Ziprasidone in adolescents with schizophrenia: Results from a placebo-controlled efficacy and long-term open-extension study

Objective: The purpose of this study was to evaluate the short- and long-term efficacy, safety, and tolerability of ziprasidone in adolescents with schizophrenia. Methods: Subjects ages 13-17 years with schizophrenia (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. [DSM-IV]) were enrolled in a 6 week, randomized, double-blind, placebo-controlled multicenter trial (RCT) followed by a 26 week open-label extension study (OLE). Subjects were randomized in a 2:1 ratio to flexible-dose oral ziprasidone (40-160 mg/day, based on weight) or placebo. Primary end-point was change from baseline in Brief Psychiatric Rating Scale-Anchored (BPRS-A) total score. Safety assessments included adverse events, vital signs, laboratory measures, electrocardiograms, weight and body mass index, and movement disorder ratings. Results: Planned interim analysis for the primary end-point in the RCT resulted in early termination of both studies because of futility. In the RCT, 283 subjects received ziprasidone (n=193) or placebo (n=90). In the intent-to-treat analysis population, the least squares mean (SE) BPRS-A score decrease from baseline at week 6 was not significantly different (p=0.15; -14.16 [0.78] for ziprasidone and -12.35 [1.05] for placebo). Per-protocol analysis was significant (p=0.02). In the OLE, 221 subjects entered the OLE and received ziprasidone for a median of 99 days. The mean (SD) change in BPRS-A score from end of RCT to end of OLE (last observation carried forward) was -6.9 (8.9). The most common treatment-emergent adverse events (≥10%) for all causalities during the RCT were somnolence and extrapyramidal disorders, and during OLE was somnolence only. No subjects had Fridericia's corrected QT (QTcF) ≥500 ms in the RCT or OLE phases. One completed suicide occurred during the OLE phase. For RCT and OLE, no clinically significant changes were reported in metabolic indices and laboratory measures. Conclusions: Ziprasidone failed to separate from placebo in treatment of schizophrenia in adolescents. Ziprasidone was generally well tolerated with an overall neutral weight and metabolic profile. Clinical Trials Registry: NCT00257192 and NCT00265382 at ClinicalTrials.gov.