Long-term Open-label Study Research Articles

Long-term safety and efficacy of MBA-P01 for the treatment of glabellar lines: results from a multicenter, repeated-dose, open-label extension study

Purpose Following the introduction of new type of botulinum toxin (MBA-P01), a recent phase 3 study demonstrated that MBA-P01 showed comparable efficacy and safety to onabotulinumtoxin A for reducing glabellar lines. The primary objective of this study was to evaluate the long-term safety of repeated MBA-P01 administration for the treatment of glabellar lines. Materials and methods This multicenter, single-group, repeated-dose, long-term open-label extension study evaluated repeated treatment with MBA-P01 (20 U, five treatments over 16 months), with posttreatment evaluation performed up to 52 weeks. Results Based on the safety assessment results, no specific irreversible adverse reactions were associated with the safety profile of MBA-P01. Repeated treatment with MBA-P01 was effective for a treatment duration of 3–5 months. Conclusion In conclusion, multiple cycles of treatment of glabellar lines with MBA-P01 at a dose of 20 U were well tolerated. Clinical trial registration information: This study is registered in ClincalTrials.gov (NCT05321979).

Assessment of prolonged safety and tolerability of erenumab in migraine patients in a long-term open-label study (APOLLON)

BackgroundEfficacy and safety of human monoclonal antibody erenumab used for migraine prophylaxis have been shown in clinical studies. APOLLON is an open-label, multi-center, single arm study, which permits dose adjustments of erenumab and includes an option for a drug holiday. The findings contribute to the accumulating long-term evidence regarding erenumab’s tolerability and safety profile in individuals experiencing episodic and chronic migraines.MethodsThe study population consisted of adult patients with episodic or chronic migraine, who had successfully completed the HER-MES study (NCT03828539). Patients were treated with erenumab for 128 weeks at a flexible dose of either 70 mg or 140 mg. Treatment discontinuation attempts were allowed as voluntary single treatment interruption (‘drug holiday’) of up to 24 weeks.Results701 patients were enrolled in APOLLON. The exposure associated incidence rate (EAIR) of adverse events (AEs) (N = 601) per 100 subject years was 101.71 (95% CI [92.28; 111.14]) meaning a patient could expect having about one adverse event per each year of treatment. EAIR was higher in females (n = 524, EAIR: 104.40, 95% CI [93.93; 114.86]) than in males (n = 77, EAIR: 86.55, 95% CI [65.39; 107.71]) and increased with initial monthly migraine days (MMD) and prior prophylactic treatment failures. A total of 155 patients discontinued erenumab treatment during open-label treatment phase. Of these, 29 were due to AEs (4.1% of total cohort) and out of these 65.5% (N = 19) were considered treatment-related. Safety parameters were in line with HER-MES data and did not reveal new safety signals. Drug holidays were realized by 108 patients (15.4%), of which 64.8% (N = 70) returned to treatment. The mean number of monthly headache days (MHDs), MMDs, and days with acute headache medication significantly increased during drug holiday. After resumption of erenumab treatment, a rapid reduction of the migraine parameters was observed.ConclusionsAPOLLON provides long-term safety and tolerability data confirming the beneficial safety profile of erenumab over a period of 128 weeks. In addition, reversibility of migraine deterioration during drug holiday was shown and most patients returned to their treatment with similar response rates compared to initial treatment.Trial registrationClinicalTrials.gov ID: NCT04084314 (https://clinicaltrials.gov/study/NCT04084314), First submitted: 2019-09-06.

Sustained Improvements with Once-daily Valbenazine in Chorea Associated with Huntington’s Disease: Interim Results from a Long-term Open-label Study (S30.003)

Sustained Improvements with Once-daily Valbenazine in Chorea Associated with Huntington’s Disease: Interim Results from a Long-term Open-label Study (S30.003)

Pediatric Extrapolation Approach for U.S. Food and Drug Administration Approval of Brexpiprazole in Patients Aged 13 to 17 Years with Schizophrenia.

