Adjunctive oral ziprasidone in patients with acute mania treated with lithium or divalproex, part 2: influence of protocol-specific eligibility criteria on signal detection.

Objectives: High failure rates of randomized controlled trials (RCTs) are well recognized but poorly understood. We report exploratory analyses from an adjunctive ziprasidone double-blind RCT in adults with bipolar I disorder (reported in part 1 of this article). Data collected by computer interviews and by site-based raters were analyzed to examine the impact of eligibility criteria on signal detection.

Method: Clinical assessments and a remote monitoring system, including a computer-administered Young Mania Rating Scale (YMRS(Comp)) were used to categorize subjects as eligible or ineligible on 3 key protocol-specified eligibility criteria. Data analyses compared treatment efficacy for eligible versus ineligible subgroups. All statistical analyses reported here are exploratory. Criteria were considered "impactful" if the difference between eligible and ineligible subjects on the YMRS change scores was ≥ 1 point.

Results: 504 subjects had baseline and ≥ 1 post-randomization computer-administered assessments but only 180 (35.7%) met all 3 eligibility criteria based on computer assessments. There were no statistically significant differences between treatment groups in change from baseline YMRS score on the basis of site-based rater or computer assessments. All criteria tested improved signal detection except the entry criteria excluding subjects with ≥ 25% improvement from screen to baseline.

Conclusions: On the basis of computer assessments, nearly two-thirds of randomized subjects did not meet at least 1 protocol-specified eligibility criterion. These results suggest enrollment of ineligible subjects is likely to contribute to failure of acute efficacy studies.

Trial Registration: ClinicalTrials.gov identifier: NCT00312494.