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Background Older, compared with younger, patients with treatment-resistant depression (TRD) typically have lower response and remission rates with poorer tolerability to antidepressant treatment. This post-hoc analysis compared outcomes following treatment with esketamine nasal spray (ESK) between younger (18-64 years) and older (≥65 years) patients with TRD. Methods SUSTAIN-2, an up to 1-year open-label safety and efficacy study of ESK plus an oral antidepressant, included patients with TRD either directly enrolled (≥18-year) or transferred from a phase 3 double-blind study, TRANSFORM-3 (≥65-year). Patients were treated in two phases: 4-week induction and 48-week optimization/maintenance. Results Younger (n = 624) and older (n = 178) patients had similar baseline characteristics except for hypertension history (21.5% versus 48.3%, respectively). Patients (younger versus older) had similar mean baseline Montgomery-Asberg Depression Rating Scale (MADRS) total scores and mean (SD) reductions in MADRS total scores for induction (-18.0 [7.19] versus -18.1 [9.37]; p = 0.492 [t = 0.69, df = 701]) and optimization/maintenance (week 12) (-19.9 [7.03] versus -22.2 [9.50]; p = 0.265 [t = -1.12, df = 3470]) phases. Treatment-emergent adverse events (TEAEs) reported in younger versus older patients, respectively, were: induction, 86.1% versus 74.8%; optimization/maintenance, 86.8% versus 81.0%; serious TEAEs: induction, 2.2% versus 1.9%; optimization/maintenance, 6.7% versus 4.8%; TEAEs of increased blood pressure: induction, 6.9% versus 6.5%; optimization/maintenance, 7.1% versus 9.5%; and falls: induction, 0.3% versus 0.6%; optimization/maintenance, 0.2% versus 0.8%. Cognitive tests did not show clinically meaningful differences between the age groups. Conclusions Although limited by the open-label design of SUSTAIN-2, this post-hoc analysis showed generally comparable improvement in depression between ESK-treated younger and older adult patients with TRD, with consistent safety outcomes.

Background In this post-hoc analysis, data from 2 positive, pivotal, phase 3 trials of esketamine nasal spray (ESK) in treatment-resistant depression (TRD)—short-term study (TRANSFORM-2) and maintenance study (SUSTAIN-1)—were analyzed to evaluate the relationship between dissociation and antidepressant effects of ESK. Methods Analysis by responder status, correlation analysis, and mediation analysis were performed to assess the relationships between peak Clinician Administered Dissociative States Scale (CADSS) scores after first (day 1) and last (day 25) ESK dose and change in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores at the first (day 2) and last assessments (day 28) in TRANSFORM-2 and peak CADSS after first maintenance ESK dose and time to relapse in SUSTAIN-1 (only for mediation analysis). Results In TRANSFORM-2, the percentage of responders (>50% reduction in MADRS) at day 2 and day 28 did not significantly differ between patients who did vs did not manifest significant dissociation (peak CADSS scores >4 or ≤4, respectively) following the first ESK dose. Spearman correlation coefficients between dissociation and depression improvement were nonsignificant and close to zero. CADSS scores did not significantly mediate the reduction in MADRS at day 2 or 28 in TRANSFORM-2 or the time to depression relapse in SUSTAIN-1. The mean difference in MADRS between ESK and active-control arms persisted beyond day 2 without significant change across time, although the mean peak CADSS scores significantly decreased across consecutive doses and fewer patients experienced significant dissociation after the last ESK dose compared with the first. Conclusion Within the dose range tested, the dissociative and antidepressant effects of ESK were not significantly correlated. Trial registration NCT02417064 (TRANSFORM-1); NCT02418585(TRANSFORM-2); NCT02493868 (SUSTAIN-1)

While the ICH E9(R1) Addendum on “Estimands and Sensitivity Analysis in Clinical Trials” was released in late 2019, the widespread implementation of defining and reporting estimands across clinical trials is still in progress and the engagement of non-statistical functions in this process is also in progress. Case studies are sought after, especially those with documented clinical and regulatory feedback. This paper describes an interdisciplinary process for implementing the estimand framework, devised by the Estimands and Missing Data Working Group (a group with clinical, statistical, and regulatory representation) of the International Society for CNS Clinical Trials and Methodology. This process is illustrated by specific examples using various types of hypothetical trials evaluating a treatment for major depressive disorder. Each of the estimand examples follows the same template and features all steps of the proposed process, including identifying the trial stakeholder(s), the decisions they need to make about the investigated treatment in their specific role and the questions that would support their decision making. Each of the five strategies for handling intercurrent events are addressed in at least one example; the featured endpoints are also diverse, including continuous, binary and time to event. Several examples are presented that include specifications for a potential trial design, key trial implementation elements needed to address the estimand, and main and sensitivity estimator specifications. Ultimately this paper highlights the need to incorporate multi-disciplinary collaborations into implementing the ICH E9(R1) framework.

Background Intranasal drug delivery offers a non-invasive and convenient dosing option for patients and physicians, especially for conditions requiring chronic/repeated-treatment administration. However, in some cases such delivery may be harmful to nasal and olfactory epithelia. Objective The aim of this study was to assess the potential impact of long-term intermittent treatment with esketamine nasal spray, taken in conjunction with an oral antidepressant (AD), on olfactory function and nasal tolerability in patients with treatment-resistant depression (TRD). Methods A total of 1142 patients with TRD participated from four multicenter, randomized, double-blind, phase III studies: three short-term studies (two in patients aged 18–64 years, one in patients ≥65 years), and one long-term maintenance study of esketamine nasal spray + AD versus placebo nasal spray + AD. Across the four studies, assessments were performed at 208 sites in 21 countries. Olfactory function was measured using the 40-item University of Pennsylvania Smell Identification Test (UPSIT®) and the single-staircase Snap & Sniff® Odor Detection Threshold Test (S&S-T). Nasal tolerability, including nasal examinations and a quantitative, self-administered nasal symptom questionnaire (NSQ), was also assessed. Data were analyzed using analyses of covariance. Results Of 1142 participants, 734 were women (64.3%). The mean age of all participants ranged from 45.7 to 70.0 years across the studies. Overall, 855 patients received esketamine nasal spray + AD and 432 received placebo nasal spray + AD. Objective evaluation of nasal function showed no evidence of an adverse impact following esketamine administration. Based on the UPSIT® and S&S-T results, intranasal administration of esketamine had no effect on the odor identification or threshold test scores compared with placebo nasal spray + oral AD. Similarly, repeated administration with esketamine nasal spray had no meaningful impact on assessments of nasal function. No dose–response relationship was observed between esketamine doses and the olfactory test scores. Esketamine nasal spray was well tolerated, as indicated by responses on the NSQ and negative nasal examination findings. Conclusion Findings from this analysis indicate that there was no evidence of adverse effect on either olfactory or nasal health measures with repeated intermittent administration of esketamine nasal spray at any dose over the course of short-term (4 weeks) or long-term (16–100 weeks) studies. Clinical trial registration TRANSFORM-1: NCT02417064, date of registration: 15/04/2015; TRANSFORM-2: NCT02418585, date of registration: 16/04/2015; TRANSFORM-3: NCT02422186, date of registration: 21/04/2015; SUSTAIN-1: NCT02493868, date of registration: 10/07/2015. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-021-00826-9.

