Meta-analyses of the efficacy of pharmacotherapies and sublingual allergy immunotherapy tablets for allergic rhinitis in adults and children.

BACKGROUND: Treatment options for seasonal and perennial allergic rhinitis (SAR/PAR) include pharmacotherapies and allergy immunotherapy. These meta-analyses evaluated the efficacy of pharmacotherapies and sublingual immunotherapy tablets (SLIT-tablets) versus placebo on nasal symptoms associated with SAR and PAR. METHODS: Randomized, double-blind, placebo-controlled trials were identified from systematic PubMED/EMBASE searches through 7/18/2019 (PROSPERO protocol CRD42018105632). The primary outcome was mean numerical difference in total nasal symptom score (TNSS; 0-12) between active treatment and placebo at the end of the assessment period. Random-effects meta-analyses estimated the mean difference for each medication group weighted by the inverse of the trial variance. Publication bias assessments and sensitivity analyses were conducted. RESULTS: Rescue symptom-relieving pharmacotherapy was prohibited in most pharmacotherapy trials but was allowed in all SLIT-tablet trials. For adult/adolescent SAR, the mean numerical difference (95% CI) in TNSS versus placebo was: intranasal corticosteroids (INCS)=1.38 (1.18, 1.58; 39 trials); combination intranasal antihistamine/INCS=1.34 (1.15, 1.54; 4 trials); intranasal antihistamines=0.72 (0.56, 0.89; 13 trials); oral antihistamine=0.62 (0.35, 0.90; 18 trials); SLIT-tablets=0.57 (0.41, 0.73; 4 trials); and montelukast=0.48 (0.36, 0.60; 10 trials). For adult/adolescent PAR, mean difference in TNSS versus placebo (95% CI) was: INCS=0.82 (0.66, 0.97; 14 trials); SLIT-tablets=0.65 (0.42, 0.88; 3 trials); and oral antihistamine=0.27 (0.11, 0.42; 3 trials). The number of eligible trials limited meta-analyses for pediatric SAR/PAR. CONCLUSIONS: All treatments significantly improved nasal symptoms versus placebo. SLIT-tablets provided improvement in TNSS despite access to rescue symptom-relieving pharmacotherapy. Extensive trial heterogeneity and strong indications of publication bias preclude the comparison of treatment effects among treatment classes.

Roflumilast for asthma: Safety findings from a pooled analysis of ten clinical studies.

BACKGROUND: The safety profile of roflumilast, a phosphodiesterase 4 inhibitor, has been extensively researched in patients with chronic obstructive pulmonary disease (COPD). Adverse events (AEs) including headache, diarrhoea and weight loss have been reported. Much less is known about the safety of roflumilast treatment in patients with bronchial asthma. AIM: To evaluate the safety and tolerability of roflumilast using safety data from one open-label and ten pooled placebo-controlled phase II and III clinical studies completed between 1997 and 2005. SUBJECTS AND METHODS: The studies were conducted at sites in Europe, North and South America, Africa, Australasia and Asia and study length varied from 4 to 40 weeks. Data for 5169 patients between 12 and 70 years of age, of whom 2851 received roflumilast at doses of 125, 250 and 500 µg, were analyzed. At randomization patients had a forced expiratory flow of 45-100%. RESULTS: Headache was the most frequent AE with an incidence rate of 50 and 29.2 per 100 patient-years in the 500 µg roflumilast and placebo groups, respectively. Gastrointestinal AEs were common. Nausea and diarrhoea occurred in 28.7 and 28.3 per 100 patient-years in the 500 µg roflumilast and placebo groups, respectively. The extent of weight loss in roflumilast-treated patients was small. AEs reported in 465 patients in the 4-week open-label follow-up study reflected those of the pooled studies. CONCLUSIONS: The severity and incidence of AEs reported from this pooled safety analysis confirm that roflumilast is generally well tolerated by patients with asthma. This reflects the general safety profile reported previously in patients with COPD. All studies were funded by Takeda. Trial registration numbers available on ClinicalTrials.gov: NCT00073177, NCT00076076, NCT00163527.

