Aripiprazole for the treatment of pediatric bipolar I disorder: a 30‐week,randomized, placebo‐controlled study

Objective: To evaluate the long‐term efficacy, safety, and tolerability of aripiprazole in pediatric subjects with bipolar I disorder. Methods: A randomized, double‐blind, 30‐week, placebo‐controlled study of aripiprazole (10 or 30 mg/day) in youths (10–17 years) with bipolar I disorder (manic or mixed) ± psychotic features (n = 296) was performed. After four weeks, acute treatment completers continued receiving ≤26 weeks of double‐blind treatment (n = 210). The primary outcome was Young Mania Rating Scale (YMRS) total score change. Results: Of the 210 subjects who entered the 26‐week extension phase, 32.4% completed the study (45.3% for aripiprazole 10 mg/day, 31.0% for aripiprazole 30 mg/day, and 18.8% for placebo). Both aripiprazole doses demonstrated significantly (p < 0.001) greater improvements in YMRS total score at endpoint compared with placebo in protocol‐specified last observation carried forward analyses, but not in observed case or mixed‐model repeated measures at week 30. Overall time to all‐cause discontinuation was longer for aripiprazole 10 mg/day (15.6 weeks) and aripiprazole 30 mg/day (9.5 weeks) compared with placebo (5.3 weeks; both p < 0.05 versus placebo). Both aripiprazole doses were significantly superior to placebo regarding response rates, Children’s Global Assessment of Functioning and Clinical Global Impressions‐Bipolar severity of overall and mania scores at endpoint in all analyses. Commonly reported adverse events included headache, somnolence, and extrapyramidal disorder. Conclusions: Aripiprazole 10 mg/day and 30 mg/day were superior to placebo and generally well tolerated in pediatric subjects with bipolar I disorder up to 30 weeks. Despite the benefits of treatment, completion rates were low in all treatment arms.     

Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial

BACKGROUND: Paliperidone extended-release tablet (paliperidone ER) is an investigational oral psychotropic developed for schizophrenia treatment. It utilizes OROS technology to provide a unique pharmacokinetic profile, eliminating the need for titration and potentially leading to improved tolerability. Furthermore, paliperidone undergoes limited hepatic metabolism. METHODS: The efficacy and safety of once-daily paliperidone ER (6 mg, 9 mg and 12 mg) were assessed versus placebo in 628 patients with acute schizophrenia in a 6-week, multicenter, double-blind, randomized, parallel-group study. RESULTS: All doses of paliperidone ER demonstrated significant improvement in PANSS score, all PANSS Marder factor scores (p<0.001) and personal and social functioning versus placebo (p<0.001). The PANSS total score also improved significantly in the olanzapine treatment arm. Significantly higher percentages of paliperidone ER patients demonstrated a > or =30% reduction in PANSS total score versus placebo (p<0.001). The incidence of movement disorder-related AEs and rating scales measurements were similar to placebo for the paliperidone ER 6 mg group and higher in the 9 mg and 12 mg groups. In the paliperidone ER groups there were no reports of glucose-related AEs or clinically relevant changes in plasma lipid levels and changes in mean bodyweight<1 kg. CONCLUSION: In this study, all doses of paliperidone ER were effective in significantly improving the symptoms of schizophrenia and personal and social functioning and were generally well tolerated. Paliperidone ER offers a distinctive treatment profile and may provide a valuable new treatment option for patients with schizophrenia.     

A double-blind, placebo-controlled pilot study of quetiapine for depressed adolescents with bipolar disorder

Objective: To conduct a pilot study comparing the effects of quetiapine and placebo for the treatment of depressive episodes in adolescents with bipolar I disorder. Method: Thirty‐two adolescents (ages 12–18 years) with a depressive episode associated with bipolar I disorder were randomized to eight weeks of double‐blind treatment with quetiapine, 300–600 mg/day, or placebo. This two‐site study was conducted from March 2006 through August 2007. The primary efficacy measure was change in Children’s Depression Rating Scale–Revised Version (CDRS‐R) scores from baseline to endpoint. Secondary efficacy measures included change in CDRS‐R scores over the eight‐week study period (PROC MIXED), changes from baseline to endpoint in Hamilton Anxiety Rating Scale (HAM‐A), Young Mania Rating Scale (YMRS), and Clinical Global Impression–Bipolar Version Severity (CGI‐BP‐S) scores, as well as response and remission rates. Safety and tolerability were assessed weekly. Results: There was no statistically significant treatment group difference in change in CDRS‐R scores from baseline to endpoint (p = 0.89, effect size =?0.05, 95% confidence interval: ?0.77–0.68), nor in the average rate of change over the eight weeks of the study (p = 0.95). Additionally, there were no statistically significant differences in response (placebo =67% versus quetiapine = 71%) or remission (placebo = 40% versus quetiapine = 35%) rates, or change in HAM‐A, YMRS, or CGI‐BP‐S scores (all p > 0.7) between treatment groups. Dizziness was more commonly reported in the quetiapine (41%) than in the placebo (7%) group (Fisher’s exact test, p = 0.04). Conclusions: The results suggest that quetiapine monotherapy is no more effective than placebo for the treatment of depression in adolescents with bipolar disorder. However, limitations of the study, including the high placebo response rate, may have contributed to our findings and should be considered in the design of future investigations of pharmacological interventions for this population.     

