Safety of a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate in children: A randomized clinical trial.

BACKGROUND: The safety of a novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP) has been established in adults and adolescents with allergic rhinitis but not in children <12 years old. OBJECTIVE: To evaluate the safety and tolerability of an intranasal formulation of AZE and FP in children ages 4-11 years with allergic rhinitis. METHODS: The study was a randomized, 3-month, parallel-group, open-label design. Qualified patients were randomized in a 3:1 ratio to AZE/FP (n = 304) or fluticasone propionate (FP) (n = 101), one spray per nostril twice daily, and to one of three age groups: ≥4 to <6 years, ≥6 to <9 years, and ≥9 to <12 years. Safety was assessed by child- or caregiver-reported adverse events, nasal examinations, vital signs, and laboratory assessments. RESULTS: The incidence of treatment-related adverse events (TRAEs) was low in both the AZE/FP (16%) and FP-only (12%) groups after 90 days' continuous use. Epistaxis was the most frequently reported TRAE in both groups (AZE/FP, 9%; FP, 9%), followed by headache (AZE/FP, 3%; FP, 1%). All other TRAEs in the AZE/FP group were reported by ≤1% of the children. The majority of TRAEs were of mild intensity and resolved spontaneously. Results of nasal examinations showed an improvement over time in both groups, with no cases of mucosal ulceration or nasal septal perforation. There were no unusual or unexpected changes in laboratory parameters or vital signs. CONCLUSION: The intranasal formulation of AZE and FP was safe and well tolerated after 3 months' continuous use in children with allergic rhinitis.The study was registered on ClinicalTrials.gov (NCT01794741).

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.

Intranasal triamcinolone and growth velocity.

BACKGROUND: Inadequate designs and conflicting results from previous studies prompted the US Food and Drug Administration to publish guidelines for the design of clinical trials evaluating the effects of orally inhaled and intranasal corticosteroids on the growth of children. This study conformed to these guidelines to evaluate the effect of triamcinolone acetonide aqueous nasal spray (TAA-AQ) on the growth of children with perennial allergic rhinitis (PAR). METHODS: This randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluated the effect of once-daily TAA-AQ (110 µg) on the growth velocity (GV) of children aged 3-9 years with PAR by using stadiometry at baseline (4-6 months), during treatment (12 months), and at follow-up (2 months). Hypothalamus-pituitary-adrenal (HPA) axis function was assessed by measuring urinary cortisol levels. Details of adverse events were recorded. RESULTS: Of 1078 subjects screened, 299 were randomized, and 216 completed the study (placebo, 107; TAA-AQ, 109). In the primary analysis (modified intent-to-treat: placebo, 133; TAA-AQ, 134), least-squares mean GV during treatment was lower in the TAA-AQ group (5.65 cm/year) versus placebo (6.09 cm/year). The difference (-0.45 cm/year; 95% confidence interval: -0.78 to -0.11; P = .01), although clinically nonsignificant, was evident within 2 months of treatment and stabilized thereafter. At follow-up, the GV approached baseline (6.70 cm/year) in the TAA-AQ group (6.59 cm/year) and decreased slightly in the placebo group (5.89 cm/year vs 6.06 cm/year at baseline). No HPA axis suppression was observed. CONCLUSIONS: By using rigorous Food and Drug Administration-recommended design elements, this study detected a small, statistically significant effect of TAA-AQ on the GV of children with PAR.

A phase 3 trial assessing the efficacy and safety of grass allergy immunotherapy tablet in subjects with grass pollen-induced allergic rhinitis with or without conjunctivitis, with or without asthma.

