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Abstract Background Paliperidone palmitate 6-month (PP6M) demonstrated noninferiority to paliperidone palmitate 3-month in preventing relapse in patients with schizophrenia in a phase 3 double-blind (DB) study (NCT03345342). Here, we report long-term efficacy and safety results from a 2-year single-arm, open-label extension (OLE; NCT04072575) of this DB study. Methods Participants who completed the DB study without relapse were enrolled and followed-up every 3 months up to 2 years. Participants received 4 PP6M gluteal injections (700/1000 mg eq.) at baseline, 6-month, 12-month, and 18-month visits. Efficacy endpoints included assessment of relapse, Positive and Negative Syndrome Scale total score, Personal and Social Performance score, and Clinical Global Impression-Severity scale change from baseline. Safety was assessed by treatment-emergent adverse events (TEAEs), physical examinations, and laboratory tests. Results Of 178 participants enrolled, 154 (86.5%) completed the OLE (mean age: 40.4 years, men: 70.8%; mean duration of PP6M exposure during OLE: 682.1 days). Overall, 7/178 (3.9%) participants relapsed between 20 and 703 days after enrolment. Mean (SD) changes from baseline to endpoint were as follows: Positive and Negative Syndrome Scale total score, 0.7 (8.22); Clinical Global Impression-Severity, 0.0 (0.51); and Personal and Social Performance Scale, 0.5 (7.47). Overall, 111/178 participants (62.4%) reported ≥1 TEAE; most common (>5%) TEAEs were headache (13.5%) and increased blood prolactin/hyperprolactinemia (18.0%); 8/178 (4.5%) participants experienced serious TEAEs, and 6/178 (3.4%) participants withdrew due to TEAEs. No deaths were reported. Conclusions The relapse rate observed with PP6M during the 2-year OLE was low (3.9%). Clinical and functional improvements demonstrated in the DB study were maintained during OLE, and no new safety concerns were identified. Trial registration ClinicalTrials.gov Identifier: NCT04072575; EudraCT number: 2018-004532-30.

Abstract Background Paliperidone palmitate once-monthly (PP1M) is a long-acting injectable formulation that eliminates the need for daily dosing, ensures sustained plasma levels for several weeks, and helps clinicians reliably monitor adherence. We examined the efficacy and safety of PP1M in patients with schizophrenia according to baseline (BL) disease activity, which was based on the frequency of prior psychiatric hospital admissions. Methods This was a post hoc analysis of a 17-wk, open-label (OL) treatment period from a large, multicenter, phase 3 noninferiority study (NCT01515423) that compared the efficacy and safety of paliperidone palmitate once-every-3-months and PP1M in patients with schizophrenia. During the 17-wk OL period, patients received flexibly dosed PP1M (day 1 [234 mg]; day 8 [156 mg]; wks 5, 9, and 13 [78, 117, 156, or 234 mg]). Patients were grouped according to the number of hospital admissions for psychosis that occurred 24 months before study entry: no prior hospitalizations (low activity), 1 prior hospitalization (moderate activity), and ≥2 prior hospitalizations (high activity). Assessments included change in Positive and Negative Syndrome Scale (PANSS) total scores, change in Clinical Global Impression-Severity (CGI-S) scores, and the percentage of patients who attained symptomatic remission (defined as a score ≤3 on the following PANSS symptom score items: P1 [delusions], P2 [conceptual disorganization], P3 [hallucinatory behavior], N1 [blunted affect], N4 [social withdrawal], N6 [lack of spontaneity], G5 [mannerisms/posturing], and G9 [unusual thought content]) at OL end point (wk 17). Subgroup differences were examined using ANCOVA models for continuous end points and by the Cochran-Mantel-Haenszel test for categorical variables. No adjustments were made for multiplicity as the OL period was used to determine acceptability for entry to the double-blind period. Results Of 1,146 patients, 450 (39.3%) had no prior hospitalizations, 426 (37.2%) had 1 prior hospitalization, and 270 (23.6%) had ≥2 prior hospitalizations within the previous 24 months. BL demographics and disease characteristics were similar between groups. Mean age ranged from 37.6 to 41.0 years, patients were predominantly male (range, 51.6%-58.9%), and most were from non–European Union/non–United States regions (range, 51.5%-60.6%). For low, moderate, and high disease activity groups, mean [SD] total PANSS scores were 85.8 (10.51), 85.6 (10.74), and 86.0 (11.3), respectively; mean (SD) CGI-S scores were 4.5 (0.67), 4.4 (0.70), and 4.4 (0.67), respectively. In each disease activity group, statistically and clinically meaningful improvements from BL were observed in all efficacy measures at all time points during the 17-wk treatment period. At OL end point, mean changes from BL in PANSS total scores were -20.5, -20.1, and -18.3 in the low, moderate, and high disease activity groups, and mean changes from BL in CGI-S scores were -1.1, -1.0, and -0.9, respectively; there was no statistically significant difference in PANSS total scores or CGI-S scores between disease activity groups. The percentages of patients who attained symptomatic remission at the OL end point were 49.4%, 53.1%, and 49.1%, respectively. The most common adverse events (≥5% in any group) were insomnia, anxiety, akathisia, injection site pain, nasopharyngitis, and weight increase. Discussion Findings from the 17-wk OL period demonstrated that treatment with PP1M produced a rapid, beneficial effect in patient symptom scores that was significant from week 1 onward. PP1M was rapidly effective in patients with schizophrenia regardless of BL disease activity. Safety was consistent with previous acute trials evaluating PP1M.

