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Fevipiprant, an oral antagonist of the prostaglandin DLUSTER-1 and LUSTER-2 were two phase 3 randomised, double-blind, placebo-controlled, parallel-group, replicate 52-week studies; LUSTER-1 took place at 174 clinical sites in 25 countries and LUSTER 2 took place at 169 clinical sites in 19 countries. Fevipiprant or placebo was added to Global Initiative for Asthma Steps 4 and 5 therapy in adolescents and adults with severe asthma. Patients aged 12 years or older with uncontrolled asthma on dual or triple asthma therapy were randomly assigned by use of interactive response technology to one of three treatment groups (once-daily fevipiprant 150 mg, fevipiprant 450 mg, or placebo) in a 1:1:1 ratio within each of the randomisation strata: peripheral blood eosinophil counts (250 cells per μL or ≥250 cells per μL), patient age (18 years or ≥18 years), and use or non-use of oral corticosteroids as part of their standard of care asthma therapy. The primary efficacy endpoint was the annualised rate of moderate to severe asthma exacerbations with 150 mg or 450 mg doses of fevipiprant once daily compared with placebo over 52 weeks, in patients with high blood eosinophil counts (≥250 cells per μL) and in the overall study population. All patients who underwent randomisation and received at least one dose of study medication were included in efficacy and safety analyses. These trials are registered with ClinicalTrials.gov, NCT02555683 (LUSTER-1) and NCT02563067 (LUSTER-2), and are complete and no longer recruiting.Between Dec 11, 2015, and Oct 25, 2018, 894 patients were randomly assigned to fevipiprant 150 mg (n=301), fevipiprant 450 mg (n=295), or placebo (n=298) in LUSTER-1. Between Dec 3, 2015, and July 10, 2018, 877 patients were randomly assigned to fevipiprant 150 mg (n=296), fevipiprant 450 mg (n=294), or placebo (n=287) in LUSTER-2. In the high eosinophil population, in LUSTER-1 the annualised rate ratio of moderate to severe exacerbations compared with placebo was 1·04 (95% CI 0·77-1·41) for fevipiprant 150 mg and 0·83 (0·61-1·14) for fevipiprant 450 mg, and in LUSTER-2 it was 0·69 (0·50-0·96) for fevipiprant 150 mg and 0·72 (0·52-1·01) for fevipiprant 450 mg. In the overall population, in LUSTER-1 the annualised rate ratio of moderate to severe exacerbations compared with placebo was 0·96 (95% CI 0·75-1·22) for fevipiprant 150 mg and 0·78 (0·61-1·01) for fevipiprant 450 mg and in LUSTER-2 it was 0·82 (0·62-1·07) for fevipiprant 150 mg and 0·76 (0·58-1·00) for fevipiprant 450 mg. In the overall pooled population of both studies, serious adverse events occurred in 53 (9%) patients in the fevipiprant 150 mg group, 50 (9%) in the fevipiprant 450 mg group, and 50 (9%) in the placebo group. Adverse events leading to death occurred in two (1%) patients in the fevipiprant 450 mg group and three (1%) in the placebo group.Although neither trial showed a statistically significant reduction in asthma exacerbations after adjusting for multiple testing, consistent and modest reductions in exacerbations rates were observed in both studies with the 450 mg dose of fevipiprant.Novartis.

Recent insight into the pathophysiology of severe coronavirus disease 2019 (COVID-19) has implicated hyperactivation of the immune response, resulting in a “cytokine storm,” which can lead to excessive immune-cell infiltration of the lungs, alveolar damage, decreased lung function, and death. Several cytokines implicated in the COVID-19–associated cytokine storm predominantly signal through the Janus kinase (JAK)/signal transducer and activator of transcription pathway. Ruxolitinib is a selective inhibitor of JAK1 and JAK2 that has been explored in small studies of patients with COVID-19–associated cytokine storm. Early clinical data from these trials, combined with a body of preclinical and clinical evidence in other inflammatory conditions, support exploration of the efficacy and safety of ruxolitinib in these patients in larger, well-controlled trials. Here we describe the designs of three such ongoing clinical trials. RUXCOVID is a phase 3 randomized, double-blind, multicenter study of ruxolitinib 5 mg twice daily (BID) vs placebo (both plus standard of care) in patients with COVID-19–associated cytokine storm. 369-DEVENT is a phase 3, randomized, double-blind, placebo-controlled, multicenter study of ruxolitinib 5 or 15 mg BID vs placebo (all plus standard of care) in patients with COVID-19–associated acute respiratory distress syndrome who require mechanical ventilation. Patients with severe COVID-19–associated cytokine storm who are ineligible for these trials can receive ruxolitinib through an Expanded Access Program (EAP) in the United States and similar programs outside of the United States. RUXCOVID and 369-DEVENT will provide insight into the efficacy and safety of ruxolitinib in hospitalized patients prior to or during ventilator use. If these trials are successful, ruxolitinib could improve outcomes for patients with COVID-19 as well as lessen the overall burden on the health care system. © 2020, Delaware Academy of Medicine. All rights reserved.

Background These studies assessed the efficacy and safety of fevipiprant, an oral antagonist of the prostaglandin D2 (PGD2) receptor (DP2), compared with placebo when added to standard-of-care (SoC) asthma therapy in patients with uncontrolled asthma. Methods ZEAL-1 (NCT03215758) and ZEAL-2 (NCT03226392) are two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies in which fevipiprant 150 mg once daily (o.d.) or placebo was added to SoC asthma therapy in patients aged ≥12 years with uncontrolled asthma. Primary endpoint: change from baseline in pre-dose forced expiratory volume in 1 s (FEV1) after 12 weeks’ treatment. Key secondary endpoints: daytime asthma symptom score, short-acting β-agonist (SABA) use and Asthma Quality-of-Life Questionnaire (AQLQ+12) score after 12-weeks treatment. Findings 662 patients in ZEAL-1 and 685 patients in ZEAL-2 completed the treatment period. In ZEAL-1, the least squares (LS) mean change from baseline in pre-dose FEV1 was 112 mL in fevipiprant vs 71 mL in placebo group (difference [∆]:41 mL; 95% CI: −6, 88; adjusted p-value 0·088). In ZEAL-2, the LS mean change in pre-dose FEV1 was 126 mL and 157 mL in the fevipiprant and placebo groups, respectively (∆:−31 mL; 95% CI: −80, 18; adjusted p-value 0·214). For both studies, there were no statistically significant differences in the key secondary objectives between the treatment groups. Interpretation The ZEAL studies did not demonstrate significant improvement in lung function or other clinical outcomes. These results suggest that DP2 receptor inhibition with fevipiprant is not effective in the studied patient population.