BACKGROUND: Design and execution of immunotherapy trials for seasonal allergies may be complicated by numerous factors including variable allergy testing methods, pollen levels, and timing and intensity of other seasonal allergens. We evaluated grass allergy immunotherapy tablet (AIT) treatment in North American adults with grass pollen-induced allergic rhinitis with or without conjunctivitis (AR/C), with/without asthma. METHODS: Subjects age 18-65 with clinical history of grass pollen-induced AR/C, with/without asthma were randomized 1:1 to once-daily 2800 BAU Timothy grass AIT (oral lyophilisate, Phleum pratense, 75,000 SQ-T, containing approximately 15 µg of Phl p 5) or placebo. The AR/C symptom and medication scores were recorded daily. The primary end point was the average AR/C daily symptom score (DSS) during the entire grass pollen season (GPS). Ranked key secondary end points were Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score, daily medication score (DMS), and percentage of well days, all over entire GPS. Safety was monitored through adverse event reporting. RESULTS: Efficacy analysis included 289 subjects. Over the entire GPS, mean DSS was 6% lower with AIT versus placebo (5.69 vs. 6.06), but this difference was not statistically significant (p = 0.3475) despite significantly higher immunological response in the grass AIT group. No significant between-group differences were seen for key secondary end points. In general, DSS was high before GPS began and no clear relationship between DSS and grass pollen counts was seen during GPS. In post hoc analysis of subjects with pre-seasonal DSS ≤3, mean DSS and DMS were both significantly lower with grass AIT versus placebo (27%; p = 0.0327 and 68%; p = 0.0060, respectively). In this subgroup a relationship between DSS and grass pollen counts was observed. Grass AIT was generally well tolerated, with no events of anaphylactic shock or respiratory compromise. CONCLUSIONS: In this trial, 2800 BAU grass AIT did not demonstrate significant symptom improvement versus placebo. Lack of relationship between pollen count and symptom score in the study population, and post hoc findings among subjects with low pre-seasonal symptoms, suggest that the symptoms reported in this study were not primarily reflective of the effects of grass pollen exposure. TRIAL REGISTRATION: NCT00421655.

Randomized controlled trial of ragweed allergy immunotherapy tablet efficacy and safety in North American adults.

BACKGROUND: Ragweed is an important cause of allergic rhinitis with or without conjunctivitis (AR/C) in North America and elsewhere. Allergen immunotherapy enabling safe patient self-administration is considered an unmet clinical need. Allergy immunotherapy tablet (AIT) treatment has shown promising efficacy and safety for grass allergy but has not been assessed for ragweed allergy. OBJECTIVE: To evaluate efficacy and safety of 2 short ragweed AIT doses in patients with AR/C. METHODS: Adults with ragweed pollen-induced AR/C were randomized 1:1:1 to daily ragweed AIT (6 or 12 Amb a 1 units) or placebo before, throughout, and after ragweed season (approximately 52 weeks). Patients could use predefined allergy rescue medications in season. Efficacy end points included peak and entire season total combined score (TCS) and its components daily symptom score (DSS), and daily medication score (DMS). Safety assessments included adverse events. RESULTS: A total of 565 patients were randomized. During peak season, the 6- and 12-Amb a 1 unit ragweed AIT doses showed 21% (-1.76 score) and 27% (-2.24 score) improvement in TCS vs placebo (P < .05). The 6- and 12-Amb a 1 unit AIT doses significantly improved DSS and DMS vs placebo (P < .05). Peak and entire season efficacy were comparable. The 12-Amb a 1 unit AIT dose reduced peak-season TCS vs placebo by 21% and 25% in subgroups with and without local application-site reactions, respectively. Most treatment-related adverse events were mild, oral reactions; no systemic allergic reactions were reported. One patient in the 6-Amb a 1 unit group received epinephrine at an emergency facility for sensation of localized pharyngeal edema. CONCLUSION: In this trial, ragweed AIT was effective and well tolerated in ragweed-allergic North American adults. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00783198.