A pharmacokinetic (PK) bridging approach was successfully employed to support the dosing regimen and approval of brexpiprazole in pediatric patients aged 13-17 years with schizophrenia. Brexpiprazole was approved in 2015 for the treatment of schizophrenia and the adjunctive treatment of major depressive disorder in adults based on efficacy and safety data from clinical trials. On January 13, 2020, the US Food and Drug Administration issued a general advice letter to sponsors highlighting the acceptance of efficacy extrapolation of certain atypical antipsychotics from adult patients to pediatric patients considering the similarity in disease and exposure-response relationships. Brexpiprazole is the first atypical antipsychotic approved in pediatrics using this approach. The PK data available from pediatric patients aged 13-17 years have shown high variability due to the limited number of PK evaluable subjects, which limits a robust estimation of differences between adult and pediatric patients. The PK model-based approach was thus utilized to evaluate the appropriateness of the dosing regimen by comparing PK exposures in pediatric patients aged 13-17 years with exposures achieved in adults at the approved doses. In addition to exposure matching, safety data from a long-term open-label clinical study in pediatric patients informed the safety profile in pediatric patients. This report illustrates the potential of leveraging previously collected efficacy, safety, and PK data in adult patients to make a regulatory decision in pediatric patients for the indication of schizophrenia.

Efficacy and Safety of Mepolizumab in the Management of Severe Eosinophilic Asthma: A Systematic Review.

Severe eosinophilic asthma (SEA) is characterized by persistent airway inflammation and frequent exacerbations despite standard treatments. Mepolizumab, a monoclonal antibody that reduces eosinophil levels by targeting interleukin-5, has emerged as an add-on therapy for patients with SEA. This systematic review evaluated mepolizumab's efficacy and safety for treating SEA. A comprehensive literature search was conducted across major databases. Thirty-two studies with over 6,000 patients were included, comprising randomized controlled trials, open-label extensions, and real-world observational analyses. Study quality and risk of bias were assessed using standard tools. Meta-analysis was deemed inappropriate due to heterogeneity. Instead, a narrative synthesis was performed. Mepolizumab significantly reduced exacerbation rates by around 50% and improved symptoms and lung function compared to placebo in pivotal trials. Long-term open-label studies showed sustained reductions in exacerbations and stable lung function for up to 4.5 years. Real-world data demonstrated consistent 50%-90% exacerbation decreases across diverse patient populations over 6-24 months. Mepolizumab exhibited an acceptable safety profile, with mild injection site reactions and headaches as most common adverse events. While specific subgroups may show enhanced responses, mepolizumab displayed broad efficacy regardless of patient demographics or phenotypes. The extensive evidence provides robust support for mepolizumab as an efficacious and safe add-on treatment option for patients with severe, refractory eosinophilic asthma. Further high-quality comparative effectiveness research is warranted to optimize patient selection and positioning among emerging biologics.

Short-term risk and long-term incidence rate of infection and malignancy with IL-17 and IL-23 inhibitors in adult patients with psoriasis and psoriatic arthritis: a systematic review and meta-analysis.

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022363127.

ICEBERG study: an indirect adjusted comparison estimating the long-term benefit of esketamine nasal spray when compared with routine treatment of treatment resistant depression in general psychiatry.

