S226. A STUDY COMPARING WEIGHT GAIN FROM ALKS 3831 TO OLANZAPINE IN EARLY-ILLNESS YOUNG ADULTS WITH SCHIZOPHRENIFORM, SCHIZOPHRENIA, OR BIPOLAR I DISORDER
ABSTRACT: Abstract Background Optimal pharmacological efficacy is crucial in first-episode and early-episode schizophrenia and bipolar I disorder. Olanzapine (OLZ) is a highly efficacious antipsychotic indicated for the treatment of schizophrenia and bipolar I disorder. However, the clinical utility of OLZ may be limited by a propensity to cause significant weight gain and increased metabolic side effects, especially for patients early in the course of their illness. ALKS 3831 is composed of a flexible dose of olanzapine (OLZ) and a fixed dose of 10 mg of samidorphan (SAM), formulated as a bilayer tablet. ALKS 3831 has been shown in Phase 1 and Phase 2 studies to result in significantly less weight gain than OLZ while delivering equivalent antipsychotic efficacy. This Phase 3, 12-week study, is designed to evaluate the effect of ALKS 3831 on body weight in young adults early in the course of diagnosis of a serious mental illness, including a schizophreniform, schizophrenia, or bipolar I disorder diagnosis. Methods This is an international (Austria, Germany, Ireland, Israel, Italy, Poland, Spain, UK, and USA) two-arm, double-blind, active-comparator–controlled, multicentre study (planned N=250) that started enrollment in 2017. Key inclusion criteria are a primary diagnosis of schizophreniform disorder, schizophrenia, or bipolar I disorder; a body-mass index (BMI) of ?18.0 and ?27.0 kg/m2; and meeting specific criteria for duration of illness and prior antipsychotic exposure. Patients with a bipolar I diagnosis must be in the manic phase. In the US sites, men and women must be aged ?16 to <40 years at screening, and in Europe, aged ?18 to <40 years. Exclusion criteria include diagnosis of additional psychiatric conditions and use of prohibited drugs. Results Patients will be randomised 1:1 to receive either OLZ or ALKS 3831 treatment for 12 weeks. ALKS 3831 (OLZ + SAM) and matched OLZ + placebo (OLZ + PBO) will be provided as bilayer tablets to be taken by mouth once daily and doses will include ALKS 3831 (OLZ/SAM) 5/10 mg, 10/10 mg, 15/10 mg, 20/10 mg, or (OLZ/PBO) 5 mg, 10 mg, 15 mg, or 20 mg. The primary endpoint will be percent change in body weight from baseline to Week 12. Secondary and exploratory endpoints will include the proportion of patients who gain ?7% and ?10% of baseline body weight, metabolic parameters (change in fasting lipids and glucose), body composition measured through bioimpedance, clinical global impression, and safety, pharmacokinetic, and pharmacodynamic parameters. Patients will be offered a supportive clinical care programme during the 12-week treatment period, and also receive a daily medication-adherence monitoring and reminder system (via smartphones). Discussion Patients who complete the study will have the option to participate in an open-label 2-year extension of ALKS 3831 (based on clinician and patient decision). EudraCT number: 2017-000497-11; ClinicalTrials.gov identifier: NCT03187769
Project description:The objective of this study was to evaluate the relative bioavailability of olanzapine in 3 olanzapine-containing tablet formulations. ALKS 3831 is a fixed-dose combination of olanzapine (OLZ, an atypical antipsychotic) and samidorphan (SAM, a μ-opioid receptor antagonist with low intrinsic activity at δ- and κ-opioid receptors), intended to provide the efficacy of OLZ while mitigating its known weight and metabolic effects. Relative bioavailability of OLZ in ALKS 3831, a bilayer tablet containing OLZ and SAM, a matching bilayer tablet containing OLZ only (OLZ), and Zyprexa (brand olanzapine [B-OLZ]) was assessed in an open-label study. Forty-eight healthy volunteers were randomly assigned to receive single oral doses of ALKS 3831 (10 mg OLZ/10 mg SAM), OLZ (10 mg OLZ), and B-OLZ (10 mg B-OLZ) on day 1 of each treatment period. Blood samples for pharmacokinetic evaluation were collected before and after each dose. Ratios of OLZ AUC0-∞ , AUC0-t , and Cmax were compared between treatments and tested for bioequivalence, determined by 90%CIs of the geometric mean ratios (GMRs). GMRs of OLZ AUC0-∞ , AUC0-t , and Cmax were close to 1, and the 90%CIs of the GMRs were contained within the bioequivalence limit of 80%-125% for comparison of ALKS 3831 with B-OLZ, ALKS 3831 with OLZ, and OLZ with B-OLZ, demonstrating bioequivalence of OLZ in ALKS 3831, OLZ, and B-OLZ.
