Background— Necuparanib, a rationally engineered low molecular weight heparin, combined with gemcitabine/nab-paclitaxel showed an encouraging safety and oncologic signal in a phase Ib trial. This randomized multi-center phase II trial evaluates the addition of necuparanib or placebo to gemcitabine/nab-paclitaxel in untreated metastatic pancreas ductal adenocarcinoma (PDAC). Patients and Methods— Eligibility included 18 years, histologically or cytologically confirmed metastatic PDAC, measurable disease and ECOG performance status of 0–1. Patients were randomly assigned to necuparanib (5 mg/kg subcutaneous injection once daily) or placebo (subcutaneous injection once daily) and gemcitabine/nab-paclitaxel on days 1, 8, 15 of 28-day cycles. The primary endpoint was median overall survival and secondary endpoints included median progression-free survival, response rates and safety. Results— One-hundred and ten patients were randomized, 62 to necuparanib arm and 58 to placebo arm. The futility boundary was crossed at a planned interim analysis and the study was terminated by the Data Safety Monitoring Board. The median overall survival was 10.71 months (95% Confidence interval [CI] 7.95, 11.96) for necuparanib arm and 9.99 months (95% CI 7.85, 12.85) for placebo arm (Hazard Ratio: 1.12, 95% CI 0.66, 1.89, p-value: 0.671). The necuparanib arm had a higher incidence of hematologic toxicity relative to placebo patients (83% and 70%). Conclusion— The addition of necuparanib to standard of care treatment for advanced PDAC did not improve overall survival. Safety was acceptable. No further development of necuparanib is planned although targeting the coagulation cascade pathway remains relevant in PDAC.

Background. Necuparanib is derived from unfractionated heparin and engineered for reduced anticoagulant activity while preserving known heparin-associated antitumor properties. This trial assessed the safety, pharmacokinetics (PK), pharmacodynamics, and initial efficacy of necuparanib combined with gemcitabinenab-paclitaxel in patients with metastatic pancreatic cancer. Methods. Patients received escalating daily subcutaneous doses of necuparanib plus 1,000 mg/m(2) gemcitabine (days 1, 8, 15, and every 28 days). The protocol was amended to include 125 mg/m(2) nab-paclitaxel after two cohorts (following release of the phase III MPACT data). The necuparanib starting dose was 0.5 mg/kg, with escalation via a modified 3+3 design until the maximum tolerated dose (MTD) was determined. Results. Thirty-nine patients were enrolled into seven cohorts (necuparanib 0.5, 1 mg/kg+gemcitabine; necuparanib 1, 2, 4, 6, and 5 mg/kg+nab-paclitaxel+gemcitabine). The most common adverse events were anemia (56%), fatigue (51%), neutropenia (51%), leukopenia (41%), and thrombocytopenia (41%). No deaths and two serious adverse events were potentially related to necuparanib. Measurable levels of necuparanib were seen starting at the 2 mg/kg dose. Of 24 patients who received at least one dose of necuparanib+nab-paclitaxel+gemcitabine, 9 (38%) achieved a partial response and 6 (25%) achieved stable disease (63% disease control rate). Given a cellulitis event and mild activated partial thromboplastin time increases at 6 mg/kg, the 5 mg/kg dose was considered the MTD and selected for further assessment in phase II. Conclusion. Acceptable safety and encouraging signals of activity in patients with metastatic pancreatic cancer receiving necuparanib, nab-paclitaxel, and gemcitabine were demonstrated.