Treatment resistant depression (TRD) affects 10-30% of patients with major depressive disorder. In 4-week trials, esketamine nasal spray (NS) was efficacious vs. placebo when both were initiated in addition to a new selective serotonin or serotonin norepinephrine reuptake inhibitor. However, comparison with an extended range of real-world treatments (RWT) is lacking. ICEBERG was an adjusted indirect treatment comparison using propensity score-based inverse probability weighting, performed on 6-month response and remission data from patients receiving esketamine NS plus oral antidepressant from the SUSTAIN-2 (NCT02497287; clinicaltrials.gov) study, compared with patients receiving other RWT from the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov) study. SUSTAIN-2 was a long-term open-label study of esketamine NS, while the EOTC was conducted at a time when esketamine NS was not available as RWT. Threshold and sensitivity analyses were conducted to assess how robust the primary analyses were. Patients receiving esketamine NS had a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6-53.9]) and remission (33.6% [95% CI 29.7-37.6]) vs. patients receiving RWT (26.4% [95% CI 21.5-31.4] and 18.2% [95% CI 13.9-22.5], respectively), according to rescaled average treatment effect among treated estimates. Resulting adjusted odds ratios (OR) and relative risk (RR) favoured esketamine NS over RWT for 6-month response (OR 2.756 [95% CI 2.034-3.733], p < 0.0001; RR 1.882 [95% CI 1.534-2.310], p < 0.0001) and remission (OR 2.276 [95% CI 1.621-3.196], p < 0.0001; RR 1.847 [95% CI 1.418-2.406], p < 0.0001). Threshold analyses suggested that differences between the two studies were robust, and results were consistent across extensive sensitivity analyses. ICEBERG supports that, at 6 months, esketamine NS has a substantial and significant benefit over RWT for patients with TRD. While results may be affected by unobserved confounding factors, threshold analyses suggested these were unlikely to impact the study conclusions.To view an animated summary of this publication, please click on the Supplementary video.

416 Long-term efficacy of dupilumab in adults with moderate-to-severe atopic dermatitis: results from an open-label extension trial up to 5 years

Abstract Topical therapies often cannot sufficiently control moderate-to-severe atopic dermatitis (AD), a chronic inflammatory skin disease. Systemic immunosuppressants are not recommended for the long-term treatment of moderate-to-severe AD due to safety concerns. Dupilumab is a fully human monoclonal antibody that blocks the shared receptor component for interleukin (IL)-4 and IL-13, inhibiting the key drivers of type 2 inflammation. Data from the open-label extension (OLE) study, LIBERTY AD OLE, (NCT01949311) previously demonstrated acceptable safety and sustained efficacy of dupilumab in adult patients for up to 204 weeks (approximately 4 years). This study aims to assess the long-term efficacy and safety of dupilumab in adult patients with moderate-to-severe AD up to 5 years (the end of this OLE study). Adults (≥18 years) with moderate-to-severe AD who had participated in any dupilumab parent study (phase 1 through phase 3) were enrolled into the long-term, multicenter OLE with a duration of up to 5 years. Initially, patients enrolled in the OLE were treated with 300-mg dupilumab weekly. In 2019, patients remaining in the study transitioned to dupilumab 300 mg every 2 weeks in alignment with the approved dupilumab dose regimen. Concomitant treatments for AD were permitted, including topical corticosteroids and topical calcineurin inhibitors. Data are presented as observed for the overall study population (n = 2677). Of the 2677 patients who enrolled, 2207 completed treatment up to Week 52, 362 up to Week 172 and 334 up to Week 260. The most common reason for study withdrawals during the OLE study period was dupilumab approval and commercialization in the patient’s country of enrollment [708 (51.3%)]. Fifty (1.9%) patients withdrew due to lack of efficacy. At the end of the study period, 88.9% of patients achieved a 75% reduction in Eczema Area and Severity Index (EASI) score from parent study baseline (PSBL) and 76.2% of patients achieved a 90% reduction in EASI score from PSBL. At Week 260, 66.5% of patients achieved a ≥4-point reduction in the Peak Pruritus Numerical Rating Scale score from PSBL. A total of 2276 (85.0%) patients reported treatment-emergent adverse events, and 101 (3.8%) patients discontinued treatment permanently due to reported adverse events. Dupilumab had an acceptable safety profile over 5 years of treatment. In this long-term (5 year/260 weeks) open-label study, dupilumab demonstrated robust efficacy substantiated by sustained improvement of AD signs and symptoms (including skin lesions and pruritus) in adult patients with moderate-to-severe AD. The safety profile was acceptable and consistent with the known safety profile observed in previous dupilumab placebo-controlled studies.

