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.

[1]  P. O'Brien.  Procedures for comparing samples with multiple endpoints. , 1984, Biometrics.

[2]  J. Lieberman,et al.  The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development. , 2003, Schizophrenia bulletin.

[3]  T. Stroup,et al.  Assessing Clinical and Functional Outcomes in the Clinical Antipsychotic Trials of Intervention Effectiveness (catie) Schizophrenia Trial Send Reprint Requests to Clinical Outcome Measures: Primary Outcome Clinical and Functional Outcomes Table 1. Catie Schizophrenia Trial Centers' Clinical and Func , 2022 .

[4]  S H Ferris,et al.  Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study. , 1997, Alzheimer disease and associated disorders.

[5]  C. Bombardier,et al.  Pharmacoeconomic evaluation of new treatments: efficacy versus effectiveness studies? , 1999, Annals of the rheumatic diseases.

[6]  D. Revicki,et al.  Pharmacoeconomic evaluation in the real world. Effectiveness versus efficacy studies. , 1999, PharmacoEconomics.

[7]  G Wassmer,et al.  Procedures for two-sample comparisons with multiple endpoints controlling the experimentwise error rate. , 1991, Biometrics.

[8]  Russell D. Wolfinger,et al.  Multiple Comparisons and Multiple Tests Using the SAS System , 1999 .

[9]  G. Koch.  Discussion for 'Alpha calculus in clinical trials: considerations and commentary for the new millennium'. , 2000, Statistics in medicine.

[10]  Y. Hochberg.  A sharper Bonferroni procedure for multiple tests of significance , 1988 .

[11]  K. Davis,et al.  National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer disease trial methodology. , 2001, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[12]  P. Sen,et al.  Log‐Rank Scores, Statistics, and Tests , 2004 .

[13]  P. Diggle.  Analysis of Longitudinal Data , 1995 .

[14]  S. Kay,et al.  The positive and negative syndrome scale (PANSS) for schizophrenia. , 1987, Schizophrenia bulletin.

[15]  J. Morris,et al.  Validity and Reliability of the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) , 1997 .

[16]  P Bauer,et al.  Multiple testing in clinical trials. , 1991, Statistics in medicine.

[17]  L. Moye.  Alpha calculus in clinical trials: considerations and commentary for the new millennium. , 2000, Statistics in medicine.