Duane B Snavely

• Merck & Co.

Background: We evaluated the orexin receptor antagonist filorexant (MK-6096) for treatment augmentation in patients with major depressive disorder (MDD). Methods: Six-week, double-blind, placebo-controlled, parallel-group, Phase II, proof-of-concept study. Patients with MDD (partial responders to ongoing antidepressant therapy) were randomized 1...

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 <65 years) with insomnia re...

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 an...

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 non-elderly (18-64 years) and elderly (≥65 years) patients with insomnia. Suvorexant doses of 40/30mg (non-elderly/elderly)...

ight-time administration of orexin receptor antagonists is hypothesized to dampen orexin-mediated wakefulness, facilitating sleep. Here, we provide an overview of the clinical profile of suvorexant, an investigational orexin receptor antagonist for the treatment of insomnia, in Phase-3 trials.DESIGN/METHODS: The Phase-3 program comprised two 3-mont...

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. We did a randomised, placebo-controlled, parallel-group trial at 106 investigational centres in the Americas, Australia, Europe, and South Africa from December, 2009,...

We aimed to evaluate the efficacy of the selective H3 receptor inverse agonist MK-0249 to treat excessive daytime sleepiness (EDS). 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...

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...

This study aimed to evaluate whether the T-type calcium channel antagonist MK-8998 was effective in treating acute psychosis in patients with schizophrenia. This was a randomized, double-blind, parallel-group study. After a placebo lead-in, acutely psychotic inpatients with schizophrenia were randomized to 4 weeks of MK-8998 12/16 mg daily (N = 86)...

Objective: To assess the utility of orexin receptor antagonism as a novel approach to treating insomnia. Methods: 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 s...

Objectives: Suvorexant is a potent orexin receptor antagonist being developed for the treatment of insomnia. Suvorexant was effective and well-tolerated in a 4-week study in patients with primary insomnia. Here we report results from one of two 3-month Phase 3 trials. Methods: This trial (Trial #2) was a randomized, double-blind, placebo-controlle...

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. A randomized, double-blind, placebo-controlled, incomplete block, 2-period crossover study of MK-0249 5-10 mg/d and osmo...

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 i...

Proof-of-concept in clinical trials has traditionally focused on the identification of a maximum tolerated dose with the assumption that the higher doses provide better efficacy. However, adverse events associated with a maximum tolerated dose may have a negative effect on efficacy. We present an efficient adaptive dose-finding strategy that concen...

To evaluate the efficacy and safety of gaboxadol in the treatment of Primary Insomnia. Two studies were performed in patients 18 to 65 years of age with Primary Insomnia. After a 7-day single-blind placebo run-in, patients were randomized to double-blind treatment with gaboxadol 15 mg (N = 310), 10 mg (N = 308), or placebo (N = 309) over 3 months i...

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), or > or =65 y (elderly study). Adult study: gaboxadol 15 mg (GBX15; N =...

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 hetero...

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...

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. Five 8-week, randomized, double-blind, parallel-groups, placebo-controlled, multicenter trials in outpatients with Major Depre...

In clinical trials sponsored by Merck the unblinded statistician is typically an employee of the company. From a pharmaceutical industry perspective, advantages of this approach include ensuring that the unblinded statistician is knowledgeable regarding the experimental treatments, therapeutic area and study objectives; that the quality of the anal...

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-...

The pharmacokinetics and pharmacodynamics of 7 days of treatment with losartan 50 mg/hydrochlorothiazide 12.5 mg were evaluated in 14 patients with normal renal function and in 12 patients with mild to moderate renal impairment. The efficacy of losartan 50 mg/hydrochlorothiazide 12.5 mg titrated to losartan 100 mg/hydrochlorothiazide 25 mg was exam...

