Effectiveness of Treatments for Ocular Toxoplasmosis.

Purpose: To evaluate the effectiveness of treatments for ocular toxoplasmosis (OT).Methods: A review of charts was conducted from patients who experienced an active episode of OT treated at the Federal University of São Paulo and associated sites. OT charts were reviewed to determine treatment effectiveness based on clinical judgment, taking clinical course and outcome into consideration in addition to change in best-corrected visual acuity. Treatment emergent adverse events (TEAEs) were used to assess safety.Results: Overall, 451/1200 patient charts met the inclusion criteria. The most commonly prescribed treatment was trimethoprim + sulfamethoxazole (52.3%) followed by pyrimethamine + sulfadiazine (28%). Treatment was successful in 96.9% of patients. Irrespective of the treatment, active lesions were resolved in 63.9% of patients within 6 weeks. Vision improved in 56.3% of patients. The incidence of TEAEs was low (10%).Conclusions: All treatments were effective for active episodes of OT, with few side effects.

Proof-of-concept study: Homomorphically encrypted data can support real-time learning in personalized cancer medicine.

BACKGROUND: The successful introduction of homomorphic encryption (HE) in clinical research holds promise for improving acceptance of data-sharing protocols, increasing sample sizes, and accelerating learning from real-world data (RWD). A well-scoped use case for HE would pave the way for more widespread adoption in healthcare applications. Determining the efficacy of targeted cancer treatments used off-label for a variety of genetically defined conditions is an excellent candidate for introduction of HE-based learning systems because of a significant unmet need to share and combine confidential data, the use of relatively simple algorithms, and an opportunity to reach large numbers of willing study participants. METHODS: We used published literature to estimate the numbers of patients who might be eligible to receive treatments approved for other indications based on molecular profiles. We then estimated the sample size and number of variables that would be required for a successful system to detect exceptional responses with sufficient power. We generated an appropriately sized, simulated dataset (n = 5000) and used an established HE algorithm to detect exceptional responses and calculate total drug exposure, while the data remained encrypted. RESULTS: Our results demonstrated the feasibility of using an HE-based system to identify exceptional responders and perform calculations on patient data during a hypothetical 3-year study. Although homomorphically encrypted computations are time consuming, the required basic computations (i.e., addition) do not pose a critical bottleneck to the analysis. CONCLUSION: In this proof-of-concept study, based on simulated data, we demonstrate that identifying exceptional responders to targeted cancer treatments represents a valuable and feasible use case. Past solutions to either completely anonymize data or restrict access through stringent data use agreements have limited the utility of abundant and valuable data. Because of its privacy protections, we believe that an HE-based learning system for real-world cancer treatment would entice thousands more patients to voluntarily contribute data through participation in research studies beyond the currently available secondary data populated from hospital electronic health records and administrative claims. Forming collaborations between technical experts, physicians, patient advocates, payers, and researchers, and testing the system on existing RWD are critical next steps to making HE-based learning a reality in healthcare.

Efficacy and safety of aripiprazole lauroxil once-monthly versus aripiprazole once-monthly long-acting injectable formulations in patients with acute symptoms of schizophrenia: an indirect comparison of two double-blind placebo-controlled studies.

BACKGROUND: Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic recently approved for the treatment of schizophrenia. OBJECTIVE: To indirectly compare the safety and efficacy of AL and aripiprazole once-monthly (AOM). METHODS: A systematic search was performed to identify randomized, controlled trials of AOM and AL that met criteria for indirect comparison according to Bayesian network meta-analysis. The analysis indirectly compared AL and AOM treatment groups for efficacy by mean change in Positive and Negative Syndrome Scale (PANSS) total score and ≥30% reduction in PANSS total score, as well as tolerability including adverse events, akathisia, and weight gain. RESULTS: Two studies were selected, resulting in three active-treatment groups: AL 441 mg, AL 882 mg, and AOM 400 mg. All active treatments were efficacious compared with placebo. There were no differences in indirect comparisons of akathisia. All three groups showed some weight gain, but only the AOM 400 mg group was significantly greater than placebo. CONCLUSIONS: Results of this indirect comparison found that both doses of AL and the single AOM dose were therapeutic and efficacious for the treatment of schizophrenia with a similar safety profile.