Interim Analysis of Safety and Hematological Parameters of an Ongoing Long-Term Open-Label Extension Study of Investigational PI3Kδ Inhibitor Leniolisib for Patients with Activated PI3K Delta Syndrome (APDS) through December 2021

Interim Analysis of Safety and Hematological Parameters of an Ongoing Long-Term Open-Label Extension Study of Investigational PI3Kδ Inhibitor Leniolisib for Patients with Activated PI3K Delta Syndrome (APDS) through December 2021

34039 Maintenance of skin clearance in a long-term open-label study of fixed-combination halobetasol propionate and tazarotene lotion for psoriasis in participants with prior use of topical treatments

Background: Most patients with psoriasis are dissatisfied with their current treatment, primarily because of limited effectiveness. This post hoc subgroup analysis evaluated long-term efficacy and safety of fixed-combination halobetasol propionate (0.01%) and tazarotene (0.045%) lotion (HP/TAZ) in participants with use of topical corticosteroid (TCS; 137/550 [24.9%]) or other antipsoriatic topical medications (51/550 [9.3%]) before entry in an open-label study of HP/TAZ (NCT02462083).

Safety and Efficacy of 10 kHz Spinal Cord Stimulation for the Treatment of Refractory Chronic Migraine: A Prospective Long-Term Open-Label Study

BackgroundRefractory chronic migraine (rCM) is a highly disabling condition for which novel safe and effective treatments are needed. Safety and long-term efficacy of paresthesia-free high cervical 10 kHz spinal cord stimulation (SCS) were here prospectively evaluated for the treatment of rCM. Materials and MethodsTwenty adults with rCM (mean numbers of preventive treatments failed: 12.2 ± 3.1) were enrolled in this single-center, open-label, prospective study and implanted with a 10 kHz SCS system (Senza™ system, Nevro Corp), with the distal tip of the lead(s) positioned epidurally at the C2 vertebral level. Safety and effectiveness outcomes, such as adverse events, headache and migraine reductions, responder rates, Migraine Disability Assessment (MIDAS), Headache Impact Test-6 (HIT-6), and Migraine-Specific Quality-of-Life (MSQ), were captured up to 52 weeks after implantation. ResultsCompared to baseline, at 52 weeks postimplantation, there was a significant reduction of mean monthly migraine days (MMD) by 9.3 days (p < 0.001). Sixty percent and 50% of patients obtained respectively at least 30% and at least 50% reduction in mean MMD. By week 52, 50% of patients' chronic pattern converted to an episodic pattern. The proportion of subjects classified with severe headache-related disability on the HIT-6, decreased from 100% to 60% at week 52. Meaningful improvements of headache-related quality of life measured by the MSQ scale were observed with mean gain of 24.9 ± 23.1 (p < 0.001) points at 52 weeks. No unanticipated adverse device effects occurred. No patients required any additional device surgical revision. Conclusion10 kHz SCS may a be safe and effective neurostimulation option for rCM patients. The paresthesia-free waveform constitutes an unprecedented advantage for future methodologically sound sham-controlled studies in headache neuromodulation.

Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome

PurposeTo assess the impact of fenfluramine (FFA) on the expected mortality incidence, including sudden unexpected death in epilepsy (SUDEP), in persons with Dravet syndrome (DS). MethodsIn this pooled analysis, total time of exposure for persons with DS who were treated with FFA in phase 3 clinical trials, in United States and European Early Access Programs, and in two long-term open-label observational studies in Belgium was calculated. Literature was searched for reports of SUDEP mortality in DS, which were utilized as a comparison. Mortality rates were expressed per 1000 person-years. ResultsA total of 732 persons with DS were treated with FFA, representing a total of 1185.3 person-years of exposure. Three deaths occurred, all in the phase 3 program: one during placebo treatment (probable SUDEP) and two during treatment with FFA (one probable SUDEP and one definite SUDEP). The all-cause and SUDEP mortality rates during treatment with FFA was 1.7 per 1000 person-years (95% CI, 0.4 to 6.7), a value lower than the all-cause estimate of 15.8 per 1000 person-years (95% CI, 9.9 to 25.4) and SUDEP estimate of 9.3 (95% CI, 5.0 to 17.3) reported by Cooper et al. (Epilepsy Res 2016;128:43−7) for persons with DS receiving standard-of-care. ConclusionAll-cause and SUDEP mortality rates in DS patients treated with FFA were substantially lower than in literature reports. Further studies are warranted to confirm that FFA reduces SUDEP risk in DS patients and to better understand the potential mechanism(s) by which FFA lowers SUDEP risk.Clinical Trial Registration: NCT02926898, NCT02682927, NCT02826863, NCT02823145, NCT03780127.