In practice, both testable and untestable assumptions are generally required to draw inference about the mean outcome measured at the final scheduled visit in a repeated measures study with drop-out. Scharfstein et al. (2014) proposed a sensitivity analysis methodology to determine the robustness of conclusions within a class of untestable assumptions. In their approach, the untestable and testable assumptions were guaranteed to be compatible; their testable assumptions were based on a fully parametric model for the distribution of the observable data. While convenient, these parametric assumptions have proven especially restrictive in empirical research. Here, we relax their distributional assumptions and provide a more flexible, semi-parametric approach. We illustrate our proposal in the context of a randomized trial for evaluating a treatment of schizoaffective disorder.

Abstract Background “Dissociation” comprises distinct phenomena, some of which are associated with esketamine treatment and some may overlap with positive symptoms of psychosis. Relationships between dissociation and psychotic symptoms assessed by ­clinician report vs conventional rating scales were investigated in a post hoc analysis of data from the initial treatment session in an ­open-label, ­long-term safety, phase 3 study of esketamine plus a newly initiated oral antidepressant in patients with treatment-resistant depression. Methods Adverse events of dissociation or psychosis were examined via investigator report and the Clinician Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale-Plus, respectively, 40 minutes post first esketamine dose. The range of CADSS total scores associated with investigator-reported severity of dissociation was determined by equipercentile linking. Logistic regression models and receiver operating curve analysis explored the CADSS cutoff point for determining presence/absence of dissociation. Frequency of response to specific CADSS items was examined to investigate qualitative differences in the pattern of symptoms reported across investigator-reported levels of adverse event severity. Results Dissociation was reported as an adverse event in 14.3% (109/764) of patients. Severity of most CADSS items increased with the severity of investigator-reported dissociation. No CADSS cutoff point discriminated well between the presence and absence of dissociation events. Hallucinations were reported as adverse events in 5 patients; none reported delusions. Conclusions CADSS scores and severity of dissociation adverse events move generally in the same direction; however, there is substantial variability in this relationship. No signature profile of dissociative experiences was revealed, and psychotic symptoms were uncommon. Trial Registration Clinical Trials.gov identifier: NCT02497287

ObjectiveEsketamine nasal spray (ESK) is approved in combination with an oral antidepressant (OAD) for the treatment of adults with treatment-resistant depression (TRD); however, direct comparisons with atypical antipsychotics for TRD are limited. This secondary analysis of the ESCAPE-TRD study compared rates of remission and response, and improvements in depressive symptoms over time, between ESK and quetiapine extended-release (XR) in patients with TRD treated in accordance with US prescribing information (USPI).MethodsESCAPE-TRD (NCT04338321) was a randomized, open-label, rater-blinded phase 3b trial investigating ESK versus quetiapine XR for acute and maintenance treatment of patients with TRD. This secondary analysis included patients aged 18–64 years who were treated/dosed according to USPI. The primary endpoint was remission, defined as Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≤ 10. Treatment-emergent adverse events (TEAEs) leading to discontinuation were summarized descriptively.ResultsAmong 636 patients in this secondary analysis (ESK, n = 316; quetiapine XR, n = 320), significantly more ESK-treated patients achieved remission starting at week 8 (28.3% versus 18.6%; P = 0.005) through week 32 (55.7% versus 36.3%; P < 0.001), compared with quetiapine XR–treated patients. There were clinically and statistically significant improvements in MADRS scores with ESK versus quetiapine XR at each visit from day 8 onwards. Fewer patients discontinued treatment because of TEAEs with ESK (4.5%) versus quetiapine XR (10.1%).ConclusionsConsistent with the primary analysis, this secondary analysis demonstrated that ESK improves short- and long-term outcomes compared with quetiapine XR in patients with TRD treated according to USPI.