Background: Severe COVID-19 can result in pneumonia, with many patients (pts) requiring hospitalization and oxygen support. Severe COVID-19 may also be complicated by acute respiratory distress syndrome, sepsis and septic shock, and/or multiorgan failure. Many of these pts have features consistent with cytokine release syndrome (CRS) and its associated hyperinflammation. Given their immunomodulatory effects, Janus kinase (JAK) inhibitors have been suggested as a potential therapeutic option in pts with severe COVID-19. Ruxolitinib—a potent JAK1/JAK2 inhibitor approved for treating myelofibrosis, polycythemia vera, and steroid-refractory acute graft-vs.-host disease (GvHD; US only)—has been associated with reduced levels of inflammatory cytokines in disorders where cytokine dysregulation plays a role, including GvHD and secondary hemophagocytic lymphohistiocytosis. Additionally, findings from a small, randomized, phase 2 study (N = 43; Cao Y et al., J Allergy Clin Immunol 2020) showed that treatment with ruxolitinib plus standard of care (SOC) reduced CRS-associated hyperinflammation in pts with severe COVID-19 vs placebo plus SOC, with significant improvement seen in chest computed tomography (CT) features. Although no statistically significant differences were observed, ruxolitinib-treated pts also had a numerically shorter median time to clinical improvement, a lower proportion requiring intensive care/mechanical ventilation, and reduced mortality, with ruxolitinib having a favorable safety profile. Methods: RUXCOVID (NCT04362137) is a global, randomized (2:1), double-blind, placebo-controlled, 29-day, phase 3 study evaluating the efficacy and safety of ruxolitinib plus SOC compared with placebo plus SOC in pts with COVID-19. Pts are eligible for the study if they are ≥ 12 years old, have confirmed COVID-19, are hospitalized, and meet ≥ 1 of the following: pulmonary infiltrates (by chest x-ray or CT scan), respiratory frequency ≥ 30 breaths/min, requirement of supplemental oxygen, oxygen saturation (SpO2) ≤ 94% on room air, or arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2) < 300 mm Hg (1 mm Hg = 0.133 kPa). Pts with a need for intensive care or intubation are not eligible. Pts will be randomized to ruxolitinib 5 mg twice daily or placebo and treated for 14 days. Pts may be treated for an additional 14 days if no improvement occurs and the potential benefit outweighs the potential risk per investigator assessment. The primary endpoint is the proportion of pts who die, develop respiratory failure (require mechanical ventilation), or require intensive care by day 29. Secondary endpoints include improvement in clinical status, in-hospital outcomes, change in National Early Warning Score, change in SpO2:FiO2 ratio, mortality rate, change in inflammatory biomarkers, and safety. Target enrollment is 402 pts. Sponsored by Novartis Pharmaceuticals and Incyte. Citation Format: MeiLan K. Han, Rachel Ann Bender Ignacio, Amparo Lopez Bernus, Katrin Milger-Kneidinger, Amesika N. Nyaku, Ben Parker, Victoria Potter, Sinisa Savic, Valerie Campello-Iddison, Weihua Cao, Peter Langmuir, Barbara Knorr. RUXCOVID: A phase 3, randomized, placebo-controlled study evaluating the efficacy and safety of ruxolitinib in patients with COVID-19–associated cytokine storm [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-002.

Leukotriene B4 (LTB(4)) is a potent inflammatory mediator in asthma, and is increased in more severe asthma. Targeting LTB(4), in addition to cysteinyl leukotrienes, could be beneficial in asthma. This was a randomized, double-blind trial of once-daily MK-0633, a potent 5-lypoxygenase inhibitor, 10 mg, 50 mg, and 100 mg, and placebo in patients 18-70 years with a history of chronic asthma, and FEV(1) ≥45 and ≤85% predicted. There was a 6-week main period and optional 18-week and 34-week periods (52 weeks total), the latter two comparing only MK-0633 100 mg and placebo. The primary endpoint was the change from baseline in FEV(1) over the last 4 weeks of the 6-week primary treatment period. Secondary endpoints included symptom scores, β-agonist use, peak expiratory flow (PEF), asthma quality of life questionnaire (AQLQ), asthma control questionnaire (ACQ), asthma attacks, exacerbations, days with asthma control, post-β-agonist FEV(1), and blood eosinophils. MK-0633 100 mg was significantly more effective than placebo for the change from baseline in FEV(1) (0.20 L vs. 0.13 L; p = 0.004). The other MK-0633 doses were not significantly more effective than placebo. MK-0633 (at various doses) was also more effective than placebo for β-agonist use, AQLQ, AM and PM PEFR, ACQ, and post-β-agonist FEV(1) (p 0.05 for all). MK-0633 was associated with a dose-dependent increase in elevated aspartate aminotransferase and alanine aminotransferase. Because of the relative benefit-risk ratio, the optional study periods were terminated after unblinding for the main study period. Overall, the benefit-risk ratio did not support the clinical utility of MK-0633 in asthma.

Current treatments for acute asthma provide inadequate benefit for some patients. Intravenous montelukast may complement existent therapies.To evaluate efficacy of intravenous montelukast as adjunctive therapy for acute asthma.A total of 583 adults with acute asthma were treated with standard care during aor = 60-minute screening period. Patients with FEV(1)or =50% predicted were randomly allocated to intravenous montelukast 7 mg (n = 291) or placebo (n = 292) in addition to standard care. This double-blind treatment period lasted until a decision for discharge, hospital admission, or discontinuation from the study. The primary efficacy endpoint was the time-weighted average change in FEV(1) during 60 minutes after drug administration. Secondary endpoints included the time-weighted average change in FEV(1) at various intervals (10-120 minutes) and percentage of patients with treatment failure (defined as hospitalization or lack of decision to discharge by 3 hours postadministration).Montelukast significantly increased FEV(1) at 60 minutes postdose; the difference between change from baseline for placebo (least-squares mean of 0.22 L; 95% CI, 0.17, 0.27) and montelukast (0.32 L; 95% CI, 0.27, 0.37) was 0.10 L (95% CI, 0.04, 0.16). Similar improvements in FEV(1)-related variables were seen at all time points (all P.05). Although treatment failure did not differ between groups (OR 0.92; 95% CI, 0.63, 1.34), a prespecified subgroup analysis suggests likely benefit for intravenous montelukast at US sites.Intravenous montelukast added to standard care in adults with acute asthma produced significant relief of airway obstruction throughout the 2 hours after administration, with an onset of action as early as 10 minutes.

Summary. Background: Montelukast is a potent leukotriene-receptor antagonist administered once daily that provides clinical benefit in the treatment of asthma and allergic rhinitis in children and adults. Because of its wide use as a pediatric controller, there is a need for a further review of the safety and tolerability of montelukast in children. Objective: To summarize safety and tolerability data for montelukast from previously reported as well as from unpublished placebo-controlled, double-blind, pediatric studies and their active-controlled open-label extension/extended studies. Methods: These studies evaluated 2,751 pediatric patients 6 months to 14 years of age with persistent asthma, intermittent asthma associated with upper respiratory infection, or allergic rhinitis. These patients were enrolled in seven randomized, placebo-controlled, double-blind registration and post-registration studies and three active-controlled open-label extension/ extended studies conducted by Merck Research Laboratories between 1995 and 2004. Results: Montelukast was well tolerated in all studies. Clinical and laboratory adverse experiences for patients treated with montelukast were generally mild and transient. The most frequent clinical adverse events for all treatments (placebo, montelukast, active control/usual care) in virtually all studies were upper respiratory infection, worsening asthma, pharyngitis, and fever. Conclusion: The clinical and laboratory safety profile for montelukast was similar to that observed for placebo or active control/usual care therapies. The safety profile of montelukast did not change with long-term