BackgroundPatients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment.MethodsThis double-blind study (ASPIRE II) randomized adults (aged 18–64 years) with MDD having active suicidal ideation with intent to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks, given with comprehensive standard of care (hospitalization ≥5 days and newly initiated or optimized oral antidepressant[s]). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale total score (primary efficacy endpoint) was analyzed using ANCOVA. Clinical Global Impression–Severity of Suicidality–revised (key secondary endpoint) was analyzed using ANCOVA on ranks of change.ResultsOf 230 patients who were randomized (115 per arm), 227 received study drug and were included in efficacy/safety analyses; 184 (80.0%) completed double-blind treatment. Greater improvement in Montgomery-Asberg Depression Rating Scale total score was observed with esketamine (mean [SD]: –15.7 [11.56]) vs placebo (–12.4 [10.43]), each with standard of care, at 24 hours (least-squares mean difference [SE]: –3.9 [1.39], 95% CI: –6.60, –1.11; 2-sided P = .006). This was also noted at the earlier (4-hour) timepoint (least-squares mean difference –4.2, 95% CI: –6.38, –1.94). Patients in both treatment groups experienced rapid reduction in Clinical Global Impression–Severity of Suicidality–revised score; the between-group difference was not statistically significant. The most common adverse events among esketamine-treated patients were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia.ConclusionThis study confirmed rapid and robust reduction of depressive symptoms with esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent.Trial Registration: Clinical Trials.gov identifier: NCT03097133

In clinical trials, placebo response is considered a beneficial effect arising from multiple factors, including the patient's expectations for the treatment. Its presence makes the classical parallel study design suboptimal and can bias the inference. The sequential parallel comparison design (SPCD), a two-stage design where the first stage is a classical parallel study design, followed by another parallel design among placebo subjects from the first stage, was proposed to address the shortcomings of the classical design. In SPCD, in lieu of treatment effect, a weighted average of the mean treatment difference in Stage I among all randomized subjects and the mean treatment difference in Stage II among placebo non-responders was proposed as the efficacy measure. However, by linking two possibly different populations, this weighted average lacks interpretability, and the choice of weight remains controversial. In this work, under the principal stratification framework, we propose a causal estimand for the treatment effect under each of three clinically important principal strata: Always Responders, Never Responders, and Drug-only Responders. To make the stratum treatment effect identifiable, we introduce a set of assumptions and two sensitivity parameters. By further considering the strata as latent characteristics, the sensitivity parameters can be estimated. An extensive simulation study is conducted to evaluate the operating characteristics of the proposed method. Finally, we apply our method on the ADAPT-A study data to assess the benefit of low-dose aripiprazole adjunctive to antidepressant therapy treatment.

Objective:About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients wi...

Background This double-blind (DB), randomized, parallel-group study was designed to evaluate efficacy and safety of paliperidone palmitate 6-month (PP6M) formulation relative to paliperidone palmitate 3-month (PP3M) formulation in patients with schizophrenia. Methods Following screening, patients entered an open-label (OL) maintenance phase and received 1 injection cycle of paliperidone palmitate 1-month (PP1M; 100 or 150 mg eq.) or PP3M (350 or 525 mg eq.). Clinically stable patients were randomized (2:1) to receive PP6M (700 or 1000 mg eq., gluteal injections) or PP3M (350 or 525 mg eq.) in a 12-month DB phase; 2 doses of PP6M (corresponding to doses of PP1M and PP3M) were chosen. Results Overall, 1036 patients were screened, 838 entered the OL phase, and 702 (mean age: 40.8 years) were randomized (PP6M: 478; PP3M: 224); 618 (88.0%) patients completed the DB phase (PP6M: 416 [87.0%]; PP3M: 202 [90.2%]). Relapse rates were PP6M, 7.5% (n = 36) and PP3M, 4.9% (n = 11). The Kaplan-Meier estimate of the difference (95% CI) between treatment groups (PP6M − PP3M) in the percentages of patients who remained relapse free was −2.9% (−6.8%, 1.1%), thus meeting noninferiority criteria (95% CI lower bound is larger than the pre-specified noninferiority margin of −10%). Secondary efficacy endpoints corroborated the primary analysis. Incidences of treatment-emergent adverse events were similar between PP6M (62.1%) and PP3M (58.5%). No new safety concerns emerged. Conclusions The efficacy of a twice-yearly dosing regimen of PP6M was noninferior to that of PP3M in preventing relapse in patients with schizophrenia adequately treated with PP1M or PP3M. Trial Registration Clinical Trials.gov identifier: NCT03345342

Many Phase I trial designs have been developed to improve upon the standard 3 + 3 design. These designs can be classified as long-memory designs, for example, the continual reassessment method (CRM), and short-memory designs such as the modified toxicity probability interval (mTPI) design. Long-term memory designs use all data but their performance can be negatively affected by the model misspecification. Short-term memory designs only use data at the current dose and might lose efficiency as a result. To overcome these issues, we propose a regularized CRM (rCRM). The rCRM offers a trade-off between long-term memory and short-term memory methods. The rCRM gives more weight to data obtained at the doses with the estimated probability of toxicity closer to the target toxicity rate. The addition of a regularization term has an effect of shrinking the dimension of the model and leads to improved performance of the 2-parameter CRM. The rCRM is a good design choice to guide assignments in an expansion cohort phase of a dose-finding trial since dose assignments do not seem to change as often as in corresponding CRMs.

Objective To compare esketamine to placebo, each in addition to standard-of-care treatment, for rapidly reducing major depressive disorder symptoms, including suicidal ideation. Methods This phase 3, double-blind, multicenter study (ASPIRE I), conducted between June 2017 and December 2018, enrolled 226 adults having major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) criteria, active suicidal ideation with intent, and need for psychiatric hospitalization. Patients were randomized 1:1 to esketamine 84 mg or placebo nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care treatment (initial psychiatric hospitalization and newly initiated or optimized oral antidepressant[s] therapy). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score (primary endpoint) was analyzed using analysis of covariance (ANCOVA), and change in Clinical Global Impression of Severity of Suicidality Revised version (CGI-SS-r; key secondary endpoint) score was analyzed using ANCOVA on ranks with treatment difference estimated using the Hodges-Lehmann estimate. Results Greater improvement in MADRS total score was observed with esketamine + standard-of-care versus placebo + standard-of-care at 24 hours (least-squares mean difference [SE]: -3.8 [1.39]; 95% CI, -6.56 to -1.09; 2-sided P = .006), as well as at earlier (4 hours) and later time points during 4-week double-blind treatment. The difference between groups in the severity of suicidality was not statistically significant (median of treatment difference [95% CI]: 0.0 [-1.00 to 0.00]; 2-sided P = .107). The most common adverse events among esketamine-treated patients were dizziness, dissociation, headache, nausea, and somnolence. Conclusions These findings demonstrate rapid and robust efficacy of esketamine nasal spray in reducing depressive symptoms in severely ill patients with major depressive disorder who have active suicidal ideation with intent. Trial registration ClinicalTrials.gov identifier: NCT03039192.