Corrigendum

In Volume 10, Supplement 1, February 2008, this Abstract was omitted from the Poster Session. The correct citation for the Abstract is Bipolar Disord 2008; 10 (Suppl. 1). We apologize for this error. A DOUBLE‐BLIND, PLACEBO‐CONTROLLED STUDY WITH ACUTE AND CONTINUATION PHASE OF QUETIAPINE AND LITHIUM IN ADULTS WITH BIPOLAR DEPRESSION (EMBOLDEN I) AH Young^a, A Carlsson^b, B Olausson^b, B Paulsson^b and M Brecher^{c a}Department of Psychiatry, Institute of Mental Health, The University of British Columbia, Vancouver, Canada, ^bAstraZeneca, Södertälje, Sweden, ^cAstraZeneca Pharmaceuticals LP, Wilmington, DE, USA Background and aims: Evaluate the efficacy and tolerability of quetiapine and lithium monotherapy for major depressive episodes in bipolar disorder during an acute 8‐week period and up to 52‐week continuation phase. Methods: A total of 802 patients (499 bipolar I, 303 bipolar II) were randomized to quetiapine 300 mg/day (n = 265), quetiapine 600 mg/day (n = 268), lithium 600 mg/day (n = 136), or placebo (n = 133) for 8 weeks. Primary endpoint was change from baseline to 8 weeks in MADRS total score. After 8 weeks, patients with MADRS ≤ 12 and YMRS ≤ 12 entered a 26–52‐week continuation phase of quetiapine (300 mg/day or 600 mg/day) or placebo. Patients on lithium received 300 mg/day of quetiapine (results of continuation phase not included here and to be presented separately). Results: LSM MADRS score change at 8 weeks was ?15.36 (quetiapine 300 mg/day), ?16.10 (quetiapine 600 mg/day), ?13.60 (lithium), and ?11.81 (placebo; p < 0.001 for both quetiapine doses, p = 0.123 for lithium, versus placebo; LOCF ANCOVA). Quetiapine (both doses)‐treated, but not lithium‐treated, patients showed significantly greater improvements (p ≤ 0.05) in MADRS response and remission rates, HAM‐D, CGI‐BP‐S, CGI‐BP‐change, and HAM‐A at Week 8 versus placebo; MADRS item 10 (suicidal thoughts) improved with quetiapine 600 mg/day versus placebo (p = 0.013). Most common adverse events considered drug‐related included somnolence, dry mouth, and dizziness with quetiapine (both doses) and nausea with lithium. Conclusions: Quetiapine (300 mg/day or 600 mg/day) was more effective than placebo for the treatment of acute depressive episodes in bipolar I and bipolar II disorder. Quetiapine treatment was generally well tolerated.     

Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): results of a 6-week, randomized, placebo-controlled study

BACKGROUND: Paliperidone extended-release tablet (paliperidone ER) is an oral psychotropic agent developed for schizophrenia treatment. Paliperidone (9-OH-risperidone, metabolite of risperidone), when used with OROS technology has a unique pharmacokinetic profile undergoing limited hepatic metabolism. METHODS: The efficacy and safety of once-daily paliperidone ER (3 mg, 9 mg and 15 mg) were compared with placebo in 618 patients with acute schizophrenia in a 6-week, multicenter, double-blind, randomized, parallel-group study. An assay sensitivity group with known efficacy was included to confirm trial validity (olanzapine 10 mg). RESULTS: All doses of paliperidone ER demonstrated significant improvements in PANSS total and PANSS factors scores (p<0.05) and in personal and social functioning (p<0.001) compared with placebo. Symptom improvement has been observed at the first observation assessment (Day 4) (p<0.001) compared with placebo, suggesting a rapid onset of action for paliperidone ER. Paliperidone ER was associated with a low incidence of treatment-emergent adverse events. The incidence of movement disorder-related adverse events and rating scale scores were similar in the paliperidone ER 3 mg and placebo groups and increased with dose. Increases in prolactin plasma levels and dose-related increases in body weight (<2 kg) were observed; there were no significant changes in serum lipid or glucose levels. CONCLUSION: In this study, all doses of paliperidone ER were effective in significantly improving the symptoms of schizophrenia and personal and social functioning and were generally well tolerated. As such, paliperidone ER may provide a valuable new treatment option for patients with schizophrenia.     

