Influence of baseline neurologic severity on disease progression and the associated disease-modifying effects of tafamidis in patients with transthyretin amyloid polyneuropathy.

BACKGROUND: Emerging evidence suggests that several factors can impact disease progression in transthyretin amyloid polyneuropathy (ATTR-PN). The present analysis used longitudinal data from Val30Met patients participating in the tafamidis (selective TTR stabilizer) clinical development program to evaluate the impact of baseline neurologic severity on disease progression in ATTR-PN. METHODS: A linear mixed-effects model for repeated measures (MMRM) was constructed using tafamidis and placebo data from the intent-to-treat Val30Met population of the original registration study as well as tafamidis data from the two consecutive open-label extension studies. The second extension study is ongoing, but a prospectively-planned interim analysis involving a cleaned and locked database was conducted (cut-off: December 31, 2014). Val30Met patients are presented by treatment groups as those who received tafamidis during the registration and open-label studies (T-T group), or who received placebo during the registration study and were switched to tafamidis in the open-label studies (P-T group). Neurologic functioning was assessed at baseline and subsequent visits using the Neuropathy Impairment Score-Lower Limbs (NIS-LL). The analysis focused on the disease trajectory over the first 18 months of treatment. RESULTS: The T-T (n = 64) and P-T (n = 61) cohorts were predominantly Caucasian and presented with early-stage neurologic disease (mean [standard deviation] baseline NIS-LL values were 8.4 [11.4] and 11.4 [13.5], respectively). The MMRM analysis demonstrated that baseline severity is an independent significant predictor of disease progression in addition to the treatment effect: patients with a lower baseline NIS-LL showed less progression than those with a higher baseline NIS-LL (p < 0.0001). Neurologic progression in the T-T group was less than in the P-T group across all levels of baseline NIS-LL (p = 0.0088), and the degree of separation increased over the 18-month period. Similar results were seen with the NIS-LL muscle weakness subscale. CONCLUSIONS: This analysis of patients with Val30Met ATTR-PN demonstrates that neurologic disease progression strongly depends on baseline neurologic severity and illustrates the disease-modifying effect of tafamidis relative to placebo across a range of baseline levels of neurologic severity and treatment durations. These data also underscore the benefit of early diagnosis and treatment with tafamidis in delaying disease progression in ATTR-PN. TRIAL REGISTRATION: NCT00409175 , NCT00791492 and NCT00925002 registered 08 December 2006, 14 November 2008 (retrospectively registered), and 19 June 2009, respectively.

Efficacy, long-term safety, and tolerability of ziprasidone in children and adolescents with bipolar disorder.

OBJECTIVE: The purpose of this study was to evaluate the short- and long-term efficacy and safety of ziprasidone in children and adolescents with bipolar I disorder. METHODS: Subjects 10-17 years of age with a manic or mixed episode associated with bipolar I disorder participated in a 4 week, randomized, double-blind, placebo-controlled multicenter trial (RCT) followed by a 26 week open-label extension study (OLE). Subjects were randomized 2:1 to initially receive flexible-dose ziprasidone (40-160 mg/day, based on weight) or placebo. Primary outcome was the change in Young Mania Rating Scale (YMRS) scores from baseline. Safety assessments included weight and body mass index (BMI), adverse events (AEs), vital signs, laboratory measures, electrocardiograms, and movement disorder ratings. RESULTS: In the RCT, 237 subjects were treated with ziprasidone (n=149; mean age, 13.6 years) or placebo (n=88; mean age, 13.7 years). The estimated least squares mean changes in YMRS total (intent-to-treat population) were -13.83 (ziprasidone) and -8.61 (placebo; p=0.0005) at RCT endpoint. The most common AEs in the ziprasidone group were sedation (32.9%), somnolence (24.8%), headache (22.1%), fatigue (15.4%), and nausea (14.1%). In the OLE, 162 subjects were enrolled, and the median duration of treatment was 98 days. The mean change in YMRS score from the end of the RCT to the end of the OLE (last observation carried forward) was -3.3 (95% confidence interval, -5.0 to -1.6). The most common AEs were sedation (26.5%), somnolence (23.5%), headache (22.2%), and insomnia (13.6%). For both the RCT and the OLE, no clinically significant mean changes in movement disorder scales, BMI z-scores, liver enzymes, or fasting lipids and glucose were observed. One subject on ziprasidone in the RCT and none during the OLE had Fridericia-corrected QT interval (QTcF) ≥ 460 ms. CONCLUSION: These results demonstrate that ziprasidone is efficacious for treating children and adolescents with bipolar disorder. Ziprasidone was generally well tolerated with a neutral metabolic profile. CLINICAL TRIALS REGISTRY: NCT00257166 and NCT00265330 at ClinicalTrials.gov.

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 .

Characterizing relapse prevention in bipolar disorder with adjunctive ziprasidone: clinical and methodological implications.

BACKGROUND: Ziprasidone, adjunctive to either lithium or valproate, has previously been shown to be associated with a significantly lower risk of relapse in bipolar disorder compared with lithium or valproate treatment alone. METHODS: This placebo-controlled outpatient trial with ziprasidone adjunctive to lithium or valproate or lithium and valproate alone, for subjects with a recent or current manic or mixed episode of bipolar I disorder, comprised a 2.5- to 4-month, open-label stabilization period, followed by a 6-month, double-blind maintenance period. These post hoc analyses characterize the relapse outcomes by dose, relapse types and timing as well as all-reason discontinuations during the maintenance period. RESULTS: Time to relapse and all-reason discontinuation were both statistically significant in favor of the ziprasidone 120mg/day group compared with placebo (p=0.004 and 0.001, respectively) during the 6-month double-blind period. There was no difference in time to relapse in the 80 and 160mg/day dose groups compared with placebo (p=0.16 and 0.40, respectively) and, likewise, for time to all-reason discontinuation (p=0.20 for both doses). The majority of relapses in each group occurred prior to week 8, and most were depressive in nature. LIMITATIONS: The primary study was not designed to compare relapse rates by dose groups. CONCLUSIONS: These analyses confirm the effectiveness of ziprasidone (80-160mg/day) in preventing relapses in subjects with bipolar disorder, with the 120mg/day dosage appearing to have the highest relapse prevention rate.