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To evaluate the efficacy and safety of aripiprazole monotherapy as acute and continuation therapy for acute bipolar I mania.
Patients with acute bipolar I mania were randomized (1:1:1) to double-blind aripiprazole (15–30 mg/day; n=155), placebo (n=165) or lithium (900–1500 mg/day; n=160) for 3 weeks. At the end of Week 3, patients randomized to placebo were blindly switched to aripiprazole. Key efficacy outcome measures were mean change from baseline in YMRS Total score at Week 3 (LOCF; primary endpoint) and Week 12.
Improvements in YMRS Total scores from baseline were significantly greater versus placebo as early as Day 2 with aripiprazole (p=0.003) and Day 7 with lithium (p=0.040; LOCF). At Week 3, improvements from baseline in mean YMRS Total scores were significantly greater with aripiprazole (–12.96; p<0.001) and lithium (–12.03; p=0.005) versus placebo (–9.01; LOCF). These improvements were maintained to Week 12 (LOCF) with both aripiprazole (–14.48) and lithium (–12.71). Response rate was significantly greater versus placebo as early as Day 2 with aripiprazole (p=0.026), and Day 10 with lithium (p=0.006; LOCF). Response rates continued to increase over the study period and at Week 12 were 56.5% with aripiprazole and 49.0% with lithium.
Aripiprazole significantly improved symptoms as early as Day 2 and throughout the 3-week, placebo-controlled portion of this study in acutely manic patients. The beneficial effects of aripiprazole were sustained through Week 12 and were similar to lithium, confirming the robust efficacy of aripiprazole in these patients.
To compare the efficacy of aripiprazole and haloperidol for the treatment of acute relapse in chronic schizophrenia.
Across two 52-week double-blind studies, 1294 patients with acute relapse of chronic schizophrenia were randomized to aripiprazole 30 mg/day (n=861) or haloperidol 10 mg/day (n=433). The mean change in (Positive and Negative Syndrome Scale) PANSS Total score, PANSS Positive score were secondary endpoints in both studies. Post-hoc, a measure of excitement and hostility was derived from PANSS score items by factor analysis. The scales were administered at baseline and at each double-blind study visit (Weeks 1-8, 10, 12, 14, then every 4 weeks to Week 52).
Aripiprazole produced similar improvements to haloperidol in PANSS Total score (last observation carried forward, LOCF). Among those patients who completed the study, aripiprazole showed a significantly greater improvement in PANSS Total score compared with haloperidol at Weeks 26 and 52. A similar improvement in PANSS Positive score was seen with aripiprazole and haloperidol (LOCF and observed cases [OC]). Symptoms of excitement and hostility also improved similarly with both agents throughout the study (LOCF and OC).
Aripiprazole showed similar efficacy to haloperidol over the 52-week study, and significantly greater efficacy among those patients who stayed on treatment. Thus, aripiprazole is a useful agent for long-term maintenance therapy in schizophrenia.
Akathisia occurs less frequently in second generation antipsychotics (SGAs) compared to first generation antipsychotics (FGAs). This analysis was performed to quantify and qualify akathisia in schizophrenia patients receiving one of two SGAs, aripiprazole or olanzapine, or a FGA, haloperidol, in the first 12 weeks of treatment.
A post hoc analysis of the safety dataset was conducted to assess akathisia parameters in three double-blind randomized trials: a 52-week comparison of aripiprazole 30mg/d (n=859) versus haloperidol 10mg/d (n=431); and pooled data from two trials (26- and 52-week) comparing aripiprazole 15-30mg/d (n=504) and olanzapine10-20mg/d (n=505).
In the haloperidol comparative trial, akathisia was reported by 12.5% in the aripiprazole group and 24.1% in the haloperidol group. Akathisia occurred within the first 12 weeks after randomization in 89.6% of aripiprazole-related events and 92.5% of haloperidol-related events. In the olanzapine comparative trials, akathisia was reported by 10.7% of aripiprazole-treated patients and 6.1% of olanzapine-treated patients. Akathisia occurred within the first 12 weeks in 94.4% of aripiprazole-related events and 90.2% of olanzapine-related events. Akathisia was rated as mild or moderate by the majority of patients (≥80% of reports).
Consistent with previous reports, the FGA haloperidol was associated with higher rates of akathisia than the SGAs aripiprazole and olanzapine. Under double-blind conditions, for all antipsychotics, akathisia occurred early in treatment, was time-limited, and of mild to moderate severity. Contrary to previous reports, akathisia was not associated with high rates of discontinuation.
