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Metabolic and Endocrine Profiles During 1-Year Treatment of Outpatients with Schizophrenia with Aripiprazole Lauroxil.

ABSTRACT: BACKGROUND:We assessed long-term metabolic and endocrine profiles of outpatients with schizophrenia participating in a one-year open-label extension study of monthly aripiprazole lauroxil (AL), a long-acting injectable antipsychotic. METHODS:Patients (N = 478) were enrolled in a 52-week, open-label extension study of AL monotherapy administered by intramuscular injection every 4 weeks. Of these, most (368) received AL 882 mg and the remainder AL 441 mg as their fixed-dose regimen. Among the patients entering the long-term study, 181 (38%) had already received three prior AL injections. The baseline values for this analysis were obtained from the visit before the first AL injection. Patients were followed for the full year of the extension study unless they discontinued early. Changes in metabolic parameters (weight, fasting blood sugar, lipids) and serum prolactin were assessed over the duration of AL exposure, which could extend to a total of 16 AL injections. Data presented are last observation carried forward from baseline to last visit. RESULTS:Most patients remained for most of the follow-up period, with 409 (86%) remaining at 6 months and 326 (68%) completing the one-year treatment period. The mean (standard deviation) changes from baseline in the overall population were: +1.1 (27.5) mg/dL for glucose, +0.07 (0.6)% for glycated hemoglobin (HbA1c), -3.3 (35.8) mg/dL for total cholesterol and -5.3 (101.9) mg/dL for triglycerides. Prolactin change from baseline was -8.7 ng/mL (14.7) for men and -14.9 (43.4) ng/mL for women. Overall, the mean weight change was +0.8 (5.9) kg. In terms of categorical weight change, 88 patients (18%) gained ?7% body weight, and 59 (12%) lost ?7% body weight. Overall, there was no clinically meaningful difference between any of these variables and AL dose. CONCLUSION:Long-term treatment with AL in outpatients with schizophrenia was associated with a modest lowering of serum prolactin for both genders and relatively modest changes in average weight, fasting glucose, and HbA1c values. There appeared to be little net change in lipid parameters. This presentation extends a recently published report on the short-term metabolic and endocrine effects of AL over a period of 12 weeks. The present study increased the follow-up period to more than a year and was careful to use the first exposure to AL as the baseline. Limitations include lack of a comparison group and difficulty disentangling effects of medication treatment versus factors. Overall, the metabolic, weight, and endocrine effects reported here are consistent with other long-term effects of oral aripiprazole treatment. This study was funded by Alkermes, Inc.

SUBMITTER: Nasrallah HA

PROVIDER: S-EPMC5546549 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Metabolic and Endocrine Profiles During 1-Year Treatment of Outpatients with Schizophrenia with Aripiprazole Lauroxil.

Nasrallah Henry A HA Aquila Ralph R Stanford Arielle D AD Jamal Hasan H HH Weiden Peter J PJ Risinger Robert R

Psychopharmacology bulletin 20170801 3

<h4>Background</h4>We assessed long-term metabolic and endocrine profiles of outpatients with schizophrenia participating in a one-year open-label extension study of monthly aripiprazole lauroxil (AL), a long-acting injectable antipsychotic.<h4>Methods</h4>Patients (N = 478) were enrolled in a 52-week, open-label extension study of AL monotherapy administered by intramuscular injection every 4 weeks. Of these, most (368) received AL 882 mg and the remainder AL 441 mg as their fixed-dose regimen. ...[more]