IntroductionIn ESCAPE-TRD (NCT04338321), a randomized, open-label, rater-blinded, long-term, phase 3b trial, augmentation with esketamine nasal spray (ESK) demonstrated increased probability of achieving meaningful clinical benefit versus quetiapine extended release (QUE XR) in patients (pts) with treatment-resistant depression (TRD). This subgroup analysis of ESCAPE-TRD evaluated the incidence, duration, and impact of treatment-emergent adverse events (TEAEs) on treatment discontinuation in adults with TRD treated with ESK or QUE XR according to US prescribing information.MethodsPts aged 18-64 years were randomly assigned to receive flexibly dosed ESK (56 or 84 mg) or QUE XR (150-300 mg), both consistent with US label dosing and in combination with an ongoing oral antidepressant. The incidence and duration of the most commonly occurring TEAEs, as well as the most common TEAEs leading to treatment discontinuation, were summarized descriptively. All randomly assigned participants receiving ≥1 dose of study drug were included in the safety analyses.ResultsAmong the 636 pts included in the subgroup analysis, 316 and 320 were randomly assigned to ESK and QUE XR, respectively; 314 and 316 were included in the safety population. In the combined acute and maintenance phases, TEAEs occurred in 92.0% of pts in the ESK group and 78.5% of pts in the QUE XR group. The most commonly reported TEAEs with ESK or QUE XR in the combined acute and maintenance phases were dizziness (47.1% and 7.9%, respectively), headache (25.5% and 13.0%, respectively), somnolence (15.0% and 23.4%, respectively), and nausea (29.9% and 3.2%, respectively). Across all TEAE events reported in >5% of pts in either arm, 91.8% (5831 of 6351) resolved within 1 day in the ESK arm compared to 11.6% (90 of 776) with QUE XR. For specific TEAE events of clinical interest for ESK, same-day resolution rates for increased blood pressure, sedation, and dissociation in the ESK group were 93.5% (116 of 124), 96.2% (127 of 132), and 99.6% (740 of 743), respectively. The majority of TEAEs of clinical interest in the ESK group that occurred on the same day of dosing resolved within the first 2 hours after dosing. For the most frequently reported TEAEs with QUE XR, same-day resolution rates for somnolence, headache, and fatigue were 7.8% (8 of 103), 49.2% (29 of 59), and 9.5% (4 of 42), respectively. Fewer pts treated with ESK discontinued treatment due to TEAEs compared to QUE XR (4.4% versus 10.6%).ConclusionsSafety data from this subgroup analysis were consistent with the overall study population as well as the known tolerability profile of each treatment. TEAEs were reported at higher incidence with ESK than with QUE XR; however, the majority of TEAEs occurring with ESK were transient in nature and did not result in a higher rate of treatment discontinuation compared to QUE XR.FundingJanssen Scientific Affairs, LLC