370 Background: The Phase 1 portion of a Phase 1/2 trial of Necuparanib (“Necu”) combined with nab-paclitaxel (nabP) + gemcitabine (gem) in patients with metastatic pancreatic cancer (ClinicalTrials.gov Identifier NCT01621243) showed acceptable safety and tolerability and encouraging signals of activity and established a dose for the randomized, placebo (PBO)-controlled Phase 2 portion. Methods: In Phase 2, patients received daily s.c. injections of either 5 mg/kg Necu daily or PBO, combined with i.v. 125 mg/m2 nabP and 1000 mg/m2 gem (Days 1, 8, 15 of each 28-day cycle). The primary endpoint was overall survival (OS); other endpoints included progression-free survival (PFS), response rates, safety, and CA19.9 levels. An interim futility analysis was conducted in July 2016 once 57 deaths (50% of the target number of 114 events required for trial completion) had occurred. Results: The analysis was conducted on data from 120 randomized patients (62 Necu, 58 PBO). The Z-score for futility was -0.42 (prespecified boundary of -0.148 was crossed as actual score was lower). Median OS was Necu = 10.71 and PBO = 9.99 months; hazard ratio (HR) = 1.12 (favoring PBO); OS curves were intertwined. PFS was Necu = 5.52 and PBO = 6.93 months; HR = 0.97. RECIST response rates were comparable between arms: complete response, Necu = 0%, PBO = 3%; partial response, Necu = 26%, PBO = 26%; stable disease, Necu = 31%, PBO = 34%; disease control rate, Necu = 56%, PBO = 64%. The most common Grade 3+ adverse events (AEs) were neutropenia (Necu = 33%, PBO = 33%), thrombocytopenia (Necu = 27%, PBO = 5%), and anemia (Necu = 22%, PBO = 11%). There were lower rate of serious AEs with Necu (48%) vs. PBO (60%). Modest increases in APTT, AST, and ALT were noted following Necu relative to PBO. 23% of Necu and 5% of PBO patients were IgG positive with an anti-heparin/PF4 antibody titer of ≥ 0.4 at any time. There were no treatment differences for decreases in CA19.9. Conclusions: No new safety signals were observed and the toxicity profile was considered manageable; however, Necu in combination with nabP and gem did not show a sufficient level of efficacy in metastatic pancreatic cancer to warrant continued enrollment. Clinical trial information: NCT01621243.

OBJECTIVE:To evaluate the efficacy and safety of eszopiclone 3 mg, a nonbenzodiazepine medication/hypnotic indicated for the treatment of insomnia with comorbid rheumatoid arthritis (RA).METHOD:This multicenter, double-blind, placebo-controlled pilot study was conducted in 153 patients aged 25-64 years with American College of Rheumatology-defined RA who met DSM-IV criteria for insomnia. The data were collected from February to November of 2004. Patients were randomly assigned to either eszopiclone or placebo nightly for 4 weeks, followed by a 2-week placebo run out. Efficacy was evaluated using patient reports of sleep (wake time after sleep onset [WASO], sleep latency [SL], and total sleep time [TST]), daytime function, pain, and RA assessments. Insomnia severity was evaluated using the Insomnia Severity Index. Safety was also evaluated.RESULTS:Eszopiclone significantly improved all patient-reported sleep measures (WASO, SL, and TST), sleep quality, depth of sleep, and daytime function (P < .05 vs placebo). At week 4, 48% of eszopiclone-treated patients had no clinically meaningful insomnia as assessed by ISI score (versus 30% of placebo-treated patients, P = .03). Eszopiclone was significantly better than placebo on some RA-associated pain measures: (1) overall (P = .05), pain (P = .006), and pain and other symptoms (P = .02) scores of the Arthritis Self-Efficacy Scale, (2) tender joint counts (P = .03) and pain severity scores (P = .023), (3) the activities domain of the Health Assessment Questionnaire-Disability Index (P = .04), and (4) the role physical (P = .03) and bodily pain (P = .01) scales of the 36-item Medical Outcomes Study Short-Form General Health Survey. The most commonly reported adverse events with eszopiclone were unpleasant taste and transient increases in RA symptoms.CONCLUSIONS:In this pilot study of patients with insomnia comorbid with RA, eszopiclone 3 mg improved all assessed sleep and daytime function measures over the treatment period, as well as some measures of RA-associated pain, disability, and quality of life.TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT00367965.

Objective: To evaluate the effects of eszopiclone on measures of respiration and sleep using polysomnography in patients with mild to moderate obstructive sleep apnea syndrome (OSAS).Methods: This double-blind, randomized crossover study included patients (35-64 years) with mild-to-moderate OSAS [apnea and hypopnea index (AHI) range >= 10 and <= 40]. Patients received either eszopiclone 3 mg or placebo for two consecutive nights, with a 5-7 day washout between treatments. Continuous positive airway pressure (CPAP) was not allowed on nights in the sleep laboratory.Results: The primary endpoint, mean total AHI, was not significantly different from placebo (16.5 with placebo and 16.7 with eszopiclone; 90% confidence interval (CI) -1.7, 1.9). No significant differences in total arousals, respiratory arousals, duration of apnea and hypopnea episodes, or oxygen saturation were noted. Significant differences in spontaneous arousals (13.6 versus 11.4 for placebo and eszopiclone, respectively; 90% CI -3.7, -0.7), sleep efficiency (85.1% and 88.4%; p = 0.0075), wake time after sleep onset (61.8 and 48.1 min; p = 0.0125), and wake time during sleep (55.9 and 43.2 min; p = 0.013) were noted after eszopiclone treatment. Eszopiclone was well tolerated.Conclusions: In this pilot study, eszopiclone did not worsen AHI, and it improved sleep maintenance and efficiency. Further study is warranted to determine whether eszopiclone could improve CPAP compliance or next-day function in patients with OSAS. (C) 2006 Elsevier B.V. All rights reserved.

