Albert F. Finn

A double-blind, placebo-controlled trial of fexofenadine HCl in the treatment of chronic idiopathic urticaria.

BACKGROUND Symptoms of chronic idiopathic urticaria (CIU) include relentless itching and painful wheals, which can be physically and psychologically debilitating. Half of all patients with urticaria have angioedema, which is often disfiguring. OBJECTIVE To evaluate the safety and efficacy of fexofenadine HCl for the treatment of CIU symptoms. METHODS In this 4-week, multicenter, placebo-controlled study, 439 patients with moderate to severe pruritus and urticaria received 1 of 4 oral doses of fexofenadine HCl (20, 60, 120, or 240 mg twice a day) or placebo. Patients reflectively assessed (over the previous 12 hours) the severity of pruritus, the number of wheals, and the interference with sleep (7 AM) and normal activities (7 PM) due to urticaria. Efficacy measures included a change from baseline of daily mean pruritus score (MPS), daily mean number of wheals (MNW) score, daily mean total symptom score (MTSS) (ie, the sum of the wheal and pruritus scores), and mean interference with sleep and daily activities due to urticaria. RESULTS All 4 doses of fexofenadine were statistically superior to placebo (P </=.0238) for MPS, MNW score, and MTSS. Patients receiving fexofenadine HCl also experienced significantly less interference with sleep and daily activities than patients receiving placebo (P </=.0001). Efficacy results were similar in the 60-, 120-, and 240-mg groups and were quantitatively better than those in the 20-mg group. Adverse events were mild and occurred with similar incidence in all treatment groups. CONCLUSIONS Fexofenadine HCl is well tolerated and is statistically superior to placebo in reducing signs and symptoms of CIU and in ameliorating interference with sleep and daily activities due to urticaria. Doses of 60 mg twice a day or greater are most effective.

A dose-ranging study of mometasone furoate aqueous nasal spray in children with seasonal allergic rhinitis

BACKGROUND The efficacy and safety of mometasone furoate aqueous nasal spray (MFNS; Nasonex) 200 microg once daily for the treatment and prophylaxis of seasonal allergic rhinitis (SAR) and treatment of perennial rhinitis have been demonstrated in adults. However, the dose response of MFNS in pediatric patients has not yet been characterized. OBJECTIVE This study was conducted to determine the dose-response relationship of 3 different doses of MFNS in a pediatric population. METHODS This was a multicenter, double-blind, active- and placebo-controlled study of 679 children 6 to 11 years of age with histories of SAR and documented positive skin test responses. Patients were randomized to one of the following treatment groups for 4 weeks: MFNS 25 microgram once daily, MFNS 100 microgram once daily, MFNS 200 microgram once daily, beclomethasone dipropionate 84 microgram twice daily (168 microgram/day), or placebo. Physician evaluations were performed at days 4, 8, 15, and 29, and patient evaluations were analyzed for days 1 to 15 and 16 to 29. RESULTS The mean reduction from baseline in physician-evaluated total nasal symptom scores at day 8 (the primary efficacy variable) was significantly greater in the MFNS and beclomethasone dipropionate groups than in the placebo group (P </=.02). No significant differences were observed among the 3 MFNS groups. However, as treatment continued, symptoms in patients treated with MFNS 100 or 200 microgram once daily continued to improve, whereas those treated with MFNS 25 microgram once daily demonstrated little further improvement. By day 29, MFNS 100 and 200 microgram once daily both were significantly more effective than MFNS 25 microgram once daily in relieving symptoms of SAR, but MFNS 200 microgram provided no additional benefit over MFNS 100 microgram. All doses of MFNS were well tolerated, and cosyntropin stimulation tests performed before and after treatment found no evidence of hypothalamic-pituitary-adrenal axis suppression. CONCLUSION These results indicate that the most appropriate therapeutic dosage of MFNS in the treatment of SAR in children 6 to 11 years of age is 100 microgram once daily. In addition, MFNS at doses up to 200 microgram once daily for 4 weeks was well tolerated and had no detectable effects on hypothalamic-pituitary-adrenal axis function.

