A post hoc analysis of the effect of nightly administration of eszopiclone and a selective serotonin reuptake inhibitor in patients with insomnia and anxious depression.

OBJECTIVE: Patients with major depressive disorder (MDD) and significant anxiety are less responsive to antidepressants than those without anxiety. In this post hoc analysis of patients with insomnia and comorbid anxious depression, eszopiclone cotherapy with a selective serotonin reuptake inhibitor (SSRI) was compared with placebo cotherapy. METHOD: Data were pooled from 2 randomized, double-blind, 8-week trials. One trial (conducted from January 2004 to October 2004) included patients with DSM-IV insomnia and comorbid MDD treated with fluoxetine concurrently with eszopiclone 3 mg/d or placebo. The other trial (conducted from July 2005 to April 2006) included patients with DSM-IV-TR insomnia and comorbid generalized anxiety disorder treated with escitalopram concurrently with eszopiclone 3 mg/d or placebo. Anxious depression was defined as a baseline 17-item Hamilton Depression Rating Scale (HDRS-17) score ≥ 14 (excluding insomnia items) and an anxiety/somatization factor score ≥ 7. Treatment group differences were determined for mean changes in HDRS-17 scores (with and without insomnia items), HDRS anxiety/somatization scores, and response and remission rates. Severity of insomnia was assessed by the Insomnia Severity Index (ISI). RESULTS: In the combined dataset, 347 of 1,136 patients (30.5%) had insomnia and comorbid anxious depression. Significant improvements in insomnia were observed for eszopiclone cotherapy relative to placebo cotherapy (mean change from baseline on the ISI: -11.0 vs -7.8, respectively; P < .001). There were greater reductions in HDRS-17 scores at week 8 following cotherapy with eszopiclone compared with placebo when the insomnia items were included (mean change: -14.1 vs -11.2, respectively; P < .01) or excluded (-10.6 vs -8.9; P < .01), but not for anxiety/somatization (-4.3 vs -4.1; P = .23). Response rates were greater for eszopiclone cotherapy than for placebo cotherapy (55.6% vs 42.0%, respectively; P = .01; 50.0% vs 44.4% when insomnia items were removed; P = .3). Remission rates were not significantly different (32.6% vs 27.2%, respectively; P = .28). CONCLUSIONS: In this post hoc analysis of patients with insomnia and comorbid anxious depression derived from 2 trials, 8 weeks of eszopiclone therapy coadministered with an SSRI resulted in significantly greater improvements in insomnia, significantly greater reductions in HDRS-17 total score, and significantly greater HDRS-17 response rates compared with placebo coadministration. There were no significant differences in response rates (when insomnia items were excluded) and remission rates, as well as in anxiety/somatization scores. Further research is warranted to determine whether these modest antidepressant effects can be replicated, and anxiolytic effects demonstrated, when evaluated in a prospective manner.

Economic outcomes of eszopiclone treatment in insomnia and comorbid major depressive disorder.

