Timothy Peters-Strickland

Aripiprazole once-monthly for treatment of schizophrenia: double-blind, randomised, non-inferiority study

BACKGROUND Long-acting injectable formulations of antipsychotics are treatment alternatives to oral agents. AIMS To assess the efficacy of aripiprazole once-monthly compared with oral aripiprazole for maintenance treatment of schizophrenia. METHOD A 38-week, double-blind, active-controlled, non-inferiority study; randomisation (2:2:1) to aripiprazole once-monthly 400 mg, oral aripiprazole (10-30 mg/day) or aripiprazole once-monthly 50 mg (a dose below the therapeutic threshold for assay sensitivity). ( TRIAL REGISTRATION clinicaltrials.gov, NCT00706654.) RESULTS A total of 1118 patients were screened, and 662 responders to oral aripiprazole were randomised. Kaplan-Meier estimated impending relapse rates at week 26 were 7.12% for aripiprazole once-monthly 400 mg and 7.76% for oral aripiprazole. This difference (-0.64%, 95% CI -5.26 to 3.99) excluded the predefined non-inferiority margin of 11.5%. Treatments were superior to aripiprazole once-monthly 50 mg (21.80%, P < or = 0.001). CONCLUSIONS Aripiprazole once-monthly 400 mg was non-inferior to oral aripiprazole, and the reduction in Kaplan-Meier estimated impending relapse rate at week 26 was statistically significant v. aripiprazole once-monthly 50 mg.

Qualify: a randomized head-to-head study of aripiprazole once-monthly and paliperidone palmitate in the treatment of schizophrenia

OBJECTIVE To directly compare aripiprazole once-monthly 400mg (AOM 400) and paliperidone palmitate once-monthly (PP) on the Heinrichs-Carpenter Quality-of-Life Scale (QLS), a validated health-related quality of life and functioning measure in schizophrenia. METHOD This 28-week, randomized, non-inferiority, open-label, rater-blinded, head-to-head study (QUALIFY) of AOM 400 and PP in adult patients (18-60 years) comprised oral conversion, initiation of AOM 400 or PP treatment, and continuation with intramuscular injections every 4weeks. The primary endpoint assessed non-inferiority and superiority on QLS total score analyzed using a mixed model for repeated measurements. RESULTS Of 295 randomized patients, 100/148 (67.6%) of AOM 400 and 83/147 (56.5%) of PP patients completed 28weeks of treatment. A statistically significant least squares mean difference in change from baseline to week 28 on QLS total score (4.67 [95%CI: 0.32;9.02], p=0.036) confirmed non-inferiority and established superiority of AOM 400 vs PP. There were also significant improvements in Clinical Global Impression - Severity scale and the Investigators Assessment Questionnaire for AOM 400 vs PP, and pre-defined sub-group analyses revealed a consistent pattern of significance favoring AOM 400 in patients ≤35years. Common treatment-emergent adverse events in the treatment continuation phase were more frequent with PP vs AOM 400, and adverse events were the most frequent reason for discontinuation (27/137 [19.7%] for PP and 16/144 [11.1%] for AOM 400). All-cause discontinuation was numerically lower with AOM 400. CONCLUSION Superior improvements on clinician-rated health-related quality of life and a favorable tolerability profile suggest greater overall effectiveness for aripiprazole once-monthly vs paliperidone palmitate. ClinicalTrials.gov identifier:NCT01795547.

