Evaluation of the ocular safety associated with the exhalation delivery system with fluticasone.

Background: Intranasal corticosteroids (INCS) are the cornerstone of treatment for chronic rhinosinusitis. Although INCS are generally considered safe and effective, there is a concern that chronic use may lead to ocular adverse effects. Objective: To assess ocular safety of the exhalation delivery system with fluticasone propionate (EDS-FLU) in patients with chronic rhinosinusitis with nasal polyps. Methods: Ocular safety data were collected during two randomized, double-blind, placebo controlled studies with open-label extensions. Ophthalmologists performed tonometry, slit-lamp, and visual acuity examinations to assess intraocular pressure (IOP) and the presence of cataracts. Ocular examinations were conducted before double-blind treatment, at the end of the 16-week double-blind phase, and at the end of the 8-week open-label phase. The results of pooled data from patients who received EDS-FLU 186 µg (n = 160), EDS-FLU 372 µg (n = 161), and EDS-placebo (n = 161) twice daily are reported here. Results: At the end of the double-blind phase, six patients developed elevated average IOP > 21 mm Hg: two patients (1.2%) in the EDS-placebo group, three patients (1.9%) in the EDS-FLU 186 µg group, and one patient (0.6%) in the EDS-FLU 372 µg group. In addition, 6 of 482 patients developed cataracts: 3 patients in the EDS-placebo group, 2 patients in the EDS-FLU 186 µg group, and 1 patient in the EDS-FLU 372 µg group. At the end of the open-label phase, two additional patients showed IOP > 21 mm Hg and two additional patients developed cataracts. Conclusion: No increased risk of elevated IOP was detected with EDS-FLU; the rate of cataract development was similar to EDS-placebo and to that reported with other INCS.Clinical trials NCT01622569 and NCT01624662, www.clinicaltrials.gov.

The Effect of EDS-FLU on Objective and Patient-Reported Subjective Outcomes for Patients with Chronic Rhinosinusitis with Nasal Polyps.

BACKGROUND: Exhalation delivery system with fluticasone (EDS-FLU) delivers medication high and deep in the nasal passages and has been shown to reduce nasal polyp (NP) grade, an objective measure of efficacy, and to yield clinically meaningful improvements on subjective measures of symptoms in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). OBJECTIVES: To better characterize EDS-FLU treatment, we analyzed responder rates for four outcome measures used in the EDS-FLU pivotal trials, in the overall study population as well as in subgroups of patients with or without prior sinus surgery or prior use of a standard intranasal corticosteroid spray (INS). METHODS: Data were pooled from two randomized, 24-week (16-week, double-blind + 8-week, open-label), placebo-controlled studies (NAVIGATE I and II). Results for patients receiving EDS-FLU (186 µg [n = 161] or 372 µg [n = 160]) or EDS-placebo (n = 161) twice daily during the double-blind phase are described. Responder criteria included NP grade reduction (≥1-point), 22-item Sino-Nasal Outcome Test (SNOT-22) reduction (>12-points), Patient Global Impression of Change (PGIC) (much/very much improved), and congestion score improvement (>0.5-points). RESULTS: More patients in the EDS-FLU group responded to each of the four responder criteria compared with EDS-placebo. More patients receiving EDS-FLU responded to ≥ 1 criterion compared with EDS-placebo at week 4 (82.7% and 60.4%, respectively) and week 16 (95.7% and 80.3%, respectively). Patients responded similarly irrespective of prior sinus surgery or prior INS use. Patient-reported outcome measures showed earlier responses than NP scores. CONCLUSIONS: Meaningful improvements were seen across multiple response criteria with EDS-FLU, suggesting that the broad treatment effect of EDS-FLU includes objective reduction in polyp grade and improvements in several patient-reported outcomes. TRIAL REGISTRATION: ClinicalTrials.gov (NAVIGATE I: NCT01622569 and NAVIGATE II: NCT01624662).

Randomized, double-blind trial of carisoprodol 250 mg compared with placebo and carisoprodol 350 mg for the treatment of low back spasm.

BACKGROUND: Carisoprodol, a centrally active skeletal muscle relaxant, is widely used for the treatment of acute, painful musculoskeletal disorders. When administered at a dose of 350 mg four times daily, carisoprodol demonstrated significant clinical benefit in its early clinical development trials; however, some unfavorable side effects, such as drowsiness and dizziness, were reported. Recently, research was conducted to determine if a lower dose of carisoprodol would retain efficacy but improve tolerability compared to the higher 350-mg dose. OBJECTIVE: The purpose of this multicenter study was to compare the efficacy and safety of carisoprodol 250-mg tablets four times daily to 350-mg tablets four times daily and to placebo in patients with acute, painful musculoskeletal spasm of the lower back. RESEARCH DESIGN AND METHODS: In this 1-week double-blind, placebo-controlled, parallel-group multicenter trial, patients 18 to 65 years of age with moderate to severe back spasm were randomly assigned to treatment with carisoprodol 250-mg tablets (n = 264), 350-mg tablets (n = 273), or matching placebo tablets (n = 269) three times daily and at bedtime. MAIN OUTCOME MEASURES: The coprimary efficacy variables were patient-rated relief from starting backache and patient-rated global impression of change assessed on treatment day 3. RESULTS: The carisoprodol 250-mg regimen was significantly more effective than placebo as assessed by both patient-rated relief from starting backache (p = 0.0001) and patient-rated global impression of change (p = 0.0046). There were no significant differences between the 250-mg and 350-mg dosages for the coprimary efficacy endpoints, and patients improved with or without sedation. Fewer than 1% of patients in the carisoprodol 250-mg group discontinued prematurely because of treatment-emergent adverse events, and no patient discontinued because of drowsiness. CONCLUSIONS: When administered three times daily and at bedtime, carisoprodol 250 mg was as effective as 350 mg three times daily and at bedtime with a lower incidence of adverse events and fewer discontinuations of therapy due to adverse events. Patients improved whether or not they reported sedation as an adverse event.