BACKGROUND: Eszopiclone is effective for the treatment of insomnia in patients with insomnia and comorbid major depressive disorder (MDD). Both conditions impose significant economic burden, with the US societal cost of depression estimated at USD 50 billion annually. AIMS OF THE STUDY: The purpose of this analysis was to examine the costs and benefits of eszopiclone co-administered with fluoxetine (ESZ+FLX) compared to placebo co-administered with fluoxetine (PBO+FLX) in adults meeting the DSM-IV criteria for insomnia and MDD. METHODS: Data from 434 patients enrolled in an 8-week clinical trial who met the economic-subanalysis criteria were examined. The costs of medical care (in 2007 USUSD ) and lost work time were estimated from the Hamilton Depression Scale (HAM-D17) scores using published algorithms. Cost of lost productivity while at work was based on responses to the Work Limitations Questionnaire. The impact of therapy on quality-adjusted life years (QALYs) was estimated by transforming HAM-D17 (base case analysis) or Short Form Health Survey (SF-12) (scenario analyses) responses into health utility scores using published algorithms. Drug costs were estimated based on average wholesale price. RESULTS: The mean 8-week increases in QALYs from baseline were 0.0392 and 0.0334 for the ESZ+FLX and PBO+FLX groups, respectively. Mean per-patient costs were USD 1,279 and USD 1,198 for the respective groups. Thus, co-treatment resulted in net increases of 0.0058 QALYs and USD 81, leading to an incremental cost per QALY gained of approximately USD 14,000. DISCUSSION AND LIMITATIONS: Co-administration of eszopiclone and fluoxetine improved patients' insomnia symptoms and appeared to be a cost-effective treatment strategy for patients with insomnia and comorbid MDD. One limitation of this study is that optimal utility estimation techniques were not available. Utilities were instead derived indirectly using the HAM-D17 (disease-specific, not generic) or SF-12 (generic, but potentially insensitive to important changes in some conditions) instruments. IMPLICATIONS FOR HEALTH CARE PROVISION: Sleep disturbance is predictive of depression relapse, and is the most common residual symptom in patients who have been successfully treated with fluoxetine for depression. Thus, identifying cost-effective strategies for the treatment of insomnia symptoms is important for this patient population. IMPLICATIONS FOR HEALTH POLICIES: Treatment guidelines and drug coverage decisions should be based on clinical evidence, effectiveness, and economic criteria (i.e., whether an effective drug therapy produces sufficient benefits given its costs). This information about the overall value of eszopiclone can be measured as the cost per QALY gained with the use of ESZ+FLX compared with FLX alone. In order to make decisions based on value, payers and policy makers must have access to reliable cost-effectiveness information. IMPLICATIONS FOR FURTHER RESEARCH: The residual efficacy observed in the clinical trial following the discontinuation of co-therapy should be explored further to determine whether intermittent treatment with ESZ+FLX is a cost-effective strategy.

A 12-week, randomized, double-blind, placebo-controlled study evaluating the effect of eszopiclone 2 mg on sleep/wake function in older adults with primary and comorbid insomnia.

BACKGROUND: Longer-term pharmacologic studies for insomnia in older individuals are sparse. OBJECTIVE: To evaluate the efficacy and safety of 12 weeks of nightly eszopiclone in elderly outpatients with insomnia. METHODS: Participants (65-85 years) met DSM-IV-TR criteria for insomnia with total sleep times (TST) < or = 6 h, and wake time after sleep onset (WASO) > or = 45 min. Participants were randomized to 12 weeks of eszopiclone 2 mg (n = 194) or placebo (n = 194), followed by a 2-week single-blind placebo run-out. Subject-reported measures of sleep (sTST, sleep latency [sSL], sWASO) and daytime function (alertness, concentration, wellbeing, ability to function) were assessed. AEs were monitored. RESULTS: Subjects treated with 2 mg eszopiclone slept longer at night on average and at every individual time point compared to baseline than placebo subjects, as measured by TST over the 12-week double-blind period (P < 0.0001). Mean sTST over the double-blind period for eszopiclone-treated subjects was 360.08 min compared to 297.86 min at baseline, a mean change of 63.24 min. Over the double-blind period, eszopiclone-treated subjects also experienced a significantly greater improvement in sSL compared to placebo, with a mean decrease of 24.62 min versus a mean decrease of 19.92 min, respectively (P = 0.0014). Eszopiclone subjects also experienced a significantly greater decrease in WASO (mean decrease of 36.4 min) compared to placebo subjects (decrease of 14.8 min) (P < 0.0001). Post-discontinuation, sleep parameters were statistically improved versus baseline for eszopiclone (P-values < or = 0.01), indicating no rebound. The most common AEs (> or = 5%) were headache (eszopiclone 13.9%, placebo 12.4%), unpleasant taste (12.4%, 1.5%), and nasopharyngitis (5.7%, 6.2%). CONCLUSION: In this Phase IV trial of older adults with insomnia, eszopiclone significantly improved patient-reported sleep and daytime function relative to placebo. Improvements occurred within the first week and were maintained for 3 months, with no evidence of rebound insomnia following discontinuation. The 12 weeks of treatment were well tolerated. CLINICAL TRIAL INFORMATION: A Long-Term Safety and Efficacy Study of Eszopiclone in Elderly Subjects With Primary Chronic Insomnia; Registration #NCT00386334; URL - http://www.clinicaltrials.gov/ct2/show/NCT00386334?term=eszopiclone&rank=24

Interpreting score differences in the Insomnia Severity Index: using health-related outcomes to define the minimally important difference.