Linear growth and bone maturation are unaffected by 1 year of therapy with inhaled flunisolide hydrofluoroalkane in prepubescent children with mild persistent asthma: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Inhaled corticosteroids (ICS) are the preferred long-term therapy for subjects with persistent asthma. However, concerns remain about potential effects of long-term ICS use on growth in children. OBJECTIVE: To determine the effect of 1 year of inhalation therapy with flunisolide hydrofluoroalkane (HFA) on growth velocity and bone maturation in children with mild persistent asthma. METHODS: In this double-blind, placebo-controlled study, 218 prepubescent (Tanner Stage 1) children with mild persistent asthma ranging in age from 4 to 10 years were evaluated. After a 2-week run-in period, subjects were randomized (1:1) to 2 puffs flunisolide HFA twice daily (85 µg/puff) or placebo for 52 weeks. Height was assessed by stadiometry at each visit. Growth velocity (cm/52 weeks) was estimated by the slope of the linear regression of height over time. An independent assessor scored hand and wrist radiographs for bone development pretreatment and at week 52. Analysis of covariance was used for all efficacy endpoints. RESULTS: The 2 treatment groups were similar at baseline for sex, race, age, weight, and height. At the end of double-blind treatment, mean growth velocity was 6.01 ± 1.84 cm/52 weeks for flunisolide HFA (n = 106) and 6.19 ± 1.30 cm/52 weeks for placebo (n = 112) (P = .425). Mean advancement in bone age during the 1-year study was similar for the 2 groups: 0.93 ± 0.46 years for flunisolide HFA (n = 70) and 1.01 ± 0.41 years for placebo (n = 75) (P = .128). CONCLUSIONS: In this study, flunisolide HFA did not suppress growth or bone maturation at the highest approved dose for children with persistent asthma.

Latex allergy.

Allergy to natural rubber latex is an important clinical condition that occurred after the institution of universal precautions to protect healthcare workers. A rapid increase and production of both examination and surgical gloves resulted in an epidemic of allergy to latex protein. Healthcare workers in both the medical and dental environments, as well as specific groups of individuals including those with spina bifida, myelodysplasia, and food allergies (banana, kiwi, avocado, and others), were at increased risk of sensitization. Clinical symptoms in the latex allergic individual ranged from type I hypersensitivity reaction including rhinoconjunctivitis, asthma, and systemic reaction to type IV hypersensitivity reaction, which occur from the chemicals added during the manufacturing process. Diagnosis of latex allergy is based on a clinical history that correlates the development of symptoms in relationship to exposure. In the United States there are no skin tests approved by the Food and Drug Administration. Therefore a combination of clinical judgment and serologic testing such as ImmunoCAP and Immulite is helpful. The primary treatment of latex allergy is avoidance of exposure to the latex protein.

Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents.

BACKGROUND: Allergy immunotherapy tablet (AIT) treatment might be a safe and convenient form of specific immunotherapy but it has not been investigated in North American children and adolescents. OBJECTIVE: We sought to investigate the efficacy and safety of timothy grass AIT treatment in North American children/adolescents with grass pollen-induced allergic rhinoconjunctivitis (ARC) with or without asthma. METHODS: Three hundred forty-five subjects (5-17 years old) were randomized to once-daily grass AIT treatment (2,800 bioequivalent allergen units, 75,000 standardized quality tablet, approximately 15 µg of Phl p 5) or placebo approximately 16 weeks before the 2009 grass pollen season (GPS). Treatment continued through the GPS. Daily symptoms and allergy rescue medication use were recorded. The primary end point was the total combined score (TCS) of the daily symptom score (DSS) and daily medication score (DMS) for the entire GPS. DSS, DMS, Rhinoconjunctivitis Quality of Life Questionnaire score, and Phl p 5-specific IgG4 and IgE-blocking factor levels were secondary end points. Safety was assessed through adverse events. RESULTS: Eighty-nine percent of subjects were multisensitized. TCS, DSS, DMS, and Rhinoconjunctivitis Quality of Life Questionnaire score versus placebo improved 26% (P = .001), 25% (P = .005), 81% (P = .006), and 18% (P = .04). Phl p 5-specific IgG4 and IgE-blocking factor levels were significantly higher at the peak and end of the GPS (P < .001). Treatment was well tolerated. Adverse events were generally mild and transient. Although no investigator-assessed systemic allergic reactions were reported, 1 grass AIT-treated subject experienced an event indicating a systemic reaction (lip angioedema, dysphagia, and cough). CONCLUSIONS: Use of once-daily timothy grass AIT treatment effectively treats timothy grass (cross-reactive with Festucoideae grasses) pollen-induced ARC in North American children 5 years and older. Given its convenient administration, lack of dose build-up requirement, safety profile, and efficacy, AIT treatment might become an important addition to the North American ARC treatment armamentarium.