Aripiprazole Once-Monthly in the Acute Treatment of Schizophrenia: Findings From a 12-Week, Randomized, Double-Blind, Placebo-Controlled Study

OBJECTIVE To evaluate aripiprazole once-monthly (AOM), a long-acting injectable suspension of aripiprazole, as acute treatment in patients with schizophrenia (DSM-IV-TR). METHOD Adults experiencing an acute psychotic episode were randomized to 12 weeks of double-blind treatment with AOM 400 mg or placebo (October 2012-August 2013). The primary efficacy outcome was change from baseline to endpoint (week 10) in Positive and Negative Syndrome Scale (PANSS) total score. The key secondary efficacy outcome was change from baseline in Clinical Global Impressions-Severity of Illness scale (CGI-S) score. Secondary efficacy outcomes included change from baseline in PANSS positive and negative subscale and Personal and Social Performance Scale (PSP) scores. The study took place from October 2012 through August 2013. RESULTS Patients (N = 340; 79% male, 66% black) were randomized to AOM (n = 168) or placebo (n = 172). Least squares (LS) mean change from baseline to endpoint (week 10) favored AOM versus placebo in PANSS total (treatment difference, -15.1 [95% CI, -19.4 to -10.8]; P < .0001) and CGI-S (treatment difference, -0.8 [95% CI, -1.1 to -0.6]; P < .0001) scores, as it did at all other timepoints through 12 weeks (all P ≤ .0005). LS mean change from baseline in PANSS positive and negative subscale and PSP scores favored AOM versus placebo (P < .0001). Common (> 10%) treatment-emergent adverse events (AOM vs. placebo) were increased weight (16.8% vs 7.0%), headache (14.4% vs. 16.3%), and akathisia (11.4% vs 3.5%). CONCLUSIONS Symptoms and functioning improved with AOM 400 mg versus placebo in patients with acute schizophrenia, with acceptable safety and tolerability. These data suggest that AOM 400 mg is a viable treatment option for patients experiencing an acute schizophrenia episode. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01663532.

Hospitalisation rates in patients switched from oral anti-psychotics to aripiprazole once-monthly for the management of schizophrenia

Abstract Objective: To report the design and preliminary results of a mirror-image study comparing total psychiatric hospitalisation rates pre- and post-switch to aripiprazole once-monthly, an extended release injectable solution. Methods: A multi-center, open-label mirror-image study of patients (18–65 years) with schizophrenia to compare total psychiatric hospitalisation rates between retrospective treatment with oral standard-of-care (SOC) anti-psychotics and prospective treatment with aripiprazole once-monthly in a naturalistic community setting in North America. Total psychiatric hospitalisation rates were assessed between retrospective (Months −4 to −1) and prospective treatment periods (Months 4–6) for patients who completed ≥3 months aripiprazole once-monthly. Results: One hundred and eighty-three patients entered the prospective phase. After switching to aripiprazole once-monthly, total psychiatric hospitalisation rates for the 3-month prospective period were significantly lower (p < 0.0001, Exact McNemar’s test) compared with the retrospective 3-month period when the same patients received SOC anti-psychotics (6.6% [n = 8/121] vs 28.1% [n = 34/121], respectively; rate ratio = 0.24). Similarly, total psychiatric hospitalisation rates for all patients who entered the prospective treatment phase were significantly lower (p < 0.0001, Exact McNemar’s test) for the prospective 6 months following switch to aripiprazole once-monthly, compared with the retrospective 6-month SOC period (14.2% [n = 26/183] vs 41.5% [n = 76/183], respectively; rate ratio = 0.34). Common treatment-emergent adverse events (occurring in ≥5% of patients) were psychotic disorder (7.7%), akathisia (7.2%), and insomnia (7.2%). Discontinuation (all causes) during the prospective phase was 44.8% (n = 82/183). Limitations: Mirror-image studies do not include a parallel active control; as each patient serves as their own control, it cannot be determined whether other treatments may have similar effects. Treatment and trial effects may be difficult to separate. Independent factors such as admission patterns, insurance coverage, availability of hospital beds, and community support may influence rates of hospitalisation. Conclusions: Switching to aripiprazole once-monthly substantially reduced total psychiatric hospitalisation rates compared with retrospective rates in the same patients taking oral SOC.