OBJECTIVE: To estimate the minimally important difference (MID) for the Insomnia Severity Index (ISI) by examining the association of score differences of the ISI with health-related outcomes including health-related quality of life, productivity, and fatigue. METHODS: Data came from a randomized, placebo-controlled clinical trial evaluating the long-term efficacy of eszopiclone for primary insomnia (N = 828). Logistic regression models were used to characterize the relationship between ISI change scores (from baseline to 6 months post-treatment) and outcomes/anchors from the SF-36 Health Survey, Work Limitations Questionnaire (WLQ), and Fatigue Severity Scale (FSS). Odds ratios were derived from the regression coefficients to calculate the probability of a given outcome being associated with different ISI change scores. Convergence between anchor- and distribution-based estimates was assessed. RESULTS: Higher ISI scores (indicating more severe insomnia) were significantly associated with higher probabilities of negative outcome in all models. Individuals with a 6-point score reduction in ISI scores (which corresponded to 1(1/2) standard deviations) were 48% less likely to report 'feeling worn out' (SF-36) at 6 months, 46% less likely to be 'unable to think clearly' (WLQ), and 52% less likely to report 'feeling fatigued' (FSS). Similar results were found across a broad spectrum of all selected anchors. CONCLUSIONS: Based on results of the study, a 6-point reduction is recommended to represent a clinically meaningful improvement in individuals with primary insomnia. Research on generalizability of the recommended MID in this study to other patient populations and other type of treatment interventions is needed.

Cost-effectiveness of eszopiclone for the treatment of adults with primary chronic insomnia.

STUDY OBJECTIVE: To assess the cost-effectiveness of treatment with eszopiclone for chronic primary insomnia in adults. METHODS: A model using patient-level data from a 6-month, double-blind, placebo-controlled, clinical trial (n = 824), combined with data from a claims database and published literature, was used to assess the quality-adjusted life years (QALYs) gained and costs associated with eszopiclone versus placebo in adults with primary insomnia. Quality of life data were collected during the trial via the SF-36, from which preference-based utility scores were derived using published algorithms. Medical and absenteeism costs, estimated via a retrospective analysis of a claims and absenteeism database, were assigned to patients based on the degree of severity of their insomnia, assessed via the Insomnia Severity Index collected in the clinical trial. Presenteeism costs (lost productivity while at work) were estimated from responses to the Work Limitation Questionnaire collected during the trial. Six-month gains in QALYs and costs for each treatment group were calculated to derive cost-effectiveness ratios. Uncertainty was addressed via univariate and multivariate sensitivity analyses. RESULTS: Over the 6-month period, eszopiclone use resulted in a net gain of 0.0137 QALYs over placebo at an additional cost of $67, resulting in an incremental cost per QALY gained of slightly less than $5,000. When absenteeism and presenteeism costs were excluded, the cost-effectiveness ratio increased to approximately $33,000 per QALY gained, which is below the commonly used threshold of $50,000 used to define cost-effectiveness. Extensive sensitivity analyses indicate the results are generally robust. CONCLUSION: Our model, based on efficacy data from a clinical trial, demonstrated eszopiclone was cost-effective for the treatment of primary insomnia in adults, especially when lost productivity costs were included.

Comparison of levalbuterol and racemic albuterol in hospitalized patients with acute asthma or COPD: a 2-week, multicenter, randomized, open-label study.