Project description:Abstract Background ALKS 3831, currently under development for the treatment of schizophrenia, is composed of a flexible dose of olanzapine (OLZ) and a fixed dose of 10 mg of samidorphan. In a Phase 2 study, ALKS 3831 mitigated OLZ-associated weight gain and exhibited antipsychotic efficacy similar to OLZ alone. This Phase 3 study assessed antipsychotic efficacy and safety of ALKS 3831 in patients with acute exacerbation of schizophrenia. Methods This was an international (USA, Ukraine, Serbia, and Bulgaria), 4-week, randomised, double-blind, active and placebo (PBO)-controlled study of ALKS 3831 in patients with acute exacerbation of schizophrenia (ClinicalTrials.gov: NCT02634346). Eligible patients (N=403) were randomised 1:1:1 to receive either ALKS 3831, OLZ, or PBO. Patients were treated in an inpatient setting for the first 2 weeks of the study and could be treated as inpatients or outpatients for the remaining 2 weeks. Patients were excluded if they received OLZ within 6 months prior to screening. Antipsychotic efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression–Severity (CGI-S), and CGI–Improvement (CGI-I) scales. Safety and tolerability were assessed as adverse events (AEs). Results Of 401 patients randomised and dosed to ALKS 3831, OLZ, and PBO, 91%, 89%, and 83% of patients, respectively, completed treatment. The most common reason for discontinuation was withdrawal by patient (6% in both the ALKS 3831 and PBO groups, and 7% in the OLZ group). Baseline characteristics were generally similar between groups; however, baseline mean body-mass index was higher in the OLZ group than in the ALKS 3831 group. Baseline mean ± standard deviation scores were 101.7 ± 11.9 for PANSS total score and 5.1 ± 0.7 for CGI-S score. The mean OLZ dose was 18.4 mg/day in both active treatment arms. Least squares (LS) mean difference ± standard error (SE) versus PBO from baseline to Week 4 in PANSS total score was –6.4 ± 1.8 (P<.001) for the ALKS 3831 group and –5.3 ± 1.8 (P=.004) for the OLZ group. LS mean difference ± SE vs PBO from baseline to Week 4 in CGI-S score was ?0.38 ± 0.12 (P=.002) for the ALKS 3831 group and ?0.44 ± 0.12 (P<.001) for the OLZ group. The percentage of patients with an improvement in PANSS response (?30% improvement from baseline) at Week 4 was 60%, 54%, and 38% in the ALKS 3831, OLZ, and PBO groups, respectively. The percentage of patients with an improvement in CGI-I response (score of ?2) at Week 4 was 58%, 51%, and 33% in the ALKS 3831, OLZ, and PBO groups, respectively. Discontinuation due to AEs was low in all groups. Common AEs (?5%) included weight gain, somnolence, dry mouth, anxiety, headache, and schizophrenia. Discussion ALKS 3831 demonstrated greater antipsychotic efficacy than PBO, as measured by the PANSS and CGI-S scale, and was similar to the active control, OLZ. The safety profile of ALKS 3831 was similar to OLZ.
Project description:Background: Alcohol use disorder (AUD) is a common comorbidity in patients with schizophrenia. Although pharmacological options for the management of each disease exist separately, there is no agent approved for both. Moreover, studies conducted in this patient population, who face practical and social challenges as a consequence of being diagnosed with schizophrenia and comorbid AUD, are limited. Methods: We describe the design of a Phase II, double-blind, randomized trial to evaluate adult outpatients with schizophrenia and comorbid AUD receiving a combination of olanzapine plus samidorphan (OLZ+SAM; ALKS 3831), a novel entity currently under development for the treatment of schizophrenia. The combination drug formulation of OLZ+SAM is intended to provide the antipsychotic efficacy of OLZ while mitigating the weight gain and concomitant metabolic abnormalities commonly associated with OLZ alone. In considering this patient population, the novel primary efficacy endpoint is the time from randomization to the first event of exacerbation of disease symptoms (EEDS) based on the occurrence of any of eight prespecified events related to worsening of disease symptoms and/or AUD, as confirmed by a blinded independent adjudication committee. The rate and number of EEDS, improvement in drinking level, and the safety and tolerability of OLZ in combination with SAM will also be assessed. Discussion: A limited number of studies have been conducted in patients with schizophrenia and AUD, and the need for further research in this difficult-to-study population is well documented. This study is, to our knowledge, the largest and longest trial with a randomized, double-blind, active-controlled design. In addition to providing evidence for the development of OLZ+SAM (ALKS 3831) as a therapeutic option, the study aims to provide insights into the clinical management of subjects with schizophrenia and comorbid AUD. Trial registration: Clinical trials NCT02161718, registered May 2014; EudraCT Number: 2014-001211-39.