The authors compared the efficacy of standard-of-care treatment plus intranasal esketamine or placebo for rapid reduction of symptoms of major depression, including suicidality, among individuals at imminent suicide risk.In a double-blind, multicenter, proof-of-concept study, 68 participants were randomly assigned to receive esketamine (84 mg) or placebo twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment. The primary efficacy endpoint was change in score from baseline to 4 hours after initial dose on the Montgomery-Åsberg Depression Rating Scale (MADRS). Clinician global judgment of suicide risk (from the Suicide Ideation and Behavior Assessment Tool) was also assessed. Secondary endpoints included these measures at 24 hours and double-blind endpoint at day 25.A significantly greater improvement in MADRS score was observed in the esketamine group compared with the placebo group at 4 hours (least-square mean difference=-5.3, SE=2.10; effect size=0.61) and at ∼24 hours (least-square mean difference=-7.2, SE=2.85; effect size=0.65), but not at day 25 (least-square mean difference=-4.5, SE=3.14; effect size=0.35). Significantly greater improvement was also observed in the esketamine group on the MADRS suicidal thoughts item score at 4 hours (effect size=0.67), but not at 24 hours (effect size=0.35) or at day 25 (effect size=0.29). Between-group reductions in clinician global judgment of suicide risk scores were not statistically different at any time point. The most common adverse events among participants in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache.These preliminary findings indicate that intranasal esketamine compared with placebo, given in addition to comprehensive standard-of-care treatment, may result in significantly rapid improvement in depressive symptoms, including some measures of suicidal ideation, among depressed patients at imminent risk for suicide.

Introduction 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. Methods 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–Asberg 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). Results 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 Conclusions 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. Funding Janssen Research & Development, LLC

This paper is to extend Mehta and Pocock (2011) to provide a way in doing sample size increase in survival trials. Sample space is divided by observed test statistic at interim into three zones: un...

Objective To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD). Methods This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase. Results Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Asberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]). Conclusions Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD. Trial registration ClinicalTrials.gov identifier: NCT02497287.

Elderly patients with major depression have a poorer prognosis, are less responsive to treatment, and show greater functional decline compared with younger patients, highlighting the need for effective treatment.This phase 3 double-blind study randomized patients with treatment-resistant depression (TRD) ≥65 years (1:1) to flexibly dosed esketamine nasal spray and new oral antidepressant (esketamine/antidepressant) or new oral antidepressant and placebo nasal spray (antidepressant/placebo). The primary endpoint was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to day 28. Analyses included a preplanned analysis by age (65-74 versus ≥75 years) and post-hoc analyses including age at depression onset.For the primary endpoint, the median-unbiased estimate of the treatment difference (95% CI) was -3.6 (-7.20, 0.07); weighted combination test using MMRM analyses z = 1.89, two-sided p = 0.059. Adjusted mean (95% CI) difference for change in MADRS score between treatment groups was -4.9 (-8.96, -0.89; t = -2.4, df = 127; two-sided nominal p = 0.017) for patients 65 to 74 years versus -0.4 (-10.38, 9.50; t = -0.09, two-sided nominal p = 0.930) for those ≥75 years, and -6.1 (-10.33, -1.81; t = -2.8, df = 127; two-sided nominal p = 0.006) for patients with depression onset55 years and 3.1 (-4.51, 10.80; t = 0.8, two-sided nominal p = 0.407) for those ≥55 years. Patients who rolled over into the long-term open-label study showed continued improvement with esketamine following 4 additional treatment weeks.Esketamine/antidepressant did not achieve statistical significance for the primary endpoint. Greater differences between treatment arms were seen for younger patients (65-74 years) and patients with earlier onset of depression (55 years).

The article presents concepts and methods for mediation analysis for an ordinal outcome. We give definitions of natural direct and indirect effects using counterfactuals for ordinal outcomes; in this context, there are potentially different effects for any two levels of the outcome, and we consider difference and ratio scales. The confounding assumptions required for identification are similar to that in the existing mediation analysis literature. We discuss different modeling strategies for estimation. Under a proportional odds model with a reference category that is common, the direct and indirect effects on a ratio scale can each be summarized by a single estimate and are available in closed form; otherwise the effects may differ across categories compared and can be obtained by numeric simulation methods.

Ketamine, an N-methyl-d-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect in patients with treatment-resistant depression. This study evaluated the efficacy of twice- and thrice-weekly intravenous administration of ketamine in sustaining initial antidepressant effects in patients with treatment-resistant depression.In a multicenter, double-blind study, adults (ages 18-64 years) with treatment-resistant depression were randomized to receive either intravenous ketamine (0.5 mg/kg of body weight) or intravenous placebo, administered over 40 minutes, either two or three times weekly, for up to 4 weeks. Patients who discontinued double-blind treatment after at least 2 weeks for lack of efficacy could enter an optional 2-week open-label phase to receive ketamine with the same frequency as in the double-blind phase. The primary outcome measure was change from baseline to day 15 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS).In total, 67 (45 women) of 68 randomized patients received treatment. In the twice-weekly dosing groups, the mean change in MADRS score at day 15 was -18.4 (SD=12.0) for ketamine and -5.7 (SD=10.2) for placebo; in the thrice-weekly groups, it was -17.7 (SD=7.3) for ketamine and -3.1 (SD=5.7) for placebo. Similar observations were noted for ketamine during the open-label phase (twice-weekly, -12.2 [SD=12.8] on day 4; thrice-weekly, -14.0 [SD=12.5] on day 5). Both regimens were generally well tolerated. Headache, anxiety, dissociation, nausea, and dizziness were the most common (≥20%) treatment-emergent adverse events. Dissociative symptoms occurred transiently and attenuated with repeated dosing.Twice-weekly and thrice-weekly administration of ketamine at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days.

This phase 2a, randomized, multicenter, double-blind, proof-of-concept study was designed to evaluate, efficacy, safety and tolerability of JNJ-40411813/ADX71149, a novel metabotropic glutamate 2 receptor positive allosteric modulator as an adjunctive treatment for major depressive disorder (MDD) with significant anxiety symptoms. Eligible patients (18-64 years) had a DSM-IV diagnosis of MDD, Hamilton Depression Rating Scale-17 (HDRS17) score of ≥ 18, HDRS17 anxiety/somatization factor score of ≥ 7, and an insufficient response to current treatment with a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor. The doubly-randomized, 8-week double-blind treatment phase was comprised of two 4-week periods, from which a combined test statistic was generated, with pre-determined weights assigned to each of the 2 treatment periods. Period 1: patients (n=121) were randomly assigned (1:1) to JNJ-40411813 (n=62; 50mg to 150 mg b.i.d, flexibly dosed) or placebo (n=59); Period 2: placebo-treated patients (n=22) who continued to meet entry severity criteria were re-randomized (1:1) to JNJ-40411813 or placebo, while other patients underwent sham re-randomization and continued on their same treatment. Of 121 randomized patients, 100 patients (82.6%) were completers. No efficacy signal was detected on the primary endpoint, the 6-item Hamilton Anxiety Subscale (HAM-A6, p=0.51). Efficacy signals (based on prespecified 1-sided p