Paliperidone ER: a review of the clinical trial data

Paliperidone extended-release tablet (paliperidone ER; INVEGA^™) is an oral antipsychotic for the treatment of schizophrenia. The recommended dose range is 3–12 mg per day. Paliperidone ER utilizes the OROS^® delivery system, which allows for once-daily dosing. Its pharmacokinetic profile results in a more stable serum concentration. Paliperidone is 9-hydroxyrisperidone, the chief active metabolite of risperidone. It undergoes limited hepatic metabolism, thereby minimizing the risks of hepatic drug–drug and drug–disease interactions. Three 6-week trials in patients with acute schizophrenia reported that paliperidone ER was effective, well tolerated, and produced clinically meaningful improvements in personal and social functioning compared with placebo. Post-hoc analysis of these trials in various populations, including recently diagnosed, elderly and more severely ill patients, those with sleep disturbances and those with predominant negative symptoms demonstrated improvement as well. Paliperidone ER was also significantly better than placebo in the prevention of symptom recurrence in a 6-month maintenance study. The most common clinically relevant adverse events associated with paliperidone ER were extrapyramidal symptoms, tachycardia and somnolence. The incidence of Parkinsonism, akathisia and use of anticholinergic medications increased in a dose-related manner. Further, modest QTc interval prolongation was observed but did not produce clinical symptoms. Similar to risperidone, paliperidone ER is associated with increases in serum prolactin levels. Overall, paliperidone ER was effective, well tolerated and provides a new treatment option for patients with schizophrenia.     

A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder

OBJECTIVE: To evaluate the efficacy and tolerability of quetiapine monotherapy versus placebo for the treatment of mania associated with bipolar disorder. METHOD: In an international, multicenter, double-blind, parallel-group, 12-week study, patients with a DSM-IV diagnosis of bipolar I disorder (manic episode) were randomly assigned to treatment with quetiapine (flexibly dosed up to 800 mg/day), placebo, or lithium. The primary efficacy measure was change from baseline in Young Mania Rating Scale (YMRS) score at day 21. Data were gathered from April 2001 to May 2002. RESULTS: More patients in the quetiapine (72/107) and lithium (67/98) groups completed the study compared with the placebo group (35/97). Improvement (reduction) in YMRS score was significantly greater for quetiapine than placebo at day 7 (-8.03 vs. -4.89; p < .01), and the difference between groups continued to increase over time to day 21 (-14.6 vs. -6.7; p < .001) and to endpoint at day 84 (-20.3 vs. -9.0; p < .001). Significantly more quetiapine patients compared with placebo patients fulfilled YMRS response criteria at day 21 (53.3% vs. 27.4%; p < .001) and at day 84 (72.0% vs. 41.1%; p < .001). Quetiapine was also superior to placebo in efficacy at day 21 and day 84 by all secondary measures. Lithium-treated patients improved significantly compared with placebo patients and similarly to quetiapine-treated patients on the primary efficacy measure. The most common adverse events for quetiapine were dry mouth, somnolence, and weight gain, while lithium was associated with tremor and insomnia. The quetiapine and placebo groups had similar, low levels of extrapyramidal symptom-related adverse events. CONCLUSIONS: Quetiapine demonstrated superior efficacy to placebo in patients with bipolar mania and was well tolerated.     

A double-blind,randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania

OBJECTIVES: This randomized, double-blind, placebo-controlled study examined the efficacy and tolerability of quetiapine in combination with divalproex (DVP) for acute mania in adolescents with bipolar disorder. It was hypothesized that DVP in combination with quetiapine would be more effective than DVP alone for treating mania associated with adolescent bipolar disorder. Furthermore, it was hypothesized that quetiapine would be well tolerated. METHOD: Thirty manic or mixed bipolar I adolescents (12-18 years) received an initial DVP dose of 20 mg/kg and were randomly assigned to 6 weeks of combination therapy with quetiapine, which was titrated to 450 mg/day (n = 15) or placebo (n = 15). Primary efficacy measures were change from baseline to endpoint in Young Mania Rating Scale (YMRS) score and YMRS response rate. Safety and tolerability were assessed weekly. RESULTS: The DVP + quetiapine group demonstrated a statistically significantly greater reduction in YMRS scores from baseline to endpoint than the DVP + placebo group (F(1,27) = 5.04, p =.03). Moreover, YMRS response rate was significantly greater in the DVP + quetiapine group than in the DVP + placebo group (87% versus 53%; Fisher exact test, p =.05). No significant group differences from baseline to endpoint in safety measures were noted. Sedation, rated as mild or moderate, was significantly more common in the DVP + quetiapine group than in the DVP + placebo group. CONCLUSIONS: The findings of this study indicate that quetiapine in combination with DVP is more effective for the treatment of adolescent bipolar mania than DVP alone. In addition, the results suggest that quetiapine is well tolerated when used in combination with DVP for the treatment of mania.     

