Kathleen S. Ice

A Phase 2/3, Multicenter, Randomized, Double-Masked, 2-Year Trial of Pegaptanib Sodium for the Treatment of Diabetic Macular Edema

PURPOSE To confirm the safety and compare the efficacy of intravitreal pegaptanib sodium 0.3 mg versus sham injections in subjects with diabetic macular edema (DME) involving the center of the macula associated with vision loss not due to ischemia. DESIGN Randomized (1:1), sham-controlled, multicenter, parallel-group trial. PARTICIPANTS Subjects with DME. INTERVENTION Subjects received pegaptanib 0.3 mg or sham injections every 6 weeks in year 1 (total = 9 injections) and could receive focal/grid photocoagulation beginning at week 18. During year 2, subjects received injections as often as every 6 weeks per prespecified criteria. MAIN OUTCOME MEASURES The primary efficacy endpoint was the proportion gaining ≥ 10 letters of visual acuity (VA) from baseline to year 1. Safety was monitored throughout. RESULTS In all, 260 (pegaptanib, n = 133; sham, n = 127) and 207 (pegaptanib, n = 107; sham, n = 100) subjects were included in years 1 and 2 intent-to-treat analyses, respectively. A total of 49 of the 133 (36.8%) subjects from the pegaptanib group and 25 of the 127 (19.7%) from the sham group experienced a VA improvement of ≥ 10 letters at week 54 compared with baseline (odds ratio [OR], 2.38; 95% confidence interval, 1.32-4.30; P = 0.0047). For pegaptanib-treated subjects, change in mean VA from baseline by visit was superior (P<0.05) to sham at weeks 6, 24, 30, 36, 42, 54, 78, 84, 90, 96, and 102. At week 102, pegaptanib-treated subjects gained, on average, 6.1 letters versus 1.3 letters for sham (P<0.01). Fewer pegaptanib- than sham-treated subjects received focal/grid laser treatment (week 54, 31/133 [23.3%] vs 53/127 [41.7%], respectively, P = 0.002; week 102, 27/107 [25.2%] vs 45/100 [45.0%], respectively, P = 0.003). The pegaptanib treatment group showed significantly better results on the National Eye Institute-Visual Functioning Questionnaire than sham for subscales important in this population. Pegaptanib was well tolerated; the frequencies of discontinuations, adverse events, treatment-related adverse events, and serious adverse events were comparable in the pegaptanib and sham groups. CONCLUSIONS Patients with DME derive clinical benefit from treatment with the selective vascular endothelial growth factor antagonist pegaptanib 0.3 mg. These findings indicate that intravitreal pegaptanib is effective in the treatment of DME and, taken together with prior study data, support a positive safety profile in this population. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Ziprasidone plus a mood stabilizer in subjects with bipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind trial.

OBJECTIVE To evaluate the efficacy and safety of ziprasidone adjunctive to a mood stabilizer for the maintenance treatment of bipolar mania. METHOD Subjects with DSM-IV bipolar I disorder with a Mania Rating Scale score > or = 14 were enrolled. Subjects achieving > or = 8 consecutive weeks of stability with open-label ziprasidone (80-160 mg/d) and lithium or valproate (period 1) were randomly assigned in the 6-month, double-blind maintenance period (period 2) to ziprasidone plus mood stabilizer or placebo plus mood stabilizer. The primary and key secondary end points were the time to intervention for a mood episode and time to discontinuation for any reason, respectively. Inferential analysis was performed using a Kaplan-Meier product-limit estimator (log-rank test). The study was conducted from December 2005 to May 2008. RESULTS A total of 127 and 113 subjects were randomly assigned to ziprasidone and placebo, respectively. Intervention for a mood episode was required in 19.7% and 32.4% of ziprasidone and placebo subjects, respectively. The time to intervention for a mood episode was significantly longer for ziprasidone than placebo (P = .0104). The median time to intervention for a mood episode among those requiring such an intervention (n = 61) was 43.0 days for ziprasidone versus 26.5 days for placebo. The time to discontinuation for any reason was significantly longer for ziprasidone (P = .0047). Adjunctive ziprasidone treatment was well tolerated. Among treatment-emergent adverse events occurring in > or = 5% of subjects in either treatment group during period 2, only tremor occurred more frequently in the ziprasidone versus placebo group (6.3% vs 3.6%). CONCLUSIONS Ziprasidone is an effective, safe, and well-tolerated adjunctive treatment with a mood stabilizer for long-term maintenance treatment of bipolar mania. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00280566.

Tolerability of oral ziprasidone in children and adolescents with bipolar mania, schizophrenia, or schizoaffective disorder.