The basic problem that causes the frequent failure of a standard randomized parallel placebo-controlled clinical trial with a high placebo response rate is the underestimation of the treatment effect by the observed relative treatment difference. A two-period sequential parallel enrichment design has been proposed where the first period is a standard parallel design and at the end of the first period, the placebo non-responders are identified and re-randomized in the second period. Based on such a design, available methods have primarily focused on testing either the first period treatment null hypothesis or the global null hypothesis defined as the joint period 1 and period 2 treatment effect null hypothesis by a test statistic which is either derived from a combined statistic or defined directly as a weighted z-score where the weights are functions of some population and design parameters satisfying certain power optimality criterion. However, in some cases, it is not clear what their combined statistics are estimating and in others, the combined statistics are estimating the apparent treatment effect; but generally, there is no discussion of the need to provide a proper assessment of the treatment effect for the intended study population. It should be clear that an appropriate assessment of the treatment effect for the intended study population is critical for the benefit/risk analysis as well as the proper dosage recommendation. Any benefit/risk analysis and dosage recommendation that are based on an apparent treatment effect from a standard parallel design such as the first period of a sequential parallel enrichment design tend to underestimate the benefit/risk ratio which in turn may lead to overdosing recommendation. It is the purpose of this paper to introduce the concept of an adjusted treatment effect which is derived by adjusting the apparent treatment effect from the first period of a sequential parallel enrichment design with information from the second period subject to a consistency condition. The adjustment properly compensates for the high placebo response rate. It is proposed that this adjusted treatment effect should be used to assess the treatment effect for the intended study population and should be the basis for the benefit/risk analysis and the dosage recommendation.

Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established.To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant.In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase.Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group.Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test.Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (7%) treated with an antidepressant and placebo.For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo.ClinicalTrials.gov identifier: NCT02493868.

Introduction L’efficacite a court terme d’esketamine dans la depression resistante (DRT) a ete largement demontree, mais il n’etait pas encore etabli si les effets antidepresseurs etaient maintenus a long terme. Methode Etude de phase 3 multicentrique randomisee, double aveugle, evaluant l’efficacite et la tolerance d’esketamine intranasal (ESK) administre en continu ou discontinu, associe a un antidepresseur oral (AD), chez des adultes souffrant de DRT en remission stable apres 16 semaines d’ESK + AD. Les patients ont ete randomises 1 :1 : poursuivre ESK + AD ou Placebo intranasal (PLB) + AD. Le critere d’evaluation principal d’efficacite etait le delai avant rechute chez les patients en remission stable. Le critere secondaire d’efficacite etait le delai avant rechute chez les repondeurs stables. ESK (56 ou 84 mg) etait administre 1×/semaine ou 1×/2 semaines. Resultats Sept cent cinq patients adultes ont ete directement recrutes (n = 437) ou transferes d’une des etudes de phase 3 a court terme (etude a dose fixe, n = 150 ; ou dose flexible, n = 118). Le temps median avant rechute n’a pas pu etre estime chez les patients traites par ESK + AD (taux de rechute de 50 % non atteint) ; le temps median avant rechute dans le groupe PLB + AD etait de 273,0 jours, demontrant la superiorite significative d’ESK + AD. Parmi les patients en remission stable, le risque de rechute a reduit de 51 % par ESK + AD (26,7 % traites par ESK + AD ont rechute vs 45,4 % traites par PLB + AD, p = 0,03). Parmi les repondeurs stables, le risque de rechute a reduit de 70 % avec ESK + AD (25,8 % traites par ESK + AD ont rechutes vs 57,6 % traites par PLB + AD, p 10 %) rapportes dans le groupe ESK + AD etaient : dysgueusie (26,3 %), vertiges (25,0 %), somnolence (21,1 %), etourdissements (20,4 %), cephalees (17,8 %), nausees (16,4 %), vision floue (15,8 %) et troubles dissociatifs (13,2 %). Ces EI ont ete majoritairement observes le jour de l’administration, generalement transitoires, de gravite legere ou moderee et ont disparu le jour meme. Aucun deces n’a ete rapporte. Aucun EI n’a ete rapporte chez ≥ 10 % des patients traites par PLB + AD. Conclusion Chez les patients en remission stable ou repondeurs stables apres 16 semaines de traitement par ESK + AD, continuer le traitement par ESK + AD demontre une efficacite significativement superieure a un traitement PLB + AD pour retarder la rechute. Les donnees de tolerance etaient coherentes avec les donnees des precedentes etudes de phases 2 et 3.

Introduction Major depressive disorder in the elderly is correlated with lower response and remission rates, greater disability, decreased quality of life, and greater mortality from suicide; approximately 18-40% develop treatment-resistant depression (TRD). Moreover, the elderly respond less well to currently available treatments and may be more vulnerable to their adverse effects. The severity of TRD in the elderly is exemplified by a 5-fold increased use of electroconvulsive therapy, highlighting a critical need for alternative safe and effective treatments. A companion abstract discusses results from the first large phase 3 study of esketamine nasal spray in elderly patients with TRD. Post hoc analyses presented here explored factors that may have contributed to the lack of statistical significance observed in the study, despite a numerical advantage on the primary endpoint–Montgomery Asberg Depression Rating scale (MADRS) LS mean scores–in the esketamine arm vs the control arm of the trial. Methods The primary phase 3, double-blind, multicenter, active controlled study (NCT02422186), included adults ≥65 years of age (N=138) with TRD. Patients were randomized (1:1) to flexibly-dosed esketamine nasal spray (28, 56 or 84 mg twice weekly) and a new oral antidepressant (esketamine/antidepressant), or a new oral antidepressant and placebo nasal spray (antidepressant/placebo). Change from baseline was analyzed using mixed-effects model for repeated measures (MMRM). Analyses were conducted at a 2-sided significance level of 0.05. Findings from the primary analysis are described in the companion abstract. Post hoc analyses explored factors that may have affected the study outcome including (1) impact of study stage, i.e. pre interim analysis (IA) (stage 1) or post IA (stage 2): modifications were made early in the study including training of remote MADRS raters to work with elderly and site discussions related to dose that, because of timing for implementation of the changes, had the greatest impact on stage 2; (2) impact of dose assessed by stage of the IA; (3) age subgroups (65-74 and ≥75 years); (4) age of onset of depression ( Results For reference, the primary efficacy endpoint, the LS mean (95% CI) difference for change in MADRS total scores from baseline to day 28 between the esketamine/antidepressant group and the antidepressant/placebo group using MMRM was -3.6 (−7.20, 0.07; p=0.059). Post hoc analyses included (1) a marked difference in efficacy between stages of the IA: LS mean (95% CI) difference was -1.6 (-6.85, 3.70) in stage 1 vs -5.6 (-10.78, -0.32) in stage 2. The primary analysis applied equal weight to stage 1 (51 patients) and stage 2 (87 patients) effectively down-weighting the results of stage 2. Overall analysis, without adjusting for the IA, showed LS mean (95% CI) change of -4.0 (-7.71, -0.25); (2) use of maximum dose of 84mg: 52.5% at day 25 of stage 1 vs 71.8% at day 25 of stage 2; (3) age: 65-74 years LS mean (95% CI) change of -4.9 (-8.96, -0.89) vs ≥75 years -0.4 (-10.38, 9.50); (4) age at onset of depression Conclusions While MADRS improvement with esketamine/antidepressant vs treatment with antidepressant/placebo was not statistically significant in the primary analysis, a nonsignificant favourable trend was found, with a treatment effect size similar to that seen in younger adult esketamine studies. Post hoc analyses assessed factors potentially affecting the primary outcome. In the short-term study, use of lower doses earlier in the study may have decreased efficacy. In the post hoc analysis, a 95% CI of difference that did not include 0 indicated that esketamine/antidepressant was favoured over antidepressant/placebo without the corrective weighting for the IA, as well as for patients 65-74 years of age, and for those with the onset of depression at age This research was funded by This study was funded by Janssen Research & Development, LLC.