Safety and tolerability of oral paliperidone extended-release tablets in elderly patients with schizophrenia: a double-blind, placebo-controlled study with six-month open-label extension.

OBJECTIVE: The objective of this multicenter, international study was to evaluate safety and tolerability of paliperidone extended-release (ER) tablets in elderly (age > or =65 years) patients with schizophrenia. The authors conducted a 6-week, double-blind, randomized, placebo-controlled, optional 24-week open-label extension study. Interventions consisted of flexible, once-daily doses of paliperidone ER (3-12 mg/day; 6-mg starting dose, adjusted in 3-mg dose increments) or placebo (2:1) during double-blind treatment and paliperidone ER only during open-label treatment. Measurements included adverse events, laboratory tests, physical examinations, 12-lead electrocardiograms, movement disorder rating scales, Positive and Negative Syndrome Scale, and Clinical Global Impression scale. The study was not powered to show statistical differences. RESULTS: Patients (N = 114) were predominantly female (73%); mean age was 70 years (double-blind phase). Concomitant disease presence was consistent with that of an older population. During the double-blind phase, discontinuation rates resulting from adverse events were similar between groups (paliperidone ER: 7%, placebo: 8%) as were incidences of treatment-emergent adverse events (paliperidone ER: 67%, placebo: 71%). Serious adverse events occurred in 3% of the paliperidone ER- and 8% of the placebo-treated patients. Elevated prolactin levels occurred in approximately one half of patients. No prolactin- or glucose treatment-related adverse events or noteworthy mean changes in body weight (0 kg [standard deviation: 2.1] and 0 kg [standard deviation: 2.3] for paliperidone ER and placebo, respectively) were observed. Safety and tolerability results in the extension were consistent with the shorter-term results. Efficacy measures did not show consistent statistical improvement between treatment groups. CONCLUSION: Paliperidone ER (3-12 mg/day) treatment over a 30-week period was generally well-tolerated and may improve symptom severity in elderly patients with schizophrenia.     

帕利哌酮缓释片治疗急性精神分裂症疗效及安全性的对照研究

Objective The study was designed to evaluate the efficacy and safety of flexible doses of paliperidone extended-release tablets (paliperidone ER) (3 -12) mg/d comparing with olanzapine (5 -15)mg/d in acute hospitalized patients with schizophrenia. Methods All 288 hospitalized patients with DSM-Ⅳ schizophrenia were randomized into paliperidone ER ( n = 143 ) or olanzapine ( n=145 ) treatment in a 6-week, multicenter, double-blind, parallel-group study. The primary efficacy measure was the total score changes of the Positive and Negative Syndrome Scale (PANSS). Clinical Global Impression (CGI),response rate and Visual Analogue Scale (VAS) were adopted as secondary efficacy measures. Results Both paliperidone ER and olanzapine groups demonstrated a significant improvement in total PANSS score (P<0.001). The PANSS total score in paliperidone ER group was reduced (32.3 ± 17.1) at end point,and olanzapine group (34.1 ± 17.4). There was no statistically significant difference between the two groups (P =0.369) after 6-week treatment. There were no statistical differences between two groups in CGI,response rate and VAS sleep quality assessments by the end of the treatment. The common adverse events were extrapyramidal symptoms, insomnia, constipation and prolactin increasing in paliperidone ER group,and somnolenee, EPS, abnormal liver function and abnormal lipid metabolism in olanzapine group.Conclusion Paliperidone ER and olanzapine are similarly effective in significantly improving the symptoms of inpatient with acute schizophrenia. Paliperidone ER demonstrates a favorable safety profile with fewer somnolence, abnormal liver function and abnormal lipid metabolism comparing with olanzapine.     