OBJECTIVE This study characterizes the tolerability of ziprasidone in children and adolescents with bipolar mania, schizophrenia, or schizoaffective disorder. METHOD Sixty-three subjects (aged 10-17 years) entered an open-label study consisting of a 3-week fixed-dose period (Period 1) and a subsequent 24-week flexible-dose period (Period 2). In Period 1, subjects received ziprasidone 80 or 160 mg/d in two divided doses, titrated over 10 days. In Period 2, subjects received flexible doses (20-160 mg/d). Tolerability was evaluated using movement rating scales, laboratory tests, and electrocardiograms. Clinical response was assessed using the Young Mania Rating Scale, the Brief Psychiatric Rating Scale-Anchored Version, and the Clinical Global Impressions-Severity scale. RESULTS Adverse events (AEs) occurred mostly during dose titration and in the high-dose (160 mg/d) group. The most common AEs during Period 1 were sedation (32%), somnolence (30%), and nausea (25%) and during Period 2 were sedation (30%), somnolence (30%), and headache (25%). The incidence of movement disorder AEs was 22% and 16% during Periods 1 and 2, respectively. Six percent of study participants discontinued study participation due to AEs during Period 1 and 20% discontinued in Period 2. Thirty-three percent of subjects gained >or=7% of their baseline weight. No Fridericia-corrected QT (QTcF) intervals of >450 ms were observed during Period 1 and only one occurred during Period 2. No QTcF increase >or=60 ms from baseline was observed. Symptom reductions were observed in all patient groups. CONCLUSIONS No unexpected tolerability findings were observed in this prospective trial of ziprasidone in children and adolescents with bipolar mania, schizophrenia, or schizoaffective disorder. On the basis of the results, a starting dose of 20 mg/d titrated to between 80 and 160 mg/d over 1-2 weeks appears optimal for most patients.

Ziprasidone for the Treatment of Acute Manic or Mixed Episodes Associated with Bipolar Disorder

Ziprasidone, a benzisothiazolyl piperazine-type atypical antipsychotic agent, has a unique receptor-binding profile. A potent antagonist of serotonin 5-HT2A and dopamine D2 receptors, ziprasidone has an affinity for 5-HT2A receptors >10-fold higher than its affinity for D2 receptors.Ziprasidone has been shown to be effective in the treatment of bipolar disorder in patients experiencing manic or mixed episodes. It was significantly more effective than placebo in improving manic symptoms as early as day 2 of treatment in two 3-week placebo-controlled trials as monotherapy. In a 12-week, placebo-controlled trial of patients with acute mania, ziprasidone as monotherapy showed comparable efficacy with, and fewer movement-related adverse events than, haloperidol. It has demonstrated efficacy in two 1-year open-label extension trials, both as monotherapy and in combination with lithium.Ziprasidone has a generally favourable adverse effect profile. In short-term placebo-controlled trials, there were similar discontinuation rates in active treatment and placebo recipients. While twice as many patients treated with ziprasidone compared with placebo discontinued therapy because of adverse events, the number of events was small and adverse effects were generally mild or moderate. The favourable tolerability of ziprasidone has been confirmed in long-term extension studies and its use was not associated with weight gain or dyslipidaemia. Ziprasidone-related movement disorders occurred infrequently.

Ziprasidone with adjunctive mood stabilizer in the maintenance treatment of bipolar I disorder: Long-term changes in weight and metabolic profiles

This analysis was conducted to compare the effects of adjunctive ziprasidone or placebo on metabolic parameters among patients receiving maintenance treatment with lithium or valproate. We also tested whether metabolic syndrome (MetS) and other risk factors were associated with baseline characteristics and treatment response. In the stabilization phase (Phase 1), 584 bipolar I disorder (DSM-IV) patients received 2.5-4 months of open label ziprasidone (80-160 mg/d) plus lithium or valproic acid (ZIP+MS). Patients who achieved at least 8 weeks of clinical stability were subsequently randomized into Phase 2 to 6-months of double-blind treatment with ZIP+MS (n=127) vs. placebo+MS (n=113). At baseline of Phase 1, MetS was found in 111 participants (23%). Participants with MetS (vs. non-MetS participants) were more likely to be aged 40 years or older, had significantly more severe manic symptoms, higher abdominal obesity, and higher BMI. Increase in abdominal obesity was associated with lower manic symptom improvement (p<0.05, as assessed by MRS change score) during Phase 1, while symptom improvement differed across racial groups. In the Phase 2 double-blind phase, the ZIP+MS group had similar weight and metabolic profiles compared to the placebo+MS group across visits. These results corroborate existing findings on ziprasidone which exhibits a neutral weight and metabolic profile in the treatment of schizophrenia and bipolar patients. Our findings suggest that MetS is highly prevalent in patients with bipolar disorder, may be associated with greater manic symptom severity, and may predict treatment outcomes.

P01-206 A 6-month, randomized, placebo-controlled, double blind trial of ziprasidone plus a mood stabilizer in subjects with bipolar I disorder

Background The objective of this study was to evaluate the efficacy and safety of ziprasidone adjunctive to a mood stabilizer for the maintenance treatment of bipolar mania. Methods Male and female subjects with bipolar I disorder with MRS 3 14 were enrolled. Subjects achieving ≥ 8 consecutive weeks of stability with open-label ziprasidone (80-160 mg/d) and lithium or divalproex were randomized into the 6-month double-blind maintenance period, to ziprasidone + mood stabilizer or placebo + mood stabilizer. The primary and key secondary end points were the time to intervention for a mood episode, and time to discontinuation for any reason, respectively. Inferential analysis was performed using a Kaplan-Meier product-limit estimator (Log-rank test). Results 127 and 112 subjects were randomized to and treated in the ziprasidone and placebo groups, respectively. The time to intervention for a mood episode was significantly different, favoring ziprasidone (p = 0.0104). 19.7% and 32.4% of ziprasidone and placebo subjects, respectively, required intervention for a mood episode. Time to discontinuation for any reason was significantly different (p = 0.0047), favoring ziprasidone. Among treatment-emergent adverse events occurring in the double-blind period, the only event occurring more frequently in the ziprasidone group than in the placebo group (≥ 5%) was tremor (6.3% vs 3.6%, respectively). Conclusions These results demonstrate that ziprasidone is an effective, safe, and well-tolerated adjunctive treatment with a mood stabilizer for long-term maintenance treatment of bipolar mania.