Project description:Olanzapine (Olz) is one of the most effective antipsychotic drugs commonly used for treating schizophrenia. Unfortunately, Olz administration is associated with severe weight gain and metabolic disturbances. Both patients and clinicians are highly interested in the development of new antipsychotics which are as effective as atypical antipsychotics but which have a lower propensity to induce metabolic side effects. In the present study, we examined two new derivatives of Olz; OlzEt (2-ethyl-4-(4'-methylpiperazin-1'-yl)-10Hbenzo[b]thieno[2,3-e][1,4]diazepine), and OlzHomo (2-ethyl-4-(4'-methyl-1',4'-diazepan-1'-yl)-10H-benzo[b]thieno[2,3-e] [1,4]diazepine), for their tendency to induce weight gain in rats. Weight gain and metabolic changes were measured in female Sprague Dawley rats. Animals were treated orally with Olz, OlzEt, OlzHomo (3 or 6 mg/kg/day), or vehicle (n?=?8), three times daily at eight-hour intervals for 5 weeks. Furthermore, a phencyclidine (PCP)-treated rat model was used to examine the prevention of PCP-induced hyperlocomotor activity relevant for schizophrenia therapy. Male Sprague Dawley rats were pre-treated with a single dose (3 mg/kg/day) of Olz, OlzEt, OlzHomo, or vehicle (n?=?12), for 2 weeks. Locomotor activity was recorded following a subcutaneous injection with either saline or PCP (10 mg/kg). Olz was found to induce weight gain, hyperphagia, visceral fat accumulation, and metabolic changes associated with reduced histamatergic H1 receptor density in the hypothalamus of treated rats. In contrast, OlzEt and OlzHomo presented promising antipsychotic effects, which did not induce weight gain or fat deposition in the treated animals. Behavioural analysis showed OlzEt to attenuate PCP-induced hyperactivity to a level similar to that of Olz; however, OlzHomo showed a lower propensity to inhibit these stereotyped behaviours. Our data suggest that the therapeutic effectiveness of OlzHomo may be delivered at a higher dose than that of Olz and OlzEt. Overall, OlzEt and OlzHomo may offer a better pharmacological profile than Olz for treating patients with schizophrenia. Clinical trials are needed to test this hypothesis.
Project description:A combination of the antipsychotic olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) is intended to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain. As cytochrome P450 (CYP) 1A2 and CYP3A4 are the major enzymes involved in metabolism of olanzapine and samidorphan, respectively, physiologically-based pharmacokinetic (PBPK) modeling was applied to predict any drug-drug interaction (DDI) potential between olanzapine and samidorphan or between OLZ/SAM and CYP3A4/CYP1A2 inhibitors/inducers. A PBPK model for OLZ/SAM was developed and validated by comparing model-simulated data with observed clinical study data. Based on model-based simulations, no DDI between olanzapine and samidorphan is expected when administered as OLZ/SAM. CYP3A4 inhibition is predicted to have a weak effect on samidorphan exposure and negligible effect on olanzapine exposure. CYP3A4 induction is predicted to reduce both samidorphan and olanzapine exposure. CYP1A2 inhibition or induction is predicted to increase or decrease, respectively, olanzapine exposure only.