Effect of aripiprazole lauroxil in patients with acute schizophrenia as assessed by the Positive and Negative Syndrome Scale-supportive analyses from a Phase 3 study.

OBJECTIVE: Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic that was evaluated for the treatment of schizophrenia in a randomized, placebo-controlled, Phase 3 study. Here, we present exploratory analyses of supportive efficacy endpoints. METHODS: Patients experiencing an acute exacerbation of schizophrenia received AL 441 mg intramuscularly (IM), AL 882 mg IM, or matching placebo IM monthly. Supportive endpoints included changes from baseline at subsequent time points in Clinical Global Impression-Severity (CGI-S) scale score; Positive and Negative Syndrome Scale (PANSS) Total score; PANSS Positive, Negative, and General Psychopathology subscale scores; PANSS Marder factors (post hoc); and PANSS responder rate. Overall response rate, based on PANSS Total score and Clinical Global Impression-Improvement (CGI-I) scale score, was also analyzed. RESULTS: Of 622 patients who were randomized, 596 had ≥1 post-baseline PANSS score. Patients were markedly ill at baseline (mean PANSS Total scores 92-94). Compared with placebo, CGI-S scores; PANSS Positive, Negative, and General Psychopathology subscale scores; and PANSS Marder factors were all significantly (p<0.001) improved by Day 85 with both AL doses, with significantly lower scores starting from Day 8 in most instances. Treatment response rates were significantly (p<0.001) greater with both doses of AL vs placebo. CONCLUSION: AL demonstrated robust efficacy on CGI-S score, PANSS subscale scores, PANSS Marder factors, and response rates. Study limitations included use of a fixed dose for initial oral aripiprazole and fixed monthly AL doses without the option to individualize the oral initiation dosing or injection frequency for efficacy, tolerability, or safety.

Approving cancer treatments based on endpoints other than overall survival: an analysis of historical data using the PACE Continuous Innovation Indicators™ (CII).

BACKGROUND: There is an active debate about the role that endpoints other than overall survival (OS) should play in the drug approval process. Yet the term 'surrogate endpoint' implies that OS is the only critical metric for regulatory approval of cancer treatments. We systematically analyzed the relationship between U.S. Food and Drug Administration (FDA) approval and publication of OS evidence to understand better the risks and benefits of delaying approval until OS evidence is available. SCOPE: Using the PACE Continuous Innovation Indicators (CII) platform, we analyzed the effects of cancer type, treatment goal, and year of approval on the lag time between FDA approval and publication of first significant OS finding for 53 treatments approved between 1952 and 2016 for 10 cancer types (n = 71 approved indications). FINDINGS: Greater than 59% of treatments were approved before significant OS data for the approved indication were published. Of the drugs in the sample, 31% had lags between approval and first published OS evidence of 4 years or longer. The average number of years between approval and first OS evidence varied by cancer type and did not reliably predict the eventual amount of OS evidence accumulated. CONCLUSIONS: Striking the right balance between early access and minimizing risk is a central challenge for regulators worldwide. We illustrate that endpoints other than OS have long helped to provide timely access to new medicines, including many current standards of care. We found that many critical drugs are approved many years before OS data are published, and that OS may not be the most appropriate endpoint in some treatment contexts. Our examination of approved treatments without significant OS data suggests contexts where OS may not be the most relevant endpoint and highlights the importance of using a wide variety of fit-for-purpose evidence types in the approval process.

Dynamic value assessments in oncology supported by the PACE Continuous Innovation Indicators.

AIM: Several recently developed frameworks aim to assess the value of cancer treatments, but the most appropriate metrics remain uncertain. METHODS: We use data from the Patient Access to Cancer care Excellence Continuous Innovation Indicators to examine the relationship between hazard ratios (HRs) from clinical trials and dynamic therapeutic value accumulating over time. RESULTS: Our analysis shows that HRs from initial clinical trials poorly predict the eventual therapeutic value of cancer treatments. CONCLUSION: Relying strongly on HRs from registration trials to predict the long-term success of treatments leaves a lot of the variance unexplained. The Continuous Innovation Indicators offer a complementing, dynamic method to track the therapeutic value of cancer treatments and continuously update value assessments as additional evidence accumulates.

