantly. Moreover, after considering the effect of attrition, there were no significant treatment effects on the more comprehensive generalized estimating equation analyses of the continuous dependent measures. CONCLUSIONS: More than 50% of chronically depressed antidepressant nonresponders benefited from a switch from imipramine to sertraline, or vice versa, despite a high degree of chronicity. As in the initial trial, sertraline was generally better tolerated than imipramine. Switching to a standard antidepressant of a different class is a useful treatment strategy for antidepressant nonresponders and could be considered a standard of comparison for future studies of novel alternate strategies.