Roflumilast for asthma: Efficacy findings in placebo-controlled studies.

BACKGROUND: The role of roflumilast as a potential asthma treatment is not yet fully understood. A series of placebo-controlled trials were undertaken in order to investigate the safety and efficacy of roflumilast in asthma. AIM: To evaluate the efficacy of roflumilast in nine randomized proof-of-concept, placebo-controlled monotherapy and combination therapy phase II and III clinical studies performed between 1997 and 2005. METHODS: The studies were conducted at sites in Europe, North and South America, Africa, Australasia and Asia and study length varied from 4 to 24 weeks. Data were analyzed from 4873 patients, 12-70 years of age, of whom 2668 received roflumilast. At randomization patients had a forced expiratory flow (FEV1) of 45-90%. Roflumilast was investigated at doses of 125, 250 and 500 µg versus placebo. In two studies, 500 µg roflumilast was added on top of standard therapy with inhaled corticosteroids (ICS), 250 µg fluticasone propionate, or 400 µg beclomethasone dipropionate (BDP). Improvement in FEV1 from baseline was the primary endpoint in seven studies. Key secondary endpoints included asthma symptom scores and time to first severe exacerbation. RESULTS: Roflumilast consistently improved FEV1 across the nine studies compared with placebo, reaching statistical significance in three studies. When given in addition to ICS, roflumilast provided additional improvements in FEV1 which was statistically significant for 500 µg roflumilast/400 µg BDP versus placebo/400 µg BDP. CONCLUSION: Together these studies show that roflumilast has potential as an effective anti-inflammatory therapy for the treatment of asthma. Additional beneficial effects are observed when given in combination with ICS, which warrant further investigation. All studies were funded by Takeda. Trial registration numbers available on ClinicalTrials.gov: NCT00073177, NCT00076076, NCT00163527.

Clinical development of an advanced intranasal delivery system of azelastine hydrochloride and fluticasone propionate.

There is no shortage of pharmacologic treatments available for the management of allergic rhinitis (AR), but none regularly provide full relief from all symptoms. MP29-02 (Dymista®) is a novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP), benefiting from an enhanced formulation and improved device characteristics compared to marketed intranasal corticosteroid (INS) formulations. Results from large, randomized, double-blind, placebo-controlled, head-to-head trials versus first-line therapies, confirmed MP29-02 as the evidence-based drug-of-choice for AR treatment. MP29-02 was twice as effective as AZE or FP for nasal and ocular symptom relief in moderate to severe seasonal AR patients, with superiority documented regardless of season, and in more severe patients. More MP29-02-treated patients experienced clinically relevant responses (i.e., halving of nasal symptom burden and complete/near-to-complete relief) days faster than those on INS or intranasal antihistamine monotherapy. MP29-02's efficacy was sustained long-term versus FP (up to 52 weeks) in chronic rhinitis patients (perennial AR or nonallergic rhinitis), with 7 out of 10 patients first becoming symptom-free following 1 month's treatment with MP29-02, and days faster than with the INS. These results confirm MP29-02's superiority over the historical gold-standard therapy for AR (i.e., INS), and position it now as first-line treatment for moderate to severe AR patients, the majority of whom are uncontrolled on existing medications.

Mometasone furoate/formoterol reduces asthma deteriorations and improves lung function.

This study evaluated the effect of mometasone furoate (MF)/formoterol (F) versus its monocomponents, each administered via metered-dose inhaler, on asthma deteriorations and lung function. This 26-week, multicentre, double-blind, placebo-controlled study included subjects aged ≥12 yrs with not well-controlled asthma on low-dose inhaled corticosteroids. After a 2-3-week open-label run-in (MF 100 µg b.i.d.), 746 subjects were randomised to receive placebo, F 10 µg, MF 100 µg or MF/F 100/10 µg b.i.d. Co-primary end-points were time to first asthma deterioration (MF/F versus F to assess effect of MF) and change in forced expiratory volume in 1 s (FEV(1)) area under the curve of serial spirometry measurements over the 12-h period following the morning dose (AUC(0-12h)) (baseline to week 12; MF/F versus MF to assess effect of F). The therapeutic effect of MF in the combination was demonstrated by a reduction in asthma deterioration incidence with MF/F versus F and a delayed time to first asthma deterioration (p<0.001). Asthma deterioration incidence was also reduced with MF/F versus MF (p=0.006). The therapeutic effect of F in the combination was demonstrated by MF/F versus MF in FEV(1) AUC(0-12h) change (4.00 versus 2.53 L·h, respectively; p=0.001). MF/F treatment also resulted in a marked improvement in health-related quality of life. MF/F 100/10 µg b.i.d. treatment showed greater clinical efficacy than its individual components or placebo; both components contributed to the efficacy of MF/F.

Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications.

Intranasal corticosteroids (INSs) are effective treatments for allergic rhinitis, rhinosinusitis, and nasal polyposis. In recent years, increased understanding of corticosteroid and glucocorticoid receptor pharmacology has enabled the development of molecules designed specifically to achieve potent, localized activity with minimal risk of systemic exposure. Pharmacologic potency studies using affinity and other assessments have produced similar rank orders of potency, with the most potent being mometasone furoate, fluticasone propionate, and its modification, fluticasone furoate. The furoate and propionate ester side chains render these agents highly lipophilic, which may facilitate their absorption through nasal mucosa and uptake across phospholipid cell membranes. These compounds demonstrate negligible systemic absorption. Systemic absorption rates are higher among the older corticosteroids (flunisolide, beclomethasone dipropionate, triamcinolone acetonide, and budesonide), which have bioavailabilities in the range of 34-49%. Studies, including 1-year studies with mometasone furoate, fluticasone propionate, and budesonide that evaluated potential systemic effects of INSs in children have generally found no adverse effects on hypothalamic-pituitary-adrenal axis function or growth. Clinical data suggest no significant differences in efficacy between the INSs. Theoretically, newer agents with lower systemic availability may be preferable, and may come closer to the pharmacokinetic/pharmacologic criteria for the ideal therapeutic choice.

Pill swallowing ability and training in children 6 to 11 years of age.

Despite the widespread view that children have difficulty swallowing pills, data are limited. In an observational cohort study, pill swallowing ability (small oral tablet) was assessed in children age 6 to 11 years. A total of 113 of 124 subjects (91%) swallowed a tablet using an ordinary cup or a patented pill cup. All 57 subjects who initially said they could swallow a pill were capable. Forty-seven learned with an ordinary cup and nine with the pill cup. Eleven did not learn. The majority of children (91%) age 6 to 11 years were able to successfully swallow a small oral tablet.

Pharmacologic and anti-IgE treatment of allergic rhinitis ARIA update (in collaboration with GA2LEN).

The pharmacologic treatment of allergic rhinitis proposed by ARIA is an evidence-based and step-wise approach based on the classification of the symptoms. The ARIA workshop, held in December 1999, published a report in 2001 and new information has subsequently been published. The initial ARIA document lacked some important information on several issues. This document updates the ARIA sections on the pharmacologic and anti-IgE treatments of allergic rhinitis. Literature published between January 2000 and December 2004 has been included. Only a few studies assessing nasal and non-nasal symptoms are presented as these will be discussed in a separate document.

Nasal allergies and beyond: a clinical review of the pharmacology, efficacy, and safety of mometasone furoate.

Mometasone furoate nasal spray (MFNS; Nasonex, Schering-Plough Corporation, Kenilworth, NJ, USA) is an effective and well-tolerated intranasal corticosteroid approved for the prophylactic treatment of seasonal allergic rhinitis, and the treatment of perennial allergic rhinitis. MFNS is a potent molecule with a rapid onset of action and excellent safety and efficacy profiles. Having recently received approval for the treatment of nasal polyposis, data indicate that MFNS may also be effective in rhinosinusitis.

Montelukast improves symptoms of seasonal allergic rhinitis over a 4-week treatment period.

