Comparative analysis of the safety and tolerability of eslicarbazepine acetate in older (≥60 years) and younger (18-59 years) adults.

Objective: To investigate the safety and tolerability of eslicarbazepine acetate (ESL), a once-daily oral anti-seizure drug (ASD), in older and younger adult patient populations.

Methods: Two post-hoc pooled data analyses were performed: one from three Phase III studies in patients with focal (partial-onset) seizures who were taking 1-3 concomitant ASDs; the other from five Phase II studies in patients from non-epilepsy populations not taking other ASDs chronically and/or at a clinically-effective anti-seizure dose. The frequencies of treatment-emergent adverse events (TEAEs) were calculated for the older (≥60 years) and younger (18-59 years) adults separately.

Long-term safety and tolerability of adjunctive eslicarbazepine acetate in children with focal seizures.

Objective: The objective of this study was to evaluate long-term safety and tolerability outcomes in two open-label extension (OLE) studies of adjunctive eslicarbazepine acetate (ESL) in children with focal seizures.

Methods: Safety data from patients aged 4-17 years in OLEs of Studies 2093-208 and -305 were pooled and analyzed. Studies 208 and 305 were randomized, double-blind, placebo-controlled studies of adjunctive treatment with ESL in children with focal seizures refractory to treatment with 1-2 antiseizure drugs; patients could continue into uncontrolled OLEs (up to 5 years total duration).

Efficacy and Safety of Nebulized Glycopyrrolate/eFlow® Closed System in Patients with Moderate-to-Very-Severe Chronic Obstructive Pulmonary Disease with Pre-Existing Cardiovascular Risk Factors.

The purpose of this study was to assess the effect of pre-existing cardiovascular (CV) risk factors on the efficacy and safety of nebulized glycopyrrolate (GLY) in patients with chronic obstructive pulmonary disease (COPD). A total of 2379 patients from 3 phase III studies (12-week, placebo-controlled Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer [GOLDEN] -3 and -4, and 48-week, active-controlled GOLDEN-5) stratified by high (n=1526) or low (n=853) CV risk were randomized to placebo, GLY 25 mcg or 50 mcg twice daily, or tiotropium (TIO; 18 mcg once daily). Safety, lung function, patient-reported outcomes (PROs), and exacerbations were assessed by CV risk.

Efficacy and safety of a novel, nebulized glycopyrrolate for the treatment of COPD: effect of baseline disease severity and age; pooled analysis of GOLDEN 3 and GOLDEN 4.

Background: The efficacy and safety of nebulized glycopyrrolate inhalation solution (GLY), administered twice daily (BID) via the innovative eFlow Closed System nebulizer (PARI Pharma GmbH, Starnberg, Germany), were demonstrated in two replicate, placebo-controlled, 12-week Phase III studies (GOLDEN 3 and GOLDEN 4). This report evaluates the efficacy and safety of GLY by baseline disease severity and age in the pooled GOLDEN 3 and GOLDEN 4 patient population (N=1,294).

Methods: Patients were grouped by baseline predicted post-bronchodilator FEV (<50%, ≥50%) and age (<65, ≥65, ≥75 years).

Health-Related Quality of Life Improvements in Moderate to Very Severe Chronic Obstructive Pulmonary Disease Patients on Nebulized Glycopyrrolate: Evidence from the GOLDEN Studies.

Symptoms of chronic obstructive pulmonary disease (COPD) may diminish patients' health-related quality of life (HRQoL). We report effects of Longhala™ Magnair™ (glycopyrrolate) Inhalation Solution, a drug/device combination of the long-acting antimuscarinic glycopyrrolate administered using the eFlow® closed system (eFlow CS) nebulizer, on HRQoL from the Glycopyrrolate for Obstructive Lung Disease Via Electronic Nebulizer (GOLDEN) clinical studies. Data consisted of a pooled analysis of 2 phase 3, 12-week efficacy studies (GOLDEN-3 and -4) of glycopyrrolate/eFlow CS (25 or 50 mcg twice daily [BID]) versus placebo, and a 48-week, open-label safety study (GOLDEN-5) of glycopyrrolate/eFlow CS 50 mcg BID versus tiotropium 18 mcg once daily in patients with moderate to very severe COPD.

Effect of background long-acting beta-agonist therapy on the efficacy and safety of a novel, nebulized glycopyrrolate in subjects with moderate-to-very-severe COPD.

Background: Phase III studies demonstrated efficacy and safety of nebulized glycopyrrolate inhalation solution (GLY) in subjects with COPD. Secondary analyses were performed to examine the effect of background long-acting beta-agonist (LABA) use on the efficacy and safety of nebulized GLY.

Methods: In two 12-week placebo-controlled studies (GOLDEN 3 and GOLDEN 4) and one 48-week, open-label active-controlled study (GOLDEN 5), a total of 2,379 subjects were stratified by background LABA use (LABA-yes: n=861; LABA-no: n=1,518) and randomized to placebo vs GLY 25 or 50 µg twice daily, or GLY 50 µg twice daily vs tiotropium (TIO) 18 µg once daily.

Dose selection for glycopyrrolate/eFlow phase III clinical studies: results from GOLDEN (Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer) phase II dose-finding studies.