We sought to identify predictors of asthma development following severe early childhood RSV bronchiolitis. Different definitions of asthma were also compared.This longitudinal, observational study (N = 343) followed patients (2 years old) from a placebo-controlled trial (N = 979) of montelukast after RSV bronchiolitis to identify clinical, demographic, or biochemical predictors of asthma, atopic disorders, and chronic asthma therapy use at 6 years of age (Clinical Trials Registry Number: NCT01140048). Asthma (primary definition) was based on parental identification of wheeze at 6 AND 12 months before 6 years of age; definitions based on physician diagnosis as well as parental identification of wheeze at 6 OR 12 months (to consider seasonal effect) were also assessed. Post-hoc analyses evaluated agreement among asthma diagnosis criteria.Prevalence of asthma (primary definition by parental identification), asthma (physician diagnosis), atopic disorders, and chronic asthma therapy use (parental identification) was 6.1%, 22.4%, 36.2%, and 14.5%, respectively. Predictors for asthma (primary definition) included male gender, a relative with asthma, and RAST positive for dog dander; for physician diagnosis of asthma, high severity score for RSV bronchiolitis, high respiratory rate, and asthma diagnosis before enrollment. Predictors of atopic disorders included allergic rhinitis before enrollment, a relative with asthma, and the plasma biomarkers IL-5, IL-16, and IL-18. Predictors of chronic asthma therapy use included asthma diagnosis before enrollment and geographic region (Europe and Africa). Only 42% of patients with asthma (primary definition) also met the asthma definition by physician diagnosis and chronic asthma therapy use.Among children with early RSV bronchiolitis, hereditary factors (i.e., having a relative with asthma) and RSV bronchiolitis severity were predictors of asthma and atopic disorders at 6 years of age. Of interest, there was poor agreement among the asthma definitions evaluated. Pediatr Pulmonol. 2016;51:1382-1392. © 2016 Wiley Periodicals, Inc.

Antileukotrienes and inhaled corticosteroids are asthma controller agents widely used in the treatment of pediatric asthma.To evaluate the effects of montelukast and beclomethasone on linear growth in prepubertal asthmatic children for 1 year.This was a 30-center study of boys (6.4-9.4 years old) and girls (6.4-8.4 years old) at Tanner stage I with mild, persistent asthma. After a placebo run-in period, 360 patients were randomized in equal ratios to double-blind, double-dummy treatment with 5 mg of montelukast, 200 microg of beclomethasone twice daily (positive control), or placebo for 56 weeks; 90% of the patients completed the study. The primary end point was linear growth velocity, measured using a stadiometer.Linear growth rates were similar between the montelukast and placebo groups; the mean difference for the year was 0.03 cm. The mean growth rate with beclomethasone was significantly less than with placebo (-0.78 cm) or montelukast (0.81 cm) (P.001 for both). Median percentage of days with beta-agonist use was greater with placebo (14.58%) vs montelukast (10.55%) or beclomethasone (6.65%) (P.05 for all). More patients used oral corticosteroid rescue with placebo (34.7%) than with montelukast (25.0%) or beclomethasone (23.5%). An imbalance in bone marker levels was seen with beclomethasone but not with montelukast.In prepubertal asthmatic children, montelukast did not affect linear growth, whereas the growth rate with beclomethasone was significantly decreased during 1 year of treatment.

Perennial allergic rhinitis (PAR) is a persistent allergic inflammation of the upper respiratory tract due to year-round allergen exposure.To evaluate the leukotriene receptor antagonist montelukast for the treatment of PAR.Protocol 265 was a 2-arm study performed during the winter. After a placebo run-in period, adults with perennial allergen sensitivity and active symptoms of PAR were randomized to receive 10 mg of montelukast (n=1002) or placebo (n=990) once daily during a 6-week, double-blind, active-treatment period. The primary end point was the daytime nasal symptoms score, defined as the average of scores for nasal congestion, rhinorrhea, and sneezing rated daily by patients.Statistically significant improvements in PAR symptoms were seen in patients treated with montelukast. Their daytime nasal symptoms scores were reduced during treatment compared with those of the placebo group: the difference between treatments in least squares mean change from baseline was -0.08 (95% confidence interval [CI], -0.12 to -0.04; P.001). Montelukast treatment also improved global evaluations of allergic rhinitis by patients and Rhinoconjunctivitis Quality of Life Questionnaire scores: differences vs the placebo group were -0.15 (95% CI, -0.27 to -0.04; P.01) and -0.15 (95% CI, -0.24 to -0.06; P.001), respectively. Other end points that showed statistically significant improvement with montelukast treatment were nighttime symptoms and each of the 4 nasal symptoms (congestion, rhinorrhea, sneezing, and itching). The treatment effects of montelukast were stable and persistent during the entire 6 weeks of treatment.Montelukast provided statistically significant relief of PAR symptoms during 6 weeks of treatment.

The purpose of this study was to determine the safety and tolerability profile of montelukast 4-mg oral granules compared with placebo in children aged 6-24 months with asthma.This was a randomized, double-blind, placebo-controlled, parallel-group study. Children 6-24 months of age at first visit with a history of at least three episodes of physician-diagnosed asthma or 'asthma-like' symptoms and in need of controller therapy were randomized to either montelukast 4-mg oral granules or placebo once daily in the evening for 6 weeks. The primary variables were the frequency of clinical and laboratory adverse experiences. The exploratory efficacy endpoints included days without beta-agonist use, beta-agonist use per day, unscheduled physician or hospital visits for asthma, oral corticosteroid rescues for asthma, asthma attacks, discontinuation due to worsening of asthma, and total blood peripheral eosinophil counts.The most common clinical adverse experiences were upper respiratory tract infection, asthma, fever, diarrhea, and vomiting occurring with similar frequencies between treatment groups. There were no clinically meaningful differences between the two treatment groups in clinical or laboratory adverse experiences and no significant differences in frequency of patients with elevated serum transaminases. Differences between the montelukast and placebo treatment groups in the exploratory efficacy endpoints of days without beta-agonist use, oral corticosteroid rescues, emergency care, asthma attacks, and discontinuations due to worsening asthma were not significant.Montelukast, 4-mg oral granules, was well tolerated over 6 weeks of treatment in children aged 6-24 months with asthma.

Objectives: Montelukast is a potent leukotriene receptor antagonist effective for treating asthma symptoms in adult and pediatric patients. The purpose of this analysis was to assess the clinical efficacy of montelukast, a potent leukotriene-receptor antagonist, in a subgroup analysis of patients aged 6 years-14 years with milder asthma, defined as a percentage predicted forced expiratory volume in 1 s (FEV 1 ) > 75% using data from a clinical trial of pediatric patients with a broad range of asthma severities. Research design and methods: The original previously published clinical trial was an 8-week multi-center, randomized, double-blind, parallel-group study conducted in 47 centers in the United States and Canada. The study compared the efficacy of once daily montelukast 5 mg to placebo in patients 6 years-14 years old with persistent asthma and an FEV 1 ranging from 50% to 85% of predicted. A total of 87 patients in the montelukast group and 51 patients in the placebo group were selected from the original cohort of 336 patients based on percentage predicted FEV 1 of > 75%. The primary endpoint was percentage change in FEV 1 from baseline compared with placebo over 8 weeks of active treatment. Results: Montelukast significantly improved the primary endpoint of percentage change in FEV 1 compared with placebo (p = 0.005). Other efficacy endpoints were significantly improved on montelukast similar to efficacy in the original study. Conclusion: Montelukast significantly improved FEV 1 , clinic measured peak expiratory flow (PEF), reduced nocturnal awakenings, and improved quality of life in children with milder persistent asthma defined as an FEV 1 > 75% of predicted.

Montelukast, a leukotriene receptor antagonist, has demonstrated efficacy and tolerability in the treatment of asthma in patients age 6 years and older. The purpose of this open, one-period, multicenter population pharmacokinetic study was to identify a chewable tablet (CT) dose of montelukast for administration to children ages 2 to 5 years with asthma, yielding a single-dose pharmacokinetic profile (area under the plasma concentration-time curve [AUC]) comparable to that of the 10 mg film-coated tablet (FCT) dose in adults. Because patient numbers were small and the volume of blood that could be collected from individual 2- to 5-year-old patients was limited, a population pharmacokinetic approach was used to estimate population AUC (AUCpop). The 4 mg CT dose of montelukast was well tolerated and yielded an AUCpop (2721 ng.h/mL) similar to that of the adult AUCpop (2595 ng.h/mL) observed after a 10 mg FCT dose. These results support the selection of a 4 mg once-daily CT dose of montelukast for future efficacy and safety studies in children ages 2 to 5 years with asthma.