Efficacy and safety of levocetirizine in improving symptoms and health-related quality of life in US adults with seasonal allergic rhinitis: a randomized, placebo-controlled study.

BACKGROUND: Levocetirizine, a second-generation antihistamine for symptomatic treatment of allergic rhinitis and chronic idiopathic urticaria, has not been previously studied in US patients. OBJECTIVE: To assess the efficacy and safety of levocetirizine in improving symptoms and health-related quality of life in US adults with seasonal allergic rhinitis (SAR). METHODS: This multicenter, double-blind trial randomized adults with SAR, sensitized to at least 1 grass allergen, to receive levocetirizine, 5 mg, or placebo once daily in the evening for 2 weeks. The primary end point was the 24-hour reflective Total 5-Symptom Score (T5SS; sum of rhinorrhea, sneezing, nasal congestion, and nasal and ocular pruritus) during the entire treatment period. Secondary assessments included the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), Work Productivity and Activity Impairment-Allergy Specific (WPAI-AS) questionnaire, and Epworth Sleepiness Scale (ESS), each assessed at week 1, week 2, and the end of treatment. RESULTS: The intent-to-treat population comprised 287 patients taking levocetirizine and 290 taking placebo, with no significant between-group differences at baseline. Levocetirizine resulted in significantly greater improvement from baseline vs placebo in the T5SS (P < .001), overall RQLQ score (P < .001), general and work-related WPAI-AS subscores (P < .05), and ESS score (P < .001). Overall incidence of treatment-emergent adverse events was 14.4% for levocetirizine and 18.4% for placebo. The incidence of somnolence and fatigue was 0.7% and 1.8% with levocetirizine and 1.0% and 0% with placebo, respectively. CONCLUSIONS: Levocetirizine was well tolerated and was significantly more effective than placebo in improving the naso-ocular symptoms and health-related quality of life in US patients with SAR.

Pollinex Quattro Tree: allergy vaccine.

An overview of short-term specific immunotherapy (ST-SIT) highlighting Pollinex Quattro (PQ) Tree is presented. The product development of this novel allergy vaccine using modifying agent glutaraldehyde, adjuvant monophosphoryl lipid and L-tyrosine have heralded a superior ST-SIT. Since 1999 when PQ was founded in Germany, various research trials assessing both the standardization and clinical studies have been done. A review of these studies demonstrates the efficacy and safety of PQ Tree in both pediatric and adult trials. The uniqueness of this product allows a shorter course of four pre-seasonal injections to provide control of allergy symptomatology in seasonal rhinitis patients. The PQ Tree product studies show a similar efficacy and safety profile to the grass formulation trial.

Successful treatment of previously uncontrolled adult asthma with budesonide inhalation suspension: five-year case histories.

OBJECTIVE: To determine whether nebulized budesonide inhalation suspension (BIS) is effective in treating adults with asthma that has been uncontrolled by inhaled therapies. CASE SUMMARIES: Three adults with severe persistent asthma were switched to BIS after poor outcomes with other controller medications, including inhaled corticosteroids (ICSs). BIS dosages were initiated with 1 mg twice daily. Based on physician discretion as symptoms improved, dosages were decreased to 0.5 mg twice daily (2 pts.) or once daily (1 pt.). Patients were instructed to self-manage their asthma, increasing their dosages during periods of asthma worsening. Peak expiratory flow (PEF) was assessed before and after the initiation of BIS. The number of healthcare visits and oral corticosteroid courses recorded in patient medical records during the 3 years before and 5 years after initiation of BIS therapy were compared. In all 3 cases, BIS improved asthma control. BIS consistently increased PEF and reduced the number of urgent care visits and oral corticosteroid courses. All patients reported satisfaction with BIS therapy. DISCUSSION: Despite proven effectiveness of ICSs for persistent asthma, some patients fail to respond optimally to treatment administered via an inhaler. These 3 case reports suggest that BIS is effective in treating adults with severe persistent asthma who fail to respond optimally to treatment with other ICS preparations. Failure to use inhalers properly, previous poor adherence in 1 case, or patient preference for the nebulizer might explain why nebulized BIS was more effective than other inhaler therapies. CONCLUSIONS: Switching adults with uncontrolled asthma to BIS therapy may be a valuable treatment option for those who are unable to achieve optimal asthma control, despite asthma education and training on inhaler technique.