Project description:Antipsychotic drugs (AP) are used to treat a multitude of psychiatric conditions including schizophrenia and bipolar disorder. However, APs also have metabolic side effects including increased food intake and body weight, but the underlying mechanisms remain unknown. We previously reported that minocycline (MINO) co-treatment abrogates olanzapine (OLZ)-induced hyperphagia and weight gain in mice. Using this model, we investigated the changes in the pharmacometabolome in the plasma and hypothalamus associated with OLZ-induced hyperphagia and weight gain. Female C57BL/6 mice were divided into groups and fed either i) control, CON (45% fat diet) ii) CON?+?MINO, iii) OLZ (45% fat diet with OLZ), iv) OLZ?+?MINO. We identified one hypothalamic metabolite indoxylsulfuric acid and 389 plasma metabolites (including 19 known metabolites) that were specifically associated with AP-induced hyperphagia and weight gain in mice. We found that plasma citrulline, tricosenoic acid, docosadienoic acid and palmitoleic acid were increased while serine, asparagine and arachidonic acid and its derivatives were decreased in response to OLZ. These changes were specifically blocked by co-treatment with MINO. These pharmacometabolomic profiles associated with AP-induced hyperphagia and weight gain provide candidate biomarkers and mechanistic insights related to the metabolic side effects of these widely used drugs.
Project description:Disruption of conditioned avoidance response (CAR) in rodents is one trademark feature of many antipsychotic drugs. In adult rats, repeated olanzapine (OLZ) treatment causes an enhanced disruption of avoidance response (sensitization), whereas repeated clozapine (CLZ) treatment causes a decreased disruption (tolerance). The present study addressed (1) whether OLZ sensitization and CLZ tolerance can be induced in adolescent rats, and (2) the extent to which OLZ sensitization and CLZ tolerance induced in adolescence persists into adulthood. Male adolescent Sprague-Dawley rats (approximate postnatal days (?P) 43-47) were first treated with OLZ (1.0 or 2.0 mg/kg, subcutaneously (sc)) or CLZ (10 or 20 mg/kg, sc) daily for 5 consecutive days in the CAR model. They were then tested for the expression of OLZ sensitization or CLZ tolerance either in adolescence (?P 50) or after they matured into adults (?P 76 and 92) in a challenge test during which all rats were injected with either a lower dose of OLZ (0.5 mg/kg) or CLZ (5.0 mg/kg). When tested in adolescence, rats previously treated with OLZ showed a stronger inhibition of CAR than those previously treated with vehicle (ie, sensitization). In contrast, rats previously treated with CLZ showed a weaker inhibition of CAR than those previously treated with vehicle (ie, tolerance). When tested in adulthood, the OLZ sensitization was still detectable at both time points (?P 76 and 92), whereas the CLZ tolerance was only detectable on ?P 76, and only manifested in the intertrial crossing. Performance in the prepulse inhibition and fear-induced 22 kHz ultrasonic vocalizations in adulthood were not altered by adolescence drug treatment. Collectively, these findings suggest that atypical antipsychotic treatment during adolescence can induce a long-term specific alteration in antipsychotic effect that persists into adulthood despite the brain maturation. As antipsychotic drugs are being increasingly used in children and adolescents in the past two decades, findings from this study are important for understanding the impacts of adolescent antipsychotic treatment on the brain and behavioral developments. This work also has implications for clinical practice involving adolescence antipsychotic treatments in terms of drug choice, drug dose, and schedule.