BACKGROUND: The National Heart, Lung, and Blood Institute guideline recommends that dosing racemic albuterol be administered every 1 to 4 hours for treating patients with asthma or chronic obstructive pulmonary disease (COPD) in the hospital. Previously published preliminary and retrospective studies suggested that levalbuterol can be administered every 8 hours for the treatment of bronchoconstriction in hospitalized patients. However, it is unclear how the different dosing regimens affect the total number of nebulizations (scheduled plus as-needed treatments) and the costs of treatment of bronchoconstriction in a hospital setting. Moreover, it is not clear how the different dosing regimens affect symptom outcomes and health status in hospitalized patients with asthma or COPD. OBJECTIVE: The aim of this study was to evaluate these issues in hospitalized patients with acute asthma or COPD. METHODS: In this prospective, multicenter, randomized, open-label study, hospitalized patients aged > or = 18 years were randomly assigned to receive 14-day treatment with levalbuterol 1.25 mg q6-8h or racemic albuterol 2.5 mg q1-4h, administered per routine hospital practice at each institution. The primary efficacy end point was total number of nebulizations during hospitalization. Pulmonary function, symptom evaluation (subject general well-being score [SGWB], disease symptom assessment [DSA], and beta-mediated adverse effect scores), hospital costs (excluding medication costs) and hospital length of stay (LOS) were also evaluated. RESULTS: In the intent-to-treat population (n = 479; levalbuterol, 241;racemic albuterol, 238), the mean (SE) age was 55.3 (16.9) years, the majority of patients were white (57.8%), and the mean (SE) weight was 80.9 (24.5) kg. Demographic characteristics were similar between the 2 treatment groups, except that there were more females with COPD in the levalbuterol treatment group (63.88%) compared with the racemic albuterol treatment group (45.5%) (P = 0.005). Patients treated with levalbuterol required significantly fewer median total nebulizations (10 vs 12; P = 0.031) and scheduled nebulizations (9 vs 11; P = 0.009) compared with those in the racemic albuterol group. The 2 treatment groups required 0 rescue nebulizations. Mean (SD) forced expiratory volume in 1 second improved from baseline with both levalbuterol and racemic albuterol (0.06 [0.43] and 0.10 [0.37] L, respectively); these improvements were maintained throughout the hospital stay (0.11 [0.48] and 0.16 [0.52] L). DSA and SGWB scores improved significantly from baseline in both treatment groups, and beta-mediated adverse effects mean scores were significantly greater with levalbuterol versus racemic albuterol (P < 0.001). In the levalbuterol and racemic albuterol treatment groups, hospital LOS (70.6 and 65.7 hours, respectively), time to discharge (66.0 and 62.8 hours), and total hospital costs (least squares mean [SE], US $4869.30 [$343.58] and $4899.41 [$343.20]) were similar. CONCLUSIONS: In these hospitalized patients with acute asthma or COPD treated with levalbuterol every 6 to 8 hours or racemic albuterol every 1 to 4 hours, significantly fewer total nebulizations were required with levalbuterol, without an increased need for rescue nebulizations during 14 days of hospitalization. Both treatments were associated with improvements from baseline in symptoms and health status. The costs of treating bronchoconstriction in hospitalized patients were similar between the levalbuterol and racemic albuterol groups.

A polysomnographic placebo-controlled evaluation of the efficacy and safety of eszopiclone relative to placebo and zolpidem in the treatment of primary insomnia.

STUDY OBJECTIVES: To evaluate the polysomnographic efficacy and the safety of a range of doses of eszopiclone relative to placebo in patients with primary insomnia. Zolpidem 10 mg was included as an active control. METHODS: This multicenter, randomized, crossover study enrolled patients aged 21-64 years meeting the DSM-IV criteria for primary insomnia (n = 65). Patients received 2 nights treatment each with placebo, eszopiclone 1 mg, 2 mg, 2.5 mg, or 3 mg, and zolpidem 10 mg after randomization to one of 6 treatment sequences. Visits were separated by a 3-7 day washout. Objective efficacy was assessed by polysomnography (PSG). The primary endpoint was latency to persistent sleep (LPS); key secondary endpoints were sleep efficiency (SE) and wake time after sleep onset (WASO); other endpoints included wake time during sleep (WTDS) and number of awakenings (NAW), as well as patient-reported variables. RESULTS: LPS and SE were significantly different than placebo for all active treatments (p < 0.05 for all). Significant differences from placebo were noted in the 3 objective sleep maintenance measures (WASO, WTDS, and NAW) for eszopiclone 3 mg (p < 0.05), which was not the case for zolpidem 10 mg or the other eszopiclone doses. The incidence of central nervous system adverse events was 23.4% for zolpidem 10 mg, 6.2% to 12.5% for the eszopiclone doses, and 7.9% for placebo. CONCLUSIONS: Relative to placebo, all active treatments were effective in reducing LPS and increasing SE. Eszopiclone 3 mg was significantly different from placebo on the 3 PSG measures of sleep maintenance (WASO, WTDS, and NAW). Significant differences between zolpidem 10 mg and eszopiclone (2 mg or 3 mg) were not observed for PSG-measured outcomes, although the study was not powered to detect differences between the active drug conditions.

Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder.