Safety and tolerability of once monthly aripiprazole treatment initiation in adults with schizophrenia stabilized on selected atypical oral antipsychotics other than aripiprazole

Abstract Objective: Safety and tolerability assessment of initiating treatment with a once monthly long-acting injectable form of aripiprazole (aripiprazole once monthly) in patients stabilized on oral antipsychotics other than aripiprazole. Methods: Patients with schizophrenia treated with oral atypical antipsychotics other than aripiprazole and with a history of aripiprazole tolerability were enrolled. Patients were stabilized per investigator’s judgment for ≥14 days on oral atypical antipsychotics during screening. Patients then received one dose of aripiprazole once monthly (400 mg). Concomitant with aripiprazole once monthly, subjects received their current oral atypical antipsychotic for 14 ± 1 days at doses reduced to the mid/lower recommended dose range. Safety and tolerability were assessed for the 28-day treatment phase. For pharmacokinetic analyses, aripiprazole plasma concentrations were measured on Days 7, 14, and 28. Results: Sixty patients were enrolled and initiated with aripiprazole once monthly while continuing treatment with oral olanzapine (n = 3), quetiapine (n = 28), risperidone (n = 24) or ziprasidone (n = 5). Duration of co-administered oral antipsychotic treatment varied, ranging from 0 to 15 days. Treatment was well tolerated. Frequently reported treatment-emergent adverse events (TEAEs) were injection-site pain and toothache (4/60 subjects each, 6.7%), followed by dystonia, fatigue, increased blood creatine phosphokinase, insomnia and restlessness (3/60 subjects each, 5.0%). Most TEAEs occurred in the first 8 days of co-administration irrespective of days of oral overlap. No clinically relevant mean changes from baseline were observed for laboratory values or fasting metabolic parameters. Psychotic symptoms remained stable. Aripiprazole plasma concentrations were similar to those observed following daily doses of oral aripiprazole. Conclusions: The adverse-event profile of patients receiving aripiprazole once monthly concomitant with oral atypical antipsychotics other than aripiprazole was consistent with previous reports of aripiprazole once monthly concomitant with oral aripiprazole. Adverse events were similar irrespective of prior atypical antipsychotic and duration of oral antipsychotic overlap, suggesting that patients can be safely switched from their existing oral antipsychotic to aripiprazole once monthly without requiring an intermediate stabilization phase with oral aripiprazole. Aspects of the study design (open-label trial and short duration) and patient population (predominantly male and of African–American ethnicity) may limit the generalizability of these findings. Clinical trial registration: Safety and Tolerability Trial of Aripiprazole IM Depot Treatment in Adult Subjects With Schizophrenia Stabilized on Oral Antipsychotics Other Than Aripiprazole. ID number: NCT01552772. Registry: clinicaltrials.gov.

Hospitalization rates in patients switched from oral anti-psychotics to aripiprazole once-monthly: final efficacy analysis.

Abstract Objective: To compare hospitalization rates in patients with schizophrenia treated prospectively with aripiprazole once-monthly 400 mg (AOM 400; an extended-release injectable suspension) vs the same patients’ retrospective rates with their prior oral anti-psychotic therapy. Research design and methods: Multi-center, open-label, mirror-image, naturalistic study in a community setting in North America. Patients who required a change in treatment and/or would benefit from long-acting injectable anti-psychotic therapy were treated prospectively for 6 months with AOM 400. Retrospective data on hospitalization rates were obtained. Clinical trial registration: ClinicalTrials.gov: NCT01432444. Main outcome measures: The proportion of patients with ≥1 psychiatric inpatient hospitalization with oral anti-psychotic therapy examined retrospectively (months –4 to –1 before oral conversion) and after switching to AOM 400 (months 4–6 after initiating AOM 400). Results: Psychiatric hospitalization rates were significantly lower when patients were treated with AOM 400 compared with oral anti-psychotic therapy both in the 3-month primary efficacy sample (2.7% [n = 9/336] vs 27.1% [n = 91/336], respectively; p < 0.0001) and in the total sample (6-month prospective rate: 8.8% [n = 38/433] vs 6-month retrospective rate: 38.1% [n = 165/433]; p < 0.0001). Discontinuations due to adverse events (AEs) during cross-titration were lower in patients cross-titrated on oral aripiprazole for >1 and <4 weeks (2.9% [n = 7/239]) compared with patients cross-titrated for ≤1 week (10.4% [n = 5/48]). The most common treatment-emergent AEs during the prospective treatment phase were insomnia (6.7% [n = 29/431]) and akathisia (6.5% [n = 28/431]). Patient-rated injection-site pain decreased from the first injection to the last visit. Conclusions: In a community setting, patients with schizophrenia demonstrated significantly lower psychiatric hospitalization rates after switching from their prior oral anti-psychotic therapy to AOM 400. Patients served as their own control, and thus an active control group was not included in this study. Confounding factors, such as insurance coverage and availability of hospital beds, were not examined here and deserve further consideration.