Montelukast, a new leukotriene modifier, has several benefits in the treatment of asthma in adults and children including improved relief of asthma symptoms, rapid onset, a safety profile comparable with placebo, and oral, once-daily dosing means excellent adherence.

Objective Montelukast is a leukotriene receptor antagonist administered orally once daily for treatment of chronic asthma in adults and children. A comprehensive analysis of safety data from double-blind, randomized, placebo-controlled trials with montelukast has not been previously reported. Patients and methods A pooled analysis of safety data from 11 multicentre, randomized, controlled montelukast Phase IIb and III trials and five long-term extension studies was performed. A total of 3386 adult patients (aged 15-85 years) and 336 paediatric patients (aged 6-14 years) were enrolled in the trials; 2031 adults received montelukast for up to 4.1 years, and 257 children received montelukast for up to 1.8 years. Summary statistics comparing incidences of adverse events among treatment groups were calculated. Results The overall incidence of clinical and laboratory adverse events among montelukast-treated patients, both adult and paediatric, was similar to that among patients receiving placebo. There were no clinically relevant differences in individual adverse events, including infectious upper respiratory conditions and transaminase elevations, between montelukast and placebo groups. Discontinuations due to adverse events occurred with similar frequencies during placebo, montelukast and inhaled beclomethasone therapy. No dose-related adverse effects of montelukast were observed in adults treated with dosages as high as 200 mg per day (20 times the recommended dose) for 5 months. This tolerability profile montelukast observed in clinical trials has been generally reflected in the post-marketing safety experience seen to date. Conclusion These data indicate a tolerability profile for montelukast similar to placebo during both short-term and long-term administration, even at doses substantially higher than the recommended clinical dose of 10 mg once daily for adults and 5 mg once daily for children aged 6-14 years.

OBJECTIVE The Pediatric Asthma Diary was developed and validated to assess efficacy of interventions in children with asthma. DESIGN, PATIENTS, AND SETTING Diary validation was performed in a three week, prospective study of 106 children aged 6–14 years with asthma. Children were classified at baseline as either stable (requiring no additional asthma treatment) or new onset/worse (requiring either addition of or increase in anti-inflammatory treatment). RESULTS A daytime symptom scale and “day without asthma” were defined from diary questions. Both measures demonstrated significant validity and responsiveness to anti-inflammatory treatment. The stable group experienced a higher percentage of days without asthma during week 1 compared with the new onset/worse group (39.6% v 11.6%, respectively). The new onset/worse patients experienced significant improvement in days without asthma (24.5%) compared with stable patients (6.4%). CONCLUSIONS The Pediatric Asthma Diary daytime symptom scale and day without asthma are acceptable measures for use in asthma intervention studies of children aged 6–14 years.

Dennis E Doherty1, Donald P Tashkin2, Edward Kerwin3, Barbara A Knorr4, Tulin Shekar4, Sibabrata Banerjee4, Heribert Staudinger41Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kentucky, Lexington, KY, 2David Geffen School of Medicine at UCLA, Los Angeles, CA, 3Clinical Research Institute of Southern Oregon, Medford, OR, 4Merck Sharp & Dohme Corp, Whitehouse Station, NJ, USARationale: The purpose of this study was to investigate the clinical efficacy and safety of a fixed-dose combination of mometasone furoate/formoterol fumarate (MF/F) administered via a metered-dose inhaler in subjects with moderate-to-very severe chronic obstructive pulmonary disease (COPD).Methods: This multicenter, double-blind, placebo-controlled trial had a 26-week treatment period and a 26-week safety extension. Subjects (n = 1196), at least 40 years old, were current or ex-smokers randomized to twice-daily inhaled MF/F 400/10 µg, MF/F 200/10 µg, MF 400 µg, F 10 µg, or placebo. The trial’s co-primary endpoints were mean changes from baseline, as area under the curve (AUC), in forced expiratory volume (FEV1) over 0–12 hours (AUC0-12 h FEV1) with MF/F versus MF, and in morning (AM) pre-dose (trough) FEV1 with MF/F versus F after 13 weeks of treatment. Key secondary endpoints were the effects of MF/F on respiratory health status using the Saint George’s Respiratory Questionnaire (SGRQ), symptom-free nights, partly stable COPD at 26 weeks, and time to first COPD exacerbation.Results: The largest improvements in AUC0-12 h FEV1 were observed with MF/F 400/10 µg and MF/F 200/10 µg. Serial spirometry results demonstrated that bronchodilator effects with MF/F occurred rapidly (within 5 minutes), persisted for 12 hours after dosing, and were sustained over the 26-week treatment period. Similar findings were observed for AM pre-dose FEV1, for which effects were further investigated, excluding subjects whose AM FEV1 data were incorrectly collected after 2 days from the last dose of study treatment. Improvements in SGRQ scores surpassed the minimum clinically important difference of more than four units with both MF/F treatments. At 26 weeks, no notable between-treatment differences in the occurrence and nature of adverse events (AEs) were reported. No unexpected AEs were observed. Overall, 90 subjects reported AEs considered to be treatment-related, the most common of which were lenticular opacities, dysphonia, and oral candidiasis.Discussion: In conclusion, MF/F treatments improved lung function and respiratory health status, reduced exacerbations, and were well tolerated in subjects with moderate-to-very severe COPD.Keywords: COPD, FEV1, spirometry, exacerbation, inhaled corticosteroid, bronchodilator

Single-dose montelukast attenuates exercise-induced bronchoconstriction (EIB) in adults within 2 hours postdose and lasting through 24 hours. This study evaluated the onset and duration of EIB attenuation in children after a single dose of montelukast. A randomized, double-blind, placebo-controlled, two-period crossover study was performed. Patients (n = 66) aged 4-14 years, with preexercise forced expiratory volume in 1 second of (FEV(1)) ≥70% predicted and maximum percentage fall in FEV(1) of ≥20% at two screening exercise challenges were eligible. Patients were to receive single-dose montelukast (4 or 5 mg) or placebo before performing standardized exercise challenges at 2 and 24 hours postdose. A 3- to-7-day washout separated the two crossover periods. The primary end point was maximum percentage fall in FEV(1) after exercise challenge 2 hours postdose. Secondary end points included maximum percentage fall in FEV(1) after the 24-hour postdose challenge; each of the following at 2 and 24 hours postdose-maximum percentage fall in FEV(1) categorized as10%, 10-20%, or20%; area under the curve (AUC) during 60 minutes postchallenge; time to recovery of FEV(1) to within 5% of preexercise baseline; and need for rescue medication. The mean maximum percentage fall in FEV(1) after the 2-hour postdose exercise challenge was significantly attenuated after single-dose montelukast compared with placebo (15.35% versus 20.00%; p = 0.020). Montelukast was also significantly more effective than placebo for maximum percentage fall after the 24-hour challenge (12.92% versus 17.25%; p = 0.005), the categorized maximum percent fall in FEV(1) at 2 hours (p = 0.034), and AUC at 2 hours (p = 0.022) and 24 hours (p = 0.013). Single-dose montelukast provided rapid and sustained EIB attenuation in children. Clinicaltrials.gov identifier: NCT00534976.