CONTEXT: Insomnia and generalized anxiety disorder (GAD) are prevalent disorders that may coexist. OBJECTIVE: To determine the efficacy of eszopiclone combined with escitalopram oxalate in treating insomnia comorbid with GAD. DESIGN: Double-blind, randomized, placebo-controlled, parallel-group, add-on therapy 10-week study. SETTING: Multicenter outpatient study from July 2005 to April 2006. PATIENTS: Adults aged 18 to 64 years meeting DSM-IV-TR criteria for GAD and insomnia. INTERVENTIONS: Patients received 10 mg of escitalopram oxolate for 10 weeks and were randomized to also receive either 3 mg of eszopiclone (n = 294) or placebo (n = 301) nightly for 8 weeks. For the last 2 weeks, eszopiclone was replaced with a single-blind placebo. MAIN OUTCOME MEASURES: Sleep, daytime functioning, psychiatric measures, and adverse events. RESULTS: Compared with treatment with placebo and escitalopram, treatment with eszopiclone and escitalopram resulted in significantly improved sleep and daytime functioning (P < .05), with no evidence of tolerance. Patients taking eszopiclone and escitalopram had greater improvements in total Hamilton Anxiety Scale (HAM-A) scores at each week (P < .05) and at weeks 4 through 10 with the insomnia item removed. Clinical Global Impressions (CGI) of Improvement scores were improved with eszopiclone and escitalopram at every point (P < .02), while CGI of Severity of Illness scores were not significantly different after week 1. The HAM-A response (63% vs 49%, respectively, P = .001) and remission (42% vs 36%, respectively, P = .09) rates at week 8 were higher in patients treated with eszopiclone and escitalopram than those treated with placebo and escitalopram, and median time to onset of anxiolytic response was significantly reduced (P < or = .05). After eszopiclone discontinuation, there was no evidence of rebound insomnia, and while treatment differences in anxiety measures were maintained, differences in sleep outcomes were not. Overall adverse event rates were 77.6% with cotherapy and 67.9% with monotherapy. The most common adverse events with cotherapy were unpleasant taste, headache, dry mouth, and somnolence. CONCLUSIONS: Coadministration of eszopiclone and escitalopram was well tolerated and associated with significantly improved sleep, daytime functioning, anxiety, and mood in patients with insomnia and GAD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00235508.

An evaluation of levalbuterol HFA in the prevention of exercise-induced bronchospasm.

BACKGROUND: Exercise-induced bronchospasm (EIB) affects up to 90% of all patients with asthma. Objective. This study evaluated the ability of levalbuterol hydrofluoroalkane (HFA) 90 mug (two actuations of 45 microg) administered via metered dose inhaler (MDI) to protect against EIB in mild-to-moderate asthmatics. METHODS: This was a randomized, double-blind, placebo-controlled, two-way cross-over study. Patients with asthma (n = 15) were > or =18 years, had a > or =6-month history of EIB, > or = 70% baseline predicted forced expiratory volume in 1 second (FEV1), and a 20% to 50% decrease in FEV(1) after treadmill exercise challenge using single-blind placebo MDI. Levalbuterol or placebo was self-administered 30 minutes before exercise. Treatment sequences were separated by a 3-to 7-day washout period. Spirometry was performed predose, 20 minutes postdose/pre-exercise, and 5, 10, 15, 30, and 60 minutes post-exercise. The primary endpoint was the maximum percent decrease in FEV1 from baseline (postdose/pre-exercise). The percentage of protected (< or = 20% decrease in post-exercise FEV1) patients was also assessed. RESULTS: Levalbuterol had significantly smaller maximum percent post-exercise decrease in FEV1 compared with placebo (LS mean +/- SE; -4.8% +/- 2.8% versus -22.5% +/- 2.8%, respectively). For levalbuterol, 14/15 (93.3%) patients had < 20% decrease in post-exercise FEV1 compared with 8/15 (53.3%) for placebo (p = 0.0143). Treatment was well tolerated. CONCLUSION: Levalbuterol HFA MDI (90 microg) administered 30 minutes before exercise was significantly more effective than placebo in protecting against EIB after a single exercise challenge and was well tolerated. CLINICAL IMPLICATIONS: Levalbuterol HFA MDI when administered before exercise was effective in protecting adults with asthma from EIB.

Nightly treatment of primary insomnia with eszopiclone for six months: effect on sleep, quality of life, and work limitations.