PMID: 28839338

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Project description:BackgroundClinical practice guidelines support efforts to improve functioning in patients with schizophrenia. Discrepancies in the perception of cognitive status between clinicians, patients with schizophrenia, and their caregivers have been associated with impaired functional abilities in patients; medication side effects might worsen both cognition and daily functioning. We assessed daily/social functioning and cognition in stable patients with schizophrenia who switched to the long-acting injectable (LAI) antipsychotic aripiprazole lauroxil (AL).MethodsClinically stable adults with residual symptoms of schizophrenia or intolerance following three or more doses of paliperidone palmitate or risperidone LAI were switched to flexibly dosed open-label AL treatment (441mg, 662mg, or 882mg every 4 weeks or 882mg every 6 weeks) for six months (ClinicalTrials.gov identifier: NCT02634320). Daily/social functioning was assessed using the Personal and Social Performance Scale (PSP); total and subscale scores were summarized using descriptive statistics. The cognitive status of patients was assessed using the New York Assessment of Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT) at baseline and Month 6 or early termination, providing patient, caregiver, and clinician perspectives. A post hoc analysis assessed level of agreement in ratings of cognitive status among respondents, evaluated at baseline and last assessment, using weighted kappa coefficients (0.01-0.20, slight agreement; 0.21-0.40, fair agreement; 0.41-0.60, moderate agreement; 0.61-0.80, substantial agreement.).ResultsAll 51 enrolled patients received one or more AL doses; 35 completed the study, and 45 contributed data at last assessment. Mean age was 40.6 years; 72.5 percent of patients were male. Based on PSP total score, functioning was maintained from baseline (mean [standard deviation (SD)]: 55.1 [10.5]) through six months of AL treatment (mean [SD]: 57.7 [13.2]). Proportions of patients rating personal and social functioning issues as "not present" or "mild" remained stable between baseline and Month 6 for each PSP subscale. At baseline (n=50), cognitive difficulties were most commonly rated "not present" or "mild" in all NY-AACENT domains by patients (58-86% across domains), clinicians (62-94%), and caregivers (50-92%), and these rates were maintained or increased at last assessment for all reporters. Weighted kappa coefficients indicated fair-to-substantial agreement between patients and clinicians across domains at last assessment (0.32-0.64; baseline: 0.14-0.55); patient-caregiver agreement ranged from 0.07 to 0.50 at last assessment (baseline: 0.25-0.60).ConclusionIn clinically stable patients with schizophrenia who initiated AL, self-reported functioning was maintained over six months of treatment. Clinician-, caregiver-, and patient-reported cognitive function was stable at baseline and maintained in all NY-AACENT domains; patient-clinician agreement on level of cognitive impairment increased over six months of treatment with AL.

Project description:BackgroundContinuous antipsychotic therapy is recommended as part of long-term maintenance treatment of schizophrenia, and gaps in antipsychotic treatment have been associated with increased risks of relapse and rehospitalization. Because the use of long-acting injectable (LAI) antipsychotics may reduce the likelihood of undetected medication gaps, initiating an LAI medication may affect resource utilization and costs. The LAI aripiprazole lauroxil (AL) was approved in the United States (US) in 2015 for the treatment of schizophrenia in adults.ObjectiveThe objective of this retrospective observational cohort study was to examine treatment patterns, resource utilization, and costs following initiation of AL for the treatment of schizophrenia in adults.MethodsA retrospective analysis of Medicaid claims data identified a cohort of patients (N = 485) starting AL shortly after Food and Drug Administration approval in October 2015. Treatment patterns, resource utilization, and costs were compared 6 months before and after treatment initiation. Subgroup analyses were conducted based on the type of antipsychotic (LAI, oral, or none) received before initiation of AL.ResultsOver 6 months of follow-up, patients received an average of 4.6 injections out of a maximum of six (77%). After initiating AL, all-cause inpatient admissions decreased by 22.4%; other significant reductions were observed in mental health-related admissions and emergency room (ER) visits. All-cause inpatient costs decreased by an average of US$2836 per patient (p < 0.05) in the 6-month post-AL period, whereas outpatient pharmacy costs increased by US$4121 (p < 0.05), resulting in no significant difference in overall costs between the pre- and post-AL periods. The subgroup of patients who had been prescribed an oral antipsychotic before starting AL had significant reductions in proportion of patients with inpatient and ER visits and costs, but also reported a significant increase in pharmacy costs.ConclusionsAL was associated with a significant reduction in inpatient costs and an increase in outpatient pharmacy costs, resulting in no changes in total healthcare costs over 6 months. The adherence rate and reductions in inpatient use may indicate the potential for greater clinical stability among patients initiated on AL compared with their previous treatment.