This 12-week, open-label, multicenter study assessed the efficacy and safety of losartan/hydrochlorothiazide (HCTZ), alone or in combination with other antihypertensive agents, in the treatment of patients with severe systemic hypertension. Treatment began with once-daily losartan/HCTZ 50/12.5 mg. The dose was increased to 100/25 mg, if required, t...

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 l...

The Losartan Heart Failure ELITE Study recently found that in patients with symptomatic heart failure and a left ventricular ejection fraction of </=0.40, losartan compared to captopril improved survival with better tolerability. The objective of this study was to perform an economic evaluation of losartan versus captopril based on the results of t...

The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs...

The objective of this study was to determine the incidence of dry cough in hypertensive patients with a history of angiotensin-converting enzyme (ACE) inhibitor-induced cough after treatment with losartan (an angiotensin II-receptor antagonist), lisinopril (an ACE inhibitor), or placebo. One hundred patients from 16 outpatient treatment centers in...

Am J Hypertens (1998) 11, 110A–110A; doi: 10.1016/S0895-7061(97)91121-3 E059: Long term blood pressure control with losartan alone or in combination with hydrochlorothiazide or other antihypertensive drugs in patients with mild to moderate essential hypertension P. Aurup, R.D. Smith, A.I. Goldberg and D. Snavely

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. We randomly assigned 722 ACE inhibitor naive patien...

This study investigated the anti-hypertensive efficacy and tolerability of once-daily losartan potassium (50 mg titrated to 100 mg), an angiotensin II receptor antagonist, compared with once daily felodipine extended release (ER) (5 mg titrated to 10 mg), a calcium channel blocker, after 12 weeks of therapy in elderly hypertensive patients. Followi...

The efficacy and safety of various doses of losartan potassium, a specific and selective angiotensin II receptor antagonist, were compared with those of placebo and enalapril maleate 20 mg in patients with mild to moderate essential hypertension in a randomized, double-blind, parallel study. We randomly allocated 576 patients at the end of a 4-week...

Losartan potassium, the first nonpeptide selective blocker of angiotensin II at the AT1 receptor, has been shown to exhibit clinical antihypertensive effects. The aim of the present study was to characterize the efficacy and duration of action of losartan by ambulatory blood pressure monitoring. The study was performed in nonblack hypertensive pati...

To compare the incidence of cough in patients with a history of angiotensin converting enzyme (ACE) inhibitor-related cough who received losartan [a type 1 angiotensin II (Ang II) receptor antagonist], lisinopril (an ACE inhibitor) or hydrochlorothiazide (a diuretic). An international, multicentre, randomized double-blind, parallel-group controlled...

Objective: To compare the incidence of cough in patients with a history of angiotensin converting enzyme (ACE) inhibitor-related cough who received losartan [a type 1 angiotensin II (Ang II) receptor antagonist], lisinopril (an ACE inhibitor) or hydrochlorothiazide (a diuretic). Design: An international, multicentre, randomized, double-blind, paral...

A common adverse experience in hypertensive patients treated with angiotensin converting enzyme (ACE) inhibitors is a tickling dry cough. The aim of the present study was to review clinical observations and mechanisms of cough associated with ACE inhibitors. In addition, since the AT1-type angiotensin II antagonists (represented by losartan, MK954,...

Three hundred and twenty-two (322) persons with severe mental handicaps were given plasma-derived hepatitis B vaccine (20 micrograms dose at 0, 1 and 6 months). Following the third injection, 95% of the vaccinees were positive for anti-HBs, while 92% achieved a protective level of antibody (greater than or equal to 10 mIU ml-1) with a geometric mea...

A field test of a lens opacity rating system was run. Findings were graded in 7 categories: Cortex: (1) Waterclefts, Vacuoles, & Flakes (WVF, 4 grades), (2) Wedges & Spokes graded by number of Quadrants affected (WS-Q), and (3) Inward extent of Wedges & Spokes (WS-I, 3 grades); Nucleus: (4) Opacification (NUC-O) and (5) Coloration (NUC-C), each usi...