Aripiprazole Lauroxil Compared with Paliperidone Palmitate in Patients with Schizophrenia: An Indirect Treatment Comparison.

BACKGROUND: Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic recently approved for treatment of schizophrenia on the basis of a large-scale trial of two doses of AL versus placebo. There are no direct-comparison studies with paliperidone palmitate (PP; long-acting antipsychotic used most often in acute settings) for the acute psychotic episode. OBJECTIVES: To indirectly compare efficacy and safety of the pivotal AL study with all PP studies meeting indirect comparison criteria. METHODS: Systematic searches of MEDLINE, Embase, Cochrane CENTRAL, PsycINFO, ClinicalTrials.gov, International Clinical Trials Registry Platform, and gray literature were performed to identify randomized controlled trials of PP with similar designs to the AL trial. Bayesian network meta-analysis compared treatments with respect to symptom response and tolerability issues including weight gain, akathisia, parkinsonism, and likelihood of treatment-emergent adverse events. RESULTS: Three appropriate PP studies were identified for indirect comparison. Both doses of AL (441 mg and 882 mg monthly) were used and compared with two efficacious doses of PP (156 mg and 234 mg monthly). All four active-treatment conditions were associated with comparable reductions in acute symptoms (Positive and Negative Syndrome Scale) versus placebo and were of similar magnitude (range of mean difference -8.12 to -12.01, with overlapping 95% credible intervals). Between-group comparisons of active-treatment arms were associated with summary estimates of magnitude near 0. No clinically meaningful differences in selected safety or tolerability parameter incidence were found between active treatments. CONCLUSIONS: These results suggest that both AL and PP are effective for treatment of adults experiencing acute exacerbation of schizophrenia.

Efficacy and safety of aripiprazole lauroxil in schizophrenic patients presenting with severe psychotic symptoms during an acute exacerbation.

Aripiprazole lauroxil (AL), a new long-acting injectable antipsychotic, demonstrated safety and efficacy in treating acute exacerbation symptoms of schizophrenia in a 12-week placebo-controlled trial of two doses of AL (441mg and 882mg) administered every 4weeks. We performed a post hoc analysis of this trial to evaluate the efficacy of AL in the subgroup of patients with severe psychotic symptoms, defined as those with baseline Positive and Negative Syndrome Scale (PANSS) Total score above the median score of 92 (n=309). Change from baseline to Day 85 in PANSS Total score; Positive, Negative, and General Psychopathology subscale scores; and overall response rate were assessed. Statistically significant and clinically meaningful improvements in PANSS Total score were demonstrated with AL 441mg and AL 882mg, with placebo-adjusted differences of -14.7 (p<0.0001) and -16.6 (p<0.0001), respectively. Significant and clinically meaningful findings with both doses of AL were also demonstrated for the PANSS subscales and responder rates. Overall responder rates at Day 85 were significantly greater for AL 441mg (49%; p<0.001) and 882 mg (61%; p<0.001) groups vs. placebo (18%). Common adverse events (>5%) were schizophrenia, akathisia, headache, insomnia, and anxiety. AL demonstrated robust efficacy in treatment of the subgroup of patients experiencing severe psychotic symptoms. Both doses (441mg and 882mg) were effective, with numerically greater improvement in symptoms and proportion of responders favoring the higher dose arm. Both doses had a side effect profile consistent with the known safety profile of aripiprazole.

Open-label Study of Injectable Extended-release Naltrexone (XR-NTX) in Healthcare Professionals With Opioid Dependence.