Project description:BackgroundThis post hoc analysis of clinical trial data evaluated long-term, self-reported mental and physical health-related quality of life (HRQoL) scores in schizophrenia patients receiving aripiprazole lauroxil (AL), an atypical long-acting injectable (LAI) antipsychotic approved for the treatment of schizophrenia in adults.MethodsThe study population included 291 stable schizophrenia outpatients enrolled in 2 consecutive long-term safety studies of AL given every 4 weeks for up to 124 weeks. HRQoL was measured using the SF-36v2® Health Survey (SF-36v2) over the course of the follow-up. The primary outcome was change in SF-36v2 mental component summary (MCS) and physical component summary (PCS) scores from baseline to 124 weeks. To contextualize these scores, descriptive analyses were conducted to compare the scores with available scores for the general population as well as for other populations with chronic medical (ie, hypertension and type 2 diabetes) or psychiatric (ie, depression) conditions.ResultsResults from this post hoc analysis indicated that the mean MCS score for patients continuing AL improved significantly from baseline over 124 weeks (P < .05, all timepoints), while mean PCS score showed little change over 124 weeks. At baseline, patients had lower (worse) MCS scores than the normed general population, but by week 124, patients had MCS scores comparable to those in the general population. This pattern of change was not observed with PCS scores. Comparison of study MCS scores with those associated with other diseases showed that this schizophrenia cohort had lower scores than those with chronic medical conditions but higher scores than those with depression. PCS scores were higher in the study population than published scores for all reference populations at baseline and week 124.ConclusionsIn this post hoc analysis, outpatients with schizophrenia who continued the LAI antipsychotic AL showed gradual and sustained improvement in self-reported mental HRQoL over several years of follow-up, whereas self-reported physical HRQoL did not change. By the end of follow-up, mental health scores of study patients with schizophrenia were comparable to those of the general population and better than those of patients with depression.Trial registrationClinicalTrials.gov (NCT01626456 [trial registration date: June 15, 2012] and NCT01895452 [trial registration date: July 5, 2013]).

Project description:Objective:Schizophrenia clinical trials commonly measure observed changes in Positive and Negative Syndrome Scale (PANSS) total score. However, it is more intuitive to think of response vs nonresponse, a binary outcome. Assessing binary outcomes enables calculation of number needed to treat (NNT) for therapeutic outcomes, number needed to harm (NNH) for adverse outcomes, and likelihood to be helped or harmed (LHH) to demonstrate benefit/risk tradeoffs. Here, NNT, NNH, and LHH were used to evaluate the clinical usefulness of aripiprazole lauroxil in patients with an acute schizophrenia exacerbation. Methods:Categorical efficacy and tolerability data were taken from the pivotal Phase 3 trial evaluating aripiprazole lauroxil for treatment of an acute exacerbation of schizophrenia. NNT and NNH values, with 95% CIs, were calculated in this post hoc analysis. Results:Using the intent-to-treat population for the pooled doses of aripiprazole lauroxil (441 mg [n=196] and 882 mg [n=204] q4w), responder rates (?30% improvement from baseline PANSS total score) were 35.3% for aripiprazole lauroxil arms vs 18.4% for placebo (n=196), yielding a NNT of 6 (95% CI: 5-11). Discontinuation rates due to adverse events (AEs) were higher among patients randomized to placebo than to either aripiprazole lauroxil dose. Akathisia was the only AE with an incidence ?5% in each aripiprazole lauroxil group and at least twice that of placebo (11.6%, 11.5%, and 4.3% of the patients receiving aripiprazole lauroxil 441 mg, 882 mg, and placebo, respectively), producing a NNH of 14 (95% CI: 9-33) for pooled aripiprazole lauroxil doses vs placebo. Calculating LHH for therapeutic response vs akathisia, aripiprazole lauroxil was 2.3 times more likely to result in a therapeutic response than an incident of akathisia. Conclusion:Using metrics of NNT, NNH, and LHH, aripiprazole lauroxil was an efficacious and well-tolerated intervention in a pivotal study in patients with an acute schizophrenia exacerbation.