Background No standard, optimal treatment exists for severe intermittent (ie, episodic) asthma in children. However, evidence suggests that both daily and episode-driven montelukast are effective for this phenotype. Objective To assess the regimen-related efficacy of montelukast in treating pediatric episodic asthma. Methods A multicenter, randomized, double-blind, double-dummy, parallel-group, 52-week study was performed in children 6 months to 5 years of age comparing placebo with two regimens of montelukast 4 mg: (1) daily; or (2) episode-driven for 12 days beginning with signs/symptoms consistent with imminent cold or breathing problem. The main outcome measure was the number of asthma episodes (symptoms requiring treatment) culminating in an asthma attack (symptoms requiring physician visit, emergency room visit, corticosteroids, or hospitalization). Results Five hundred eighty-nine patients were randomized to daily montelukast, 591 to intermittent montelukast, and 591 to placebo. Compared with placebo, no significant difference was seen between daily montelukast ( P = .510) or intermittent montelukast ( P = .884) in the number of asthma episodes culminating in an asthma attack over 1 year. Daily montelukast reduced symptoms over the 12-day treatment period of asthma episodes compared with placebo ( P = .045). Beta-agonist use was reduced with both daily ( P = .048) and intermittent montelukast ( P = .028) compared with placebo. However, because of prespecified rules for multiplicity adjustments (requiring a positive primary endpoint), statistical significance for secondary endpoints cannot be concluded. All treatments were well tolerated. Conclusions Montelukast did not reduce the number of asthma episodes culminating in an asthma attack over 1 year in children 6 months to 5 years of age, although numerical improvements occurred in some endpoints.

Summary Chronic obstructive pulmonary disease (COPD) is associated with neutrophil-mediated inflammation, a potential target for treatment in COPD. We evaluated MK-0633, a 5-lipoxygenase inhibitor in patients with COPD. This was a 12 week, randomized, double-blind, multicenter study comparing MK-0633 100 mg and placebo in patients 40–75 years of age ( N = 266) with COPD, post-β-agonist forced expiratory volume in 1 s (FEV 1 ) 25%–75% predicted, and an FEV 1 /forced vital capacity ratio (FVC) ≤70%. Long-acting inhaled bronchodilators were permitted for approximately 50% of patients. The primary efficacy endpoint was the change from baseline in pre-dose (trough) FEV 1 measured over the last 2 weeks of the 12 week treatment period. The change in FEV 1 over the last 2 weeks of the 12 weeks treatment period compared to baseline was 0.015 L for MK-0633 and 0.0002 for placebo ( p = 0.556). For COPD Global Evaluation, 75.4% of patients receiving MK-0633 reported feeling better vs. 59.8% of patients receiving placebo ( p = 0.032). There were no other significant differences between treatments. MK-0633 was well-tolerated and comparable to placebo. The 5-LO inhibitor MK-0633 was not significantly more effective than placebo in improving FEV 1 from baseline in patients with COPD, although more patients reported feeling improved with MK-0633. Clinicaltrials.gov identifier: NCT00418613.

PURPOSE: The primary objective of the studies was to demonstrate bioequivalence between the oral granules formulation and chewable tablet of montelukast in the fasted state. Effect of food on the pharmacokinetics of the oral granules was also evaluated. METHODS: The Formulation Biocomparison Study (Study 1) and the Final Market Image Study (Study 2) each used an open-label, randomized, 3-period crossover design where healthy adult subjects (N = 24 and 30, respectively) received montelukast as a single 4-mg dose of the oral granules formulation and a 4-mg chewable tablet fasted, and a single 4-mg dose of the oral granules formulation with food (on 2 teaspoons of applesauce [Study 1] or after consumption of a high-fat breakfast [Study 2]). The formulations were to be considered bioequivalent if the 90% confidence intervals (CIs) for geometric mean ratios (GMRs) (oral granules/chewable tablet) for the AUC(0-infinity) and C(max) of montelukast were within the prespecified comparability bounds of (0.80, 1.25). For the food-effect assessment in Study 1, comparability bounds were prespecified as (0.50, 2.00) only for the 90% CI of the GMR (oral granules fed/oral granules fasted) for the AUC(0-infinity) of montelukast; the 90% CI of the GMR for the C(max) of montelukast, however, also was computed. In Study 2, 90% CIs of the GMRs (oral granules fed/oral granules fasted) for the AUC(0-infinity) and C(max) of montelukast were computed; comparability bounds were not prespecified. RESULTS: Comparing the exposure of the formulations, the 90% CIs of the GMRs for AUC(0-infinity) and C(max) were within the prespecified bound of (0.80, 1.25). For AUC(0-infinity), the GMRs (90% CI) for Study 1 and Study 2 were 1.01 (0.92, 1.11) and 0.95 (0.91, 0.99), respectively. For C(max), respective values were 0.99 (0.86, 1.13) and 0.92 (0.84, 1.01). When the oral granules formulation was administered with food, 90% CIs of the GMRs for both AUC(0-infinity) and C(max) in both studies were contained within the interval of (0.50, 2.00). CONCLUSIONS: The 4-mg oral granules and 4-mg chewable tablet formulations of montelukast administered in the fasted state are bioequivalent. Single 4-mg doses of the oral granules formulation and the chewable tablet of montelukast are generally well tolerated.

Montelukast is a potent leukotriene-receptor antagonist administered once daily that provides clinical benefit in the treatment of asthma and allergic rhinitis in children and adults. Because of its wide use as a pediatric controller, there is a need for a further review of the safety and tolerability of montelukast in children.To summarize safety and tolerability data for montelukast from previously reported as well as from unpublished placebo-controlled, double-blind, pediatric studies and their active-controlled open-label extension/extended studies.These studies evaluated 2,751 pediatric patients 6 months to 14 years of age with persistent asthma, intermittent asthma associated with upper respiratory infection, or allergic rhinitis. These patients were enrolled in seven randomized, placebo-controlled, double-blind registration and post-registration studies and three active-controlled open-label extension/extended studies conducted by Merck Research Laboratories between 1995 and 2004.Montelukast was well tolerated in all studies. Clinical and laboratory adverse experiences for patients treated with montelukast were generally mild and transient. The most frequent clinical adverse events for all treatments (placebo, montelukast, active control/usual care) in virtually all studies were upper respiratory infection, worsening asthma, pharyngitis, and fever.The clinical and laboratory safety profile for montelukast was similar to that observed for placebo or active control/usual care therapies. The safety profile of montelukast did not change with long-term use.

Background Asthma exacerbations in young children are prevalent. Identification of symptoms or other factors that are precursors of asthma exacerbations would be useful for early treatment and prevention. Objectives To determine whether diary symptoms and β 2 -agonist use before an exacerbation could predict an asthma exacerbation in children 2 to 5 years of age. Methods Post hoc analyses were conducted on data collected in a study of 689 patients 2 to 5 years of age with asthma symptoms, randomly assigned to montelukast, 4 mg, or placebo daily for 12 weeks. During the study, 196 patients had an exacerbation. Caregiver-reported information (daytime cough, breathing difficulties, limitation of activity, nighttime cough or awakening, daytime and nighttime β 2 -agonist use) were analyzed using general estimating equations with an exchangeable within-subject log odds ratio regression structure to identify predictors of an exacerbation. Results Average symptom scores and β 2 -agonist use increased significantly before exacerbation but at different rates. A combination of daytime cough and wheeze and nighttime β 2 -agonist use 1 day before the exacerbation was identified as strongly predictive of an exacerbation. These methods predicted 149 (66.8%) of the exacerbations with a very low false-positive rate of 14.2%. Conclusions No individual symptom was predictive of an imminent asthma exacerbation, but a combination of increased daytime cough, daytime wheeze, and nighttime β 2 -agonist use 1 day before an asthma exacerbation was a strong predictor of an exacerbation in children.