Efficacy of cenobamate for uncontrolled focal seizures: Post hoc analysis of a Phase 3, multicenter, open-label study.

ObjectiveTo report long‐term post hoc efficacy and safety data from 10 US study sites from an open‐label Phase 3 study of adjunctive cenobamate (NCT02535091).MethodsPatients with uncontrolled focal seizures taking stable doses of 1–3 antiseizure medications (ASMs) were administered increasing daily doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2‐week intervals (target dose = 200 mg/day). Further increases to 400 mg/day by 50‐mg/day increments biweekly were allowed during the maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until the last clinic visit on or after September 1, 2019.ResultsOf 255 patients, 240 with focal aware motor, focal impaired awareness, or focal to bilateral tonic–clonic seizure data while on treatment were evaluated (median [maximum] exposure = 30.2 [43.0] months across the entire study). Median baseline seizure frequency/28 days was 2.8 (mean = 18.1). Of the 240 patients, 177 (73.8%) were continuing cenobamate treatment at data cutoff. The ≥50% responder rate for the total treatment duration was 71.7% (172/240). During titration, the ≥50% responder rates were 48.1% during Weeks 1–4 (12.5–25 mg/day cenobamate) and 61.7% during Weeks 5–8 (50–100 mg/day cenobamate). Among all patients who received a dose of cenobamate in the maintenance phase (n = 214), 13.1% (28/214) and 40.2% (86/214) achieved 100% and ≥90% seizure reduction during their entire maintenance treatment duration (median = 29.5 months). Among all patients, 87 (36.3%) had any consecutive ≥12‐month duration of 100% seizure reduction. Common treatment‐emergent adverse events among all 240 patients included fatigue (34.6%), dizziness (32.1%), and somnolence (29.6%).SignificanceThis post hoc analysis of a subset of patients from the long‐term open‐label study showed high rates of sustained 100% and ≥90% seizure reduction, with many achieving response early during titration. These findings suggest durable seizure frequency reduction with cenobamate in adults with uncontrolled focal seizures.

Long-term open-label continuation study of the safety and efficacy of belimumab for up to 7 years in patients with systemic lupus erythematosus from Japan and South Korea

ObjectivesTo evaluate the long-term safety and efficacy of belimumab in patients with systemic lupus erythematosus (SLE) from Japan and South Korea.MethodsIn this phase III, open-label continuation study (BEL114333; NCT01597622), eligible...

Cariprazine, A Broad-Spectrum Antipsychotic for the Treatment of Schizophrenia: Pharmacology, Efficacy, and Safety.