Intranasal fluticasone propionate is effective for perennial nonallergic rhinitis with or without eosinophilia

BACKGROUND Although response to intranasal corticosteroid therapy has been reported in patients with nonallergic rhinitis with eosinophilic syndrome (NARES), efficacy specifically in non-NARES patients has not been fully characterized. OBJECTIVE To evaluate the efficacy of intranasal fluticasone propionate (FP) in the treatment of patients with perennial nonallergic rhinitis, with and without nasal eosinophilia. METHODS Data from 983 patients in three randomized, double-blind, placebo-controlled PNAR trials were integrated. Patients received a total daily dose of FP 200 microg (n = 332), FP 400 microg (n = 325), or placebo (n = 326) for 28 days. Patients were > or =12 years of age with perennial rhinitis and negative skin tests to all allergens relevant to the geographic region. Nasal eosinophils were evaluated using a five-point scale. Patients were classified as non-NARES with a point score of 0 (n = 674; 69%); patients with a point score between I and 4 were classified as NARES (n = 309; 31%). Efficacy of FP was evaluated by the mean change in total nasal symptom score (TNSS), a sum of patient ratings of nasal obstruction, postnasal drip, and rhinorrhea. RESULTS Patients with either NARES or non-NARES had similar statistically significant improvement with FP 200 microg or 400 microg compared with placebo; thus, the total group comprising both varieties of rhinitis responded to FP. In the total population, both FP treatment groups showed significantly greater improvement in TNSS compared with placebo during each week of treatment (P < or = 0.002), with mean changes in TNSS for day 22 to day 28 ranging from -84 and -85 in the FP 200 microg and FP 400 microg groups, respectively, to -64 in the placebo group. The three study treatment groups had similar proportions of non-NARES (68 to 69%) and NARES (31 to 32%) patients at baseline. In the non-NARES subgroup, mean changes in TNSS for each treatment group were similar to changes seen in the total population. In the NARES subgroup, mean changes in TNSS for the FP 200 microg and placebo groups were similar to changes seen in the total population; mean change in TNSS for the FP 400 microg group was somewhat greater than changes seen in the total population. CONCLUSIONS Intranasal FP is an effective treatment for perennial nonallergic rhinitis with or without nasal eosinophilia (NARES or non-NARES).

Safety and efficacy of olopatadine hydrochloride nasal spray for the treatment of seasonal allergic rhinitis

BACKGROUND A nasal spray containing the antiallergy agent olopatadine hydrochloride is being developed for the treatment of seasonal allergic rhinitis (SAR). OBJECTIVE To evaluate the safety and efficacy of 2 concentrations of olopatadine nasal spray vs placebo in patients with SAR. METHODS This was a multicenter, randomized, double-blind, placebo-controlled study. After a 3- to 21-day placebo run-in, 565 patients aged 12 to 80 years were randomized to receive 0.4% or 0.6% olopatadine or placebo, 2 sprays per nostril twice daily for 2 weeks. Patients evaluated morning and evening reflective and instantaneous nasal symptoms (sneezing, stuffy nose, runny nose, and itchy nose, which compose the total nasal symptom score [TNSS]) and ocular symptoms and completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). RESULTS Olopatadine spray (0.4% and 0.6%) was significantly superior to placebo for percentage change from baseline in overall reflective (P = .004 and P < .001, respectively) and instantaneous (P = .02 and P = .003, respectively) TNSSs. Also, 0.6% olopatadine was significantly superior to placebo for reducing the reflective and instantaneous assessments of sneezing, runny and itchy nose, and itchy eyes; the instantaneous assessments of watery eyes; and the overall and all 7 domain scores of the RQLQ (P < .05). Olopatadine spray exhibited a safety profile comparable with that of placebo. CONCLUSIONS Olopatadine nasal spray (0.4% and 0.6%) provided statistically significant improvements in allergic rhinitis symptoms compared with placebo regarding TNSSs (reflective and instantaneous) and in quality-of-life variables in patients with SAR. Olopatadine nasal spray administered twice daily was safe and well tolerated in adolescents and adults.