A Prospective Open‐Label Trial of Lamotrigine Monotherapy in Children and Adolescents with Bipolar Disorder

Aim: To evaluate the safety and efficacy of lamotrigine monotherapy as an acute treatment of bipolar mood elevation in children with bipolar spectrum disorders. Method: This was a 12‐week, open‐label, prospective trial of lamotrigine monotherapy to assess the effectiveness and tolerability of this compound in treating pediatric bipolar disorder. Assessments included the Young Mania Rating Scale (YMRS), Clinical Global Impressions‐Improvement scale (CGI‐I), Children's Depression Rating Scale (CDRS), and Brief Psychiatric Rating Scale (BPRS). Adverse events were assessed through spontaneous self‐reports, vital signs weight monitoring, and laboratory analysis. Results: Thirty‐nine children with bipolar disorder (YMRS at entry: 31.6 ± 5.5) were enrolled in the study and 22 (56%) completed the 12‐week trial. Lamotrigine was slowly titrated to an average endpoint dose of 160.7 ± 128.3 in subjects <12 years of age (N = 22) and 219.1 ± 172.2 mg/day in children 12–17 years of age (N = 17). Treatment with lamotrigine was associated with statistically significant levels of improvement in mean YMRS scores (?14.9 ± 9.7, P < 0.001) at endpoint. Lamotrigine treatment also resulted in significant improvement in the severity of depressive, attention‐deficit/hyperactivity disorder (ADHD), and psychotic symptoms. Lamotrigine was generally well tolerated with marginal increase in body weight (47.0 ± 18.0 kg vs. 47.2 ± 17.9 kg, P= 0.6) and was not associated with abnormal changes in laboratory parameters. Several participants were discontinued due to skin rash; in all cases, the rash resolved shortly after discontinuation of treatment. No patient developed Steven Johnson syndrome. Conclusions: Open‐label lamotrigine treatment appears to be beneficial in the treatment of bipolar disorder and associated conditions in children. Future placebo‐controlled, double‐blind studies are warranted to confirm these findings.     

Efficacy and tolerability of extended release quetiapine fumarate monotherapy as maintenance treatment of major depressive disorder: a randomized,placebo‐controlled trial

Background: Primary objective: evaluate the efficacy (time to recurrence of depressive symptoms) of once daily extended release quetiapine fumarate (quetiapine XR) as maintenance monotherapy treatment to prevent relapse for major depressive disorder (MDD). Methods: Time‐to‐event (maximum 52 weeks), double‐blind, multicenter, randomized withdrawal, placebo‐controlled study of quetiapine XR (50–300 mg/day) comprising four treatment phases: enrollment (up to 28 days), open‐label run‐in (4–8 weeks), open‐label stabilization (12–18 weeks), and randomization (up to 52 weeks). Seven hundred and seventy‐six patients stabilized on quetiapine XR were eligible for randomization (Montgomery–Åsberg Depression Rating Scale [MADRS] score ≤12 and Clinical Global Impression‐Severity of Illness [CGI‐S] score ≤3); 391 received quetiapine XR and 385 received placebo (same dose as last open‐label visit). Primary endpoint: time to recurrence of depressive event from randomization. Secondary outcomes included changes from randomization in MADRS total, CGI‐S, Pittsburgh Sleep Quality Index (PSQI) global, and Hamilton Anxiety Rating Scale (HAM‐A) total scores. Adverse events were recorded throughout. Results: Risk of recurrence of depressive event was significantly (P<.001) reduced by 66% (HR=.34; 95% CI: .25, .46) in patients randomized to continue with quetiapine XR versus patients randomized to switch to placebo. During the randomized phase, quetiapine XR maintained improvements in secondary outcomes (P<.001 for all): MADRS (0.15 versus 2.03), CGI‐S (−0.03 versus 0.23); PSQI global (0.06 versus 1.35), and HAM‐A total score (0.20 versus 1.58), respectively. The most common AEs (>10% any group) during the randomized period were headache and insomnia. Conclusions: Quetiapine XR maintenance therapy significantly reduced the risk of a depressive event in patients with MDD stabilized on quetiapine XR, with a safety and tolerability profile consistent with the known profile of quetiapine. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

Paliperidone extended-release tablets in patients with recently diagnosed schizophrenia