Introduction Estimates of 18-40% of elderly patients with depression suffer from treatment-resistant depression (TRD), defined as non-response to at least two antidepressants. Elderly patients experience greater disability and functional decline, decreased quality of life, and greater mortality from suicide than younger patients. Esketamine nasal spray is being investigated for treatment of TRD. We evaluated the efficacy, safety, and tolerability of flexibly dosed esketamine nasal spray (ESK) (28 mg, 56 mg or 84 mg) plus a newly initiated oral antidepressant (AD), compared with AD plus placebo nasal spray (PBO), for the treatment of TRD in elderly patients. Post hoc analyses, performed to better assess the data from this first large clinical trial of TRD in the elderly, are presented in the companion abstract. Methods Patients ≥ 65 years of age (N=138) in this phase 3, double-blind, multicenter, active-controlled study (NCT02422186) were randomized (1:1) to either ESK + AD (n=72) or AD + PBO (n=66). The primary endpoint was the change in the Montgomery–Asberg Depression Rating Scale (MADRS) total score from day 1 (baseline) to the end of a 4-week double-blind treatment phase. Statistical analysis employed mixed-effects model for repeated measures (MMRM), with a weighted combination test to account for an interim analysis for sample size re-estimation, using a one-sided 0.025 significance level. Pre-specified subgroup analyses were performed for ages 65-74 years (n=116) and ≥75 years (n=21). Remote raters, blinded to the treatment arm, conducted the MADRS assessments by telephone. Results The mean (SD) patient age was 70.0 (4.52) years and mean (SD) baseline MADRS total score was 35.2 (6.16). The mean (SD) change in MADRS total scores from baseline to day 28 was -10.0 (12.74) for ESK + AD and -6.3 (8.86) for AD + PBO. Based on MMRM analysis, the median-unbiased estimate of the difference between ESK + AD and AD + PBO was -3.6 (95% CI: -7.20, 0.07; one-sided p=0.029). A treatment difference favoring ESK+AD was seen for the 65-74 years subgroup. The difference in LS mean (SE) change at day 28 was -4.9 (2.04) for 65-74 years (one-sided p=0.009) and -0.4 (5.02) for ≥75 years (one-sided p=0.465). The most common treatment-emergent adverse events (TEAEs) in the ESK + AD group were dizziness (20.8%), nausea (18.1%), headache, fatigue, increased blood pressure, dissociation (12.5% each) and vertigo (11.1%). The most common TEAEs in the AD + PBO group were anxiety, dizziness and fatigue (7.7% each). Conclusions While treatment with ESK + AD did not demonstrate a statistically significant difference vs treatment with AD + PBO using the weighted combination test on the primary outcome, a statistically significant treatment effect was observed for patients aged 65-74 years, but not for the limited number of patients aged ≥75 years. Safety results were consistent with previous studies in younger adult populations; no new safety concerns were identified. This study was funded by Janssen Research & Development, LLC. This research was funded by Janssen Research & Development, LLC

Importance: While guidance on statistical principles for clinical trials exists, there is an absence of guidance covering the required content of statistical analysis plans (SAPs) to support transparency and reproducibility.Objective: To develop recommendations for a minimum set of items that should be addressed in SAPs for clinical trials, developed with input from statisticians, previous guideline authors, journal editors, regulators, and funders.Design: Funders and regulators (n = 39) of randomized trials were contacted and the literature was searched to identify existing guidance; a survey of current practice was conducted across the network of UK Clinical Research Collaboration–registered trial units (n = 46, 1 unit had 2 responders) and a Delphi survey (n = 73 invited participants) was conducted to establish consensus on SAPs. The Delphi survey was sent to statisticians in trial units who completed the survey of current practice (n = 46), CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guideline authors (n = 16), pharmaceutical industry statisticians (n = 3), journal editors (n = 9), and regulators (n = 2) (3 participants were included in 2 groups each), culminating in a consensus meeting attended by experts (N = 12) with representatives from each group. The guidance subsequently underwent critical review by statisticians from the surveyed trial units and members of the expert panel of the consensus meeting (N = 51), followed by piloting of the guidance document in the SAPs of 5 trials.Findings: No existing guidance was identified. The registered trials unit survey (46 responses) highlighted diversity in current practice and confirmed support for developing guidance. The Delphi survey (54 of 73, 74% participants completing both rounds) reached consensus on 42% (n = 46) of 110 items. The expert panel (N = 12) agreed that 63 items should be included in the guidance, with an additional 17 items identified as important but may be referenced elsewhere. Following critical review and piloting, some overlapping items were combined, leaving 55 items.Conclusions and Relevance: Recommendations are provided for a minimum set of items that should be addressed and included in SAPs for clinical trials. Trial registration, protocols, and statistical analysis plans are critically important in ensuring appropriate reporting of clinical trials.

BackgroundRecognizing the importance not only of the clinician’s opinion but also of the patient’s experience and perspective, Sequenced Treatment Alternatives to Relieve Depression (STAR*D) utilized both clinician-reported and patient-reported outcomes in a large-scale multi-step study on antidepressant effectiveness in real-world settings. Both approaches indicate that MethodsThis is a post-hoc analysis of a Janssen R&D Phase 2a clinical trial (ESKETINTRD2003). Subjects aged 20-64 withMDD without psychotic features (DSM IV) and a history of inadequate response to ≥2 antidepressants were randomized [3:1:1:1] to 1 week of twice-weekly treatment with intranasal placebo (n=33), esketamine 28 mg (n=11), 56 mg (n=11), or 84 mg (n=12). Participants taking oral antidepressants at study entry continued treatment during the study. Changes in depression severitywere measured using the Clinical Global Impression Severity (CGI-S) and the Patient Global Impression Severity (PGI-S) scales.ResultsAt all esketamine doses (28 mg, 56 mg, 84 mg), subjects reported a one-point mean change in PGI-S from baseline to week one compared to no change on placebo (p-values 0.005, 0.001, 0.032 respectively). Similarly, mean CGI-S scores improved for subjects receiving esketamine at all doses (p-values 0.028, 0.004, 0.049 respectively) compared to no change inplacebo subjects. These data are consistent with previously reported data based on the Montgomery Åsberg Depression Rating Scale (MADRS) and support positive correlation between patient-reported and clinician-reported outcomes.DiscussionInitial results from this Phase 2a study suggest clinically relevant improvement in depression symptoms in as early as one week when treated with twice-weekly intranasal esketamine as reported by both clinicians and patients. This work will help guide future investigations of esketamine in larger populations to provide better therapeutic options for treatment resistantMDD patients.Funding AcknowledgementsJanssen