Usability of a novel digital medicine system in adults with schizophrenia treated with sensor-embedded tablets of aripiprazole

Objective Digital medicine system (DMS) is a novel drug–device combination that objectively measures and reports medication ingestion. The DMS consists of medication embedded with an ingestible sensor (digital medicine), a wearable sensor, and software applications. This study evaluated usability of the DMS in adults with schizophrenia rated by both patients and their health care providers (HCPs) during 8-week treatment with prescribed doses of digital aripiprazole. Methods Six US sites enrolled outpatients into this Phase IIa, open-label study (NCT02219009). The study comprised a screening phase, a training phase (three weekly site visits), and a 5-week independent phase. Patients and HCPs independently rated usability of and satisfaction with the DMS. Results Sixty-seven patients were enrolled, and 49 (73.1%) patients completed the study. The mean age (SD) of the patients was 46.6 years (9.7 years); the majority of them were male (74.6%), black (76.1%), and rated mildly ill on the Clinical Global Impression – Severity scale (70.1%). By the end of week 8 or early termination, 82.1% (55/67) of patients had replaced the wearable sensor independently or with minimal assistance, based on HCP rating. The patients used the wearable sensor for a mean (SD) of 70.7% (24.7%) and a median of 77.8% of their time in the trial. The patients contacted a call center most frequently at week 1. At the last visit, 78% (47/60) of patients were somewhat satisfied/satisfied/extremely satisfied with the DMS. Conclusion A high proportion of patients with schizophrenia were able to use the DMS and reported satisfaction with the DMS. These data support the potential utility of the DMS in clinical practice.

Patient-Centered Outcomes with Aripiprazole Once-Monthly for Maintenance Treatment in Patients with Schizophrenia: Results From Two Multicenter, Randomized, Double-Blind Studies

OBJECTIVES To further characterize the clinical profile of long-term treatment with aripiprazole once-monthly 400 mg (AOM 400) by examining patient-centered outcomes in adults with schizophrenia. METHODS Data are from 2 separate studies: a 52-week, multicenter, randomized, double-blind, placebo-controlled study and a 38-week, multicenter, randomized, double-blind, active-controlled study that evaluated the clinical profile of AOM 400 as maintenance treatment in patients with schizophrenia. The studies were conducted from July 2008 through February 2011 and from September 2008 through August 2012, respectively. Both studies included the Drug Attitude Inventory (DAI), the Medication Adherence Questionnaire (MAQ), the Patient Satisfaction with Medication Questionnaire, and a resource utilization and hospitalization form as prespecified patient-centered endpoints. RESULTS A total of 710 patients entered the oral stabilization phase in the 52-week study, and 403 patients were randomized to double-blind treatment. The corresponding sample sizes in the 38-week study were 842 and 662, respectively. In both studies, mean DAI and MAQ scores remained stable across all treatment phases; mean changes from baseline during the double-blind phase were not significantly different between treatment arms. Treatment satisfaction remained high throughout both studies, and most patients reported no or fewer side effects with AOM 400 relative to their prior medication. Most patients did not have unscheduled outpatient visits or hospitalizations throughout the studies. CONCLUSIONS Data from 2 randomized, double-blind studies indicated that patient perceptions about treatment satisfaction, side effects, and medication adherence were maintained in patients with schizophrenia receiving maintenance treatment with AOM 400. TRIAL REGISTRATION ClinicalTrials.gov: NCT00705783, NCT00706654.