The purpose of this study was to evaluate the safety and efficacy of single-isomer (R)-albuterol (levalbuterol, LEV) in children aged 2-5 years. Children aged 2-5 years (n = 211) participated in this multicenter, randomized, double-blind study of 21 days of t.i.d. LEV (0.31 mg or 0.63 mg without regard to weight), racemic albuterol (RAC, 1.25 mg for children < 33 pounds (lb); 2.5 mg for children >= 33 lb), or placebo (PBO). Endpoints included adverse-event (AE) reporting, safety parameters, peak expiratory flow (PEF), the Pediatric Asthma Questionnaire (c) (PAQ), and the Pediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ). Baseline disease severity was generally mild in all groups, as defined by PAQ scores that ranged from 6.3-7.3 on a scale of 0-27 and 1.5 days/week of uncontrolled asthma. After treatment, the PAQ decreased in all groups (P = NS). In the subset of subjects able to perform PEF (51.7%), all active treatments improved in-clinic PEF after the first dose (mean +/- SD: PBO, 1.4 +/- 20.8; LEV 0.31 mg, 12.4 +/- 12; LEV 0.63 mg, 16.7 +/- 15.4; RAC, 18.0 +/- 16.5 l/min; P < 0.01). PACQLQ measurements improved more than the minimally important difference only in the LEV-treated groups, and were significant in children < 33 lb (P < 0.05). Asthma exacerbations occurred primarily in children >= 33 lb, and one serious asthma exacerbation occurred in the 2.5-mg RAC group. RAC and LEV 0.63 mg, but not LEV 0.31 mg or placebo, led to significant increases in ventricular heart rate. In this study of levalbuterol in children aged 2-5 years with asthma, LEV was generally well-tolerated, and in children able to perform PEF, led to significant bronchodilation compared with placebo.

PURPOSE: A multicenter double-blind randomized trial to evaluate Levalbuterol (LEV) vs Racemic Albuterol (RAC) in acute severe asthma.

The object of this study is a post hoc pairwise comparison of levalbuterol versus racemic albuterol for asthma in a multicenter, double-blind, randomized, placebo-controlled clinical trial. The participants are patients > or =12 years of age (n = 362) with FEV1 45-70% of predicted. The patients received nebulized levalbuterol (0.63 or 1.25 mg), racemic albuterol (1.25 or 2.5 mg), or placebo t.i.d. for 4 weeks. The primary endpoints, published in Nelson HS, Bensch G, Pleskow WW, et al. Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. J Allergy Clin Immunol 102:943-952, 1998, included comparisons of active treatments with placebo and of the combined levalbuterol with the combined racemic albuterol groups for pulmonary function and rescue medication use. After the first dose, levalbuterol 1.25 mg produced a significantly greater increase in the mean peak change in FEV1 compared with both doses of racemic albuterol (p < 0.03) in all patients and in those with more severe asthma. Levalbuterol 1.25 mg also produced a significantly greater (p < 0.05) mean area under the curve (AUC) of the FEV1 versus time plot (AUC FEV1) compared with all other treatments after the first dose in all patients and in the subset with more severe disease, illustrating better overall improvement in FEV1. Active treatment groups demonstrated significant improvements compared with the placebo group (p < 0.05), except for AUC FEV1 in the racemic albuterol 1.25-mg group at week 4. Levalbuterol in the absence of the (S)-isomer provided greater bronchodilation than the same quantity of (R)-albuterol delivered as the racemate. These data suggest that (S)-albuterol may compromise the efficacy of (R)-albuterol.