Safety and efficacy of oral fexofenadine in children with seasonal allergic rhinitis – a pooled analysis of three studies

Allergic rhinitis is one of the most common clinical conditions in children; however, data regarding the safety of antihistamines in children with seasonal allergic rhinitis are limiting. To evaluate the safety and efficacy of fexofenadine in children with seasonal allergic rhinitis, data were pooled from three, double‐blind, randomized, placebo‐controlled, parallel‐group, 2‐week trials in children (6–11 year) with seasonal allergic rhinitis. All studies assessed fexofenadine HCl 30 mg b.i.d.; two studies included fexofenadine HCl at 15 and 60 mg b.i.d. Patients (and investigators) reported any adverse events during the trial. Physical examinations, including measurements of vital signs and laboratory tests, were performed. Efficacy assessments (total symptom score and individual symptom scores) were evaluated. Exposure to fexofenadine HCl 30 mg b.i.d. and to any fexofenadine dose exceeded 10,000 and 17,000 patient days, respectively. Incidences of adverse events, and discontinuations because of adverse events, were low and similar across treatment groups. In the placebo group, 24.4% of subjects reported adverse events compared with 24.1% for fexofenadine HCl 30 mg b.i.d., and 28.4% for all fexofenadine‐treated groups. The most common adverse event overall was headache (4.3% placebo; 5.8% fexofenadine HCl 30 mg b.i.d.; and 7.2% any fexofenadine doses). Treatment‐related adverse events were similar across treatment groups with no sedative effects. Fexofenadine HCl 30 mg b.i.d. was significantly superior to placebo in reducing the total symptom score and all individual seasonal allergic rhinitis symptoms, including nasal congestion (p < 0.05). Fexofenadine, at doses of up to 60 mg b.i.d., is safe and non‐sedating, and fexofenadine HCl 30 mg b.i.d. effectively reduces all seasonal allergic rhinitis symptoms in children aged 6–11 years.

Diskus and diskhaler: efficacy and safety of fluticasone propionate via two dry powder inhalers in subjects with mild-to-moderate persistent asthma

BACKGROUND Fluticasone propionate is a topically active glucocorticoid with potent antiinflammatory activity in the treatment of asthma. OBJECTIVE This study evaluated the safety and efficacy of fluticasone propionate administered via the Diskus and Diskhaler powder delivery devices in subjects with mild-to-moderate asthma. METHODS Fluticasone propionate (500 microg twice daily) or placebo was administered via the Diskus and Diskhaler to 213 adolescent and adult asthma subjects in a randomized, double-blind, double-dummy, parallel-group study for 12 weeks. Subjects were stratified according to baseline therapy of inhaled corticosteroids or beta2-agonists alone. Subjects were dropped from the study if they met predefined criteria for lack of efficacy. RESULTS Fluticasone propionate improved pulmonary function both in subjects previously treated with inhaled corticosteroids or beta2-agonists alone. At endpoint, fluticasone propionate significantly improved forced expiratory volume in 1 second (P < .001), morning and evening peak expiratory flow (P < .001), and asthma symptom scores (P < or = .016), and significantly reduced nighttime awakenings (P = .016; Diskhaler group only) and rescue albuterol use (P < .001). Overall, efficacy measurements for the Diskus and Diskhaler were similar. More placebo-treated subjects (34%) withdrew from the study due to lack of efficacy than subjects in the Diskus (5%) or Diskhaler (5%) groups. The incidence and severity of adverse events were similar across groups. Measurement of plasma fluticasone propionate and cortisol concentrations showed no apparent influence of device on systemic exposure. CONCLUSION Fluticasone propionate powder, administered via the Diskus or Diskhaler inhalation devices, was well tolerated and effective in the treatment of mild-to-moderate persistent asthma.