Aim: Effective early and persistent antipsychotic treatment in recently diagnosed schizophrenia may positively impact long-term outcomes. Paliperidone extended-release (ER) was assessed in this population. Methods: Post hoc analysis of pooled data from three 6-week, double-blind (DB), placebo-controlled, and three 1-year open-label (OL) studies of paliperidone ER in schizophrenia patients. Data stratified by time since diagnosis (≤3 vs. >3 years). Results: At DB (n = 1193) and OL baselines (n = 744), 259 (21.9%) and 188 (25.3%) patients were diagnosed ≤3 years. At DB end point, both populations improved with paliperidone ER versus placebo on Positive and Negative Syndrome Scale (PANSS) total, Clinical Global Impressions–Severity and Personal and Social Performance (PSP) scale scores (all P < 0.05). At OL end point, there were significant improvements from DB baseline in both populations on these scales (P < 0.0001), with greater improvement in the ≤3-year population on PANSS total (P < 0.001) and PSP (P < 0.001) scores. During DB treatment, only the ≤3-year population reported adverse events (AEs) in ≥5% (placebo-adjusted rate) of subjects receiving paliperidone ER: akathisia, extrapyramidal disorder not otherwise specified and somnolence. During OL treatment, akathisia and somnolence occurred more frequently (≥5%) in the ≤3- versus >3-year population. OL study completion rates were 51.1% in ≤3-year, and 48.2% in >3-year subjects. Conclusions: Paliperidone ER significantly improved symptoms and functioning in schizophrenia patients, regardless of time since diagnosis. Recently diagnosed patients who continued treatment exhibited greater symptom reduction and functional benefit over the long term. Results also suggest that these patients may be more susceptible to certain AEs.     

Safety and efficacy from a 6‐week double‐blind study and a 52‐week open‐label extension of aripiprazole in adolescents with schizophrenia in Japan

Aim

The purpose of this study was to evaluate the safety and efficacy of aripiprazole in adolescents with schizophrenia (SCZ) in Japan.

Methods

In a 6‐week, randomized, double‐blind, dose‐comparison study, adolescents (aged 13–17 years) with SCZ were randomized to receive aripiprazole 2, 6–12, or 24–30 mg/day. Patients who completed the 6‐week study participated in a 52‐week, flexible‐dose, open‐label extension (OLE) study of aripiprazole (initial dose: 2 mg/day, maintenance dose: 6–24 mg/day, maximum dose: 30 mg/day).

Results

In the 6‐week study, the percentage of patients completing treatment was: 77.1% (27/35) for 2 mg/day; 80.0% (24/30) for 6–12 mg/day; and 85.4% (35/41) for 24–30 mg/day. The least squares mean change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to endpoint (primary efficacy endpoint, last observation carried forward) was ?19.6 for 2 mg/day, ?16.5 for 6–12 mg/day, and ? 21.6 for 24–30 mg/day. The most common (≥20% patients in any group) treatment‐emergent adverse events (TEAE) were nausea, akathisia, insomnia, and somnolence. Most TEAE were mild or moderate in severity. There were no deaths. In the OLE, 60.3% (41/68) of patients completed treatment, and the PANSS total score decreased by ?7.9 from OLE baseline to week 52. The most common (≥20% patients) TEAE were nasopharyngitis and somnolence. Most TEAE were mild or moderate in severity. There were no deaths.

Conclusion

These study results suggest that aripiprazole would be safe and well tolerated in both short‐ and long‐term treatment for adolescents with SCZ in Japan.

     

Carisbamate as adjunctive treatment of partial onset seizures in adults in two randomized,placebo‐controlled trials

Purpose: To assess the efficacy, safety, and tolerability of the investigational drug carisbamate as adjunctive treatment for partial‐onset seizures (POS). Methods: Two identical, randomized, placebo‐controlled, double‐blind studies were conducted in adults with POS uncontrolled for ≥1 year. Therapy‐refractory epilepsy patients (≥16 years) remained on stable doses of prescribed antiepileptic drugs (≤2) for an 8‐week prospective baseline phase and were then randomized (1:1:1) to carisbamate 200 mg/day, carisbamate 400 mg/day, or placebo, for a 12‐week double‐blind phase. Primary efficacy end points were percent reduction in seizure frequency and responder rate (patients with ≥50% reduction in POS frequency) during the double‐blind phase compared with the prospective baseline phase. Results: Of the 565 patients randomized in study 1, 93% completed the study; of the 562 randomized in study 2, 94% completed the study. Patient characteristics were similar across both studies and treatment arms: mean age, 35 years (study 1, range 16–75 years) and 36 years (study 2, range 16–74 years); approximately 50% were men. Treatment with carisbamate 400 mg/day resulted in significant improvement (p < 0.01) in both efficacy measures compared with placebo in study 1 but not in study 2. Carisbamate 200 mg/day did not differ statistically from placebo in either study. Among the most common treatment‐emergent adverse events (≥5% in any group), those with an incidence exceeding placebo (≥3%) were dizziness (400 mg/day group) and somnolence. Conclusions: Carisbamate 400 mg/day was effective in patients with refractory partial‐onset seizures in one of these global studies. More than 200 mg/day of carisbamate is required for efficacy. Carisbamate was well‐tolerated in both studies.     