OBJECTIVES: Healthcare professionals (HCPs) with opioid dependence are at risk for relapse and death, particularly in the first year of recovery; however, maintenance treatment with opioid agonists is controversial in this safety-sensitive group. We evaluated long-term safety, tolerability, and treatment outcomes of injectable, intramuscular, extended-release naltrexone (XR-NTX) in opioid-dependent HCPs. METHODS: This single-arm, multisite, open-label study was conducted in opioid-dependent HCPs who had been detoxified from opioids for at least 2 weeks. Subjects received monthly XR-NTX injections for up to 24 months, combined with counseling via intensive outpatient substance abuse treatment programs. Assessments included monthly urine opioid drug tests and routine safety assessments, along with a trimonthly short form (36) Health Survey, opioid craving questionnaire, and Treatment Satisfaction Questionnaire for Medication. RESULTS: Of 49 opioid-dependent HCPs screened, 38 enrolled and received at least 1 XR-NTX injection. Most were female (n = 31) and nurses or nursing assistants (n = 30). More than half (n = 21; 55.3%) received at least 12 injections. Seven discontinued due to adverse events (3 anxiety, 2 headache, 1 injection-site mass, 1 derealization). None experienced relapses to opioid dependence necessitating detoxification, overdose, or death during treatment. At 24 months, mean opioid craving fell by 45.2%, and short form (36) mental component scores improved by 31.1% from baseline and approached normal levels. Of 22 unemployed subjects at baseline, 45.5% improved employment status at 24 months. CONCLUSIONS: Long-term (2 years) XR-NTX was associated with no new safety concerns, and, compared with shorter-term studies in the general population, similar or better rates of retention, opioid-negative urines, opioid craving reduction, mental health functional quality of life improvement, and re-employment.

Toxoplasmic encephalitis relapse rates with pyrimethamine-based therapy: systematic review and meta-analysis.

Toxoplasmic encephalitis (TE) is caused by Toxoplasma gondii infection and can be a life-threatening disease in immunocompromised patients. This study evaluated the rate of relapse associated with pyrimethamine-based maintenance therapy (i.e. secondary prophylaxis) in patients with human immunodeficiency virus (HIV) or AIDs treated prior to and after the common use (i.e. 1996) of highly active antiretroviral therapy (HAART) (pre-HAART and post-HAART, respectively). PubMed, Google Scholar, and Cochrane databases were searched to 6 June 2016 using search terms: pyrimethamine, Daraprim, Fansidar, Metakelfin, Fansimef, 5-(4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine, encephalitis, cerebral, toxoplasmosis, toxoplasmic, and gondii. Single-arm cohort, retrospective, and randomized studies were included. Twenty-six studies with 1,596 patients were included in the analysis; twenty pre-HAART (n = 1,228) studies and six post-HAART (n = 368) were performed. Pooled proportions test for pyrimethamine-based therapy from pre-HAART studies indicated a relapse rate of 19.2% and 18.9% from the fixed-effects and random-effects models, respectively. The relapse rate in the post-HAART studies was 11.1% (fixed and random effects). Continuous therapy was suggestive of lower incidence of relapse compared with intermittent therapy in the pre-HAART era (range, 18.7 to 17.3% vs. 20.9 to 25.6%, respectively). These findings indicate that the likelihood of relapse associated with pyrimethamine-based therepy in patients with HIV and TE decreased after the introduction of HAART to approximately 11%. The findings have important implications as relapse may affect a patient's disease severity and prognosis, increase utilization of health care resources, and result in additional health care expenditure.

Effect of Aripiprazole Lauroxil on Metabolic and Endocrine Profiles and Related Safety Considerations Among Patients With Acute Schizophrenia.