Summary Background Phosphodiesterase-4 (PDE4) inhibitors have potential utility as a new therapeutic approach to improving symptoms and pulmonary function in asthma and COPD. This study evaluated the efficacy and safety of MK-0359, a selective and potent oral PDE4 inhibitor, in chronic asthma. Methods Adults ( N =88) with ≥1 year asthma history and an FEV 1 50–80% predicted were randomized to double-blind treatment with MK-0359 (15mg/day) or placebo for 14 days, then crossed-over to the other treatment for 14 days. The primary endpoint was the change from baseline in FEV 1 at the end of each 2-week treatment period. Secondary and other endpoints included the changes from baseline in Daytime asthma symptom score, Nighttime asthma symptom score, Total daily β-agonist use (puffs/day), AM and PM peak expiratory flow (PEF) and overall asthma-specific quality-of-life. Safety and tolerability were assessed by clinical adverse experiences. Results MK-0359 significantly improved the primary endpoint (versus placebo): the least-squares mean difference in change from baseline in FEV 1 (L) was 0.09L (95% CI 0.01, 0.18). Endpoints of Daytime asthma symptom score, Nighttime asthma symptom score, Total daily β-agonist use, AM PEF, PM PEF, and quality-of-life were also significantly improved. Nineteen patients (24.1%) on MK-0359 and 8 patients (10.4%) on placebo reported gastrointestinal clinical adverse experiences. Serious gastrointestinal clinical adverse experiences were reported in 3 patients while receiving MK-0359. Conclusion Over a 14-day treatment period, the oral PDE4 inhibitor MK-0359 improved lower airway function, symptoms and rescue medication use in chronic asthma, although at the expense of gastrointestinal adverse experiences. (Clinical trial registry number: NCT00482898.)

A pilot study (Bisgaard H; Study Group on Montelukast and Respiratory Syncytial Virus. A randomized trial of montelukast in respiratory syncytial virus postbronchiolitis. Am J Respir Crit Care Med 2003;167:379-383) reported the efficacy of montelukast in post-respiratory syncytial virus (RSV) bronchiolitic respiratory symptoms.To evaluate the efficacy and safety of montelukast, 4 and 8 mg, in treating recurrent respiratory symptoms of post-RSV bronchiolitis in children in a large, multicenter study.This was a double-blind study of 3- to 24-month-old children who had been hospitalized for a first or second episode of physician-diagnosed RSV bronchiolitis and who tested positive for RSV. Patients (n = 979) were randomized to placebo or to montelukast at 4 or 8 mg/day for 4 weeks (period I) and 20 weeks (period II). The primary end point was percentage symptom-free days (%SFD; day with no daytime cough, wheeze, and shortness of breath, and no nighttime cough).No significant differences were seen between montelukast and placebo in %SFD over period I: mean +/- SD for placebo and for montelukast at 4 and 8 mg were 37.0 +/- 30.7, 38.6 +/- 30.4, and 38.5 +/- 29.9, respectively. Least-squares mean differences (95% confidence interval) between montelukast (4 mg) and placebo and between montelukast (8 mg) and placebo were 1.9% (-2.9, 6.7) and 1.6% (-3.2, 6.5), respectively. Secondary end points were similar across treatments. Both doses were generally well tolerated. During the first two treatment weeks, average %SFD was approximately 29%. In post hoc analyses of patients (n = 523) with persistent symptoms (%SFDor = 30% over Weeks 1-2), differences in %SFD were seen between montelukast and placebo over Weeks 3-24: difference were 5.7 (0.0, 11.3) for montelukast (4 mg) minus placebo and 5.9 (0.1, 11.7) for montelukast (8 mg) minus placebo.In this study, montelukast did not improve respiratory symptoms of post-RSV bronchiolitis in children.

The single-dose pharmacokinetics of montelukast 4-mg oral granules and tolerability of daily administration of 2 different doses of montelukast (4 mg and 8 mg given once daily for 7 days) versus placebo were evaluated in 12 infants 1 to 3 months of age with bronchiolitis or a history of bronchiolitis and asthma-like symptoms. The population area under the concentration-time curve estimate after a single 4-mg dose of montelukast was 13 195.7 +/- 2309.8 (standard error) ng.hr/mL, 3.6 times higher than historical values in infants 3 to 24 months of age. Six patients had 10 total clinical adverse experiences; none was considered serious or drug related. Three patients had transient drug-related increases in aspartate aminotransferase (montelukast 8 mg [n = 2]; placebo [n = 1]). Despite increased systemic exposure after administration of a single dose of montelukast 4-mg oral granules in infants 1 to 3 months of age compared with that in pediatric patients 3 to 24 months of age, administration of montelukast at 4 and 8 mg once daily for 7 days in 1- to 3-month-old infants was generally well tolerated.

Background Inhaled corticosteroids and anti-leukotriene agents are widely used in the treatment of pediatric asthma. Although data on the effect of corticosteroids on growth are available, there are few such data on anti-leukotriene agents. The aim of this study was to assess the influence of montelukast on short-term lower leg growth rate (LLGR) in prepubertal children with asthma. Methods Forty-two boys (6- to 12-year old) and 29 girls (6- to 11-year old) with mild asthma were randomized to 1 of 2 crossover arms, with two treatment sequences per arm: montelukast 5 mg once daily/placebo or inhaled dry powder budesonide 200 µg twice daily/placebo. Budesonide was used as a positive control to ensure that the method was sensitive enough to detect a suppression of LLGR. The 3-week double-blind treatment period was followed by a 3-week washout. Primary outcome was LLGR over the 3-week treatment, measured by knemometry. Results Ninety-four percent of patients completed the study. Mean LLGR was similar between patients receiving montelukast and placebo treatments: mean difference, −0.02 mm/week [95% confidence interval −0.14, 0.11]. Mean LLGR in patients receiving budesonide was significantly less than for those receiving placebo (difference of −0.16 mm/week [−0.25, −0.06], P = 0.002). Mean LLGR was similar for patients taking placebo in the two arms (0.43 and 0.44 mm/week). Conclusion Montelukast 5 mg did not significantly affect short-term LLGR in prepubertal children. Pediatr Pulmonol. 2007; 42:838–843. © 2007 Wiley-Liss, Inc.

The purpose was to develop a population pharmacokinetic model for montelukast after intravenous administration. Clinical trial simulations were conducted using the model developed to identify the lowest intravenous dose in 6- to 14-year-old children that would give montelukast systemic exposures that were comparable to those found to be associated with efficacy in adults.Two clinical studies were conducted where montelukast was administered intravenously as a 7-mg dose to adults and as a 3.5-mg dose to children aged 6 to 14 years. Model development included defining the base pharmacostatistical model and investigating the effects of demographic variables [age and total body weight (TBW)] on the structural parameters, using a nonlinear mixed effect modeling approach.A linear three-compartment pharmacokinetic model was found to best describe the disposition of montelukast. Inclusion of TBW as a covariate caused a 35% and 63% decrease in the interindividual variabilities on clearance and central volume of distribution, respectively. Trial simulations suggested that a 5.25-mg intravenous dose of montelukast should be chosen in children aged 6 to 14 years.The model developed can adequately describe the intravenous pharmacokinetics of montelukast and can be used as a useful tool for dose selection in pediatric subpopulations.