OBJECTIVE To develop consensus recommendations for assessment of suicidal ideation/suicidal behavior (SI/SB) in clinical trials. PARTICIPANTS Stakeholders from academia, industry, regulatory agencies, National Institutes of Health, National Institute of Mental Health, and patient advocacy organizations participated in a consensus meeting that was sponsored by the International Society for CNS Clinical Trials and Methodology and held November 17-18, 2015. Prior to the meeting, teams of experts identified key areas of consensus and dissent related to SI/SB. The most critical issues were presented and discussed in the consensus meeting. EVIDENCE Literature reviews and a pre-meeting survey were conducted. Findings were discussed in pre-meeting working group sessions and at the consensus meeting. CONSENSUS PROCESS Five pre-meeting working groups reviewed (1) nomenclature and classification schemes for SI/SB, (2) detection and assessment of SI/SB, (3) analysis of SI/SB data, (4) design of clinical trials for new treatments of SI/SB, and (5) public health approaches to SI/SB. A modification of the RAND/UCLA Appropriateness Method was used to combine review of scientific evidence with the collective views of experts and stakeholders to reach the final consensus statements. After discussion, all attendees voted using an electronic interactive audience response system. Areas of agreement and areas of continuing dissent were recorded. CONCLUSIONS All 5 working groups agreed that a major barrier to advancement of the field of SI/SB research and the development of new treatments for SI/SB remains the lack of a universally accepted standardized nomenclature and classification system. Achieving alignment on definitions and classification of suicide-related phenomena is critical to improving the detection and assessment of SI/SB, the design of clinical trials for new treatments, and effective public health interventions.

High placebo response has been a major source of bias and is difficult to deal with in many central nervous system (CNS) clinical trials. This bias has led to a high failure rate in mood disorder trials even with known effective drugs. For cancer trials, the traditional parallel group design biases the inference on the maintenance effect of the new drug with the traditional time-to-treatment failure analysis. To minimize bias, we propose a doubly randomized delayed-start design for clinical trials with enrichment. The design consists of two periods. In the first period, patients can be randomized to receive several doses of a new drug or a control. In the second period, control patients of the first period of an enriched population can be rerandomized to receive the same or fewer doses of the new drug or to continue on the control. Depending on the clinical needs, different randomization ratios can be applied to the two periods. The essential feature is that the design is naturally adaptive because of the randomization for the second period. As a result, other aspects of the second period, such as the sample size, can be modified adaptively when an interim analysis is set up for the first period. At the end of the trial, response data from both randomizations are combined in an integrated analysis. Because of the enrichment in the second period, the design increases the probability of trial success and, in addition, reduces the required sample size. Thus, for clinical development, the design offers greater efficiency.

Group sequential designs are rarely used for clinical trials with substantial over running due to fast enrollment or long duration of treatment and follow-up. Traditionally, such trials rely on fixed sample size designs. Recently, various two-stage adaptive designs have been introduced to allow sample size adjustment to increase statistical power or avoid unnecessarily large trials. However, these adaptive designs can be seriously inefficient. To address this infamous problem, we propose a likelihood-based two-stage adaptive design where sample size adjustment is derived from a pseudo group sequential design using cumulative conditional power. We show through numerical examples that this design cannot be improved by group sequential designs. In addition, the approach may uniformly improve any existing two-stage adaptive designs with sample size adjustment. For statistical inference, we provide methods for sequential p-values and confidence intervals, as well as median unbiased and minimum variance unbiased estimates. We show that the claim of inefficiency of adaptive designs by Tsiatis and Mehta ( 2003 ) is logically flawed, and thereby provide a strong defense of Cui et al. ( 1999 ).

Paliperidone ER monotherapy was efficacious in treating acute mania in two 3-week studies in patients with bipolar I disorder. We assessed its efficacy in a study investigating maintenance treatment of clinically stable patients with this disorder.Patients (n=766), aged 18 to 65 years inclusive, with current manic or mixed episodes were initially randomized (4:1) to flexibly-dosed paliperidone ER (3-12 mg/day) or olanzapine (5-20 mg/day; 3-week acute treatment phase); responders continued the same treatment (12-week continuation phase). Patients on paliperidone ER who achieved remission during this phase were randomized (1:1) to fixed-dose paliperidone ER (n=152) or placebo (n=148); those on olanzapine continued to receive that at fixed dose (n=83) (maintenance phase).Median time to recurrence of any mood symptoms (primary endpoint) was: 558 days (paliperidone ER), 283 days (placebo) and not observed with olanzapine (50% of patients experienced recurrence). Time to recurrence of any mood symptoms was significantly longer with paliperidone ER than placebo (p=0.017; based on weighted Z-test at 0.0198 significance level; hazard ratio [placebo: paliperidone ER; unweighted 95% confidence interval]: 1.43 [1.03; 1.98]); the difference was significant for preventing recurrence of manic, but not depressive, symptoms. Treatment-emergent adverse events (maintenance phase) occurred more often in olanzapine group (64%) than placebo (59%) or paliperidone ER groups (55%).Responder-enriched design prevents extrapolation of data to patients not previously stabilized on paliperidone ER.Paliperidone ER significantly delayed the time to recurrence of any mood symptoms, versus placebo, in patients with bipolar I disorder. No new safety concerns emerged.

Background Combination treatment with atypical antipsychotics and a mood stabilizer is often recommended for treatment of manic or mixed episodes associated with bipolar I disorder. Methods Eligible patients ( n = 300) with a Young Mania Rating Scale (YMRS) total score ≥ 20 were randomly allocated (1:1) to continue mood stabilizer monotherapy or receive flexibly-dosed paliperidone ER (3–12 mg/day) in addition (combination treatment) for 6 weeks. The primary efficacy variable was the change from baseline to endpoint in the YMRS total score. Results The mean (SD) YMRS total score at baseline was 26.7 (5.26); 33% of patients presented with a mixed (as distinct from a manic) episode and 62% were on valproate and 38% on lithium. The mean (SD) change from baseline to endpoint in the YMRS total score was not significantly different for combination treatment (− 14.3 [10.0]) compared with mood stabilizer monotherapy (− 13.2 [10.9]; p = 0.16). Combination treatment also failed to separate from mood stabilizer monotherapy for the secondary efficacy measures. The incidence of treatment-emergent adverse events was higher with combination treatment (70%) than with mood stabilizer monotherapy (54%); insomnia was the most common adverse event in both treatment groups (11%). Limitations The relatively low doses of paliperidone ER used in this study and the conduct across different countries may have contributed to its failure to differentiate combination treatment from mood stabilizer monotherapy for the primary and secondary efficacy measures. Conclusions In this study, flexibly-dosed paliperidone ER used as adjunctive therapy to mood stabilizers did not demonstrate efficacy over mood stabilizer monotherapy. No new safety signals were observed with combination treatment in this population.