BACKGROUND: Proinflammatory mediators such as the cysteinyl leukotrienes are important in the pathophysiology of allergic rhinitis. This study evaluated the efficacy and tolerability of montelukast, a cysteinyl leukotriene receptor antagonist, given once daily in the morning for treatment of seasonal (fall) allergic rhinitis for 4 weeks. METHODS: This was a randomized, double-blind trial with a placebo run-in and a 4-week treatment period. Patients (n = 1079) with a history of allergic rhinitis and a positive skin test to seasonal pollen allergens were assigned to placebo, montelukast 10 mg, or loratadine 10 mg. Symptoms were assessed with a daily diary. RESULTS: Montelukast was more effective than placebo in improving scores for the primary endpoint of daytime nasal symptoms (P = 0.003) and the secondary endpoints of night-time, composite, and daytime eye symptoms, patient's and physician's global evaluations of allergic rhinitis, and rhinoconjunctivitis quality-of-life (P

Quality of life in adults and children with allergic rhinitis.

Quality of life, when referring to an individual's health, is called health-related quality of life (HRQL). HRQL focuses on patients' perceptions of their disease and measures impairments that have significant impact on the patient. Similar symptoms may vary in their effect on different individuals; the goal of therapy should be to reduce impairments that patients consider important. HRQL can be measured with generic or specific questionnaires. Specific questionnaires may be more sensitive and are much more likely to detect clinically important changes in patients' impairments. Specific questionnaires used to assess HRQL in rhinitis are the Rhinoconjunctivitis Quality of Life Questionnaire, the Adolescent Rhinoconjunctivitis Quality of Life Questionnaire, and the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire. HRQL issues in adult rhinitis patients include fatigue, decrease in energy, general health perception, and social function; impairment of HQRL generally increases with increasing degree of symptoms and severity of disease. In children, HRQL issues include learning impairment, inability to integrate with peers, anxiety, and family dysfunction. Comorbid disorders often associated with rhinitis, including sinusitis, otitis media, and frequent respiratory infections, can further compromise HRQL. Pharmacologic treatments can have both positive and negative effects on HRQL. Agents that have troublesome adverse effects such as sedation can have a negative impact, whereas nonsedating antihistamines and intranasal cortico-steroids can significantly improve HRQL in patients of all ages with rhinitis.

Safety of fexofenadine in children treated for seasonal allergic rhinitis.

BACKGROUND: The incidence of allergic rhinitis in children is increasing. OBJECTIVE: To evaluate the safety of fexofenadine HCI in children ages 6 through 11 years for treatment of seasonal allergic rhinitis. METHODS: Two large, double-blind, randomized, placebo-controlled, parallel studies with identical protocols included patients with a positive skin test to fall allergen(s) and allergic rhinitis symptoms. Patients were randomized to receive fexofenadine 15, 30, or 60 mg or placebo twice daily for 2 weeks after a 1-week placebo lead-in. Safety was evaluated through adverse event reporting, electrocardiograms, and pre- and posttreatment laboratory panels and physical examinations. RESULTS: A total of 875 patients from both studies were eligible for safety analyses. Ten patients (5 on placebo, 5 on fexofenadine) discontinued because of an adverse event; no event that resulted in discontinuation was judged to be caused by study medication. Incidence of adverse events was similar in active and placebo groups, and did not increase with increasing fexofenadine dose: 36.2% (83 of 229) in the placebo group versus 35.3% (79 of 224), 36.8% (77 of 209), and 34.7% (74 of 213) in the 15, 30, and 60 mg twice-daily fexofenadine groups, respectively. Headache was the most commonly reported adverse event (6.6%, 8.0%, 7.2%, and 9.4% in the placebo, 15, 30, 60 mg twice-daily fexofenadine groups, respectively). Clinical, vital sign, electrocardiogram, and laboratory measures were similar in active and placebo groups. There was no statistically significant mean change from baseline in any electrocardiogram parameter after fexofenadine treatment. CONCLUSIONS: Fexofenadine, 15, 30, and 60 mg twice daily, was safe and well tolerated in this large pediatric patient population.

Onset of therapeutic effect of fluticasone propionate aqueous nasal spray.

