Effects of suvorexant on the Insomnia Severity Index in patients with insomnia: analysis of pooled phase 3 data.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. placebo <0.001) 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. placebo <0.001). 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. CONCLUSIONS: 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. GOV IDENTIFIER: NCT01097616, NCT01097629.

Suvorexant in Elderly Patients with Insomnia: Pooled Analyses of Data from Phase III Randomized Controlled Clinical Trials.

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).

Clinical profile of suvorexant for the treatment of insomnia over 3 months in women and men: subgroup analysis of pooled phase-3 data.

RATIONALE: Sex-related differences in the clinical profiles of some insomnia medications have been previously reported. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: Suvorexant was generally effective and well-tolerated in both women and men with insomnia. ClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629, NCT01021813.

Suvorexant in Patients with Insomnia: Pooled Analyses of Three-Month Data from Phase-3 Randomized Controlled Clinical Trials.

STUDY OBJECTIVES: Suvorexant 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. METHODS: Prespecified 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. RESULTS: Suvorexant 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. CONCLUSIONS: Suvorexant 20/15 mg improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629.

Suvorexant in Patients With Insomnia: Results From Two 3-Month Randomized Controlled Clinical Trials.

BACKGROUND: Suvorexant is an orexin receptor antagonist for treatment of insomnia. We report results from two pivotal phase 3 trials. METHODS: 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. RESULTS: 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, with <5% 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. CONCLUSIONS: Suvorexant improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated.

Addition of an NK1 receptor antagonist to an SSRI did not enhance the antidepressant effects of SSRI monotherapy: results from a randomized clinical trial in patients with major depressive disorder.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Concomitant use of aprepitant + paroxetine for 6 weeks did not provide greater antidepressant benefit compared with paroxetine + placebo in patients with major depression.

Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial.

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<0·0001) and sTSO (-18·0 min 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.

Randomized controlled study of the histamine H3 inverse agonist MK-0249 in adult attention-deficit/hyperactivity disorder.

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.

A randomized, double-blind, crossover comparison of MK-0929 and placebo in the treatment of adults with ADHD.

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.

Effect of gaboxadol on sleep in adult and elderly patients with primary insomnia: results from two randomized, placebo-controlled, 30-night polysomnography studies.

STUDY OBJECTIVES: To evaluate the efficacy and tolerability of gaboxadol in the treatment of adult and elderly patients with primary insomnia. DESIGN: Randomized, double-blind, placebo-controlled, multicenter, 30-night, polysomnography studies. SETTING: Sleep laboratory. PATIENTS: Primary insomnia, 18-64 y (adult study), or > or =65 y (elderly study). INTERVENTIONS: 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). MEASUREMENTS AND RESULTS: 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 (P < or = 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. CONCLUSIONS: 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.

Is bigger better for depression trials?

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-D17 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.

Confidence intervals for an exposure adjusted incidence rate difference with applications to clinical trials.

To summarize safety data such as clinical adverse experiences in clinical trials with a moderate to long-term follow-up, we may use a measurement which accounts for the potential differences in the follow-up duration between treatment groups. The incidence rate, which uses the total person-time follow-up in a treatment group as the denominator, is one of these measures. When treatment comparisons are based on the difference of the incidence rates, it is of interest to construct confidence intervals for the rate differences. In this paper, we first discuss the assumptions and scenarios in which the exposure adjusted incidence rate may be appropriate. Then we review several methods of calculating confidence intervals for the difference of two incidence rates assuming that the number of events come from a Poisson distribution. The methods considered include Wald's method, the two-by-two table method, the Miettinen and Nurminen (MN) method, and the conditional MN method. For all but the MN method, explicit confidence intervals can be obtained. For the MN method, some numerical iterations are required. The properties of these methods are evaluated by simulations. The results show that the MN method outperforms the other three in terms of the coverage of the confidence interval, especially when the rates and therefore the number of events are small. Lastly, data from a clinical study are used to demonstrate the application of the methods.