Evaluation of adjunctive perampanel in patients with refractory partial‐onset seizures: Results of randomized global phase III study 305

Purpose: To assess the efficacy and safety of once‐daily doses of perampanel 8 and 12 mg when added to 1–3 concomitantly administered, approved antiepileptic drugs (AEDs) in patients with uncontrolled partial‐onset seizures. Methods: Study 305 was a multicenter, double‐blind, placebo‐controlled trial in patients aged 12 years and older with ongoing seizures despite prior therapy with at least two AEDs, and currently receiving 1–3 AEDs. Equal randomization to once‐daily oral perampanel 8 or 12 mg, or placebo was performed. Patients entered a 19‐week double‐blind treatment phase comprising a 6‐week titration period, with weekly 2‐mg dose increments, followed by a 13‐week maintenance period. Primary efficacy end points were the responder rate (proportion of patients who had a ≥50% reduction in seizure frequency during treatment per 28 days relative to baseline), and the percent change in seizure frequency per 28 days relative to pre‐perampanel baseline. A secondary end point was percent change in the frequency of complex partial plus secondarily generalized seizures. Adverse events (AEs) were monitored throughout the study. Key Findings: Three hundred eighty‐six patients were randomized and treated with study medication. Of these, 321 patients completed the study. The 50% responder rates (intent‐to‐treat analysis) were 14.7%, 33.3%, and 33.9%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg, with significant improvements over placebo for both perampanel 8 mg (p = 0.002) and 12 mg (p < 0.001). The median percent change from baseline in seizure frequency per 28 days (intent‐to‐treat analysis) was ?9.7%, ?30.5%, and ?17.6% for placebo, 8 mg, and 12 mg, respectively, with significant reductions compared with placebo for both 8 mg (p < 0.001) and 12 mg (p = 0.011). For complex partial seizures plus partial seizures that secondarily generalized, the median percent change in frequency was ?32.7% (8 mg), ?21.9 (12 mg), and ?8.1% (placebo), with significant reductions for both 8 mg (p < 0.001) and 12 mg (p = 0.005). The most frequent (occurring in ≥10% of patients in any treatment group) treatment‐emergent AEs were dizziness, somnolence, fatigue, and headache, with an apparent dose effect suggested for all except headache. Significance: This phase III trial demonstrated that adjunctive treatment with once‐daily perampanel at 8 mg and 12 mg was effective in improving seizure control in patients 12 years and older with refractory partial‐onset seizures. These study results also demonstrated that once‐daily doses of 8 mg and 12 mg were safe and acceptably tolerated in this study. Perampanel demonstrated a favorable risk/benefit ratio in this population.     

Perampanel,a selective,noncompetitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor antagonist,as adjunctive therapy for refractory partial‐onset seizures: Interim results from phase III,extension study 307

Purpose: To evaluate safety, tolerability, and seizure outcome data during long‐term treatment with once‐daily adjunctive perampanel (up to 12 mg/day) in patients with refractory partial‐onset seizures. Methods: Study 307 was an extension study for patients completing the double‐blind phase of three pivotal phase III trials (studies 304, 305, and 306). The study consisted of two phases: an open‐label treatment phase (including a 16‐week blinded conversion period and a planned 256‐week maintenance period) and a 4‐week follow‐up phase. Patients were blindly titrated during the conversion period to their individual maximum tolerated dose (maximum 12 mg/day). Adverse events (AEs) were monitored throughout the study and seizure frequency recorded. The interim data cutoff date for analyses was December 1, 2010. Key Findings: In total, 1,218 patients were enrolled in the study. At the interim cutoff date, 1,186 patients were in the safety analysis set; 1,089 (91.8%) patients had >16 weeks of exposure to perampanel, 580 (48.9%) patients had >1 year of exposure, and 19 (1.6%) patients had >2 years of exposure. At the interim analysis, 840 (70.8%) patients remained on perampanel treatment. The large majority of patients (n = 1,084 [91%]) were titrated to 10 mg or 12 mg/day. Median (range) duration of exposure was 51.4 (1.1–128.1) weeks. Treatment‐emergent AEs were reported in 87.4% of patients. The most frequent were dizziness (43.9%), somnolence (20.2%), headache (16.7%), and fatigue (12.1%). Serious AEs were reported in 13.2% of patients. In the intent‐to‐treat analysis set (n = 1,207), the frequency of all seizures decreased over the first 26 weeks of perampanel treatment in patients with at least 26 weeks of exposure to perampanel (n = 1,006 [83.3%]); this reduction was maintained in patients with at least 1 year of exposure (n = 588 [48.7%]). The overall median percent changes in seizure frequency in patients included in each 13‐week interval of perampanel treatment were ?39.2% for weeks 14–26 (n = 1,114), ?46.5% for weeks 40–52 (n = 731), and ?58.1% for weeks 92–104 (n = 59). Overall responder rates in patients included in each 13‐week interval of perampanel treatment were 41.4% for weeks 14–26 (n = 1,114), 46.9% for weeks 40–52 (n = 731), and 62.7% for weeks 92–104 (n = 59). During the blinded conversion period, the reduction in seizure frequency in patients previously randomized to placebo (?42.4%, n = 369) was similar to that in patients previously randomized to perampanel (?41.5%, n = 817). Significance: Consistent with pivotal phase III trials, these interim results demonstrated that perampanel had a favorable tolerability profile in patients with refractory partial‐onset seizures over the longer term. The decrease in seizure frequency was consistent and maintained in those patients over at least 1 year of perampanel exposure.     

