Susan Lu

Efficacy and tolerability of montelukast alone or in combination with loratadine in seasonal allergic rhinitis: a multicenter, randomized, double-blind, placebo-controlled trial performed in the fall.

BACKGROUND Histamine and cysteinyl leukotrienes seem to be important mediators of allergic rhinitis. OBJECTIVE This multicenter, randomized, double-blind, parallel-group, placebo-controlled trial evaluated the effectiveness and tolerability of montelukast, loratadine, and combination therapy with montelukast and loratadine for treating patients with fall seasonal allergic rhinitis. METHODS After a 1-week, single-blind, placebo run-in period, 907 male and female patients aged 15 to 82 years were randomized to 1 of 4 treatments: montelukast 10 mg (n = 155), loratadine 10 mg (n = 301), combination montelukast 10 mg and loratadine 10 mg (n = 302), or placebo (n = 149), administered once daily at bedtime for 2 weeks. The primary endpoint was the daytime nasal symptoms score (mean of congestion, rhinorrhea, pruritus, and sneezing). RESULTS Mean symptom scores at baseline were similar for the four treatment groups. For each of the three active treatments, the difference was significant for the mean change from baseline compared with placebo (P < or = 0.001). However, the effect of montelukast/loratadine compared with loratadine alone, the primary comparison, was not significantly different. Differences for each therapy alone compared with placebo were also significant for most secondary endpoints, including nighttime symptom scores, eye symptoms scores, and rhinitis-specific quality of life. Differences for montelukast/loratadine compared with each therapy alone generally showed numerical superiority, and a few endpoints showed differences that were statistically significant. All active treatments showed a safety profile generally similar to placebo. CONCLUSIONS Montelukast alone or in combination with loratadine is well tolerated and provides clinical and quality-of-life benefits for patients with seasonal allergic rhinitis.

Safety of house dust mite sublingual immunotherapy standardized quality tablet in children allergic to house dust mites

BACKGROUND Sublingual immunotherapy (SLIT) tablets could be an important alternative to subcutaneous immunotherapy for house dust mite (HDM) allergy in children. OBJECTIVE To characterize the safety, tolerability, and duration of local adverse events (AEs) of an HDM SLIT tablet (MK-8237; Merck, ALK Abellò, and Torii) in North American children 12 to 17 years old with HDM allergic rhinitis with and without conjunctivitis and with or without asthma. METHODS In this phase 1, multicenter, double-blinded, randomized trial (NCT01678807), children received placebo, HDM SLIT tablet 6 standardized quality (SQ) HDM, or 12 SQ-HDM once daily for 28 days. The primary end point was the proportion of subjects with treatment-emergent AEs receiving active treatment vs placebo. The secondary end point was the proportion of subjects who discontinued owing to AEs. RESULTS In total 195 subjects were randomized. The 2 HDM SLIT tablet doses were well tolerated. No anaphylactic reactions, systemic allergic reactions, AEs requiring epinephrine, serious AEs, or local swellings in the mouth or throat assessed as severe were reported. The proportion of subjects with treatment-emergent AEs was 54% with 6 SQ-HDM and 57% with 12 SQ-HDM (nonsignificant vs 43% with placebo). Local AEs were the most commonly reported treatment-emergent AEs. On day 1, the median duration of individual local AEs ranged from 1 to 43 minutes. The proportion of subjects who discontinued owing to AEs was 0%, 6.2%, and 6.2%, and who experienced treatment-related AEs was 25%, 45%, and 52% for the placebo, 6 SQ-HDM, and 12 SQ-HDM groups, respectively. CONCLUSION The 6 and 12 SQ-HDM doses of the HDM SLIT tablet MK-8237 were well tolerated, and local AEs were of short duration. TRIAL REGISTRATION ClinicalTrials.gov, identifier NCT01678807.

Quality assurance of asthma clinical trials

Accuracy and repeatability of spirometry measurements are essential to obtain reliable efficacy data in randomized asthma clinical trials. We report our experience with a centralized spirometry quality assurance program that we implemented in our phase III asthma trials. Six asthma trials of 4 to 21 weeks in duration were conducted at 232 clinical centers in 31 countries. Approximately 23,100 prebronchodilator and 13,700 postbronchodilator spirometry tests were collected from 2523 adult and 336 pediatric asthmatic patients. The program used a standard spirometer (the Renaissance spirometry system) with maneuver quality messages and automated quality grading of the spirometry tests. Each clinical center transmitted spirometry data weekly to a central database, where uniform monitoring of data quality was performed and feedback was provided in weekly quality reports. Seventy-nine percent of all patients performed spirometry sessions with quality that either met or exceeded American Thoracic Society standards and improved over time. Good-quality spirometry was associated with (1) less severe asthma; (2) active treatment; (3) infrequent nocturnal awakenings; (4) age above 15 years; and (5) low body weight. Maneuver-induced bronchospasm was rare. Good-quality spirometry was observed in multicenter asthma clinical trials that employed a standard spirometer and continuous monitoring. Both within- and between-patient variability decreased. Spirometry quality improved with time as study participants and technicians gained experience.