Project description:BackgroundAripiprazole lauroxil (AL) is an FDA-approved treatment for schizophrenia. AL is a non-ester prodrug of aripiprazole that results in extended systemic release of aripiprazole after intramuscular (IM) administration. This Phase-1 study evaluated the pharmacokinetics (PK) and safety of a new AL dose (1064 mg)* for 2-month dose intervals. The study also evaluated 4- and 6-week dose intervals of AL at the 441 mg and 882 mg doses, respectively.MethodsA total of 139 patients diagnosed with schizophrenia and stabilized on a first-line antipsychotic (other than aripiprazole) were randomized to one of 3 dose/dose-interval groups: a 4-week interval of AL 441 mg (n = 35), a 6-week interval of AL 882 mg (n = 34), and an 8-week interval of AL 1064 mg IM injection (n = 70). After randomization, AL assignment was open label and administered as gluteal injections over 24 weeks. The total number of injections over this time period was related to the interval: 7 injections for the 441 mg group, 5 for the 882 mg group, and 4 for the 1064 mg group. PK and safety assessments occurred every 2 weeks and extended for an additional 20 weeks after the last injection. Patients continued their prior antipsychotic throughout, such that the safety (but not the PK) findings also reflect a second antipsychotic co-prescribed with AL.ResultsPK findings: administration of AL 1064 mg every 8 weeks and AL 882 mg every 6 weeks provided continuous exposure to aripiprazole. Compared with the AL 441 mg every 4 weeks group, the longer dose-interval groups had consistently higher plasma concentrations for the entirety of the 6- and 8-week dose intervals for the 882 mg and 1064 mg dose groups. Safety findings: the overall safety profile of the group randomized to the 8 week/1064 mg combination was comparable to the 6 week/882 mg and 4 week/441 mg groups. The most common adverse event (AE) for all groups was injection-site reaction (pain). There was no apparent dose-AE signal for extrapyramidal symptoms, akathisia, sedation, or weight gain. In particular, there was no other safety signal identified with the longest interval/highest-dose AL group of 8 weeks/1064 mg.ConclusionAL allows for a range of dose/dose-interval combinations. The PK results from this study show that a dosing interval of every 8 weeks for the 1064 mg dose resulted in aripiprazole concentrations within the established therapeutic window for AL. There was no safety signal directing any particular concern to any of the three doses/dose intervals studied. All patients continued their primary antipsychotics without any apparent tolerability issue arising from the addition of the AL injections. The results of this study show that 1064 mg AL may be suitable for a 2-month dose interval. The three doses/dose intervals studied have the potential to help clinicians and patients expand their choice of AL treatment to best meet the needs of the individual patient.

Project description:BACKGROUND AND OBJECTIVES: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia, requires 21 days of oral aripiprazole supplementation upon initiation (21-day initiation regimen). An alternative 1-day initiation regimen utilizing a nano-crystalline milled dispersion of AL (ALNCD) plus a single 30 mg oral aripiprazole dose achieved aripiprazole concentrations associated with therapeutic doses of aripiprazole in the same time frame as the 21-day initiation regimen when starting AL (441 or 882 mg). A population pharmacokinetic (PopPK) model was developed to describe aripiprazole pharmacokinetics following administration of ALNCD, AL and oral aripiprazole, and evaluate dosing scenarios likely to be encountered in clinical practice. METHODS:In total, 12,768 plasma aripiprazole concentrations from 343 patients (from 4 clinical studies) were included in the PopPK analysis and used to construct the model. RESULTS:Concomitant administration of the 1-day initiation regimen with all approved AL dosing regimens (441, 662, or 882 mg monthly, 882 mg every 6 weeks, or 1064 mg every 2 months) is predicted to achieve aripiprazole concentrations associated with therapeutic doses of AL using the 21-day initiation regimen within 4 days, maintaining these concentrations until the next AL dose. Administration of the first AL injection 10 days after the 1-day initiation regimen resulted in median aripiprazole concentrations just before the second dose of AL ≥ 77% of that when coadministered on the same day. Coadministration of AL with a single ALNCD injection was predicted to be effective in rapidly re-establishing concentrations associated with therapeutic doses of AL following dose delay. CONCLUSIONS:Model-based simulations demonstrate that the 1-day initiation regimen is suitable for starting treatment with all AL doses, allowing a window of ≤ 10 days between initiation and AL administration. ALNCD may also be used to re-establish concentrations associated with therapeutic doses of AL in conjunction with a delayed AL dose.

Dataset Information

Metabolic and Endocrine Profiles During 1-Year Treatment of Outpatients with Schizophrenia with Aripiprazole Lauroxil.

Publications

Metabolic and Endocrine Profiles During 1-Year Treatment of Outpatients with Schizophrenia with Aripiprazole Lauroxil.

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