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Suvorexant is an orexin receptor antagonist that is approved in the US, Japan and Australia for the treatment of insomnia. Using outcomes from the Insomnia Severity Index (ISI) in the core registration studies, we explored suvorexant effects on sleep problems and their impact on daytime function.Data were pooled from two similar Phase 3, randomized, double-blind, placebo-controlled, parallel-group, three-month trials in elderly (≥65 years) and non-elderly (18-64 years old) insomnia patients. Age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg were evaluated. The ISI, a 7-item self-rated questionnaire with each item rated on 0-4 scale (higher score corresponds to increasing severity), was administered to patients as an exploratory assessment in both studies at baseline and one and three months after randomization.The analysis included 1824 patients. Suvorexant improved change-from-baseline ISI total scores to a greater extent than placebo (Month three: 20/15 mg = -6.2, 40/30 mg = -6.7, placebo = -4.9, p-values for both active arms vs. placebo0.001) and resulted in a greater proportion of responders than placebo using a variety of definitions (eg, ≥6-point improvement from baseline at Month three: 20/15 mg = 55.5%, 40/30 mg = 54.9%, placebo = 42.2%, p-values for both active arms vs. placebo0.001). Additionally, the "impact of insomnia" component, which assesses the impact of insomnia on daytime function/quality-of-life, was improved to a greater extent by suvorexant than placebo.Suvorexant 20/15 mg and 40/30 mg improved sleep to a greater extent than placebo as assessed by the ISI in patients with insomnia. Improvement in sleep onset/maintenance as well as a reduction of the impact of sleep problems on daytime function contributed to the overall improvement observed in ISI total score. CLINICALTRIALS.NCT01097616, NCT01097629.

Objective Suvorexant is an orexin receptor antagonist approved for treating insomnia at doses of 10–20 mg. Previously reported phase III results showed that suvorexant was effective and well-tolerated in a combined-age population (elderly and nonelderly adults). The present analysis evaluated the clinical profile of suvorexant specifically in the elderly. Methods Prespecified subgroup analyses of pooled 3-month data from two (efficacy) and three (safety) randomized, double-blind, placebo-controlled, parallel-group trials. In each trial, elderly (≥65 years) patients with insomnia were randomized to suvorexant 30 mg, suvorexant 15 mg, and placebo. By design, fewer patients were randomized to 15 mg. Patient-reported and polysomnographic (subset of patients) sleep maintenance and onset endpoints were measured. Results Suvorexant 30 mg (N = 319) was effective compared with placebo (N = 318) on patient-reported and polysomnographic sleep maintenance, and onset endpoints at Night 1 (polysomnographic endpoints)/Week 1 (patient-reported endpoints), Month 1, and Month 3. Suvorexant 15 mg (N = 202 treated) was also effective across these measures, although the onset effect was less evident at later time points. The percentages of patients discontinuing because of adverse events over 3 months were 6.4% for 30 mg (N = 627 treated), 3.5% for 15 mg (N = 202 treated), and 5.5% for placebo (N = 469 treated). Somnolence was the most common adverse event (8.8% for 30 mg, 5.4% for 15 mg, 3.2% for placebo). Conclusion Suvorexant generally improved sleep maintenance and onset over 3 months of nightly treatment and was well-tolerated in elderly patients with insomnia (clinicaltrials.gov; NCT01097616, NCT01097629, NCT01021813).

Author(s): Connor, Kathryn M; Ceesay, Paulette; Hutzelmann, Jill; Snavely, Duane; Krystal, Andrew D; Trivedi, Madhukar H; Thase, Michael; Lines, Christopher; Herring, W Joseph; Michelson, David | Abstract: BackgroundWe evaluated the orexin receptor antagonist filorexant (MK-6096) for treatment augmentation in patients with major depressive disorder.MethodsWe conducted a 6-week, double-blind, placebo-controlled, parallel-group, Phase II, proof-of-concept study. Patients with major depressive disorder (partial responders to ongoing antidepressant therapy) were randomized 1:1 to once-daily oral filorexant 10 mg or matching placebo.ResultsDue to enrollment challenges, the study was terminated early, resulting in insufficient statistical power to detect a prespecified treatment difference; of 326 patients planned, 129 (40%) were randomized and 128 took treatment. There was no statistically significant difference in the primary endpoint of change from baseline to week 6 in Montgomery Asberg Depression Rating Scale total score; the estimated treatment difference for filorexant-placebo was -0.7 (with negative values favoring filorexant) (P=.679). The most common adverse events were somnolence and suicidal ideation.ConclusionsThe interpretation of the results is limited by the enrollment, which was less than originally planned, but the available data do not suggest efficacy of orexin receptor antagonism with filorexant for the treatment of depression. (Clinical Trial Registry: clinicaltrials.gov: NCT01554176).