Schizophrenia is characterized by positive, negative, cognitive, and affective symptoms. Antipsychotic medications, which work by blocking the dopamine D2 receptor, are the foundation of pharmacotherapy for schizophrenia to control positive symptoms. Cariprazine is a dopamine D3 receptor-preferring D3/D2 partial agonist antipsychotic that is approved for the treatment of schizophrenia (USA and European Union [EU]) and manic and depressive episodes associated with bipolar I disorder (USA). Partial agonist agents have a lower intrinsic activity at receptors than full agonists, so they act as either functional agonists or functional antagonists depending on the surrounding neurotransmitter environment. Beyond efficacy against positive symptoms, the unique D3-preferring partial agonist pharmacology of cariprazine suggests potential advantages against negative symptoms, and cognitive and functional impairment, which are challenging to treat. The efficacy and safety of cariprazine in adult patients with schizophrenia have been demonstrated in four short-term randomized, double-blind, placebo-controlled clinical trials, two long-term open-label studies, one relapse prevention study, and one prospective negative symptom study versus the active comparator risperidone. Additional post hoc investigations have supported efficacy across individual symptoms and domains in schizophrenia, as well as in diverse areas of interest including cognition, functioning, negative symptoms, hostility, and global well-being. This comprehensive review of cariprazine summarizes its pharmacologic profile, clinical trial evidence, and post hoc investigations. Collective evidence suggests that the pharmacology of cariprazine may offer broad-spectrum efficacy advantages for patients with schizophrenia, including effects against difficult-to-treat negative and cognitive symptoms, as well as functional improvements. Cariprazine was generally safe and well tolerated in patients with short- and long-term exposure and no new safety concerns were associated with longer-duration treatment.Trial registration ClinicalTrials.gov identifiers, NCT00404573, NCT00694707, NCT01104766, NCT01104779, NCT01412060, NCT00839852, NCT01104792.

Rimegepant is Safe and Tolerable for the Acute Treatment of Migraine in Patients Using Preventive Migraine Medications: Results from a Long-Term Open-Label Safety Study (2370)

Rimegepant is Safe and Tolerable for the Acute Treatment of Migraine in Patients Using Preventive Migraine Medications: Results from a Long-Term Open-Label Safety Study (2370)

Preference for Rimegepant and Improved Clinical Global Impression of Change Among Adults With a History of Triptan Treatment Failure: Results from a Long-Term Open-Label Safety Study (5084)

Preference for Rimegepant and Improved Clinical Global Impression of Change Among Adults With a History of Triptan Treatment Failure: Results from a Long-Term Open-Label Safety Study (5084)

Cardiometabolic Safety of Lumateperone (ITI−007): Post Hoc Analyses of Short-Term Randomized Trials and an Open-Label Long-Term Study in Schizophrenia

Current treatments for schizophrenia are often associated with increased rates of metabolic syndrome (MetSy). MetSy is defined as meeting 3 of the following 5 criteria: waist circumference >40in (men) or >35in (women), triglycerides =150mg/dL, high density lipoprotein cholesterol (HDL) <40mg/dL (men) or <50mg/dL (women), systolic blood pressure (BP) =130mmHg or diastolic BP =85mmHg, fasting glucose =100mg/dL. Patients with MetSy have an elevated risk of developing type II diabetes and increased mortality due to cardiovascular disease. Lumateperone (lumateperone tosylate, ITI-007), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA approved for the treatment of schizophrenia. This distinct pharmacological profile has been associated with favorable tolerability and a low risk of adverse metabolic effects in clinical trials. This post hoc analysis of 2 randomized, double-blind, placebo-controlled studies of patients with an acute exacerbation of schizophrenia compared rates of MetSy with lumateperone and risperidone. Data from an open-label long-term trial of lumateperone were also evaluated. The incidence and shift in MetSy were analyzed in data pooled from 2 short-term (4 or 6 week) placebo- and active-controlled (risperidone 4mg) studies of lumateperone 42mg (Studies 005 and 302). The pooled lumateperone data were compared with data for risperidone. Data from an open-label 1-year trial (Study 303) evaluated MetSy in patients with stable schizophrenia switched from prior antipsychotic (PA) treatment to lumateperone 42mg. In the acute studies (n=256 lumateperone 42mg, n=255 risperidone 4mg), rates of MetSy were similar between groups at baseline (16% lumateperone, 19% risperidone). At the end of treatment (EOT), MetSy was less common with lumateperone than with risperidone (13% vs 25%). More lumateperone patients (46%) compared with risperidone (25%) patients improved from having MetSy at baseline to no longer meeting MetSy criteria at EOT. Conversely, more patients on risperidone than on lumateperone developed MetSy during treatment (13% vs 5%). Differences in MetSy conversion rates were driven by changes in triglycerides and glucose. In the long-term study (n=602 lumateperone 42mg), 33% of patients had MetSy at PA baseline. Thirty-six percent of patients (36%) with MetSy at PA baseline improved to no longer meeting criteria at EOT. Fewer than half that percentage shifted from not meeting MetSy criteria to having MetSy (15%). In this post hoc analysis, lumateperone 42mg patients had reduced rates of MetSy compared with risperidone patients. In the long-term study, patients with MetSy on PA switched to lumateperone 42mg had a reduction in the risk of MetSy. These results suggest that lumateperone 42mg is a promising new treatment for schizophrenia with a favorable metabolic profile. Intra-Cellular Therapies, Inc.