Ipratropium Bromide Nasal Spray* 0.03% Provides Additional Relief from Rhinorrhea When Combined With Terfenadine# in Perennial Rhinitis Patients; A Randomized, Double-Blind, Active-Controlled Trial:

Medical treatment of perennial rhinitis is aimed at providing symptomatic relief of individual symptoms. Multiple agents are administered when no single agent provides complete relief. Studies assessing the benefit/risk of combined therapy are important, especially for newly available agents such as ipratropium bromide nasal spray, a topical anticholinergic agent approved for the treatment of rhinorrhea in allergic and nonallergic perennial rhinitis. The objective was to determine whether the combined use of ipratropium bromide nasal spray 0.03% (42 mcg per nostril) administered three times daily with a nonsedating antihistamine (terfenadine, 60 mg administered twice daily) is safe and provides greater clinical benefit than use of the placebo nasal spray plus terfenadine. Our method was a multicenter, 6-week, double-blind, randomized, active-controlled, crossover trial of 205 patients with perennial rhinitis (114 allergic and 91 nonallergic), 18 to 75 years of age, who had clinically significant rhinorrhea. After a 1-week run-in period, patients were treated for 2 weeks with one of the two treatment regimens, followed by a 1-week washout period, and then were treated for another 2 weeks with the other treatment regimen. Daily diary symptoms scores of rhinorrhea, congestion, and sneezing were obtained, as well as biweekly patient and physician global assessments of treatment effectiveness of each of the nasal symptoms. Ipratropium bromide nasal spray plus terfenadine was more effective than vehicle plus terfenadine in reducing the average severity (38% versus 28%) and duration (46% versus 30%) of rhinorrhea during the 2 weeks of treatment from baseline (p < 0.05). The advantage of ipratropium bromide nasal spray plus terfenadine was evident by the second day of treatment and continued throughout the 2-week treatment period. Of patients who responded more to one treatment than another, 69% responded to ipratropium bromide nasal spray plus terfenadine, compared to 31% to vehicle plus terfenadine (p < 0.05). Both physicians and patients rated control of rhinorrhea and sneezing by ipratropium bromide nasal spray plus terfenadine as superior to vehicle plus terfenadine (p < 0.05). The symptom of congestion was controlled equally well by both treatments. Combined active therapy was well tolerated with no increase in adverse events over that seen previously with ipratropium bromide nasal spray alone. The combination of ipratropium bromide nasal spray with terfenadine is more effective than vehicle plus terfenadine for the treatment of rhinorrhea, and does not result in a potentiation of adverse drug reactions.

Comparison of cetirizine-pseudoephedrine and placebo in patients with seasonal allergic rhinitis and concomitant mild-to-moderate asthma: randomized, double-blind study

BACKGROUND Allergic rhinitis (AR) and asthma are common concurrent conditions. OBJECTIVES To evaluate the effects of cetirizine hydrochloride (5 mg)-pseudoephedrine hydrochloride (120 mg) (cetirizine-D) twice daily on AR and asthma symptoms, pulmonary function, and asthma-related quality of life in 274 patients with confirmed seasonal AR and concomitant mild-to-moderate asthma. METHODS In this multicenter, randomized, double-blind, placebo-controlled study, after a 1-week screening period, patients took cetirizine-D or placebo for 4 weeks. The primary efficacy variable, AR total symptom severity complex score, was derived from patient daily diary ratings of sneezing, runny nose, itchy nose, postnasal drip, and nasal congestion. Asthma symptom severity total scores were derived from twice-daily diary ratings of wheezing, coughing, shortness of breath, and chest tightness. Pulmonary function was tested at clinic visits and by patients each morning and evening. Patients completed the Asthma Quality of Life Questionnaire at each visit. All tests were 2-sided, with statistical significance at the .05 level. RESULTS Cetirizine-D reduced total symptom severity complex scores by 42.3% overall vs 23.6% with placebo (P < .001). Asthma symptom severity total scores were significantly improved with cetirizine-D at most times vs placebo. Cetirizine-D treatment was also associated with significantly improved Asthma Quality of Life Questionnaire overall scores. Pulmonary function test results were neutral. Cetirizine-D was well tolerated, with discontinuation and adverse event rates similar to placebo. Somnolence occurred in 8 patients (5.8%) taking cetirizine-D and in 1 (0.7%) taking placebo. CONCLUSIONS Treatment with cetirizine-D twice daily significantly reduced rhinitis and asthma symptoms and improved overall asthma quality of life in patients with seasonal AR and concomitant mild-to-moderate asthma.