Project description:When treating schizophrenia, improving patients' productivity level is a major goal considering schizophrenia is a leading cause of functional disability. Productivity level has been identified as the most preferred treatment outcome by patients with schizophrenia. However, little has been done to systematically investigate productivity levels in schizophrenia. We set out to better understand the change in productivity level among chronically ill patients with schizophrenia treated with olanzapine compared with other antipsychotic medications. We also assessed the links between productivity level and other clinical outcomes.This post hoc analysis used data from 6 randomized, double-blind clinical trials of patients with schizophrenia or schizoaffective disorder, with each trial being of approximately 6 months duration. Change in productivity level was compared between olanzapine-treated patients (HGBG, n = 172; HGHJ, n = 277; HGJB, n = 171; HGLB, n = 281; HGGN, n = 159; HGDH, n = 131) and patients treated with other antipsychotic medications (separately vs. haloperidol [HGGN, n = 97; HGDH, n = 132], risperidone [HGBG, n = 167; HGGN, n = 158], quetiapine [HGJB, n = 175], ziprasidone [HGHJ, n = 271] and aripiprazole [HGLB, n = 285]). Productivity was defined as functional activities/work including working for pay, studying, housekeeping and volunteer work. Productivity level in the prior 3 months was assessed on a 5-point scale ranging from no useful functioning to functional activity/work 75% to 100% of the time.Chronically ill patients treated with olanzapine (OLZ) experienced significantly greater improvement in productivity when compared to patients treated with risperidone (RISP) (OLZ = 0.22 ± 1.19, RISP = -0.03 ± 1.17, p = 0.033) or ziprasidone (ZIP) (OLZ = 0.50 ± 1.38, ZIP = 0.25 ± 1.27, p = 0.026), but did not significantly differ from the quetiapine, aripiprazole or haloperidol treatment groups. Among first episode patients, OLZ therapy was associated with greater improvements in productivity levels compared to haloperidol (HAL), during the acute phase (OLZ = -0.31 ± 1.59, HAL = -0.69 ± 1.56, p = 0.011) and over the long-term (OLZ = 0.10 ± 1.50, HAL = -0.32 ± 1.91, p = 0.008). Significantly more chronically ill and first episode patients treated with olanzapine showed moderately high (>50%-75% of the time) and high levels of productivity (>75%-100% of the time) at endpoint, when compared to risperidone or haloperidol-treated patients (p < .05), respectively. Higher productivity level was associated with significantly higher study completion rates and better scores on the positive, negative, disorganized thoughts, hostility and depression subscales of the Positive and Negative Symptom Scale (PANSS).Some antipsychotic medications significantly differed in beneficial impact on productivity level in the long-term treatment of patients with schizophrenia. Findings further highlight the link between clinical and functional outcomes, showing significant associations between higher productivity, lower symptom severity and better persistence on therapy.clinicaltrials.gov identifier NCT00088049; NCT00036088.
Project description:Drug abuse and addiction are excessively common in schizophrenia. Chronic antipsychotic treatment might contribute to this comorbidity by inducing supersensitivity within the brain's dopamine system. Dopamine supersensitivity can enhance the incentive motivational properties of reward cues, and reward cues contribute to the maintenance and severity of drug addiction. We have shown previously that rats withdrawn from continuous haloperidol (HAL) treatment (via subcutaneous minipump) develop dopamine supersensitivity and pursue reward cues more vigorously than HAL-naive rats following an amphetamine (AMPH) challenge. Atypical antipsychotic drugs are thought to be less likely than typicals to produce dopamine supersensitivity. Thus, we compared the effects of HAL and the atypical antipsychotic olanzapine (OLZ) on the pursuit of reward cues. Rats were trained to associate a light-tone cue with water then treated with HAL or OLZ. Following antipsychotic withdrawal, we assessed AMPH-induced enhancement of lever pressing for the cue. Withdrawal from HAL, but not from OLZ, enhanced this effect. HAL, but not OLZ, also enhanced AMPH-induced psychomotor activation and c-fos mRNA expression in the caudate-putamen. Thus, prior HAL, but not OLZ, enhanced conditioned reward following an AMPH challenge, and this was potentially linked to enhanced behavioral sensitivity to AMPH and AMPH-induced engagement of the caudate-putamen. These findings suggest that HAL, but not an atypical like OLZ, modifies reward circuitry in ways that increase responsiveness to reward cues. Because enhanced responsiveness to reward cues can promote drug-seeking behavior, it should be investigated whether atypical antipsychotics might be a preferential option in schizophrenic patients at risk for drug abuse or addiction.
Project description:This analysis examined patient-reported attitudes toward antipsychotic medication and the relationship of these attitudes with clinical outcomes and pharmacotherapy adherence. The analysis included three randomized, double-blind studies in patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders 4th Edition and randomly assigned to treatment with olanzapine 5-20 mg/day or another antipsychotic (haloperidol 2-20 mg/day, risperidone 2-10 mg/day, or ziprasidone 80-160 mg/day). Patient-reported improvements were significantly greater for olanzapine (n = 488) versus other treatments (haloperidol n = 145, risperidone n = 158, or ziprasidone n = 271) on multiple Drug Attitude Inventory items. A positive attitude toward medication reported by patients was significantly associated with greater clinical improvement on the Positive and Negative Syndrome Scale and lower discontinuation rates. These results suggest that patients' perceptions of treatment benefits are associated with objective clinical measures, including reduction of symptom severity and lower discontinuation rates. Furthermore, olanzapine may be associated with more positive treatment attitudes. These findings may contribute to a better understanding of reasons for treatment adherence from patients' own perspectives.