Sex-related differences in the clinical profiles of some insomnia medications have been previously reported. To evaluate the clinical profile of suvorexant, a novel orexin receptor antagonist approved for treating insomnia at doses up to 20 mg, by sex subgroups. Efficacy analyses by sex were based on pooled data from two similar phase 3, randomized, double-blind, placebo-controlled, 3-month trials in elderly (≥65 years) and non-elderly (18–64 years) insomnia patients. Two age-adjusted (non-elderly/elderly) dose regimes of 40/30 and 20/15 mg were evaluated, with fewer patients assigned to 20/15 mg. Efficacy was assessed by patient-reported outcomes (N = 1264 women, 707 men) and by polysomnography endpoints in ~75% of patients. Safety analyses by sex (N = 1744 women, 1065 men) included pooled data from the two 3-month trials plus 3-month data from a safety trial of 40/30 mg. The sex subgroup efficacy analyses mirrored the improvements seen for suvorexant 40/30 and 20/15 mg over placebo on patient-reported outcomes and polysomnography sleep maintenance and onset endpoints in the primary analyses; 95% CIs excluded zero in favor of suvorexant for most endpoints in both sexes, and similar efficacy was observed between sexes (95% CIs overlapped). Suvorexant was well-tolerated in women and men, although women in all treatment groups (including placebo) reported more adverse events than men. The most frequent adverse event was somnolence (women: 11.1% for 40/30 mg, 8.5% for 20/15 mg, 2.3% for placebo; men: 10.1% for 40/30 mg, 3.4% for 20/15 mg, 4.2% for placebo). Suvorexant was generally effective and well-tolerated in both women and men with insomnia. ClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629, NCT01021813.

Study objectivesSuvorexant is an orexin receptor antagonist approved for treating insomnia at a maximum dose of 20 mg. Phase-3 trials evaluated two age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg with the primary focus on 40/30 mg. We report here results from pooled analyses of the 20/15 mg dose-regime, which was evaluated as a secondary objective in the trials.MethodsPrespecified analysis of pooled data from two identical randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in non-elderly (18-64 years) and elderly (≥ 65 years) patients with insomnia. Patients were randomized to suvorexant 20/15 mg (non-elderly/elderly), suvorexant 40/30 mg (non-elderly/elderly), or placebo; by design, fewer patients were randomized to 20/15 mg. Efficacy was assessed by self-reported and polysomnography (PSG; subset of patients) sleep maintenance and onset endpoints.ResultsSuvorexant 20/15 mg (N = 493 treated) was effective compared to placebo (N = 767 treated) on patient-reported and PSG sleep maintenance and onset endpoints at Night-1 (PSG endpoints) / Week-1 (subjective endpoints), Month-1 and Month-3, except for effects on PSG sleep onset at Month-3. Suvorexant 20/15 mg was generally well tolerated, with 3% of patients discontinuing due to adverse events over 3 months vs. 5.2% on placebo. Somnolence was the most common adverse event (6.7% vs. 3.3% for placebo). There was no systematic evidence of rebound or withdrawal signs or symptoms when suvorexant was discontinued after 3 months of nightly use.ConclusionsSuvorexant 20/15 mg improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated.Clinical trial registrationClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629.