STUDY OBJECTIVES: To evaluate 6 months' eszopiclone treatment upon patient-reported sleep, fatigue and sleepiness, insomnia severity, quality of life, and work limitations. DESIGN: Randomized, double blind, controlled clinical trial. SETTING: 54 research sites in the U.S. PATIENTS: 830 primary insomnia patients who reported mean nightly total sleep time (TST) < or = 6.5 hours/night and/or mean nightly sleep latency (SL) >30 min. INTERVENTION: Eszopiclone 3 mg or matching placebo. MEASUREMENTS: Patient-reported sleep measures, Insomnia Severity Index, Medical Outcomes Study Short-Form Health Survey (SF-36), Work Limitations Questionnaire, and other assessments measured during baseline, treatment Months 1-6, and 2 weeks following discontinuation of treatment. RESULTS: Patient-reported sleep and daytime function were improved more with eszopiclone than with placebo at all months (P <0.001). Eszopiclone reduced Insomnia Severity Index scores to below clinically meaningful levels for 50% of patients (vs 19% with placebo; P <0.05) at Month 6. SF-36 domains of Physical Functioning, Vitality, and Social Functioning were improved with eszopiclone vs placebo for the Month 1-6 average (P < 0.05). Similarly, improvements were observed for all domains of the Work Limitations Questionnaire with eszopiclone vs placebo for the Month 1-6 average (P <0.05). CONCLUSIONS: This is the first placebo-controlled investigation to demonstrate that long-term nightly pharmacologic treatment of primary insomnia with any hypnotic enhanced quality of life, reduced work limitations, and reduced global insomnia severity, in addition to improving patient-reported sleep variables.

Cost effectiveness of long-term treatment with eszopiclone for primary insomnia in adults: a decision analytical model.

OBJECTIVE: Although the clinical benefits of pharmacological treatments for insomnia have been studied, no systematic assessment of their economic value has been reported. This analysis assessed, from a broad payer and societal perspective, the cost effectiveness of long-term treatment with eszopiclone (LUNESTA, Sepracor Inc., [Marlborough, MA, USA]) for chronic primary insomnia in adults in the US. METHODS: A decision analytical model was developed based on the reanalysis of a 6-month placebo-controlled trial, which demonstrated that eszopiclone 3mg significantly improved sleep and daytime function measures versus placebo in adults with primary insomnia. Patients were classified as either having remitted or not remitted from insomnia based upon a composite index of eight sleep and daytime function measures collected during the trial. These data were supplemented with quality-of-life and healthcare and lost productivity cost data from the published literature and medical and absenteeism claims databases. RESULTS: Compared with non-remitted patients, patients classified as remitted had lower monthly healthcare and productivity costs (in 2006 dollars) [a reduction of $US242 and $US182, respectively] and higher quality-adjusted life-year (QALY) weight (a net gain of 0.0810 on a scale ranging from 0 to 1). During the study, eszopiclone-treated patients were about 2.5 times more likely to have remitted than placebo-treated patients. Six months of eszopiclone treatment reduced direct (healthcare) and indirect (productivity) costs by an estimated $US245.13 and $US184.19 per patient, respectively. Eszopiclone use was associated with a cost of $US497.15 per patient over 6 months (including drug cost, dispensing fee, physician visit and time loss to receive care). Thus, after considering the above savings and the costs associated with eszopiclone treatment over 6 months, cost increased by $US252.02 (excluding productivity gains) and $US67.83 (including productivity gains) per person. However, eszopiclone treatment was also associated with a net QALY gain of 0.006831 per patient over the same period. Consequently, the incremental cost per QALY gained associated with eszopiclone was approximately $US9930 (including productivity gains [i.e. $US67.83 / 0.006831]) and $US36 894 (excluding productivity gains [i.e. $US252.02 / 0.006831]). Sensitivity analyses using a variety of scenarios suggested that eszopiclone is generally cost effective. CONCLUSIONS: This analysis suggested that long-term eszopiclone treatment was cost effective over the 6-month study period, particularly when the impact on productivity costs is considered. Given the increasing interest in new pharmacological interventions to manage insomnia, payers and clinicians alike should carefully consider the balance of health and economic benefits that these interventions offer. Accordingly, additional research in this area is warranted.

A comparison of levalbuterol with racemic albuterol in the treatment of acute severe asthma exacerbations in adults.