Assess the effectiveness and safety of transitioning patients with acute schizophrenia from IM to oral aripiprazole.
360 agitated patients (18-69 years) with PANSS Excited Component (PEC) total scores 15-32 and ≥4 on at least 2 PEC items, were randomized to ≤3 IM injections of aripiprazole 10 mg or haloperidol 6.5 mg within 24 hours. Patients (n=304) were transitioned to oral formulations (aripiprazole 10-15 mg/d or haloperidol 7-10 mg/d) for 4 days. Patients were assessed using PEC, Clinical Global Impression-Improvement (CGI-I), and Clinical Global Impression-Severity of Illness (CGI-S) Scale scores, as well as the Agitation Calmness Evaluation Scale (ACES), and the Corrigan Agitated Behavior Scale (CABS). Mean changes from baseline (last value obtained during IM treatment) to endpoint (Day 5, LOCF) were analyzed using an ANCOVA model controlling for treatment, country, and baseline value.
PEC scores were reduced 24 hours after IM injection with either aripiprazole or haloperidol (mean change of -8.3 and -8.1, respectively). Improvements in all other scales were also observed 24 hours following IM injection of aripiprazole or haloperidol. Treatment with oral aripiprazole or haloperidol for 4 days further reduced mean PEC scores (-1.4 aripiprazole, -1.4 haloperidol). Reductions in other scales were also maintained for 4 days following the transition to oral therapies. Incidence of AEs, and changes in laboratory values and vital signs were similar for both phases.
The effectiveness of aripiprazole and haloperidol appears to be maintained in patients with schizophrenia following transition from IM to oral formulations.
To evaluate the efficacy, safety and tolerability of aripiprazole plus valproate/lithium in the treatment of patients with bipolar I mania partially non-responsive to lithium or valproate monotherapy.
This multicentre, randomized study included patients with bipolar I disorder (manic/mixed episode, with/without psychotic features). Partial non-responders with therapeutic lithium (0.6–1.0 mmol/l) or valproate (50–125 μg/ml) levels were randomized (2:1) to double-blind combination aripiprazole (aripiprazole [15–30 mg/day] + lithium/valproate; n=253) or placebo + lithium/valproate (n=131). The primary endpoint was mean change from baseline in YMRS Total Score at Week 6 (LOCF).
The aripiprazole combination therapy demonstrated significant improvement from baseline in the YMRS Total score versus placebo + lithium/valproate at Week 1 and all subsequent visits (all p<0.05) up to Week 6 (–13.3 vs. –10.7, p=0.002; LOCF). Significant improvements from baseline to Week 6 were observed with aripiprazole vs. placebo + lithium/valproate in CGI-BP-S (mania) score (–1.9 vs. –1.6; p=0.014; LOCF) and the LIFE-RIFT score (–1.76 vs. –0.99; p=0.046; LOCF). At endpoint, aripiprazole plus lithium/valproate was associated with significantly greater remission rate (YMRS Total score ≤12) and response rate (≥50% improvement from baseline in YMRS Total) than placebo + lithium/valproate. Similar percentages of patients had clinically relevant weight gain (aripiprazole + lithium/valproate vs. placebo + lithium/valproate: 3.0% vs. 3.9%; p=0.718, Week 6, LOCF). Aripiprazole combination therapy was well tolerated.
In patients with bipolar mania, aripiprazole in combination with lithium/valproate is an effective and well-tolerated treatment that improves psychosocial functioning.
To evaluate efficacy and safety of intramuscular (IM) aripiprazole and IM haloperidol in patients with acute agitation associated with schizophrenia.
Patients (n=232) were randomized to IM aripiprazole 1-mg (0.5 ml of a 2-mg/ml solution), 5.25-mg (0.7 ml of a 7.5-mg/ml solution to approximate 5-mg), 9.75-mg (1.3 ml of a 7.5-mg/ml solution to approximate 10-mg), or 15-mg (2.0 ml of a 7.5-mg/ml solution), IM haloperidol 7.5-mg (1.5 ml of a 5-mg/ml solution) or IM placebo. Over 24 hours, patients received up to three injections, administered ≥2 hours apart. Primary endpoint was mean change from baseline in Positive and Negative Syndrome Scale Excited Component (PEC) score at 2 hours. Secondary endpoints included CGI-I, CGI-S and ACES scores.