Summary Background Suvorexant (MK-4305) is an orexin receptor antagonist shown to be efficacious for insomnia over 3 months. We aimed to assess its clinical profile during and after 1 year of treatment. Methods We did a randomised, placebo-controlled, parallel-group trial at 106 investigational centres in the Americas, Australia, Europe, and South Africa from December, 2009, to August, 2011. Patients aged 18 years or older with primary insomnia by DSM-IV-TR criteria were assigned using a computer-generated randomised allocation schedule to receive nightly suvorexant (40 mg for patients younger than 65 years, 30 mg for patients aged 65 years or older) or placebo at a 2:1 ratio for 1 year with a subsequent 2-month randomised discontinuation phase in which patients on suvorexant either continued suvorexant or were abruptly switched to placebo while patients on placebo remained on placebo. Treatment assignment was masked from patients and investigators. The primary objective was to assess the safety and tolerability of suvorexant for up to 1 year. Secondary objectives were to assess the efficacy of suvorexant for improving patient-reported subjective total sleep time (sTST) and time to sleep onset (sTSO) over the first month of treatment. Efficacy endpoints over the first month were assessed with a mixed model with terms for baseline value of the response variable, age, sex, region, treatment, time, and treatment by time interaction. This trial is registered with ClinicalTrials.gov, number NCT01021813. Findings 322 (62%) of 522 patients randomly assigned to receive suvorexant and 162 (63%) of 259 assigned to receive placebo completed the 1-year phase. Over 1 year, 362 (69%) of 521 patients treated with suvorexant experienced any adverse events compared with 164 (64%) of 258 treated with placebo. Serious adverse events were recorded in 27 patients (5%) who received suvorexant and 17 (7%) who received placebo. The most common adverse event, somnolence, was reported for 69 patients (13%) who received suvorexant and seven (3%) who received placebo. At month 1, suvorexant (517 patients in the efficacy population) showed greater efficacy than placebo (254 in the efficacy population) in improving sTST (38·7 min vs 16·0 min; difference 22·7, 95% CI 16·4 to 29·0; p vs −8·4 min, difference −9·5, −14·6 to −4·5; p=0·0002). Interpretation Our findings show that suvorexant was generally safe and well tolerated over 1 year of nightly treatment in patients with insomnia, with efficacy noted for subjective measures of sleep onset and maintenance. Funding Merck & Co Inc.

Background Current antipsychotic treatments have little impact on the cognitive deficits associated with schizophrenia. It has been proposed that agents which promote histamine release may enhance cognition. We evaluated whether the H3 inverse agonist MK-0249 might improve cognitive deficits in patients with schizophrenia. Methods Outpatients (N = 55) with schizophrenia between ages 21 and 55 who were clinically stable, experienced no more than mild to moderate overall symptoms (PANSS score total 36–75), and were taking a stable dose of antipsychotic medication were randomized to MK-0249 10 mg and placebo in a multi-center, randomized, double-blind, 2-period (4-weeks per period), cross-over study. The primary efficacy endpoint was the mean change from baseline at 4-weeks of treatment in the total cognitive score on the Brief Assessment of Cognition in Schizophrenia (BACS) Battery. Other assessments of cognition were also performed. Results A total of 46 patients completed the study. MK-0249 10 mg did not demonstrate a statistically significant difference compared to placebo in the mean change from baseline in the total cognitive score on the BACS battery after 4-weeks of treatment (− 0.1, 95% CI: − 2.3, 2.1) or with regard to secondary measures of attention/processing speed, episodic memory, or working memory after 4-weeks of treatment. The incidence of adverse events was greater during the MK-0249 treatment period (25/52 patients, 48.1%) compared to the placebo treatment period (15/51 patients, 29.4%). Conclusion MK-0249 10 mg once daily was not superior to placebo in the treatment of cognitive impairment in patients with schizophrenia after 4-weeks. (Clinicaltrials.gov: NCT00506077 )

To assess the utility of orexin receptor antagonism as a novel approach to treating insomnia.We evaluated suvorexant, an orexin receptor antagonist, for treating patients with primary insomnia in a randomized, double-blind, placebo-controlled, 2-period (4 weeks per period) crossover polysomnography study. Patients received suvorexant (10 mg [n = 62], 20 mg [n = 61], 40 mg [n = 59], or 80 mg [n = 61]) in one period and placebo (n = 249) in the other. Polysomnography was performed on night 1 and at the end of week 4 of each period. The coprimary efficacy end points were sleep efficiency on night 1 and end of week 4. Secondary end points were wake after sleep onset and latency to persistent sleep.Suvorexant showed significant (p values0.01) dose-related improvements vs placebo on the coprimary end points of sleep efficiency at night 1 and end of week 4. Dose-related effects were also observed for sleep induction (latency to persistent sleep) and maintenance (wake after sleep onset). Suvorexant was generally well tolerated.The data suggest that orexin receptor antagonism offers a novel approach to treating insomnia.This study provides Class I evidence that suvorexant improves sleep efficiency over 4 weeks in nonelderly adult patients with primary insomnia.