UNLABELLED: This multicenter, randomized, double-blind trial compared nebulized levalbuterol (Lev) and racemic albuterol (Rac) in the treatment of acute asthma. METHODS: Adults with acute asthma exacerbations (FEV(1) 20%-55% predicted) received prednisone and either Lev (1.25 mg, n = 315) or Rac (2.5 mg, n = 312). Nebulized treatments were administered every 20 minutes in the first hour, then every 40 minutes for 3 additional doses, then as necessary for up to 24 hours. The primary end point was time to meet discharge criteria. Secondary end points included changes in lung function and hospitalization rates. A subset of 160 patients had plasma (S)-albuterol concentrations determined at study entry. RESULTS: Time to meet discharge criteria did not differ between the 2 treatments. FEV(1) improvement was greater following Lev compared with Rac, both after dose 1 and cumulatively over the entire treatment period (dose 1 in intent to treat [ITT] group: Lev 0.50 +/- 0.43 L, Rac 0.43 +/- 0.37 L; P = .02), particularly among the 60% of patients not on recent steroid therapy (dose 1: Lev 0.58 +/- 0.47 L, Rac 0.44 +/- 0.37 L; P < .01), and patients whose entry (S)-albuterol concentrations were in the highest quartile of those measured. A small and similar proportion of Lev-treated (7.0%) and Rac-treated (9.3%) patients required hospitalization (P = .28). Among patients not on steroids, fewer Lev- than Rac-treated patients required admission (3.8% vs 9.3%, P = .03), as was also the case for patients with high plasma (S)-albuterol concentrations. Asthma relapses (5% in 30 days) were lower than in previous reports and did not differ between groups. CONCLUSIONS: This study suggests that early, regular nebulized beta(2)-agonist and systemic corticosteroid therapy may reduce hospitalization and relapse rates in patients with acute severe asthma. Lev was well tolerated and compared favorably with Rac in improving airway function, particularly in those who were not on inhaled or oral corticosteroids and in those who had high plasma (S)-albuterol concentrations at presentation.

Evaluation of the efficacy and safety of levalbuterol in subjects with COPD.

The efficacy and safety of nebulized levalbuterol in adults with chronic obstructive pulmonary disease (COPD) was evaluated in this multicenter, randomized, double-blind, parallel design study. Randomized subjects (n = 209) received levalbuterol (LEV) 0.63 mg or 1.25 mg, racemic albuterol (RAC) 2.5 mg, or placebo (PBO) TID for 6 weeks. Serial spirometry was completed in-clinic after study drug alone (weeks 0, 2, and 6) or in combination with ipratropium bromide 0.5 mg (week 4). The primary endpoint was the averaged FEV1 AUC(0-8 hrs) over weeks 0, 2 and 6 compared with placebo. Other endpoints included rescue medication use, safety parameters, COPD exacerbations, and global evaluations. All active treatments demonstrated improvements in the percent change in FEV1 AUC(0-8 hrs) over the double-blind period and at each visit vs PBO (p < 0.05). Rescue medication use vs. baseline (doses/day) changed over time: PBO +0.38 +/- 3.3; LEV 0.63 mg +0.07 +/- 3.3; LEV 1.25 mg -0.84 +/- 3.8 (p = 0.02 vs. RAC); RAC +0.97 +/- 2.5. The overall rate of adverse events was PBO 56.4%, LEV 0.63 mg 56.6%, LEV 1.25 mg 67.3%, and RAC 65.4%. Protocol-defined COPD exacerbations occurred in all groups (PBO 12.7%, LEV 0.63 mg 11.3%; LEV 1.25 mg 18.4%; RAC 21.2%). Withdrawals due to COPD exacerbations were significantly higher in the RAC group compared with PBO (PBO 0%; LEV 0.63 mg 1.9%; LEV 1.25 mg 4.1%; RAC 9.6% p = 0.01 vs. PBO). In this study, levalbuterol treatment in subjects with COPD was generally well tolerated, produced significant bronchodilation compared with PBO, and improved clinical control of COPD as evidenced by reductions in rescue medication use compared with PBO and/or RAC.

Levalbuterol compared with racemic albuterol in the treatment of acute asthma: results of a pilot study.

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.

Pairwise comparison of levalbuterol versus racemic albuterol in the treatment of moderate-to-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.