Paliperidone palmitate is a long-acting injectable antipsychotic agent. This 13-week, multicenter, randomized (1 : 1 : 1 : 1), double-blind, parallel-group study evaluated the efficacy, safety, and tolerability of fixed 25, 50, and 100 milligram equivalent (mg equiv.) doses of paliperidone palmitate vs placebo administered as gluteal injections on days 1 and 8, then every 4 weeks (days 36 and 64) in 518 adult patients with schizophrenia. The intent-to-treat analysis set (N=514) was 67% men and 67% White, with a mean age of 41 years. All paliperidone palmitate dose groups showed significant improvement vs placebo in the Positive and Negative Syndrome Scale (PANSS) total score (primary efficacy measure; 25 and 50 mg equiv., p=0.02; 100 mg equiv., p

This study assessed the efficacy and the safety of a dosing regimen that was revised from earlier studies for the investigational injectable atypical antipsychotic paliperidone palmitate (approved in the USA, August 2009) for adult patients with acutely exacerbated schizophrenia. The patients (N = 652) were randomly assigned (1:1:1:1) to paliperidone palmitate at 25, 100, or 150 mg eq. or placebo in this 13-week double-blind study. The patients received an injection of paliperidone palmitate at 150 mg eq. or placebo in the deltoid muscle on day 1 and the assigned fixed dose or placebo in the deltoid or gluteal [corrected] on day 8 and then once monthly (days 36 and 64). No oral supplementation was used. Target plasma levels were achieved by day 8 in all paliperidone palmitate groups. The mean change in Positive and Negative Syndrome Scale total score from baseline to end point improved significantly (P or =2% of patients in any of the treatment groups) that occurred more frequently in the total paliperidone palmitate group versus the placebo group (with > or =1% difference) were injection-site pain (7.6% vs 3.7%), dizziness (2.5% vs 1.2%), sedation (2.3% vs 0.6%), pain in the extremity (1.6% vs 0.0%), and myalgia (1.0% vs 0.0%). The paliperidone palmitate treatment was efficacious and generally tolerated across the dose range (25, 100, or 150 mg eq.) in adult patients with acutely exacerbated schizophrenia.

Vieta E, Nuamah IF, Lim P, Yuen EC, Palumbo JM, Hough DW, Berwaerts J. A randomized, placebo- and active-controlled study of paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I disorder. Bipolar Disord 2010: 12: 230–243. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives: To evaluate the antimanic efficacy and safety of paliperidone extended-release (ER) tablets in patients with bipolar I disorder. Methods: This study included a 3-week, double-blind, acute treatment phase (paliperidone ER versus placebo, with quetiapine as control), and a 9-week, double-blind, maintenance phase (paliperidone ER versus quetiapine). Patients [n = 493; Young Mania Rating Scale (YMRS) score ≥ 20] were randomized (2:2:1) to flexibly dosed paliperidone ER (3–12 mg/day), quetiapine (400–800 mg/day), or placebo for the acute treatment phase. During the maintenance phase, patients assigned to placebo were switched to paliperidone ER but not included in analysis of efficacy. Results: Paliperidone ER was superior to placebo at the 3-week endpoint {primary outcome; least-squares mean difference in change from baseline in YMRS scores [95% confidence interval (CI)]: −5.5 (−7.57; −3.35); p

Importance Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants. Objective To assess the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD). Design, Setting, and Participants This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings. Interventions In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks. Main Outcomes and Measures The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Results Sixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] years) were included in the efficacy and safety analyses. Change (least squares mean [SE] difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: −4.2 [2.09], P = .02; 56 mg: −6.3 [2.07], P = .001; 84 mg: −9.0 [2.13], P P Conclusions and Relevance In this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials. Trial Registration clinicaltrials.gov identifier:NCT01998958

We assessed efficacy and tolerability of the injectable atypical antipsychotic paliperidone palmitate in delaying time-to-relapse in adults with schizophrenia.Eligible patients (Positive and Negative Syndrome Scale [PANSS] total score120) were transitioned from previous antipsychotics to paliperidone palmitate during a 9-week, open-label phase. Patients received the first 2 intramuscular injections of paliperidone palmitate (50mg eq) one-week apart, then subsequent injections (25, 50, or 100mg eq, flexibly-dosed), once-monthly. Stable patients (PANSS total scoreor = 75) continued into the 24-week maintenance phase. At maintenance phase endpoint, stabilized patients were randomized (1:1 ratio) to either continue paliperidone palmitate (at stabilized dose) or begin placebo in the variable-duration, double-blind phase.The preplanned interim analysis (conducted after 68 relapse events) included 312 patients: mean age = 40 years, 55% men, 66% white, and mean transition baseline PANSS total score (SD): placebo, 69.5 (16.89); paliperidone palmitate, 69.3 (17.39). Time-to-relapse (primary endpoint) favored paliperidone palmitate (p0.0001, log-rank test) at interim and final analysis (n=408). The hazard ratio (placebo/paliperidone palmitate) at the final analysis was 3.60 (95% CI: 2.45, 5.28). Treatment-emergent adverse event rates (final analysis set) were: 67% for transition and maintenance phases, and 45% (placebo) and 44% (paliperidone palmitate) for the double-blind phase. Across phases, the incidence of glucose-related adverse events was low (or = 4%), while mean weight increased by 1.9 kg for paliperidone palmitate and remained unchanged for placebo patients. Injection site tolerability was comparable between groups.Paliperidone palmitate significantly delayed time-to-relapse compared with placebo and presented no new safety signals.

We evaluated the efficacy and safety of the investigational long-acting injectable antipsychotic agent paliperidone palmitate (PP) in the treatment of schizophrenia. Patients were randomized to receive gluteal injections of placebo or PP (50 or 100 mg eq., fixed doses), without oral supplementation, on days 1, 8, and 36 (9-wk, double-blind phase) in this phase 2b study. Patients (n=197, intent-to-treat analysis set) were 62% men, mean (s.d.) age 39 (10) yr, with a baseline mean (s.d.) Positive and Negative Syndrome Scale (PANSS) total score of 87.0 (12.5). Mean (s.d.) PANSS total scores showed significant improvement at endpoint (primary measure) for both the PP 50 mg eq. [-5.2 (21.5)] and PP 100 mg eq. [-7.8 (19.4)] groups, vs. placebo [6.2 (18.3)] (p0.001, each dose vs. placebo). This improvement was detected by day 8 and maintained to endpoint (p0.011) for both doses. In the safety analysis set (n=247), fewer PP-treated patients (2%) discontinued for treatment-emergent adverse events vs. placebo-treated (10%). Rates of treatment-emergent extrapyramidal syndrome-related adverse events were comparable between active treatment and placebo, with the exception of parkinsonism-related disorders (50 mg eq. 5%, 100 mg eq. 8%, placebo 1%). Results of other safety measures suggest PP to be generally well-tolerated. Throughout the study, investigators rated injection-site pain as absent (56-71%), mild (24-39%), moderate (2-12%), or severe (0-2%). PP (50 and 100 mg eq. doses) administered as a gluteal intramuscular injection was efficacious and generally tolerated in these patients with acute symptomatic schizophrenia.