BACKGROUND It has been suggested that the histamine subtype 3 receptor inverse agonists such as MK-0249 might be effective in treating attention-deficit/hyperactivity disorder (ADHD). We evaluated the effects of MK-0249 in adults with ADHD. METHOD A randomized, double-blind, placebo-controlled, incomplete block, 2-period crossover study of MK-0249 5-10 mg/d and osmotic-release oral system (OROS) methylphenidate 54-72 mg/d (active comparator) was performed in 72 men and women aged ≥ 18 to ≤ 55 years who met DSM-IV criteria for ADHD of either inattentive or combined subtype and who had a chronic course of behavior disorder. The study was conducted from August 2007 through April 2008 at 6 US sites. Primary efficacy was assessed by the mean change from baseline in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score after 4 weeks of treatment. RESULTS Change from baseline in AISRS at week 4 for MK-0249 was not different from placebo (P = .341), whereas a significant benefit was seen for OROS methylphenidate versus placebo (P < .001). Analysis of secondary end points, including the Conners Adult ADHD Rating Scales, showed results consistent with the AISRS. A similar percentage of patients reported adverse events for MK-0249 compared with placebo (73% versus 69%, respectively). However, a greater percentage of patients reported insomnia as an adverse event with MK-0249 treatment compared with placebo (32% versus 11%, respectively). CONCLUSIONS MK-0249 10 mg/d is not effective for the treatment of adult ADHD. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00475735.

Objective: Preclinical models, receptor localization, and genetic linkage data support the role of D4 receptors in the etiology of ADHD. This proof-of-concept study was designed to evaluate MK-0929, a selective D4 receptor antagonist as treatment for adult ADHD. Method: A randomized, double-blind, placebo-controlled, crossover study was conducted in adults with primary ADHD. The primary end point was changed from baseline in total score on the Adult ADHD Investigator Symptom Rating Scale following a 4-week treatment regimen. Additional measures included Clinical Global Impression–Severity Scale, Hospital Anxiety and Depression Scale, and Brown Attention Deficit Disorder Scale and D4 genotype analysis. Results: No statistically significant treatment differences were found between MK-0929 and placebo in any of the primary or secondary assessments. Conclusion: Results from this study suggest that blockade of the D4 receptor alone is not efficacious in the treatment of adult ADHD.

The efficacy and safety of a selective NK(1) antagonist, L-759274, was investigated in outpatients with diagnosis of major depressive disorder with melancholic features, following evidence obtained with the novel compound aprepitant that Substance P (NK(1)) antagonists may provide a unique mechanism of antidepressant activity. A randomized, double-blind placebo-controlled study was carried out. Patients, male or female, aged 18-60, scoring >/=25 points on total of first 17 items of 21-item Hamilton Depression Scale (HAMD), and scoring >/=4 (moderately ill) on Clinical Global Impressions-Severity Scale were randomized to oral L-759274 40 mg daily (n=66) or placebo (n=62) for 6 weeks. For patients receiving L-759274, improvement (mean decrease from baseline) in HAMD-17 total score was 10.7 points, compared with a mean 7.8 point improvement in patients receiving placebo (p

Suvorexant is an orexin receptor antagonist for treatment of insomnia. We report results from two pivotal phase 3 trials.Two randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in nonelderly (18-64 years) and elderly (≥65 years) patients with insomnia. Suvorexant doses of 40/30 mg (nonelderly/elderly) and 20/15 mg (nonelderly/elderly) were evaluated. The primary focus was 40/30 mg, with fewer patients randomized to 20/15 mg. There was an optional 3-month double-blind extension in trial 1. Each trial included a 1-week, randomized, double-blind run-out after double-blind treatment to assess withdrawal/rebound. Efficacy was assessed at week 1, month 1, and month 3 by patient-reported subjective total sleep time and time to sleep onset and in a subset of patients at night 1, month 1, and month 3 by polysomnography end points of wakefulness after persistent sleep onset and latency to onset of persistent sleep (LPS). One thousand twenty-one patients were randomized in trial 1 and 1019 patients in trial 2.Suvorexant 40/30 mg was superior to placebo on all subjective and polysomnography end points at night 1/week 1, month 1, and month 3 in both trials, except for LPS at month 3 in trial 2. Suvorexant 20/15 mg was superior to placebo on subjective total sleep time and wakefulness after persistent sleep onset at night 1/week 1, month 1, and month 3 in both trials and at most individual time points for subjective time to sleep onset and LPS in each trial. Both doses of suvorexant were generally well tolerated, with5% of patients discontinuing due to adverse events over 3 months. The results did not suggest the emergence of marked rebound or withdrawal signs or symptoms when suvorexant was discontinued.Suvorexant improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated.