BACKGROUND: The effectiveness of fluticasone propionate (FP) aqueous nasal spray in the treatment of rhinitis has been demonstrated in multiple controlled clinical studies. The onset of therapeutic effect of FP in these clinical trials appears to occur within 12 hours after administration of the initial dose. OBJECTIVE: This article presents an analysis from previous clinical trials that examined the efficacy of intranasal FP in patients with rhinitis to ascertain whether the time to onset of the therapeutic effect of this medication could be determined. METHODS: Completed randomized, double-blind, placebo-controlled studies with FP were evaluated to determine whether onset of effect could be evaluated based on the study designs. A study was deemed acceptable for evaluation of onset of effect if at least one evaluation of the intensity of nasal symptoms was completed within 12 hours after the initial dose of study medication and daily evaluations were made thereafter. Adult patients were included in the onset analysis if they received an initial FP dose of 200 microg. Pediatric patients who received an initial FP dose of 100 microg were also included. Onset of effect was evaluated by 1) examining the timepoints at which statistically significant differences were observed between FP and placebo in mean change from baseline for total nasal symptom score (TNSS); and by 2) using a binary probability model of success/failure to determine statistically significant differences from placebo. RESULTS: Twenty-two studies met the criteria to evaluate onset of therapeutic effect; 3,605 patients with rhinitis received FP and 2,271 patients received placebo. This database represents the largest compilation of data ever assembled to determine the onset of therapeutic effect of a corticosteroid nasal spray. Two studies used a "park design" to examine onset of effect; statistically significant differences in TNSS favoring FP were achieved at hours 2 to 4 and at hour 12, respectively. Using a binary probability model of success/failure for analysis of TNSS in the remaining 20 studies not specifically designed to evaluate onset of effect, numerically greater improvements in TNSS for FP compared with placebo were found in 19 of the 20 studies within 12 hours of the administration of the first dose (P < .001). Pairwise comparisons showed statistically significant improvement for TNSS within 12 hours postdose in five of the studies for FP compared with placebo and in none for placebo compared with FP. CONCLUSIONS: Onset of therapeutic effect occurs within 12 hours, and as early as 2 to 4 hours in some patients, after administration of the first dose of FP aqueous nasal spray.

Desloratadine: A new, nonsedating, oral antihistamine.

Desloratadine is a new, selective, H(1)-receptor antagonist that also has anti-inflammatory activity. In vitro studies have shown that desloratadine inhibits the release or generation of multiple inflammatory mediators, including IL-4, IL-6, IL-8, IL-13, PGD(2), leukotriene C(4), tryptase, histamine, and the TNF-alpha-induced chemokine RANTES. Desloratadine also inhibits the induction of cell adhesion molecules, plateletactivating factor-induced eosinophil chemotaxis, TNF-alpha-induced eosinophil adhesion, and spontaneous and phorbol myristate acetate-induced superoxide generation in vitro. In animals desloratadine had no effect on the central nervous, cardiovascular, renal, or gastrointestinal systems. Desloratadine is rapidly absorbed, has dose-proportional pharmacokinetics, and has a half-life of 27 hours. The absorption of desloratadine is not affected by food, and the metabolism and elimination are not significantly affected by the subject's age, race, or sex. There are no clinically relevant interactions between desloratadine and erythromycin, ketoconazole, or grapefruit juice. Desloratadine is not a significant substrate of the P-glycoprotein transport system. Once daily administration of desloratadine rapidly reduces the nasal and nonnasal symptoms of seasonal allergic rhinitis, including congestion. In patients with seasonal allergic rhinitis and concomitant asthma, desloratadine treatment was also associated with significant reductions in total asthma symptom score and use of inhaled beta(2)-agonists. Use of desloratadine in patients with chronic idiopathic urticaria was associated with significant reductions in pruritus, number of hives, size of the largest hive, and interference with sleep and daily activities. Clinical experience in over 2300 patients has shown that the adverse event profile of desloratadine is similar to that of placebo; desloratadine has no clinically relevant effects on electrocardiographic parameters, does not impair wakefulness or psychomotor performance, and does not exacerbate the psychomotor impairment associated with alcohol use.

Increasing asthma knowledge and changing home environments for Latino families with asthmatic children.