OBJECTIVE: Aripiprazole lauroxil, a long-acting injectable antipsychotic, demonstrated safety and efficacy in treating symptoms of schizophrenia in a double-blind, placebo-controlled trial. Because the metabolic profile of antipsychotics is an important safety feature, the effects of aripiprazole lauroxil on body weight, endocrine and metabolic profiles, and safety were examined in a secondary analysis. METHODS: Patients with schizophrenia (DSM-IV-TR criteria) were randomly assigned to aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, or placebo intramuscularly once monthly between December 2011 and March 2014. Changes in body weight, body mass index, fasting blood glucose and serum lipids, glycosylated hemoglobin (HbA1c), and prolactin over 12 weeks were assessed. The incidence of treatment-emergent adverse events (AEs) was evaluated. RESULTS: Among 622 randomized patients, no clinically relevant changes from baseline to week 12 were observed for any serum lipid, lipoprotein, plasma glucose, or HbA1c value with placebo or either dose of aripiprazole lauroxil. Both doses of aripiprazole lauroxil were associated with reductions in mean prolactin levels, whereas placebo treatment was not. The mean (standard deviation) change from baseline for body weight was 0.74 (3.9) kg, 0.86 (3.7) kg, and 0.01 (3.6) kg for aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, and placebo groups, respectively. AEs related to metabolic parameters were reported in 2.4%, 1.4%, and 2.4% of patients in the aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, and placebo groups, respectively. CONCLUSIONS: Aripiprazole lauroxil was well tolerated, with a low-risk metabolic profile relative to published data for other antipsychotics. Changes similar to those observed with placebo were observed in the aripiprazole lauroxil groups for metabolic parameters, with modest weight gain in the active treatment groups over the 12-week course. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01469039.

Clinical benefits and impact of early use of long-acting injectable antipsychotics for schizophrenia.

AIM: Results from clinical trials support the use of oral antipsychotics for treatment of early or first-episode psychosis in patients with schizophrenia. This paper will review literature on the advantages of early initiation of treatment for schizophrenia and the clinical benefits of early use of long-acting injectable antipsychotics (LAIs). METHOD: A comprehensive literature review was conducted to identify published literature on the use of LAIs early in the treatment of schizophrenia. RESULTS: Although there is a higher response rate to initial antipsychotic treatment for a first-episode of schizophrenia than with subsequent antipsychotic treatment, we have not effectively addressed this issue. Poor adherence to treatment is a primary cause of relapse and rehospitalization in subsequent years and was associated with higher relapse rates resulting in devastating effects and substantial economic burden. The costs of nonadherence were estimated to be $1.48 billion. Thus, a major challenge with the treatment of schizophrenia is changing poor adherence to persistence with antipsychotic therapy. LAIs are known to be at least as effective as oral antipsychotics for treating schizophrenia, and yet are underutilized. Further, LAIs address many of the problems associated with adherence to oral therapy. Recent evidence suggests that LAIs are effective for treating first-episode psychosis and for early initiation of treatment for schizophrenia. CONCLUSION: Although consistent antipsychotic treatment represents a critical part of treatment, a person-centred approach to treating schizophrenia is essential for all aspects of care, including establishing and maintaining a therapeutic alliance, strengthening shared decision-making and adherence, and achieving long-lasting recovery.

Effect of aripiprazole lauroxil on agitation and hostility in patients with schizophrenia.

This study aimed to evaluate the effects of aripiprazole lauroxil on hostility and aggressive behavior in patients with schizophrenia. Patients aged 18-70 years with a diagnosis of schizophrenia and currently experiencing an acute exacerbation or relapse were randomized to intramuscular (IM) aripiprazole lauroxil 441 mg (n=207), 882 mg (n=208), or placebo (n=207) for 12 weeks. In post-hoc analyses, hostility and aggression were assessed by the Positive and Negative Syndrome Scale (PANSS) Hostility item (P7) and a specific antihostility effect was assessed by adjusting for positive symptoms of schizophrenia, somnolence, and akathisia. The PANSS excited component score [P4 (Excitement), P7 (Hostility), G4 (Tension), G8 (Uncooperativeness), and G14 (Poor impulse control)], and the Personal and Social Performance scale disturbing and aggressive behavior domain were also assessed. Of the 147 patients who received aripiprazole lauroxil 882 mg and with a baseline PANSS Hostility item P7 more than 1, there was a significant (P<0.05) improvement versus placebo on the PANSS Hostility item P7 score by mixed-model repeated-measures at the end of the study, which remained significant when PANSS-positive symptoms and somnolence or akathisia were included as additional covariates. The proportion with PANSS Hostility item P7 more than 1 at endpoint was significantly (P<0.05) lower with aripiprazole lauroxil versus placebo (53.6, 46.1, and 66.3% for 441, 882 mg, and placebo). A significant (P<0.05) improvement was found with aripiprazole lauroxil versus placebo for change from baseline in the PANSS excited component score. The proportion of patients with aggressive behavior on the Personal and Social Performance scale was significantly (P<0.05) lower for aripiprazole lauroxil: 30.0% for 441 mg versus 44.1% for placebo (P=0.006) and 22.2% for 881 mg (P<0.001 versus placebo). Treatment with aripiprazole lauroxil resulted in decreases in agitation and hostility in patients with schizophrenia and this antihostility effect appears to be independent of a general antipsychotic effect.

