title: Adjunctive oral ziprasidone in patients with acute mania treated with lithium or divalproex, part 2: influence of protocol-specific eligibility criteria on signal detection.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT00312494.
authors.affiliation: Bipolar Clinic and Research Program, Massachusetts General Hospital, 50 Staniford St, 5th Floor, Boston, MA 02114, USA. SachsG@aol.com
authors.forename: Gary S
authors.initials: GS
authors.lastname: Sachs
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Vanderburg
authors.forename: Suzanne
authors.initials: S
authors.lastname: Edman
authors.forename: Onur N
authors.initials: ON
authors.lastname: Karayal
authors.forename: Sheela
authors.initials: S
authors.lastname: Kolluri
authors.forename: Mary
authors.initials: M
authors.lastname: Bachinsky
authors.forename: Idil
authors.initials: I
authors.lastname: Cavus
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D018692:Antimanic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D003936:Diagnosis, Computer-Assisted; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007406:Interview, Psychological; D016651:Lithium Carbonate / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D011594:Psychometrics; D012107:Research Design; D017603:Signal Detection, Psychological / Q000187:drug effects*; D013844:Thiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014635:Valproic Acid / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D018692:Antimanic Agents; D010879:Piperazines; D013844:Thiazoles; D016651:Lithium Carbonate; D014635:Valproic Acid; C092292:ziprasidone