Background: Long-acting muscarinic antagonists (LAMAs) are recommended for the treatment of chronic obstructive pulmonary disease (COPD). Glycopyrrolate/eFlow® is an investigational drug-device combination of the LAMA glycopyrrolate administered by an eFlow® Closed System (eFlow® CS) nebulizer. The GOLDEN 2 (NCT01706536) and GOLDEN 6 (NCT02038829) Phase II, multicenter studies were conducted to inform dose selection for the GOLDEN Phase III clinical trials.

Long-term safety of glycopyrrolate/eFlow CS in moderate-to-very-severe COPD: Results from the Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer (GOLDEN) 5 randomized study.

Background: The use of long-acting bronchodilators is an essential component of the management of chronic obstructive pulmonary disease (COPD). The GOLDEN 5 Phase III, randomized, active-controlled, open-label study was conducted to evaluate the long-term safety and tolerability of a nebulized glycopyrrolate formulation (SUN-101) delivered via the investigational eFlow Closed System (eFlow CS) nebulizer in subjects with moderate-to-very-severe COPD.

Methods: Subjects were randomized in a 4:3 ratio to nebulized glycopyrrolate 50 μg twice daily (BID) or tiotropium 18 μg once daily (OD) and treated for 48 weeks.

Efficacy and safety of glycopyrrolate/eFlow CS (nebulized glycopyrrolate) in moderate-to-very-severe COPD: Results from the glycopyrrolate for obstructive lung disease via electronic nebulizer (GOLDEN) 3 and 4 randomized controlled trials.

Background: SUN-101 is a combination of glycopyrrolate delivered through an innovative, electronic nebulizer, intended for the treatment of patients with COPD. The objective of this study was to assess the efficacy and safety of this new drug device combination.

Methods: Replicate Phase III randomized, double-blind, placebo-controlled studies were conducted to evaluate the efficacy and safety of glycopyrrolate solution administered by an investigational eFlow Closed System (eFlow CS) nebulizer in subjects with moderate-to-very-severe COPD, including those with continued background use of a long-acting beta-agonist ± inhaled corticosteroid and/or history of cardiovascular (CV) disease.

One-year safety and efficacy study of arformoterol tartrate in patients with moderate to severe COPD.

Background: Arformoterol tartrate (arformoterol, 15 μg bid) is a nebulized long-acting β2-agonist approved for maintenance treatment of COPD.

Methods: This was a multicenter, double-blind, randomized, placebo-controlled study. Patients (aged ≥ 40 years with baseline FEV1 ≤ 65% predicted, FEV1 > 0.

Missing data in clinical trials: from clinical assumptions to statistical analysis using pattern mixture models.

The need to use rigorous, transparent, clearly interpretable, and scientifically justified methodology for preventing and dealing with missing data in clinical trials has been a focus of much attention from regulators, practitioners, and academicians over the past years. New guidelines and recommendations emphasize the importance of minimizing the amount of missing data and carefully selecting primary analysis methods on the basis of assumptions regarding the missingness mechanism suitable for the study at hand, as well as the need to stress-test the results of the primary analysis under different sets of assumptions through a range of sensitivity analyses. Some methods that could be effectively used for dealing with missing data have not yet gained widespread usage, partly because of their underlying complexity and partly because of lack of relatively easy approaches to their implementation.

Clinical trial design for mild-to-moderate community-acquired pneumonia--an industry perspective.

The use of noninferiority clinical trials is problematic unless one can establish the benefit of the active control versus no treatment. In community-acquired pneumonia, there are no placebo-controlled clinical trials establishing the benefit of antibiotic treatment, because the observed benefit of sulfapyridine and, subsequently, penicillin was established before the advent of randomized clinical studies. Historical data and observational cohort studies have established the marked decrease in mortality resulting from antimicrobial therapy; however, mortality is not a suitable end point for contemporary clinical trials for mild-to-moderate community-acquired pneumonia that is treated with oral antimicrobial drugs in ambulatory patients.

Faropenem medoxomil: a treatment option in acute bacterial rhinosinusitis.

Faropenem medoxomil is the first oral penem in a new class of beta-lactam antibiotics. Faropenem medoxomil has excellent in vitro activity against Streptococcus pneumoniae, Haemophilus influenzae and other key pathogens implicated in acute bacterial rhinosinusitis. Clinical studies have demonstrated that, in the treatment of acute bacterial rhinosinusitis in adults, 7 days of treatment with faropenem medoxomil is as clinically and bacteriologically effective as 10 days of treatment with cefuroxime axetil.

Randomized double-blind study comparing 7- and 10-day regimens of faropenem medoxomil with a 10-day cefuroxime axetil regimen for treatment of acute bacterial sinusitis.

Objective: To compare the efficacy and safety of faropenem medoxomil, 300 mg twice daily for seven or ten days, with cefuroxime axetil 250 mg twice daily for ten days in adults with acute bacterial sinusitis (ABS).

Study Design And Setting: Prospective, double-blinded, phase III trial with entry criteria consistent with FDA/IDSA guidelines for diagnosis of ABS. Primary efficacy parameter was clinical response at 7 to 21 days posttherapy.