Double-blind, placebo-controlled trial of reformulated azelastine nasal spray in patients with seasonal allergic rhinitis.

BACKGROUND: Azelastine nasal spray is a topical antihistamine with a distinctive taste that may be objectionable to some patients. The primary objectives of this clinical trial were (1) to determine if a reformulated azelastine nasal spray (Astepro) with sucralose as a taste-masking agent provides comparable efficacy to the original formulation (Astelin) and (2) to evaluate dose-response relationships between groups. METHODS: Eight hundred thirty-five patients with seasonal allergic rhinitis were randomized to six treatment groups: (1) original azelastine nasal spray, 1 spray/nostril b.i.d.; (2) reformulated azelastine, 1 spray/nostril b.i.d.; (3) placebo, 1 spray/ nostril b.i.d.; (4) original azelastine nasal spray, 2 sprays/nostril b.i.d., (5) reformulated, 2 sprays/nostril b.i.d.; and (6) placebo, 2 sprays/nostril b.i.d. The primary efficacy variable was the change from baseline to day 14 in total nasal symptom score (TNSS) consisting of runny nose, sneezing, itchy nose, and nasal congestion. RESULTS: Original azelastine nasal spray and the reformulated spray produced comparable improvements in the TNSS at both dosages. There was a dose-related difference in TNSS comparing the 1- and 2-spray dosages. The percentage changes from baseline in the TNSS in the 2-sprays/nostril dosage groups were 27.9% (p<0.001) with the reformulated nasal spray, 23.5% (p<0.01) with the original formulation, and 15.4% with placebo. The incidence of bitter taste was 7% with the reformulated spray and 8% with the original at the 2-sprays/nostril dosage. CONCLUSION: The results of this study showed efficacy both with original azelastine nasal spray and with the reformulated nasal spray and a clear dose-response difference between the 1- and 2-spray dosages.

Fluorofelbamate.

The incidence of refractory seizures has remained at 30-40%, even with the approval of nine new anticonvulsants over the past 12 years. In attempts to reduce seizure frequency and severity, physicians routinely resort to combining two or more anticonvulsants, ideally with different mechanisms of action. These combinatorial therapies are difficult to administer for both patient and caregiver and often result in tolerability issues. Hence, a broad spectrum anticonvulsant, with multiple mechanisms of action, that is well tolerated, would provide physicians with an important option in their armamentarium to control seizures. Felbamate initially fit this profile and was demonstrated to effectively control both partial and generalized seizures in clinical studies supporting registration. Unfortunately, unanticipated idiosyncratic toxicity was observed after approval and the drug is now relegated to second or third line therapy, depending on patient history and seizure type. Epileptologists still prescribe this drug for refractory seizures, and a recent communication indicates that 35,000 to 46,000 new patients have tried Felbatol (MedPointe Pharmaceuticals, Somerset, NJ) since 1995. The continued utilization of Felbatol, in light of its risk:benefit issues, highlights the need for new efficacious therapeutic options. Fluorofelbamate (MedPointe Pharmaceuticals), a phase I drug candidate, was designed to retain the broad spectrum multimechanistic activity of felbamate, with a modified metabolism that has demonstrated, in vitro, to avoid the production of the reactive metabolite believed to cause the idiosyncratic toxicity. This drug candidate is one of several carbamates either in development or currently on the market for treatment of seizures and other CNS disorders.

Onset of action of azelastine nasal spray compared with mometasone nasal spray and placebo in subjects with seasonal allergic rhinitis evaluated in an environmental exposure chamber.

BACKGROUND: The objective of this study was to determine the onset of action of azelastine hydrochloride nasal spray compared with placebo and an intranasal steroid, mometasone furoate, in subjects with seasonal allergic rhinitis (SAR). METHODS: Subjects with a history of SAR and symptomatic while exposed to ragweed pollen in an environmental exposure chamber (EEC) were randomized to azelastine nasal spray (n=150), mometasone nasal spray (n=150), or placebo (n=150) and recorded total nasal symptom scores (TNSS), consisting of sneezing, nasal pruritus, rhinorrhea, and congestion, during an 8-hour study period. RESULTS: Azelastine nasal spray showed a statistically significant improvement in the TNSS at 15 minutes compared with placebo. The effect was durable at each time point during the 8-hour study. Azelastine nasal spray also was significantly more effective than mometasone at each time point. CONCLUSION: Azelastine nasal spray has a rapid (15 minute) onset of action. Azelastine nasal spray was superior to both placebo and imometasone nasal spray in reducing nasal symptoms of SAR occurring within 8 hours after an allergen challenge.