Antipsychotic Adherence and Rehospitalization in Schizophrenia Patients Receiving Oral Versus Long-Acting Injectable Antipsychotics Following Hospital Discharge.

BACKGROUND: Antipsychotic medications are a central component of effective treatment for schizophrenia, but nonadherence is a significant problem for the majority of patients. Long-acting injectable (LAI) antipsychotic medications are a recommended treatment option for nonadherent patients, but evidence regarding their potential advantages has been mixed. Observational data on newer, second-generation LAI antipsychotic medications have been limited given their more recent regulatory approval and availability. OBJECTIVE: To examine antipsychotic medication nonadherence, discontinuation, and rehospitalization outcomes in Medicaid patients receiving oral versus LAI antipsychotic medications in the 6 months after a schizophrenia-related hospitalization. METHODS: The 2010-2013 Truven Health Analytics MarketScan Medicaid research claims database was used to identify adult patients with a recent history of nonadherence (prior 6 months) who received an oral or LAI antipsychotic medication within 30 days after an index schizophrenia-related hospitalization. Primary outcome measures were nonadherence (proportion of days covered less than 0.80), discontinuation (continuous medication gap ≥ 60 days), and schizophrenia-related rehospitalization, all in the 6 months after discharge. Descriptive analyses compared users of oral versus LAI antipsychotic medication on sociodemographic, clinical, and treatment characteristics. Logistic regressions were used to examine associations between use of oral versus LAI antipsychotics and each study outcome while controlling for observed differences in sample characteristics. All outcomes were compared at 3 levels of analysis: overall LAI class, LAI antipsychotic generation (first-generation [FGA] or second-generation [SGA] antipsychotics), and individual LAI agent (fluphenazine decanoate, haloperidol decanoate, risperidone LAI, and paliperidone palmitate). RESULTS: Of the final sample, 91% (n = 3,428) received oral antipsychotics, and 9.0% (n = 340) received LAI antipsychotics after discharge. Slightly over half (n =183, 53.8%) of LAI users used an SGA LAI. A smaller percentage of patients receiving LAIs were nonadherent (51.8% vs. 67.7%, P less than 0.001); had a 60-day continuous gap in medication (23.8% vs. 39.4%, P less than 0.001); and were rehospitalized for schizophrenia (19.1% vs. 25.3%, P = 0.01) compared with patients receiving oral medications. The size of these differences was magnified when comparing SGA LAI users with users of oral antipsychotics for nonadherence. After controlling for all differences in measured covariates, LAI initiators had lower odds of being nonadherent (adjusted odds ratio [AOR] = 0.35, 95% CI = 0.27-0.46, P less than 0.001) and of having continuous 60-day gaps (AOR = 0.45, 95% CI = 0.34-0.60, P less than 0.001) when compared with patients receiving oral medications. Both FGA and SGA LAI users had lower odds of nonadherence compared with patients receiving oral antipsychotics. Similarly, FGA LAI users (AOR = 0.58, 95% CI = 0.40-0.85, P = 0.005) and SGA LAI initiators (AOR = 0.34, 95% CI =0.23-0.51, P less than 0.001) had lower odds of a 60-day continuous gap compared with patients receiving oral antipsychotics. Compared with those receiving oral antipsychotics, LAI initiators also had lower odds of rehospitalization (AOR = 0.73, 95% CI = 0.54-0.99, P = 0.041); however, when examined separately, only patients receiving SGA LAIs (AOR = 0.59, 95% CI = 0.38-0.90, P = 0.015) and not FGA LAIs (AOR = 0.90, 95% CI = 0.60-1.34, P = 0.599) had a statistically significant reduction in odds of rehospitalization. Among individual LAIs, odds of rehospitalization only among initiators of paliperidone palmitate were statistically different from those among users of oral antipsychotics (AOR = 0.53, 95% CI = 0.30-0.94, P = 0.031). While odds of rehospitalization were 33% lower among patients receiving risperidone LAI compared with those receiving oral antipsychotics, the estimate did not reach statistical significance (AOR = 0.67, 95% CI = 0.37-1.22, P = 0.194).  CONCLUSIONS: This claims-based analysis of posthospitalization adherence and rehospitalization outcomes in Medicaid patients with schizophrenia adds to the growing real-world evidence base of the benefits of LAI antipsychotic medications in routine clinical practice, particularly with regard to second-generation LAIs. As new SGA formulations become available for long-acting use, real-world studies with larger sample sizes will be needed to further delineate their potential advantages in terms of clinical outcomes and costs.