Effects of aripiprazole once-monthly on domains of personal and social performance: Results from 2 multicenter, randomized, double-blind studies

OBJECTIVE To assess the effects of maintenance therapy with aripiprazole once-monthly 400mg on personal and social functioning. METHODS Data were analyzed from 2 randomized, double-blind trials of patients with schizophrenia requiring chronic antipsychotic treatment. One study was a 52-week trial of aripiprazole once-monthly 400mg versus placebo; the other was a 38-week trial of aripiprazole once-monthly 400mg, oral aripiprazole (10-30 mg daily), and aripiprazole once-monthly 50mg (subtherapeutic dose to test assay sensitivity). Functioning was assessed using the Personal and Social Performance (PSP) scale, comprising 4 domain subscales. RESULTS In the 52-week study, 403 patients stabilized on aripiprazole once-monthly 400mg were randomized to receive aripiprazole once-monthly 400mg (n=269) or placebo (n=134). In the 38-week study, 662 patients stabilized on oral aripiprazole were randomized to receive aripiprazole once-monthly 400mg (n=265), oral aripiprazole (n=266), or aripiprazole once-monthly 50mg (subtherapeutic dose; n=131). In the 52-week study, mean changes from baseline were significantly worsened with placebo compared with aripiprazole once-monthly 400mg for PSP total score (P<0.001) and domain scores for Personal and Social Relationships (P<0.001), Self-Care (P<0.01), and Disturbing and Aggressive Behavior (P<0.0001). In the 38-week study, mean changes from baseline were significantly worsened with aripiprazole once-monthly 50mg compared with aripiprazole once-monthly 400mg for PSP total score (P<0.05) and the Personal and Social Relationships domain score (P<0.05). CONCLUSION Patient functioning, assessed using the PSP scale, was maintained in stabilized patients treated with aripiprazole once-monthly in 2 pivotal relapse studies.

Aripiprazole Once-Monthly 400 mg: Comparison of Pharmacokinetics, Tolerability, and Safety of Deltoid Versus Gluteal Administration

Abstract Background: Two open-label, randomized, parallel-arm studies compared pharmacokinetics, safety, and tolerability of aripiprazole once-monthly 400 mg following deltoid vs gluteal injection in patients with schizophrenia. Methods: In the single-dose study, 1 injection of aripiprazole once-monthly 400 mg in the deltoid (n=17) or gluteal (n=18) muscle (NCT01646827) was administered. In the multiple-dose study, the first aripiprazole once-monthly 400 mg injection was administered in either the deltoid (n=71) or gluteal (n=67) muscle followed by 4 once-monthly deltoid injections (NCT01909466). Results: After single-dose administration, aripiprazole exposure (area under the concentration-time curve) was similar between deltoid and gluteal administrations, whereas median time to maximum plasma concentration was shorter (7.1 [deltoid] vs 24.1 days [gluteal]) and maximum concentration was 31% higher after deltoid administration. In the multiple-dose study, median time to maximum plasma concentration for deltoid administration was shorter (3.95 vs 7.1 days), whereas aripiprazole mean trough concentrations, maximum concentration, and area under the concentration-time curve were comparable between deltoid and gluteal muscles (historical data comparison). Multiple-dose pharmacokinetic results for the major metabolite, dehydro-aripiprazole, followed a similar pattern to that of the parent drug for both deltoid and gluteal injection sites. Safety and tolerability profiles were similar after gluteal or deltoid injections. Based on observed data, minimum aripiprazole concentrations achieved by aripiprazole once-monthly 400 mg are comparable with those of oral aripiprazole 15 to 20 mg/d. Conclusions: The deltoid muscle is a safe alternative injection site for aripiprazole once-monthly 400 mg in patients with schizophrenia.