Background: Limited clinical data are available on the long-term effects of asthma controller therapy on the utilization of health care resources in pediatric patients with asthma. Objective: The objective of this study was to compare the effects of long-term treatment with montelukast andusual care on health care resource use in children with asthma. Methods: Pediatric patients aged 2 to 5 years with asthma who had completed a 3-month, double-blind, double-dummyclinical trial comparing montelukast 4 mg and placebo were asked to participate in an open-label, controlled extension study comparing montelukast 4 mg and usual care. Usual care was defined as cromolyn or inhaled corticosteroid therapy Health care resource utilization was measured in terms of oral corticosteroid use and numbers of physician visits, emergency department visits, and hospitalizations. Results: Of 618 patients who completed the primary phase of the study, 516 (83.5%) participated in the extension study Data from 506 patients (302 without previous asthma maintenance therapy, 204 with) were included in the analysis. During the extension phase, patients who received montelukast and had not used previous asthma maintenance therapy were followed for a mean of 329.5 days; those who received usual care and Conclusion: In this open-label study, pediatric patients aged 2 to 5 years with mild to moderate persistentasthma receiving long-term therapy with montelukast had similar rates of asthma-related health care resource utilization compared with those receiving usual care with cromolyn or inhaled corticosteroids.

Background: Young children are generally not able to consistently and reliably perform tests of airway function, and normative values are not available. Reliable and valid measures of parental reporting of asthma symptoms and functioning are needed to determine the efficacy of asthma interventions. Objective: A pediatric asthma caregiver diary was developed and validated for use in interventional asthma studies. Methods: A 3-week prospective study of 125 caregiver parents and their children, aged 2 to 5 years, with persistent asthma was conducted. At baseline, children were classified as either stable (no change to anti-inflammatory therapy) or unstable (anti-inflammatory therapy added or increased). Results: A symptom scale and day without asthma symptoms (DWAS) were defined from pediatric asthma caregiver diary questions. The scale and DWAS statistically differentiated between the stable and unstable groups at week 1 and detected change between the 2 groups (P < .01). On average, caregivers reported low symptom scores. However, the frequency of DWAS was only 43% of days in the stable group and 22% in the unstable group. Conclusion: The pediatric asthma caregiver diary scale and DWAS have acceptable measurement characteristics for use in clinical trials of children with asthma symptoms. The DWAS indicates an opportunity for improvement in asthma control in this population. (J Allergy Clin Immunol 2000;106:861-6.)

Montelukast is a selective leukotriene receptor antagonist that has been shown to be effective in the treatment of chronic asthma. It is approved in more than 70 countries for patients 6 years of age and older. For adults (≥15 years of age), a 10-mg film-coated tablet (FCT) is available, and for children (aged 6 to 14 years), a 5-mg chewable tablet (CT) is available. The adult montelukast dose (10-mg FCT) was selected on the basis of classic dose-ranging studies as the lowest dose that produces maximal improvement in both measures of airway function and patient-reported outcomes in chronic asthma and in the attenuation of exercise-induced bronchoconstriction. The strategy used for the pediatric dose selection for montelukast was based on the determination of a CT dose that would provide an overall systemic exposure to montelukast in children similar to that in adults who receive a 10-mg FCT dose. Because montelukast was to be given chronically for the treatment of asthma, the area under the plasma concentration-time curve was considered to be the pharmacokinetic measurement that best represented systemic exposure to the drug. A 5-mg CT yielded a comparable single-dose area under the plasma concentration-time curve profile to that of the adult 10-mg FCT dose and, therefore, was selected as the pediatric dose for children aged 6 to 14 years with asthma. Subsequently, 2 studies of efficacy and tolerability validated the choice of the 5-mg CT dose. (J Allergy Clin Immunol 2000;106:S171-8.)

Montelukast, an oral leukotriene-receptor antagonist, has demonstrated efficacy and tolerability for the treatment of chronic asthma in adults. A once-daily 10 mg dose (film-coated tablet) was selected as the optimal adult dose based on dose-ranging studies. Asthma is a similar disease and is treated with the same medications in children and adults. These observations suggested that a dose of montelukast in children providing overall drug exposure (i.e., montelukast plasma concentrations) similar to that of the 10 mg film-coated tablet dose in adults would be efficacious, well tolerated, and obviate the need for separate dose-ranging studies in children. Therefore, the dose of montelukast for 6- to 14-year-old children was selected by identifying the chewable tablet dose of montelukast yielding a single-dose area under the plasma concentration-time curve (AUC) comparable to that achieved with the adult 10 mg film-coated tablet dose. Based on this approach, which included dose normalization of data from several pediatric pharmacokinetic studies, a 5 mg chewable tablet dose of montelukast was selected for use in clinical efficacy studies in 6- to 14-year-old children with asthma.

Objective: To determine whether montelukast, a leukotriene receptor antagonist, attenuates exercise-induced bronchoconstriction (EIB) in 6- to 14-year-old children with asthma. Study design: Double-blind, multicenter, 2-period crossover study. Children (n = 27) with forced expiratory volume in 1 second (FEV 1 ) ≥70% of the predicted value and a fall in FEV 1 ≥ 20% after exercise on 2 occasions. Patients received montelukast (5-mg chewable tablet) or placebo once daily in the evening for 2 days in crossover fashion (at least 4 days between treatment periods). Standardized exercise challenges were performed 20 to 24 hours after the last dose in each period. End points included area above the postexercise percent fall in FEV 1 versus time curve (AAC 0-60min ), maximum percent fall in FEV 1 from pre-exercise baseline, and time to recovery of FEV 1 to within 5% of pre-exercise baseline. Results: Montelukast significantly reduced AAC 0-60min (265 vs 590 % · min for montelukast and placebo, respectively, P ≤ .05; ~59% protection relative to placebo) and the maximum percent fall (18% vs 26% for montelukast and placebo, respectively, P ≤ .05). Montelukast treatment resulted in a shorter time to recovery (18 vs 28 minutes for montelukast and placebo, respectively, P = .079). Conclusions: Montelukast attenuates EIB at the end of the dosing interval in 6- to 14-year-old children with asthma. (J Pediatr 1998;133:424-8)

Classifying asthma severity or activity has evolved, but there are no published weighted composite measures of asthma disease activity that account for the relative importance of the many individual clinical variables that are widely used.We sought to develop a weighted and responsive measure of asthma disease activity.Discriminant and multiple regression analyses based on 2 previously conducted clinical trials were used to develop the Asthma Disease Activity Score (ADAS-6).The ADAS-6 demonstrated content validity because its components assess different manifestations of asthma: FEV(1) (percent predicted), Asthma Quality of Life Questionnaire-Symptom domain, rescue β-agonist use, nocturnal awakenings, peak expiratory flow diurnal variability, and rescue β-agonist use diurnal variability. The ADAS-6 demonstrated cross-sectional and longitudinal validity. It was discriminating: it distinguished levels of disease activity and response to different treatment intensities (P.0001). Similar results were obtained with an independent clinical trial. The ADAS-6 was highly responsive to treatment effects, with a standardized effect size exceeding that of other widely used outcome measures. Using ADAS-6 as the primary end point in the montelukast pivotal trials would have significantly reduced the sample size needed to detect a comparable change in outcome. Furthermore, increments in the ADAS-6 predicted the risk of future asthma attacks. A simplified Asthma Disease Activity Score 4-variable version (ADAS-4) demonstrated similar measurement properties.The ADAS-6 and ADAS-4 are novel, weighted, and responsive measures of asthma disease activity. Use of these measures in clinical trials might better separate treatment effects, predict future asthma attacks, and substantially reduce sample size.