Post hoc analyses of an open-label long-term study of esketamine nasal spray plus an oral antidepressant comparing results in older versus younger adults with treatment-resistant depression

<h3>Introduction</h3> Major depressive disorder in the elderly is associated with lower response and remission rates, resulting in treatment-resistant depression (TRD). Furthermore, older patients are often more vulnerable to adverse drug effects. Recently published findings from a 4-week, phase 3 study of esketamine nasal spray (TRANSFORM-3), evaluated patients ≥65 years with TRD. SUSTAIN-2 was an up to one year, open-label safety and efficacy study of esketamine nasal spray in the same phase 3 program, which enrolled patients with TRD over 18 years old. In addition to patients directly enrolled in SUSTAIN-2, completers from TRANSFORM-3 (responders or non-responders) could continue into SUSTAIN-2. We present a post hoc comparison of depressive symptoms and safety between patients with TRD aged 18-64 years (younger) vs ≥65 years (older) in the SUSTAIN-2 study. <h3>Methods</h3> SUSTAIN-2 included 802 patients with TRD; 624 younger and 178 older. Patients received a new oral antidepressant and open-label, flexibly-dosed esketamine nasal spray (28 [only older patients], 56 or 84 mg) administered in two phases: induction (IND) (2X/week for 4 weeks; included direct-entry patients and transferred-entry non-responder patients) and optimization/maintenance (OP/MAINT) (weekly or bi-weekly for up to 48 weeks; included responders from the open-label IND phase of SUSTAIN-2 and transferred-entry responders from TRANSFORM-3). Post hoc analyses compared treatment outcomes and safety for both age groups for each study phase. Outcome measurements included change from baseline in each phase for the Montgomery–Åsberg Depression Rating Scale (MADRS) total score and patient-reported outcomes: Sheehan Disability Scale (SDS), Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 7-Item (GAD-7). Remission (MADRS ≤12) and response (≥50% MADRS reduction from baseline) rates were also reported by phase. Key safety assessments included adverse events, labs, electrocardiograms (ECGs), blood pressure, and dissociation measured by Clinician-Administered Dissociative States Scale (CADSS). <h3>Results</h3> Baseline demographics, other than age (mean 49.0 [range: 18-64] and 69.0 [range: 65-86] for younger and older adults, respectively) and baseline hypertension (21.5% and 48.3% for younger and older adults, respectively), were similar between subgroups, including mean baseline MADRS total scores (IND: 31.4 and 30.7, in the younger and older groups respectively). The mean (SD) change from IND baseline in MADRS total scores following the IND phase was −16.6 (8.6) vs −15.4 (9.4), in younger and older patients respectively. Remission rates at the end of IND phase were 281/624 (46.5%) vs 76/155 (50.0%) and at the end of the OP/MAINT phase (up to week 48) rates were 270/477 (56.6%) vs 81/126 (64.3%) for younger and older patients respectively. Response rates at the end of IND were 485/624 (80.3%) vs 108/155 (71.1%) and at the end of OP/MAINT were 366/477 (76.7%) vs 95/126 (75.4%) for younger and older patients respectively. The mean (SD) change in the PHQ-9 following IND was –9.5 (6.4) vs −6.9 (7.2), in younger vs older patients respectively. Similarly, the mean change (SD) in the SDS following IND was –9.6 (7.8) vs –7.8 (8.4), in younger vs older patients respectively. The mean change (SD) in the GAD-7 following IND was –6.4 (5.9) vs –3.9 (5.3), in younger vs older patients respectively. In the IND phase, treatment emergent adverse events (TEAEs) ≥5% were seen in 537/624 (86.1%) and 116/155 (74.8%) of younger vs older patients respectively; TEAEs ≥10% included: dizziness (30.8% vs 23.2%), dissociation (24.0% vs 20.6%), nausea (22.9% vs 9.0%) headache (20.2% vs 7.1%), somnolence (12.3% vs 11.0%), hypoesthesia (11.5% vs <5%) in younger vs older patients respectively. In the OP/MAINT phase, TEAEs ≥5% occurred in 414/477 (86.8%) and 102/126 (81.0%) of younger vs older patients respectively; TEAEs ≥10% included: dizziness (22.0% vs 23.8%), headache (21.2% vs 10.3%), dissociation (19.3% vs 16.7%), nausea (15.3% vs 8.7%), somnolence (13.8% vs 15.1%) and viral upper respiratory infection (10.7% vs 15.1%), in younger vs older patients respectively. Treatment-emergent acute hypertension (defined as blood pressure ≥180/110 mm Hg) occurred in 13/624 (2.1%) vs 5/155 (3.2%) in the IND, and in 10/477 (2.1%) vs 8/126 (6.3%) in the OP/MAINT for younger vs older patients. <h3>Conclusions</h3> In this post hoc descriptive analysis, patients with TRD aged 18-64 and those ≥65 showed comparable treatment outcomes using esketamine nasal spray, including change in MADRS scores, response and remission rates. Safety and tolerability findings were comparable in both age groups, except for treatment-emergent acute hypertension, which was observed more often in the elderly. <h3>Funding</h3> Janssen Research & Development, LLC