We tested an asthma education program in 204 underserved Latino families with an asthmatic child. The education program consisted of one or two sessions delivered in each family's home in the targeted participant's preferred language by a bilingual, bicultural educator. We encouraged, but did not require, attendance by the child. The curriculum was culturally-tailored, and all participants received education on understanding asthma, preventing asthma attacks, and managing asthma. Outcomes included change in asthma knowledge and change in home environment asthma management procedures. Asthma knowledge increased significantly (39 to 50% correct from pre- to post-test, P < 0.001) and participants made significant changes to the child's bedroom environment (mean number of triggers decreased from 2.4 to 1.8, P < 0.001; mean number of controllers increased from 0.7 to 0.9, P < 0.001). The results support the value of asthma education and its importance in the national agenda to reduce health disparities among minorities.

Quality of life in patients with allergic rhinitis.

LEARNING OBJECTIVES: Reading this article will familiarize the practitioner with ongoing efforts to measure the effects of allergic rhinitis symptoms and its treatments on the health-related quality of life (HRQOL) of patients. The reader will learn about instruments used to collect HRQOL data, results of studies showing the burden of illness and the effects of treatments on HRQOL, and efforts to interpret the clinical relevance of changes in HRQOL status. DATA SOURCES: Information was gleaned from articles listed in MEDLINE regarding HRQOL in allergic rhinitis between 1966 and 2000 (English language only), and from the personal experiences of the authors. STUDY SELECTION: Questionnaire validation studies and representative controlled trials employing measures to assess the effects of allergic rhinitis symptoms and its treatments on HRQOL are described. RESULTS FROM THIS REVIEW: Allergic rhinitis symptoms can have detrimental effects on the physical, psychologic, and social aspects of patients' lives. Clinical trial data suggest a variety of pharmacologic therapies can significantly improve HRQOL in patients with allergic rhinitis. Validated questionnaires are now available that can easily be used in clinical practice to measure the effects of interventions on HRQOL for individual patients. CONCLUSIONS: Evaluating the effects of interventions on HRQOL may be particularly important in a non-life-threatening condition such as rhinitis. Health-related quality of life measures can be used to indicate the risk/benefit and the cost/benefit ratios of competing treatment options. Clinicians and policy makers are already using HRQOL data to evaluate results of medical interventions to guide patient management and reimbursement decisions.

Added relief in the treatment of acute recurrent sinusitis with adjunctive mometasone furoate nasal spray. The Nasonex Sinusitis Group.

BACKGROUND: Intranasal glucocorticoids are effective in the treatment of allergic rhinitis. Their effectiveness as an anti-inflammatory adjunct in the treatment of acute recurrent sinusitis has not been adequately established in a controlled clinical study. OBJECTIVE: The purpose of this study was to test the hypothesis that intranasal corticosteroid treatment produces additional relief in the treatment of acute sinusitis with oral antibiotics. METHODS: Patients who were 12 years old and older with a history of recurrent sinusitis were treated while experiencing a new episode of acute sinusitis, which was diagnosed by symptoms and confirmed by computed tomography scan of the paranasal sinuses. Patients were treated for 21 days with amoxicillin clavulanate potassium and randomized to receive concurrent mometasone furoate nasal spray (MFNS; Nasonex [400 microg, twice daily]; n = 200 patients) or placebo spray (twice daily; n = 207 patients). Symptom scores for headache, facial pain, congestion, purulent rhinorrhea, postnasal drip, and cough were recorded at baseline and throughout treatment. RESULTS: Baseline symptom scores showed a moderate level of symptom severity comparable in both groups. Patient-recorded twice daily symptom scores showed that adjunctive treatment with MFNS caused a significantly greater decrease in total symptom score (primary efficacy variable) and in individual scores of inflammatory symptoms associated with the obstruction process (headache, congestion, and facial pain) compared with placebo. Symptoms associated with the secretory processes were improved to a lesser degree. Therapy-related local adverse events were not significantly different between groups. CONCLUSION: The addition of intranasal corticosteroid, MFNS 400 microg twice daily, to antibiotics significantly reduces symptoms of acute sinusitis compared with antibiotic treatment alone.