Prucalopride in the treatment of chronic constipation in patients from the Asia‐Pacific region: a randomized,double‐blind,placebo‐controlled study

Background The study evaluated efficacy and safety of the 2 mg dose of prucalopride compared to placebo in patients with chronic constipation (CC) from the Asia‐Pacific region. Methods Randomized, placebo‐controlled, parallel‐group, phase III study with 2‐week run‐in, 12‐week treatment phase, and 1‐week follow‐up. Adult patients with CC (≤2 spontaneous bowel movements per week) received 2 mg prucalopride or placebo, once‐daily, for 12 weeks. Primary efficacy measure was percentage of patients with average of ≥3 spontaneous complete bowel movements (SCBMs) per week (Responders) during the 12‐week treatment. A key secondary endpoint was Responders during first 4 weeks of treatment. Other efficacy assessments were based on patient diaries, their assessments of symptoms and quality of life, and investigator’s assessment on efficacy of treatment. Safety assessments included adverse events, laboratory values, and cardiovascular events. Key Results Efficacy and safety were evaluated for 501 patients who received study drug. On the primary endpoint, prucalopride was significantly more effective than placebo with 83 (33.3%) vs 26 (10.3%) patients having a weekly average of ≥3 SCBMs during the 12‐week treatment (P < 0.001). Respective percentages were 34.5%vs 11.1% over first 4 weeks (P < 0.001). On other secondary endpoints, clinical improvement was generally larger and statistically superior (P < 0.001) in the prucalopride group. Most frequently reported adverse events were diarrhea, nausea, abdominal pain, and headache. Conclusion & Inferences Prucalopride 2 mg given once‐daily significantly improved bowel function, associated symptoms, and satisfaction in CC over a 12‐week treatment period, and was safe and well tolerated by patients in the Asia‐Pacific region.     

Asenapine versus olanzapine in acute mania: a double‐blind extension study

Objective: To assess the efficacy and tolerability of asenapine versus olanzapine in the extended treatment of bipolar mania. Methods: Patients with bipolar I disorder experiencing acute manic or mixed episodes who completed either of two 3‐week, double‐blind trials with asenapine 5 or 10 mg twice daily, olanzapine 5 to 20 mg once daily, or placebo were eligible for this 9‐week, double‐blind extension study. Patients receiving active medication in the 3‐week trials continued the same regimen; those who had received placebo were blindly switched to asenapine but were assessed for safety outcomes only. The primary efficacy measure was the change from baseline to day 84 on the Young Mania Rating Scale (YMRS) total score in the per‐protocol population. Results on the primary efficacy outcome were used to determine the noninferiority of asenapine versus olanzapine. Results: A total of 504 patients (placebo/asenapine, n = 94; asenapine, n = 181; olanzapine, n = 229) were enrolled in the extension study. At day 84, the mean (SD) change from baseline in YMRS total score was ?24.4 (8.7) for asenapine and ?23.9 (7.9) for olanzapine. Prespecified statistical analysis for noninferiority indicated no significant difference between asenapine and olanzapine. The overall incidence of treatment‐emergent adverse events was similar across treatment groups (77% placebo/asenapine, 77% asenapine, 78% olanzapine). Clinically significant weight gain occurred in 10%, 19%, and 31% of the placebo/asenapine, asenapine, and olanzapine groups, respectively. Conclusions: Asenapine was efficacious, showed noninferiority to olanzapine, and was well tolerated in the extended treatment of patients experiencing manic symptoms associated with bipolar I disorder.