This was a prospective, open-label, nonrandomized pilot study to evaluate efficacy and tolerability of levalbuterol (LEV) in acute asthma. Asthmatics (forced expiratory volume in 1 second [FEV1], 20-55% predicted) were sequentially enrolled into cohorts of 12 to 14 and received 0.63, 1.25, 2.5, 3.75, or 5.0 mg LEV or 2.5 or 5.0 mg racemic albuterol (RAC) every 20 minutes x 3. After the first dose, FEV1 changes were 56% (0.6 L) for 1.25 mg LEV and 6% (0.07 L) and 14% (0.21 L) for 2.5 and 5 mg RAC respectively. After three doses, FEV1 changes were 74% (0.9 L), 39% (0.5 L), and 37% (0.6 L) for 1.25 mg, LEV 2.5 mg, RAC and 0.63 mg LEV respectively. LEV doses greater than 1.25 mg did not further improve bronchodilation. Baseline plasma (S)-albuterol levels were negatively correlated with baseline FEV1 (R = - 0.3, P = .004) and percent change in FEV1 (R = -0.3, P = .006). LEV at a dose of 1.25 mg produced effective bronchodilation that was greater than both RAC doses. The negative correlation between (S)-albuterol levels and FEV1 could suggest a deleterious effect of (S)-albuterol. Larger comparative studies are warranted.

Unilateral pulmonary edema is a distinctly unusual clinical entity, often misdiagnosed initially as one of the more common causes of focal lung disease. Predominantly lobar pulmonary edema is rarer still. We report a case of right upper lobe pulmonary edema caused by the acute onset of severe mitral regurgitation. In addition, we briefly review the other causes of unilateral pulmonary edema, focusing on the cases that have been reported in association with heart failure and valvular heart disease. The majority of cases of right upper lobe pulmonary edema have been associated with mitral regurgitation. In addition to confirming the presence of mitral regurgitation, transesophageal echocardiography proved useful in delineating the mechanism for edema formation. It detected differential gradients between the right and left pulmonary venous systems and documented the direction of the regurgitant flow.

compared to racemic albut-erol: efficacy and outcomes in patients hospitalized with COPD or asthma. Evaluation of the safety and efficacy of levalbuterol in 2–5-year-old patients with asthma. Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. The safety and efficacy of nebulized levalbuterol compared to racemic albuterol and placebo in the treatment of asthma in pediatric patients. Dose–response evaluation of levalbuterol versus racemic albuterol in patients with asthma. Low dose levalbuterol in children with asthma: safety and efficacy in comparison with placebo and racemic albuterol. comparison of levalbuterol versus racemic albuterol in the treatment of moderate-to-severe asthma. Levalbuterol has not been established to have therapeutic advantage over racemic albuterol. Inhaled ␤ 2-adrenergic agonists are among the most widely used drugs in the world and are used by most patients with asthma for symptom relief. These drugs are the most effective bronchod-ilators known for the treatment of asthma, inhibiting the effects of all known bronchoconstrictor stimuli (1). Most ␤ 2-agonists have a chiral center so that different enanti-omers exist. Epinephrine synthesis in the adrenal medulla by the enzyme dopamine ␤-hydroxylase involves the stereoselective introduction of a hydroxyl group. Endogenous epinephrine is levorotatory and has the (R)-configuration (also known as L-isomer as it deviates polarized light to the left). Chemical synthesis of all ␤ 2-selective agonists (including long-acting ␤ 2-agonists), however, results in a 50:50 mixture of the (R)-and the (S)-enantiomer (also called the D-isomer, because it is dextrorotatory). The (R)-enantiomer is active, whereas the (S)-enantiomer has little or no activity at the ␤ 2-receptor. However , it is now claimed that the (S)-enantiomer, rather than being inert, has detrimental effects in asthma, accounting for adverse effects of ␤ 2-agonists. Novel methods of manufacture are now able to produce large amounts of the purified (R)-enantiomer of the most widely used ␤ 2-agonist, albuterol (known outside the United States as salbutamol). It is argued that (R)-albuterol (often known as levalbuterol) is more effective than the racemic (R,S)-albuterol mixture, as a result of counteracting actions and 84. Jacobson GA, Chong FV, Wood-Baker R. (R,S)-salbutamol plasma concentrations in severe asthma. A comparison of levalbuterol with racemic albut-erol in the treatment of acute severe asthma exacerbations in adults. sulphate conjugation of salbutamol by human lung and bronchial epi-thelial cells. Metabolism of salbutamol differs between asthmatic patients and healthy volunteers.meric disposition of inhaled, intravenous and oral racemic salbutamol in man: no evidence of enantioselective …