Mean PEC improvements at 2 hours were significantly greater with IM aripiprazole 5.25-, 9.75- and 15-mg, and IM haloperidol versus IM placebo (Table). Compared with IM placebo, mean improvements were significantly greater in CGI-S with IM aripiprazole 9.75- and 15-mg, and in ACES with IM aripiprazole 9.75-mg and IM haloperidol (Table). Mean CGI-I was significantly better with IM aripiprazole 5.25-, 9.75- and 15-mg, and IM haloperidol versus IM placebo (Table). Overall, IM aripiprazole was well tolerated, with fewer extrapyramidal side effects versus IM haloperidol.
IM aripiprazole 9.75-mg is effective and well-tolerated for acute agitation associated with schizophrenia.
Evaluate the safety and tolerability of aripiprazole once-monthly (ARI-OM) initiation in patients stabilized on oral antipsychotics other than aripiprazole. Previous pivotal Phase III trials have evaluated initiating ARI-OM in patients stabilized on oral aripiprazole1.
Eligible patients were treated with oral atypical antipsychotics other than aripiprazole with a history of oral aripiprazole tolerability. The study included a screening phase (30 days) and a treatment phase (28 days). Patients were stabilized per investigator's judgment for ≥14 days on risperidone, olanzapine, quetiapine, or ziprasidone, before administration of ARI-OM (400 mg). Current oral antipsychotic was co-administered with ARI-OM for 2 weeks to determine safety and tolerability of a single ARI-OM dose following treatment initiation. Safety assessments were adverse events (AEs); extrapyramidal symptoms (EPSs) using standard objective rating scales; Columbia-Suicide Severity Rating Scale; clinical laboratory measures; and weight changes.
60 patients initiated ARI-OM, while continuing treatment for ≤2 weeks with oral risperidone (n=24), quetiapine (n=28), ziprasidone (n=5) or olanzapine (n=3). Treatment-emergent (TE) AEs (≥5%) were fatigue, injection-site pain, and restlessness (risperidone); insomnia, dystonia, injection-site pain, and toothache (quetiapine); and muscle spasm, tooth abscess, and toothache (ziprasidone). Prior olanzapine did not cause any AEs. Incidence of TE-EPSs were similar in all groups (< 5%). There were no unusual changes in objective EPS rating scales, suicidality, weight, laboratory values or fasting metabolic parameters across all groups.
The AE profile of patients receiving ARI-OM concomitant with oral atypical antipsychotics other than aripiprazole was consistent with prior reports1.
Evaluate the efficacy of aripiprazole combination with lithium/valproate vs. placebo combination in bipolar mania using a titration regimen with a low starting dose (5 mg/day).
Eligible adult patients with bipolar mania receiving lithium/valproate and a Young Mania Rating Scale (YMRS) Total score ≥16 who might benefit from combination treatment with aripiprazole, were randomized to aripiprazole (n=181) or placebo (n=189) with lithium/valproate. Primary endpoint was mean change from baseline to Week 12 in YMRS. Secondary endpoints were Clinical Global Impressions-Bipolar Version (CGI-BP) severity of illness score, response rate (≥50% improvement in YMRS Total score), and remission rate (YMRS ≤12). Safety and tolerability were also assessed. Enrolment yielded a 77% power to detect a 2.6-point change in YMRS Total score at endpoint.
At endpoint, the mean change in YMRS Total Score (last-observation-carried-forward [LOCF]) for aripiprazole vs. placebo was not significant (treatment difference [-2.04] in favour of aripiprazole (95% CI: -4.14, 0.07; p=0.058). Mean change from baseline to endpoint in CGI-BP showed a treatment difference (-0.30) in favour of aripiprazole vs. placebo (95% CI: - 0.59, -0.01; p=0.044). Response rates were 68.8% vs. 61.3% (p=0.128) and remission rates were 69.9% vs. 64.0% (p=0.211) for aripiprazole and placebo, respectively. No unexpected adverse events (AEs) occurred. Treatment-emergent AEs (≥5% and twice the rate of placebo) were akathisia, depression, and nausea.
The target sample size of 388 patients was not achieved in this study and the primary outcome did not reach statistical significance. Now new or unexpected AEs occurred.
Evaluate the efficacy and long-term safety of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia.