A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia.

OBJECTIVE: This study evaluated the efficacy, safety, and tolerability of aripiprazole lauroxil, a novel long-acting injectable atypical antipsychotic, for the treatment of schizophrenia. METHOD: An international multicenter, randomized, double-blind, placebo-controlled trial was conducted between December 2011 and March 2014. Patients (N = 623) aged 18 to 70 years with schizophrenia (DSM-IV-TR criteria), experiencing an acute exacerbation, were randomized in a 1:1:1 ratio to receive gluteal intramuscular injection of aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, or matching placebo once monthly for 12 weeks. The primary efficacy outcome was change in Positive and Negative Syndrome Scale (PANSS) total score from baseline to day 85. The Clinical Global Impressions-Improvement scale (CGI-I) score at day 85 was the secondary efficacy outcome. Safety and tolerability were assessed. RESULTS: The PANSS total score (mean ± standard error [SE]) improved significantly from baseline to day 85 in the aripiprazole lauroxil 441 mg and 882 mg groups, with placebo-adjusted differences of -10.9 ± 1.8 (P < .001) and -11.9 ± 1.8 (P < .001), respectively. Significant (P ≤ .004) improvements in both active treatment groups were demonstrated as early as day 8 and continued throughout the treatment period. The proportion of patients who were very much or much improved on the CGI-I was significantly greater with aripiprazole lauroxil 441 mg and 882 mg treatment versus placebo (P < .001). The most common treatment-emergent adverse events were insomnia, akathisia, headache, and anxiety. The incidence of injection site reactions was low, predominantly described as injection site pain, and was associated with the first injection. CONCLUSIONS: Aripiprazole lauroxil demonstrated robust efficacy for treatment of patients experiencing acute exacerbation of schizophrenia. The improvement in psychotic symptoms was statistically significant and clinically meaningful. Symptom improvement occurred rapidly after initiation of aripiprazole lauroxil treatment and was maintained throughout the study. Both aripiprazole lauroxil 441 mg and 882 mg doses were well tolerated. These results support aripiprazole lauroxil as an important new treatment option for schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01469039; Clinicaltrialsregister.eu identifier: 2012-003445-15.

Concurrent Oral Antipsychotic Drug Use Among Schizophrenia Patients Initiated on Long-Acting Injectable Antipsychotics Post-Hospital Discharge.