An oral selective M3 cholinergic receptor antagonist in COPD

Cholinergic antagonists have been used since the early 1900s as bronchodilators for chronic obstructive pulmonary disease (COPD). The present study investigated whether an oral muscarinic M3-selective anticholinergic agent (OrM3) would provide an improved therapeutic advantage compared with an inhaled anticholinergic agent in patients with COPD. A 6-week, multicentre, randomised, placebo- and active-controlled, parallel-group study was performed at 56 sites in the USA. In total, 412 male and female patients (aged 35–86 yrs) with a clinical history consistent with COPD were randomised to receive OrM3 0.5, 2, 3 or 4 mg orally once daily, ipratropium bromide 36 μg by inhalation four times daily or placebo. OrM3 demonstrated a significant dose-related improvement in serial forced expiratory volume in one second and a trend for dose-related improvement in patient-reported symptoms compared with placebo. However, at a dose that provided efficacy less than that of ipratropium, the incidence of dose-related, mechanism-based side-effects for OrM3 exceeded those observed for ipratropium. In patients with chronic obstructive pulmonary disease, the oral M3-selective agent did not offer a therapeutic advantage over inhaled ipratropium. These results do not support the hypothesis that high selectivity for muscarinic M3 receptors over airway neuronal M2 receptors will represent a more effective therapy than current inhaled anticholinergics in obstructive airway disease.

Clinical Studies of Combination Montelukast and Loratadine in Patients with Seasonal Allergic Rhinitis

Background. Concomitant use of montelukast and loratadine may improve symptoms of seasonal allergic rhinitis (SAR) more than treatment with either drug alone. Objective. We compared the efficacy of this combination versus placebo, nasal beclomethasone, montelukast, and loratadine in study 1 and versus placebo, montelukast, and loratadine in study 2. Methods. Patients were randomly allocated to double-blind treatment with intranasal beclomethasone 200 μ g/twice daily (study 1 only), placebo, montelukast 10 mg+loratadine 10 mg, montelukast 10 mg, or loratadine 10 mg once daily. The primary endpoint was the Composite Symptom Score (CSS): average of daily diary scores for Daytime Nasal Symptoms and Nighttime Symptoms. Results. In study 1, improvements in the change from baseline in CSS were seen for montelukast+loratadine (least-squares means [95% CI] = −0.43 [−0.51, −0.35]), beclomethasone (−0.57 [−0.64, −0.49]), montelukast, and loratadine. All treatments were significantly better than placebo; montelukast+loratadine had a significantly greater effect on CSS than montelukast alone but no difference compared to loratadine was detected. Beclomethasone provided significantly greater improvement versus montelukast+loratadine on the primary and secondary endpoints except for the rhinoconjunctivitis quality-of-life score. In study 2, the combination treatment was similar to montelukast, loratadine, and placebo for the primary and secondary endpoints. Conclusion. In study 1, montelukast+loratadine had a significantly greater effect on CSS than placebo and montelukast alone; however, in all comparisons, nasal beclomethasone had a greater effect on daily symptoms. In contrast, the combination of montelukast+loratadine in study 2 did not provide greater improvement compared with placebo, montelukast, or loratadine monotherapy, perhaps due to a large placebo effect.

Pharmacokinetics and Safety of Montelukast Oral Granules in Children 1 to 3 Months of Age With Bronchiolitis

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.

Predictors of asthma following severe respiratory syncytial virus (RSV) bronchiolitis in early childhood

We sought to identify predictors of asthma development following severe early childhood RSV bronchiolitis. Different definitions of asthma were also compared.

A Randomized Study Comparing the Effect of Loratadine Added to Montelukast with Montelukast, Loratadine, and Beclomethasone Monotherapies in Patients with Chronic Asthma