Patients requiring chronic treatment for schizophrenia, not on aripiprazole monotherapy, were cross-titrated from other antipsychotic(s) to aripiprazole in an oral conversion phase (Phase 1). All patients entered an oral aripiprazole stabilization phase (Phase 2). Patients meeting stability criteria entered an ARI-OM stabilization phase (Phase 3), with coadministration of oral aripiprazole for the first 2 weeks. Patients meeting stability criteria were randomized to ARI-OM or placebo once-monthly (placebo-OM) during a 52-week, double-blind maintenance phase (Phase 4). Primary endpoint was time-to-impending relapse. Safety and tolerability were also assessed.
710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo-OM=134). The study was terminated early because efficacy was demonstrated by a pre-planned interim analysis. Time-to-impending relapse was significantly delayed with ARI-OM vs. placebo-OM (p< 0.0001, log-rank test). Discontinuations due to treatment-emergent adverse events (AEs) were: Phase 1, 3.8% (n=24/632); Phase 2, 3.0% (n=21/709); Phase 3, 4.9% (n=28/576); Phase 4, 7.1% (n=19/269). Most AEs were mild or moderate. Insomnia was the only AE >5% incidence in any phase. Headache, somnolence, and nausea had a peak first onset within the first 4 weeks of treatment. There were no unusual shifts in all phases in laboratory values, fasting metabolic parameters, weight, or objective scales of movement disorders.
ARI-OM significantly delayed time-to-impending relapse compared with placebo-OM and was well tolerated as maintenance treatment in schizophrenia1.
Brexpiprazole is a serotonin-noradrenaline-dopamine agent that binds with high affinity to multiple serotonin, norepinephrine and dopamine receptors. In particular, Brexpiprazole is a partial agonist at dopamine D2/D3 and 5-HT1A receptors and an antagonist at 5-HT2A and norepinephrine alpha1B receptors.
We assessed the efficacy and safety of brexpiprazole versus placebo as adjunctive therapy to anti-depressant therapy (ADT) in subjects with MDD who demonstrated inadequate response to ADT.
This trial had 3 phases: a screening phase (7-28 days); a prospective phase (Phase A): 8-week, single-blind placebo plus an investigator-determined, open-label ADT; a randomized phase (Phase B): 6-week, double-blind, adjunctive brexpiprazole (2 mg/day) vs. placebo in patients with an inadequate response to ADT.
The primary efficacy endpoint was the change from the end of Phase A (Week 8) to the end of Phase B (Week 14) in MADRS Total Score. The key secondary endpoint was the change in mean SDS score. Other secondary endpoints were mean change in CGI-S, IDS-R, HAMD and HAMA.
Of 379 randomized patients, completion rates at Week 14 were high (92.9%). Statistically significant improvements in mean MADRS Total score were observed for subjects receiving adjunctive brexpiprazole 2mg/day compared with placebo (p=0.0001) at endpoint. In addition, on all secondary endpoints Brexpiprazole showed a statistically significant advantage over placebo.
Commonly reported adverse events in the brexpiprazole group (>5% and more than twice placebo) were weight gain (8.0%), akathisia (7.4%).
Brexpiprazole was effective and well tolerated as adjunctive treatment for MDD patients with an inadequate response to ADT.
Evaluate the effectiveness of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia.
Detailed methodology has been published previously1. Briefly, the study consisted of 4 phases: oral conversion to aripiprazole (Phase 1); oral aripiprazole stabilization (Phase 2); ARI-OM stabilization (Phase 3), with co-administration of oral aripiprazole for the first 2 weeks; and an ARI-OM maintenance phase (Phase 4). Effectiveness assessments included Investigator's Assessment Questionnaire (IAQ) scores, a scale that evaluates effectiveness of current treatment vs. pre-trial medication, where a negative change in score signals improvement, and Personal and Social Performance (PSP) scale scores, where negative change in score signals worsening.
710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo once-monthly [placebo- OM]=134). Mean IAQ Total scores remained stable in Phase 2 (31.3) and Phase 3 (30.6). During Phase 4, the mean change in IAQ Total score was +1.3 for ARI-OM vs. +3.8 for placebo-OM (p< 0.0001). Mean changes in PSP Total scale scores showed improvement during Phase 2 (3.0) and Phase 3 (2.6). Mean change in PSP scores during Phase 4 showed greater functional stability with ARI-OM (−1.7) compared with placebo-OM (−6.2) (p=0.0002 vs. placebo-OM).
Improvements in effectiveness, as assessed by the IAQ and PSP Total scale scores, in the Phases 2 & 3 were maintained in Phase 4 for ARI-OM compared with placebo-OM. Treatment with ARI-OM improved symptoms, overall response to treatment and functioning.
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