Aprepitant is a neurokinin 1 receptor antagonist approved for prevention of chemotherapy-induced and post-operative nausea and vomiting. Early studies demonstrated promising antidepressant activity as monotherapy, although this was unsupported by subsequent phase 3 trials. This phase 2 study evaluated whether aprepitant potentiated the antidepressant effects of paroxetine.Outpatients with major depressive disorder were randomized to aprepitant 200 mg + paroxetine 20 mg, paroxetine + placebo, or aprepitant + placebo for 6 weeks. The primary endpoint was change in HAMD-17 total score. Secondary/exploratory endpoints included changes in HAMA, CGI-S, CGI-I, and HAMD Item-1 scores at week 6.A total of 79, 78, and 79 patients received aprepitant + paroxetine, paroxetine + placebo, and aprepitant + placebo, respectively. At week 6, mean changes in HAMD-17 were -11.0 (95% confidence interval [CI]: -12.7, -9.4), -11.7 (95% CI: -13.3, -10.0), and -9.5 (95% CI: -10.9, -8.1), respectively. Pairwise comparisons of HAMD-17 change with combination therapy versus paroxetine alone demonstrated no significant difference (p = 0.567). Changes in CGI-S, CGI-I, and HAMD Item-1 scores were also comparable, although there was a greater reduction in anxiety (HAMA) with paroxetine alone than aprepitant + paroxetine (p = 0.045). Adverse events were generally more common with the combination than either monotherapy.Concomitant use of aprepitant + paroxetine for 6 weeks did not provide greater antidepressant benefit compared with paroxetine + placebo in patients with major depression.

The RENAAL Study is a double-blind, placebo-controlled trial to evaluate the renal protective effects of losartan in Type 2 diabetic patients with nephropathy. The study has enrolled 1513 patients and is expected to continue for 3.5 years after the last patient has been entered. Eligible patients must have a urinary albumin:creatinine ratio of at least 300 mg/g and serum creatinine between 1.3 to 3.0 mg/dL. Eligible hypertensive or normotensive patients are randomised to receive either losartan or placebo, in addition to their existing antihypertensive therapy. Medications that block angiotensin production or action, are excluded. The primary endpoint is a composite of the time to first event of doubling of serum creatinine, end-stage renal disease, or death; secondary endpoints include cardiovascular events, progression of renal disease, and changes in proteinuria; tertiary endpoints include quality of life, healthcare resource utilisation, and amputations. Patients include Caucasians (48.6%), Blacks (15.2%), Asians (16.7%), and Hispanics (18.2%). Baseline urinary albumin:creatinine ratio and serum creatinine levels average 1867 mg/g and 1.9 mg/dL, respectively. Mean systolic and diastolic blood pressures are 153 and 82 mmHg, respectively. RENAAL will document whether blockade of the AII receptor with losartan produces clinical benefits in patients with Type 2 diabetes and nephropathy.