Beta2-Agonist Induced Ventricular Dysrhythmias Secondary to Hyperexcitable Conduction System in the Absence of a Long QT Syndrome

BACKGROUND The use of inhaled beta 2-agonists for bronchodilation in the treatment of lower airway obstruction is accepted worldwide. These agents are used for symptomatic relief of lower airway obstruction and, as well, can be employed prophylactically in exercise-induced bronchospasm. Cardiac dysrhythmias, specifically the long QT syndrome, have been associated with cardiac events precipitated by sympathomimetics. There are reports of documented long QT syndrome in association with syncope in children; however, there are no reports of beta 2-agonist-induced syncope in the absence of long QT syndrome. OBJECTIVE To determine predisposing cardiac factors resulting in syncope associated with inhaled beta 2-agonist use. METHOD Case report. The index case was evaluated for cardiac pathology through non-invasive techniques, cardiac catheterization, and electrophysiologic studies. Electrophysiologic studies included provocative challenge with parenteral adrenergic agents. RESULTS Non-invasive studies were unremarkable. There was no evidence of prolonged QT syndrome or support for vasopressor syncope. Electrophysiologic studies revealed reproducible polymorphic ventricular tachycardia. This predisposition required a ventricular stimulation program of higher intensity while on mexilitine. CONCLUSIONS This case of syncope associated with inhaled, short-acting beta 2-agonist resulted from a hyperexcitable conduction system rather than the presence of a long QT syndrome.

Efficacy, safety, and optimal dose selection of beclomethasone dipropionate nasal aerosol for seasonal allergic rhinitis in adolescents and adults.

Abstract Objective: Some patients with allergic rhinitis (AR) may prefer nonaqueous intranasal corticosteroid aerosols because of unwanted attributes of aqueous formulations. The mandatory removal of chlorofluorocarbon-propelled nonaqueous aerosols from the market limited available treatment options. To fulfill this unmet need, a nonaqueous, hydrofluoroalkane-propelled beclomethasone dipropionate (BDP) nasal aerosol was developed and approved for treatment of AR nasal symptoms. As part of the development program, this dose-ranging study evaluated three doses of BDP nasal aerosol to determine the optimally safe and effective dose for adolescent and adult patients (≥12 years old) with seasonal AR (SAR). Methods: After a 7 to 21 day placebo run-in period, eligible patients with SAR were randomly assigned to once-daily BDP nasal aerosol 80 µg, 160 µg, 320 µg, or placebo. The primary endpoint was the change from baseline in average a.m. and p.m. patient-reported reflective total nasal symptom scores (rTNSS) over 2 weeks. Safety and tolerability were also assessed. A potential study limitation could be lack of objective assessment of AR symptoms. Results: Significant improvements were seen in average a.m. and p.m. rTNSS (least squares [LS] mean treatment difference, −0.63; 95% CI: −1.13, −0.13; p = 0.013) as well as in average a.m. and p.m. instantaneous TNSS (iTNSS; LS mean treatment difference, −0.60; 95% CI: −1.09, −0.11; p = 0.016) with BDP nasal aerosol 320 µg/day compared with placebo. Although there were numerical improvements from baseline in patient-reported rTNSS and iTNSS with BDP nasal aerosol 80 µg and 160 µg, these doses did not achieve statistical significance compared with placebo. BDP nonaqueous nasal aerosol was well tolerated at all doses tested, with a safety profile comparable to that of placebo. Conclusions: These data indicate that 320 µg/day of BDP nasal aerosol is the optimally safe and effective dose for the treatment of SAR in adolescent and adult patients. Trial registration NCT: #NCT00854360.