Pharmacological treatment is central to effective management of schizophrenia. Prescribing clinicians have an increasing array of options from which to choose, and oral antipsychotic polypharmacy is common in routine clinical practice. Practice guidelines recommend long-acting injectable (LAI) formulations, typically viewed as monotherapeutic alternatives, for patients with established nonadherence. Yet there are limited data on the prevalence and nature of concurrent oral antipsychotic prescriptions in patients receiving LAIs. Our observational, claims-based study examined the frequency and duration of concurrent oral prescriptions in 340 Medicaid patients receiving LAI therapy. Specifically, we examined patients with a recent history of nonadherence and hospitalization for schizophrenia and included both first-generation antipsychotic depot medications (fluphenazine decanoate, haloperidol decanoate) and more recently available second-generation injectables (LAI risperidone, paliperidone palmitate). Of all patients initiated on LAIs, 75.9% had a concurrent oral antipsychotic prescription in the 6 months post-hospital discharge. Patients receiving concurrent prescriptions were frequently prescribed an oral formulation of their LAI agent, but many first-generation LAI users received a concurrent second-generation oral medication. The lowest rate of concurrent prescribing (58.8%) was found with paliperidone palmitate, whereas the highest rate was with LAI risperidone (88.9%). Overlap in oral and LAI prescriptions typically occurred for a substantial period of time (ie, >30 days) and for a notable percentage of the days covered by LAIs (often 50% or more). Our findings highlight the need to further examine such prescribing patterns, to probe the reasons for them, and to clarify the optimal roles of different antipsychotic treatments in clinical practice.

Treating Opioid Dependence With Injectable Extended-Release Naltrexone (XR-NTX): Who Will Respond?

OBJECTIVES: Once-monthly intramuscular extended-release naltrexone (XR-NTX) has demonstrated efficacy for the prevention of relapse in opioid dependence, providing an alternative to agonist or partial agonist maintenance (ie, methadone and buprenorphine). The question remains, for whom is this unique treatment most efficacious and can patient-treatment matching factors be identified? METHODS: A moderator analysis was conducted on a previously reported 24-week, placebo-controlled, multisite, randomized controlled trial of XR-NTX (n = 126) versus placebo (n = 124) among recently detoxified opioid-dependent adults in Russia, which showed XR-NTX superior to placebo in proportion of opioid abstinent weeks. The moderator analysis examined a dichotomous indicator of good clinical response-achieving at least 90% of weeks abstinent over the 24-week trial. A series of logistic regression models were fit for this outcome as functions of treatment (XR-NTX vs placebo), each baseline moderator variable, and their interactions. The 25 baseline variables included demographics, clinical severity (Addiction Severity Index, SF-36, and Clinical Global Impression-Severity), functioning (EQ-5D), craving, and HIV serostatus (HIV+). RESULTS: More XR-NTX patients achieved 90% abstinence (64/126, 51%) versus placebo (39/124, 31%; P = 0.002). There were no significant interactions between baseline variables and treatment. There was a significant main effect of Clinical Global Impression-Severity score (P = 0.02), such that higher severity score was associated with a lower rate of Good Clinical Response. CONCLUSIONS: The absence of significant baseline by treatment interactions indicates that no patient-treatment matching variables could be identified. This suggests that XR-NTX was effective in promoting abstinence from opioids across a range of demographic and severity characteristics.

Impact of long-acting injectable antipsychotics on medication adherence and clinical, functional, and economic outcomes of schizophrenia.

Schizophrenia is a debilitating chronic disease that requires lifelong medical care and supervision. Even with treatment, the majority of patients relapse within 5 years, and suicide may occur in up to 10% of patients. Poor adherence to oral antipsychotics is the most common cause of relapse. The discontinuation rate for oral antipsychotics in schizophrenia ranges from 26% to 44%, and as many as two-thirds of patients are at least partially nonadherent, resulting in increased risk of hospitalization. A very helpful approach to improve adherence in schizophrenia is the use of long-acting injectable (LAI) antipsychotics, although only a minority of patients receive these. Reasons for underutilization may include negative attitudes, perceptions, and beliefs of both patients and health care professionals. Research shows, however, significant improvements in adherence with LAIs compared with oral drugs, and this is accompanied by lower rates of discontinuation, relapse, and hospitalization. In addition, LAIs are associated with better functioning, quality of life, and patient satisfaction. A need exists to encourage broader LAI use, especially among patients with a history of nonadherence with oral antipsychotics. This paper reviews the impact of nonadherence with antipsychotic drug therapy overall, as well as specific outcomes of the schizophrenia patient, and highlights the potential benefits of LAIs.