The 3 paliperidone palmitate (PP) long-acting injectable antipsychotic formulations, PP 1-month (PP1M), PP 3-month (PP3M), and PP 6-month (PP6M), have shown to reduce the risk of relapse in schizophrenia. The current phase-4 study constructed external comparator arms (ECAs) using real-world data for PP3M and PP1M and compared relapse prevention rates with PP6M from an open-label extension (OLE) study in adult patients with schizophrenia. PP6M data were derived from a single-arm, 24-month, OLE study (NCT04072575), which included patients with schizophrenia who completed a 12-month randomized, double-blind, noninferiority, phase-3 study (NCT03345342) without relapse. Patients in the PP3M and PP1M ECAs were identified from the IBM® MarketScan® Multistate Medicaid Database based on similar eligibility criteria as the PP6M cohort. A total of 178 patients were included in each cohort following propensity score matching. Most patients were men (>70%; mean age: 39-41 years). Time to relapse (primary analysis based on Kaplan-Meier estimates) was significantly delayed in the PP6M cohort (P < .001, log-rank test). The relapse rate was lower in the PP6M cohort (3.9%) vs PP3M (20.2%) and PP1M (29.8%) cohorts. Risk of relapse decreased significantly (P < .001) by 82% for PP6M vs PP3M (HR = 0.18 [95% CI = 0.08 to 0.40]), 89% for PP6M vs PP1M (HR = 0.11 [0.05 to 0.25]), and 35% for PP3M vs PP1M (HR = 0.65 [0.42 to 0.99]; P = .043). Sensitivity analysis confirmed findings from the primary analysis. Although the ECAs were matched to mimic the characteristics of the PP6M cohort, heterogeneity between the groups could exist due to factors including prior study participation, unmeasured confounders, variations in data capture and quality, and completeness of clinical information. In a clinical trial setting, PP6M significantly delayed time to relapse and demonstrated lower relapse rates compared with PP3M and PP1M treatments in real-world settings among adult patients with schizophrenia. ClinicalTrials.gov Identifier: NCT04072575; EudraCT number: 2018-004532-30.

To assess the likelihood of attaining response/remission of depressive symptoms with esketamine nasal spray (ESK) plus standard of care (SoC) vs placebo nasal spray (PBO) plus SoC at 4 weeks in patients with major depressive disorder and active suicidal ideation with intent (MDSI) without early response. A post hoc analysis of pooled data from ASPIRE I and ASPIRE II evaluated ESK plus SoC vs PBO plus SoC in adults with MDSI without response (≥50% improvement from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] score) at 24 hours after the first dose or at week 1 after the first two doses (ie, 24-hour and week 1 nonresponders). Response and remission (MADRS score ≤ 12) rates were assessed on day 25. The analysis included 362 patients (n = 182, ESK plus SoC; n = 180, PBO plus SoC). Among 24-hour nonresponders, more patients receiving ESK plus SoC vs PBO plus SoC achieved response (63.9% vs 48.0%, = .010) and remission (35.1% vs 24.4%, = .074) at day 25. Odds of response/remission were higher with ESK plus SoC vs PBO plus SoC (response: 1.89, 95% CI, 1.17-3.05; remission: 1.48, 95% CI, 0.93-2.35). Similar findings were observed among week 1 nonresponders for response (48.4% vs 34.5%, = .075), remission (25.0% vs 13.1%, = .060), and odds of response/remission (response: 2.03, 95% CI, 1.22-3.40; remission: 1.63, 95% CI, 1.01-2.62). Patients with MDSI not responding within the first week of treatment with ESK plus SoC may still benefit from a full 4-week treatment course.

Abstract Background Esketamine nasal spray was recently approved for treatment-resistant depression. The current analysis evaluated the impact of symptom-based treatment frequency changes during esketamine treatment on clinical outcomes. Methods This is a post-hoc analysis of an open-label, long-term (up to 1 year) study of esketamine in patients with treatment-resistant depression (SUSTAIN 2). During a 4-week induction phase, 778 patients self-administered esketamine twice weekly plus a new oral antidepressant daily. In responders (≥50% reduction in Montgomery-Åsberg Depression Rating Scale total score from baseline), esketamine treatment frequency was thereafter decreased during an optimization/maintenance phase to weekly for 4 weeks and then adjusted to the lowest frequency (weekly or every other week) that maintained remission (Montgomery-Åsberg Depression Rating Scale ≤ 12) based on a study-defined algorithm. The relationship between treatment frequency and symptom response, based on clinically meaningful change in Clinical Global Impression–Severity score, was subsequently evaluated 4 weeks after treatment frequency adjustments in the optimization/maintenance phase. Results Among 580 responders treated with weekly esketamine for the first 4 weeks in the optimization/maintenance phase (per protocol), 26% continued to improve, 50% maintained clinical benefit, and 24% worsened. Thereafter, when treatment frequency could be reduced from weekly to every other week, 19% further improved, 49% maintained benefit, and 32% worsened. For patients no longer in remission after treatment frequency reduction, an increase (every other week to weekly) resulted in 47% improved, 43% remained unchanged, and 10% worsened. Conclusions These findings support individualization of esketamine nasal spray treatment frequency to optimize treatment response in real-world clinical practice. Trial Registration ClinicalTrials.gov identifier: NCT02497287