Paliperidone palmitate is an investigational, injectable atypical antipsychotic. The safety and tolerability of initiating treatment with paliperidone palmitate via deltoid versus gluteal injections given once monthly, and of switching injection sites, in adults with stable schizophrenia were assessed. In this crossover trial, stable outpatients (N=252) were randomly assigned 1:1:1 to 3 dose groups (paliperidone palmitate 50, 75, or 100 mg eq.) and 2 treatment sequences (blinded to dose): deltoid muscle (period 1 [13 weeks]) followed by gluteal muscle (period 2 [12 weeks]) or the reverse. The intent-to-treat analysis set had 249 patients: mean age=43 (SD: 12.8) years; 57% men, 81% white, baseline mean Positive and Negative Syndrome Scale (PANSS) total score=56 (SD: 11.5). A total of 170 (68%) patients completed the study, with a similar proportion completing each treatment sequence. The incidence of systemic treatment-emergent adverse events (TEAEs) was similar between the 2 injection sites across doses during period 1 (deltoid [D]: 61% to 67%; gluteus [G]: 58% to 65%), and during the last 8 weeks of the 2 study periods (DG: 32% to 45% [period 1], 29% to 42% [period 2]; GD: 31% to 40% [period 1], 30% to 41% [period 2]). During the first treatment week, median plasma paliperidone concentrations were higher with treatment initiation in the deltoid muscle compared with the gluteal muscle. At apparent steady state, there was little difference in plasma paliperidone concentrations between the deltoid and gluteus sites for a given dose. Local tolerability was slightly better with gluteal injections. Patient preference for injection sites differed between geographical regions, e.g. patients from the US preferred deltoid to gluteal sites. The most common (>or=5% overall) TEAEs were: (period 1) insomnia, anxiety, headache, and agitation; and (period 2) insomnia, psychotic disorder, weight increased, and tachycardia. Paliperidone palmitate treatment was tolerated, irrespective of injection site, and thus could offer the choice of administration into either the deltoid or gluteal muscle to meet patient and physician preference.

Objective The objective of this multicenter, international study was to evaluate safety and tolerability of paliperidone extended-release (ER) tablets in elderly (age ≥65 years) patients with schizophrenia. The authors conducted a 6-week, double-blind, randomized, placebo-controlled, optional 24-week open-label extension study. Interventions consisted of flexible, once-daily doses of paliperidone ER (3–12 mg/day; 6-mg starting dose, adjusted in 3-mg dose increments) or placebo (2:1) during double-blind treatment and paliperidone ER only during open-label treatment. Measurements included adverse events, laboratory tests, physical examinations, 12-lead electrocardiograms, movement disorder rating scales, Positive and Negative Syndrome Scale, and Clinical Global Impression scale. The study was not powered to show statistical differences. Results Patients (N = 114) were predominantly female (73%); mean age was 70 years (double-blind phase). Concomitant disease presence was consistent with that of an older population. During the double-blind phase, discontinuation rates resulting from adverse events were similar between groups (paliperidone ER: 7%, placebo: 8%) as were incidences of treatment-emergent adverse events (paliperidone ER: 67%, placebo: 71%). Serious adverse events occurred in 3% of the paliperidone ER- and 8% of the placebo-treated patients. Elevated prolactin levels occurred in approximately one half of patients. No prolactin- or glucose treatment-related adverse events or noteworthy mean changes in body weight (0 kg [standard deviation: 2.1] and 0 kg [standard deviation: 2.3] for paliperidone ER and placebo, respectively) were observed. Safety and tolerability results in the extension were consistent with the shorter-term results. Efficacy measures did not show consistent statistical improvement between treatment groups. Conclusion Paliperidone ER (3–12 mg/day) treatment over a 30-week period was generally well-tolerated and may improve symptom severity in elderly patients with schizophrenia.

Background Paliperidone extended-release tablet (paliperidone ER; Invega, Janssen L.P., Titusville, New Jersey) is an oral psychotropic for schizophrenia treatment. Methods Efficacy and safety of once-daily paliperidone ER (6 and 12 mg) were assessed versus placebo in 444 patients with acute schizophrenia in a 6-week, multicenter, double-blind, randomized, parallel-group study. An olanzapine (10 mg) treatment arm was included to confirm trial validity. Results Both doses of paliperidone ER demonstrated significant improvement in Positive and Negative Syndrome Scale (PANSS) total score ( p ≤ .006) and certain PANSS Marder factor scores compared with placebo ( p ≤ .025); PANSS total score also improved in the olanzapine treatment arm. Paliperidone ER 6 mg ( p ≤ .008), but not 12 mg, was associated with significant improvements in personal and social performance. The incidence of treatment-emergent adverse events (AEs) for paliperidone ER 6 mg was comparable with placebo and slightly greater with paliperidone ER 12 mg. Changes in blood glucose and lipid levels with paliperidone ER were comparable with placebo. Two patients treated with paliperidone ER experienced glucose-related AEs. Body-weight increases of 1-2 kg were observed with paliperidone ER. Although there were increases in plasma prolactin levels with paliperidone ER treatment, the incidence of prolactin-related AEs was ≤1%. Conclusions In this study, paliperidone ER, particularly the 6-mg dose, was effective and well tolerated, and provides a valuable new treatment option for schizophrenia.

Background Paliperidone extended-release tablet (paliperidone ER) is an oral psychotropic agent developed for schizophrenia treatment. Paliperidone (9-OH-risperidone, metabolite of risperidone), when used with OROS technology has a unique pharmacokinetic profile undergoing limited hepatic metabolism. Methods The efficacy and safety of once-daily paliperidone ER (3 mg, 9 mg and 15 mg) were compared with placebo in 618 patients with acute schizophrenia in a 6-week, multicenter, double-blind, randomized, parallel-group study. An assay sensitivity group with known efficacy was included to confirm trial validity (olanzapine 10 mg). Results All doses of paliperidone ER demonstrated significant improvements in PANSS total and PANSS factors scores (p

Paliperidone extended-release tablet (paliperidone ER) is an investigational oral psychotropic developed for schizophrenia treatment. It utilizes OROS technology to provide a unique pharmacokinetic profile, eliminating the need for titration and potentially leading to improved tolerability. Furthermore, paliperidone undergoes limited hepatic metabolism.The efficacy and safety of once-daily paliperidone ER (6 mg, 9 mg and 12 mg) were assessed versus placebo in 628 patients with acute schizophrenia in a 6-week, multicenter, double-blind, randomized, parallel-group study.All doses of paliperidone ER demonstrated significant improvement in PANSS score, all PANSS Marder factor scores (p0.001) and personal and social functioning versus placebo (p0.001). The PANSS total score also improved significantly in the olanzapine treatment arm. Significantly higher percentages of paliperidone ER patients demonstrated aor =30% reduction in PANSS total score versus placebo (p0.001). The incidence of movement disorder-related AEs and rating scales measurements were similar to placebo for the paliperidone ER 6 mg group and higher in the 9 mg and 12 mg groups. In the paliperidone ER groups there were no reports of glucose-related AEs or clinically relevant changes in plasma lipid levels and changes in mean bodyweight1 kg.In this study, all doses of paliperidone ER were effective in significantly improving the symptoms of schizophrenia and personal and social functioning and were generally well tolerated. Paliperidone ER offers a distinctive treatment profile and may provide a valuable new treatment option for patients with schizophrenia.