Donald P Tashkin1, Dennis E Doherty2, Edward Kerwin3, Carlos E Matiz-Bueno4, Barbara Knorr5, Tulin Shekar5, Davis Gates5, Heribert Staudinger51David Geffen School of Medicine at UCLA, Los Angeles, CA, 2Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kentucky, Lexington, KY, 3Clinical Research Institute of Southern Oregon, Medford, OR, USA; 4Fundación Salud Bosque, Bogota, Colombia, 5Merck Sharp & Dohme Corp, Whitehouse Station, NJ, USABackground: The clinical efficacy and safety of a mometasone furoate/formoterol fumarate (MF/F) fixed-dose combination formulation administered via a metered-dose inhaler was investigated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD).Methods: Two 52-week, multicenter, double-blind, placebo-controlled trials with identical study designs were conducted in current or ex-smokers (aged ≥40 years), and pooled study results are presented herein. Subjects (n = 2251) were randomized to 26 weeks of twice-daily treatment with MF/F 400/10 µg, MF/F 200/10 µg, MF 400 µg, F 10 µg, or placebo. After the 26-week treatment period, placebo subjects completed the trial and 75% of subjects on active treatment entered a 26-week safety extension. Coprimary efficacy variables were mean changes in forced expiratory volume in one second (FEV1), area under the curve from 0 to 12 hours postdose (AUC0–12 h), and morning predose/trough FEV1 from baseline to the week 13 endpoint. Key secondary efficacy variables were St George’s Respiratory Questionnaire scores, symptom-free nights, time-to-first exacerbation, and partly stable COPD at the week 26 endpoint.Results: In the 26-week treatment period, significantly greater increases in FEV1 AUC0–12 h occurred with MF/F 400/10 versus MF 400 and placebo at the week 13 and week 26 endpoints (P ≤ 0.032). These increases were over three-fold greater with MF/F 400/10 than with MF 400. Also, significantly greater increases in morning predose/trough FEV1 occurred with MF/F 400/10 versus F 10 and placebo at the week 13 endpoint (P < 0.05). The increase was four-fold greater with MF/F 400/10 than with F 10. All active treatment groups achieved minimum clinically important differences from baseline (>4 units) in St George’s Respiratory Questionnaire scores at week 26. Symptom-free nights increased by ≥14% in the MF/F 400/10, MF 400, and F 10 groups (P ≤ 0.033 versus placebo). The incidence of exacerbations was lower in the MF/F groups (≤33.3%) than it was in the MF, formoterol, and placebo groups (≥33.8%) over the 26-week treatment period. The incidence of adverse events was similar in the active-treated and placebo-treated subjects across 26 weeks of treatment. Over the 1-year study period, there were no notable differences in the incidence or types of adverse events between the MF/F 400/10 and MF/F 200/10 groups compared with the MF or formoterol groups. Differences in rates of individual treatment-emergent adverse events were

Background In recent years, a number of drugs and drug classes have come under scrutiny by the US Food and Drug Administration regarding suicidality (including suicidal behavior and ideation). Objective We sought to perform 2 reviews (requested by the US Food and Drug Administration) of the number of events possibly related to suicidality reported in Merck clinical trials of montelukast. Methods Method 1 was a descriptive review of clinical adverse experiences (AEs) from 116 studies (double-blind and open-label, adult and pediatric, and single- and multiple-dose studies) completed as of March 2008. Summaries were constructed from investigator-reported AE terms possibly related to suicidality (completed suicide, suicide attempt, and suicidal ideation) or self-injurious behavior. Method 2 used a retrospective adjudication of investigator-reported AEs and other events listed in the study database described as possibly suicidality-related adverse events (PSRAEs) in a prespecified set of 41 double-blind, placebo-controlled trials completed as of April 2008. Results No completed suicides were reported in any study. For the descriptive review, 20,131 adults and children received montelukast, 9,287 received placebo, and 8,346 received active control; AEs possibly related to suicidality were rare and were similar between the montelukast and placebo or active-control groups. For the adjudicated review across 22,433 patients, there were 730 adjudicated events. In 9,929 patients taking montelukast, 1 PSRAE was identified (classified as suicidal ideation); none were identified in 7,780 and 4,724 patients taking placebo and active control, respectively. Conclusions Assessed by using 2 complementary methods, there were no reports of completed suicide, and reports of PSRAEs were rare in patients receiving montelukast and similar to those seen in control subjects.

Background Frequencies of behavior-related adverse experiences (BRAEs) in controlled clinical studies of leukotriene modifier drugs have not been summarized. Objective We sought to compare the frequency of BRAEs in patients receiving montelukast or placebo in a retrospective analysis of Merck clinical trial data. Methods An adverse experience database was constructed to include all double-blind, placebo-controlled trials of montelukast meeting prespecified criteria. BRAEs (described using the Medical Dictionary for Regulatory Activities controlled vocabulary dictionary) were prespecified to include any term in the Psychiatric Disorders System Organ Class, selected terms related to general disorders, and terms related to akathisia. Frequencies of BRAEs (overall, leading to study discontinuation, and/or serious) were summarized. Analyses estimated the odds ratios (ORs) for montelukast versus placebo based on the frequency of patients with BRAEs in each study. Results In total 35 adult and 11 pediatric placebo-controlled trials were included; 11,673 patients received montelukast, 8,827 received placebo, and 4,724 received active control. The frequency of patients with 1 or more BRAEs was 2.73% and 2.27% in the montelukast and placebo groups, respectively; the OR for montelukast versus placebo was 1.12 (95% CI, 0.93-1.36). The frequency of patients with a BRAE leading to study discontinuation was 0.07% and 0.11% in the montelukast and placebo groups, respectively (OR, 0.52; 95% CI, 0.17-1.51). The frequency of patients with a BRAE considered serious was 0.03% in both treatment groups. Conclusion Reports of BRAEs were infrequent in clinical trials of montelukast. Those leading to study discontinuation or considered serious were rare. Frequencies were similar regardless of treatment group.

Background Bronchiolitis is a common respiratory disease in young children. Evidence suggests CysLTs are involved in its pathophysiology and treatment with montelukast (MNT) may be beneficial. Since there are no MNT pharmacokinetic (PK) data in children aged 3–6 months, the single-dose population estimate of AUC(0-∞) (area under the concentration-time curve[AUCpop]), maximum plasma concentration[Cmax], and time to Cmax[Tmax] of MNT 4-mg oral granules were investigated. Data were compared to historical data in children aged 6–24 months. Methods 14 children aged 3–6 months with active bronchiolitis or a history of bronchiolitis with “asthma-like” symptoms had plasma samples obtained and assayed for MNT after a single, oral 4-mg dose of MNT granules. Due to sparse sampling, a population PK approach with a nonlinear mixed-effect, 1-compartment model with first order absorption and elimination was used to fit the data. Ninety-five (95) % confidence intervals (CIs) for the AUC pop ratio (3–6 months/6–24 months) were provided. Results MNT 4-mg oral granules, in children aged 3–6 months, yielded systemic exposure (AUCpop) (3644.3±481.5 ng•hr/mL) similar to that in children aged 6–24 months (3226.3± 250.0 ng•hr/mL), with an AUCpop ratio of 1.13[95% CI (0.83–1.55)]. Similarly, no clinically meaningful differences were seen for other PK parameters. Conclusion Systemic exposure after administration of 4-mg MNT oral granules is similar in children aged 3–6 months and 6–24 months. Clinical Pharmacology & Therapeutics (2005) 77, P39–P39; doi: 10.1016/j.clpt.2004.12.042