Safety of switching to brexpiprazole in Japanese patients with schizophrenia: A post-hoc analysis of a long-term open-label study.

ObjectivesTo determine the long‐term safety of switching to brexpiprazole from aripiprazole or non‐aripiprazole dopamine antagonists.MethodsPost‐hoc analysis of 56‐week study of Japanese outpatients with schizophrenia switched to brexpiprazole 2 mg/day over 4‐week switching period with further titration (1–4 mg/day) allowed during the 52‐week, open‐label period. Major assessment items: total/low‐density lipoprotein (LDL)‐/high‐density lipoprotein (HDL)‐cholesterol, triglycerides, blood glucose, body weight and prolactin. Secondary evaluations were related to efficacy, treatment emergent adverse events (TEAEs), extrapyramidal symptoms, and corrected QT interval (QTc).Results84/186 (45.2%) patients (aripiprazole, 32.9%; non‐aripiprazole, 54.8%) discontinued treatment over 56 weeks mainly because of consent withdrawal/adverse events. From baseline to Week 56, both groups showed minimal mean changes in total/LDL‐/HDL‐cholesterol, triglycerides, and glucose levels and a slight increase in mean (SD) body weight (aripiprazole, 1.1 [4.4] kg; non‐aripiprazole, 0.4 [4.6] kg). Mean prolactin levels increased slightly in the aripiprazole group, but decreased in the non‐aripiprazole group. Symptom severity scores decreased similarly in both groups. TEAEs occurred in 161/186 (86.6%) patients (aripiprazole, 84.1% [serious, 9.8%]; non‐aripiprazole, 88.5% [serious, 14.4%]). Few changes occurred in extrapyramidal symptom scales or QTc interval.ConclusionsSwitching to brexpiprazole is associated with a low long‐term risk for metabolic abnormalities (including weight gain), hyperprolactinemia, extrapyramidal symptoms and QTc changes and minimal changes in psychiatric symptoms.