Summary Background To determine whether specific angiotensin II receptor blockade with losartan offers safety and efficacy advantages in the treatment of heart failure over angiotensin-converting-enzyme (ACE) inhibition with captopril, the ELITE study compared losartan with captopril in older heart-failure patients. Methods We randomly assigned 722 ACE inhibitor naive patients (aged 65 years or more) with New York Heart Association (NYHA) class II-IV heart failure and ejection fractions of 40% or less to double-blind losartan (n=352) titrated to 50 mg once daily or captopril (n=370) titrated to 50 mg three times daily, for 48 weeks. The primary endpoint was the tolerability measure of a persisting increase in serum creatinine of 26·5 μmol/L or more (≥0·3 mg/dL) on therapy; the secondary endpoint was the composite of death and/or hospital admission for heart failure; and other efficacy measures were total mortality, admission for heart failure, NYHA class, and admission for myocardial infarction or unstable angina. Findings The frequency of persisting increases in serum creatinine was the same in both groups (10·5%). Fewer losartan patients discontinued therapy for adverse experiences (12·2% vs 20·8% for captopril, p=0·002). No losartan-treated patients discontinued due to cough compared with 14 in the captopril group. Death and/or hospital admission for heart failure was recorded in 9·4% of the losartan and 13·2% of the captopril patients (risk reduction 32% [95% CI -4% to +55%], p=0·075). This risk reduction was primarily due to a decrease in all-cause mortality (4·8% vs 8·7%; risk reduction 46% [95% CI 5–69%], p=0·035). Admissions with heart failure were the same in both groups (5·7%), as was improvement in NYHA functional class from baseline. Admission to hospital for any reason was less frequent with losartan than with captopril treatment (22·2% vs 29·7%). Interpretation In this study of elderly heart-failure patients, treatment with losartan was associated with an unexpected lower mortality than that found with captopril. Although there was no difference in renal dysfunction, losartan was generally better tolerated than captopril and fewer patients discontinued losartan therapy. A further trial, evaluating the effects of losartan and captopril on mortality and morbidity in a larger number of patients with heart failure, is in progress.

Background: Filorexant (MK-6096) is an orexin receptor antagonist; here, we evaluate the efficacy of filorexant in the treatment of insomnia in adults. Methods: A double-blind, placebo-controlled, randomized, two 4-week–period, adaptive crossover polysomnography study was conducted at 51 sites worldwide. Patients (18 to

Objectives We aimed to evaluate the efficacy of the selective H3 receptor inverse agonist MK-0249 to treat excessive daytime sleepiness (EDS). Methods In this three-period, double-blind, crossover study, 125 patients (100 men, 25 women; mean age, 48.6years) with obstructive sleep apnea receiving nasal continuous positive airway pressure therapy who had refractory EDS were randomized to 2weeks each of daily MK-0249 (5, 8, 10, or 12mg, adaptively assigned), modafinil 200mg, and placebo. At baseline and after each treatment period, six maintenance of wakefulness tests (MWT) and Psychomotor Vigilance Tasks (PVT) were conducted at 2-h intervals, beginning 1h postdose (∼09:00). The Epworth sleepiness scale (ESS), Clinical Global Impression of Severity (CGIS) and Digit Symbol Substitution Test (DSST) also were assessed. The primary end point was MWT sleep latency averaged over the first four time points (MWT-early). Results MWT-early mean change from baseline sleep latency at week 2 was 1.2min for placebo, 2.1min for MK-0249 (top two doses pooled; P >.05 vs placebo), and 5.9min for modafinil ( P ⩽.001 vs placebo). MK-0249 showed improvements vs placebo on secondary and exploratory end points of ESS, CGIS, PVT, and DSST. Insomnia adverse events (AEs) were greater for MK-0249 (combined doses, 17.5%) than for placebo (0.9%) or modafinil (1.8%). Conclusion MK-0249 did not significantly affect MWT sleep latency. However, the pattern of improvement on subjective ratings and psychomotor performance end points suggested that MK-0249 was associated with changes in aspects of cognition and performance not captured by the MWT.

