Joint modeling of dropout and outcome in three pivotal clinical trials of schizophrenia.

Abstract

BACKGROUND:

Dropout is a serious challenge to clinical trials in psychiatry, yet standard outcome analyses with mixed models do not account for dropout, while joint modeling uses dropout from a survival model to adjust the outcome from a mixed model, but is untested in clinical trials of schizophrenia.

AIMS:

To compare mixed and joint modeling in three acute phase pivotal placebo controlled trials of schizophrenia.

METHOD:

Data were reanalyzed on 611 in-patients with acute schizophrenia who participated in three pivotal randomized controlled trials that compared placebo with olanzapine or risperidone (dropout rates placebo: 62.6% and medication: 37.4%). The outcome measures were BPRS or PANSS total change scores. Mixed-effects models for repeated measures and joint models were computed and compared to examine the time-treatment interaction. Effect size comparisons were made.

RESULTS:

Antipsychotic treatment was superior to placebo across analyses. Time treatment interactions were significant (p<.05) for the mixed (beta=2.33) and joint models (beta=2.62). Compared with mixed modeling, joint modeling reduced the estimated change score for treatment (21.24 vs 19.74) and placebo (1.64 vs -1.11). The effect size differences between placebo and treatment groups were greater for joint (ES=.89) than mixed modeling (ES=0.83). Sensitivity analysis replicated this trend of results in each of the three trials.

CONCLUSION:

Compared to mixed modeling, joint modeling results in a greater separation between treatment and placebo groups. This offers preliminary evidence that joint modeling may be useful in the analysis of antipsychotic placebo controlled RCTs.

• Authors: Stephen Z Levine, Yair Goldberg, Myrto Samara, John M Davis, Stefan Leucht
• Journal: Schizophrenia research (Schizophr Res) Vol. 164 Issue 1-3 Pg. 122-6 (May 2015) ISSN: 1573-2509 [Electronic] Netherlands
• PMID: 25790904 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Antipsychotic Agents
• Risperidone

Topics

• Antipsychotic Agents (therapeutic use)
• Female
• Humans
• Male
• Models, Theoretical
• Patient Dropouts (statistics & numerical data)
• Psychiatric Status Rating Scales
• Randomized Controlled Trials as Topic
• Regression Analysis
• Risperidone (therapeutic use)
• Schizophrenia (drug therapy)
• Treatment Outcome