Aspirin challenge and desensitization for aspirin-exacerbated respiratory disease: a practice paper.

Aspirin desensitization is indicated for patients who have aspirin-exacerbated respiratory disease and whose asthma and/or rhinosinusitis is suboptimally controlled with inhaled corticosteroids and leukotriene-modifying drugs. In this practice paper, the general requirements for aspirin desensitization are presented, the locations where desensitizations can be safely performed are outlined, prechallenge patient preparation is discussed, an oral aspirin challenge protocol is presented, treatment of adverse reactions is reviewed, and maintenance of aspirin desensitization is discussed.

Triamcinolone acetonide aqueous nasal spray and fluticasone propionate are equally effective for relief of nasal symptoms in patients with seasonal allergic rhinitis.

OBJECTIVE: We compared 220 microg daily intranasal aqueous triamcinolone acetonide (TAA AQ) with 200 microg daily fluticasone propionate (FP) for relief of seasonal allergic rhinitis symptoms. Study design and setting Randomized, parallel-group, investigator-blind study included patients with symptomatic seasonal allergic rhinitis. After a baseline period, TAA AQ or FP was taken for about 21 days. Nasal symptom (discharge, stuffiness, itching, sneezing) severity was recorded twice daily; total nasal symptom score was calculated. Health-related quality of life was assessed by Rhinoconjunctivitis Quality of Life Questionnaire. RESULTS: Reductions in individual symptoms and total nasal symptom score were statistically significant versus baseline and were equivalent between treatments: -3.15 +/- 0.19 with TAA AQ (n = 148) and approximately 3.17 +/- 0.18 with FP (n = 147) (95% confidence interval for the difference, -0.7391 to 0.3693). Clinically and statistically significant improvements in Rhinoconjunctivitis Quality of Life Questionnaire scores were comparable. CONCLUSION: TAA AQ and FP were equally efficacious in relieving seasonal allergic rhinitis symptoms and improving health-related quality of life. SIGNIFICANCE: Differences in molecular potency of intranasal steroids do not confer differences in efficacy.

Relief of cough and nasal symptoms associated with allergic rhinitis by mometasone furoate nasal spray.

BACKGROUND: Cough commonly occurs as a symptom of seasonal allergic rhinitis (SAR), an inflammatory condition of the nasal mucous membranes that results in rhinorrhea, nasal stuffiness/congestion, nasal itching, and sneezing. Mometasone furoate nasal spray (MFNS, Nasonex, Schering, Kenilworth, NJ), an anti-inflammatory nasal corticosteroid, has been shown to be safe and effective in reducing the nasal inflammation of SAR. OBJECTIVE: To examine the effectiveness of MFNS in relieving SAR-associated cough, in addition to nasal symptoms. METHODS: This was a multicenter, randomized, double-blind study. Patients 12 years of age or older with > or = 1-year history of SAR symptoms, positive skin test to a prevailing seasonal allergen, moderate nasal symptoms, and moderate cough were treated for 14 days with MFNS 200 microg daily (n = 122) or placebo (n = 123). RESULTS: The group treated with MFNS showed significant improvement in the daytime cough severity score at endpoint compared with placebo (P = 0.049). Improvement in the nighttime cough severity score showed a trend in favor of MFNS treatment. Treatment with MFNS significantly improved total nasal symptoms in both the daytime and nighttime compared with placebo at endpoint (P < or = 0.017). Overall daytime symptom scores (cough + total nasal) improved significantly compared with placebo at endpoint (P = 0.005). Overall nighttime symptom scores improved significantly compared with placebo at endpoint (P = 0.028). Treatments were well tolerated, with no significant differences in the incidence of adverse events. CONCLUSIONS: MFNS is effective and well tolerated in the treatment of daytime cough associated with SAR.