To evaluate the efficacy and tolerability of gaboxadol in the treatment of adult and elderly patients with primary insomnia.Randomized, double-blind, placebo-controlled, multicenter, 30-night, polysomnography studies.Sleep laboratory.Primary insomnia, 18-64 y (adult study), oror =65 y (elderly study).Adult study: gaboxadol 15 mg (GBX15; N = 148), 10 mg (GBX10; N = 154), or placebo (N = 156); elderly study: GBX10 (N = 157), gaboxadol 5 mg (GBX5; N = 153), or placebo (N=176).Primary endpoints were wake after sleep onset (WASO) and latency to persistent sleep (LPS). Slow wave sleep (SWS) was a secondary endpoint. Analyses were based on the change from baseline for the average of nights 1/2, and nights 29/30, and compared gaboxadol versus placebo. Exploratory endpoints included patient's subjective assessment of total sleep time (sTST), WASO (sWASO), time to sleep onset (sTSO), and number of awakenings (sNAW); these analyses were based on weekly means. 1) Adult study. GBX15 significantly (Por = 0.05) improved WASO through nights 29/30 but had no significant effects on LPS. No significant differences were seen for GBX10 versus placebo on WASO or LPS. GBX15 and GBX10 enhanced SWS. GBX15 significantly improved sTST, sWASO, sTSO, and sNAW at weeks 1 and 4. 2) Elderly study. GBX10 significantly improved WASO through nights 29/30; a significant improvement was also seen for GBX5 at nights 1/2 but this was not maintained through nights 29/30. GBX10 significantly improved LPS at nights 1/2 but the improvement was not maintained through nights 29/30; no significant differences were seen for GBX5 versus placebo on LPS. GBX10 and GBX5 enhanced SWS. GBX10 significantly improved sTST at week 1, and sTST, sWASO, and sNAW at week 4. Gaboxadol was generally well tolerated in both studies.The maximum studied doses of gaboxadol (GBX15 in adult patients and GBX10 in elderly patients) were effective at enhancing objective polysomnography measures of sleep maintenance and SWS, and also some subjective sleep measures, over 30 nights but had little or no effects on sleep onset. The clinical relevance of the enhancement of SWS by gaboxadol is unclear.

Objective A key assumption underlying the principle that power increases with sample size is that the standardized effect size is fixed over time. In therapeutic areas where it may be difficult to continually recruit from a homogeneous population, this assumption may not be valid; patients randomized toward the end of enrollment may derive from a more heterogeneous population and negatively impact the power of a study. Post hoc analyses were performed on clinical data from four phase III depression trials with paroxetine to evaluate this possibility. Methods Each study used a randomized, double-blind, placebo-controlled design and enrolled approximately 150 patients per treatment arm. Plots of observed p -values for the treatment difference between paroxetine and placebo (on the HAM-D 17 change from baseline score at week 8) by cumulative enrollment were made for each study. Results As previously reported, three of the four studies showed an overall significant treatment effect and one did not. In each study, a significant treatment effect was observed before approximately 100 patients had been enrolled per treatment arm. Continuing to enroll additional patients did not maintain the achieved level of significance in most instances, and in one case appeared to alter a potentially positive study into a failed study. Plots of p -values versus cumulative enrollment by patient quarters using combined data from all four studies suggested that late-enrolling patients were more likely to be placebo responders than early-enrolling patients. Hypothesized explanations for this finding include a depleted pool of depressed patients and the rush for patient recruitment at the end of a study in order to meet completion timelines. However, no corroborative evidence could be found to support either possibility. Conclusions This analysis demonstrates that bigger is not necessarily better for depression trials.

Background An early clinical trial suggested that the substance P (neurokinin 1 receptor) antagonist, aprepitant, might provide a unique mechanism of antidepressant activity. Phase III trials were conducted to confirm these findings. Methods Five 8-week, randomized, double-blind, parallel-groups, placebo-controlled, multicenter trials in outpatients with Major Depressive Disorder were performed. Aprepitant 160 mg and placebo were included in all trials. Aprepitant 80 mg and paroxetine 20 mg (active comparator) were included in three trials. Approximately 150 patients were enrolled per treatment group in each trial. The primary end point was the mean change-from-baseline of the first 17 items of the Hamilton Rating Scale for Depression (HAM-D 17 ) score at 8 weeks. A positron emission tomography (PET) study was also performed in normal subjects to determine the relationship between neurokinin 1 receptor occupancy and aprepitant plasma concentrations in dosing regimens relevant to the trials. Results No statistically significant differences from placebo on the HAM-D 17 were observed at week 8 for either dose of aprepitant in any of the trials, whereas paroxetine 20 mg was significantly ( p ≤ .05) more effective than placebo at week 8 in each of the three trials in which it was included. Results from the PET study indicated that the aprepitant dosing regimens provided continuously high levels of neurokinin 1 receptor blockade over 8 weeks. Conclusions Because the methodology employed confirmed the antidepressant efficacy of paroxetine, the absence of an effect for aprepitant indicates that it was not an effective treatment for depression. The concept of neurokinin 1 receptor antagonism as an antidepressant mechanism was not supported.