Background. Loratadine added to montelukast has been suggested to improve endpoints of asthma. Objective. This study investigated the additive effects of concomitant montelukast and loratadine when compared with montelukast, loratadine, and inhaled beclomethasone monotherapies in asthma. Methods. Patients (N = 406) were 15 to 65 years of age with a forced expiratory volume in 1 second (FEV1)-predicted of 50% to 85%, FEV1 reversibility ≥ 15%, and a minimal level of daytime symptoms and β -agonist use. This three-part 2X2 crossover-study consisted of two double-blind 6-week treatment periods where patients were administered once daily oral montelukast 10 mg, loratadine 10 mg, montelukast 10 mg + loratadine 10 mg, or twice daily inhaled beclomethasone 200 μ g. A subsequent 48-week extension study compared montelukast+loratadine with beclomethasone. The primary endpoint was the percentage change from baseline in FEV1. Results. Over 6 weeks of double-blind treatment, significant improvements (p < 0.05) in the primary endpoint of FEV1 were seen for montelukast+loratadine versus loratadine (least-square mean percentage-point difference of 5.8%), beclomethasone versus montelukast+loratadine (2.35%), montelukast versus loratadine (5.94%), and beclomethasone versus montelukast (4.65%); a numerical improvement (p = 0.054) was seen for montelukast+loratadine versus montelukast (1.60%). Significant improvements for montelukast+loratadine versus montelukast were seen in some secondary endpoints (evening peak expiratory flow, nocturnal asthma symptom score, nocturnal awakenings, and asthma-specific quality of life) but not others. Significant improvements in most endpoints except daytime asthma symptoms score were seen for montelukast+loratadine versus loratadine. In the extension study, both montelukast+loratadine and beclomethasone improved several endpoints. All treatments were generally comparable in the percentage of patients with clinical and laboratory adverse experiences. Conclusion. In this study, the addition of loratadine to montelukast produced a small numerical, but not statistically significant, improvement in FEV1 and, in general, no consistent improvement in other asthma endpoints. No improvement of montelukast+loratadine versus beclomethasone was seen in any endpoint.

Sublingual immunotherapy tablets as a disease-modifying add-on treatment option to pharmacotherapy for allergic rhinitis and asthma

ABSTRACT Allergic rhinitis (AR) with or without conjunctivitis (AR/C) is associated with a significant health and economic burden, and is often accompanied by asthma. Pharmacotherapies are the mainstay treatment options for AR and asthma, but guidelines also recommend allergy immunotherapy (AIT). Unlike pharmacotherapies, AIT has the ability to modify the underlying immunologic mechanisms of AR and asthma with the potential for long-term benefits after treatment is discontinued. Immunotherapy may also prevent progression of AR/C to asthma. Sublingual immunotherapy (SLIT)-tablets are a self-administered alternative to subcutaneous immunotherapy that provide the benefits of AIT without the cost and inconvenience of frequent office visits or the discomfort of injections. SLIT-tablets are also an option that can be utilized by primary care clinicians. Pharmacotherapies are generally effective in mild disease although a number of patients remain uncontrolled. SLIT-tablets have proven efficacy for AR in adults, children, and poly-sensitized allergic patients. Indirect comparisons indicate that SLIT-tablets have superior or comparable efficacy compared with traditional pharmacotherapies for seasonal AR, and superior efficacy for perennial AR. House dust mite (HDM) SLIT-tablets have also demonstrated clinically relevant benefits for asthma, with significant observed reductions in daily inhaled corticosteroid use, risk of asthma exacerbations, and asthma symptoms. SLIT-tablets are well tolerated, with minimal risk of systemic allergic reactions. The most common treatment-related adverse events are oral site reactions such as oral pruritus and throat irritation. Based on the favorable efficacy and safety profile, as well as the convenience of at-home oral administration and disease-modifying effects, SLIT-tablets should be considered as an alternative or add-on treatment to pharmacotherapy for AR/C, and as an add-on treatment for HDM allergic asthma.

Safety of fixed-dose loratadine/montelukast in subjects with allergic rhinitis

The safety of loratadine (second-generation antihistamine) and montelukast (leukotriene receptor antagonist) as monotherapies is well documented. Safety of the fixed-dose, single-tablet therapy loratadine/montelukast (L/M; SCH 445761, containing loratadine [10 mg]/montelukast [10 mg]), for treatment of the symptoms of allergic rhinitis in >3800 subjects is described. Safety data from 19 randomized clinical studies in which subjects were administered L/M are presented. Adverse events (AEs) were defined as any unfavorable and unintended sign, symptom, or laboratory data, including onset of new illness and exacerbation of preexisting conditions. Only AEs with an onset during the treatment period (i.e., treatment emergent) are summarized. Safety was also assessed via clinical laboratory evaluations and monitoring of vital signs and electrocardiogram (ECG). Overall, the incidence of AEs reported with L/M in the 19 studies was low and comparable with placebo, loratadine monotherapy, and montelukast monotherapy. The most frequently reported AE across all studies was headache. Most AEs were not severe and the duration of such events was short lived. Three AEs (headache [4.5%], fatigue [1.2%], and pharyngolaryngeal pain [1.2%]), regardless of relation to treatment, were reported by >1% of subjects in the L/M treatment group of multiple-dose, placebo-controlled studies. There were no clinically significant changes in clinical laboratory analyses or in vital signs, physical findings, or ECG found to be clinically relevant. Administration of the fixed-dose, single-tablet formulation of L/M was well tolerated. In these clinical studies, the safety of L/M was comparable with placebo, loratadine, and montelukast.