Pharmacokinetics, Safety, and Tolerability of a Single 5-Day Treatment of Tirbanibulin Ointment 1% in 100 cm2 : A Phase 1 Maximal-Use Trial in Patients with Actinic Keratosis.

Tirbanibulin ointment 1% is approved in the United States and Europe for the treatment of actinic keratosis with demonstrated efficacy, safety, and tolerability when applied over a field up to 25 cm2 . This Phase 1 maximal-use trial determines the plasma pharmacokinetics, safety, and tolerability of tirbanibulin ointment 1% applied to 100 cm2 of the face or balding scalp in adults with actinic keratosis. Twenty-eight patients self-applied tirbanibulin once daily for a single 5-day treatment course. On Day 5, the mean maximum plasma concentration was 1.06 ng/mL and area under the plasma concentration-time curve during a dosing interval was 16.2 ng â€¢ h/mL. Systemic exposure was approximately 4-fold higher than in a previous pharmacokinetic study with a 25 cm2 field, consistent with the increase in the treated area. Tirbanibulin applied to a 100-cm2 treatment field showed favorable safety and tolerability. The most common treatment-emergent adverse events were application site reactions (in 35.7% of patients). All treatment-emergent adverse events and most of the tolerability signs were mild/moderate and resolved or returned to baseline by Day 29. In summary, under maximal-use conditions, tirbanibulin ointment 1% was safe and well tolerated supporting its potential use over a field up to 100 cm2 .

High Tolerability, Favorable Safety, and Subjects' Preference for a Single 200 mg/2 mL Tildrakizumab Injection: A Phase I, Open-Label, Randomized Crossover Trial in Healthy Volunteers.

INTRODUCTION: Tildrakizumab 200 mg/2 mL pre-filled syringe is a new preparation of tildrakizumab that is developed to facilitate patients' compliance. This phase I clinical trial compares the local tolerability, safety, and subjects' preferred method of administration of tildrakizumab when administered as a new single 200 mg/2 mL subcutaneous injection or as two 100 mg/1 mL subcutaneous injections in healthy subjects. METHODS: Visual analogue scores were used to self-assess injection site pain immediately (< 1 min) after each administration and at 1 h and 48 h after each administration. Treatment injection site reactions were assessed at 1 h and 48 h after each administration. Treatment safety was monitored throughout the study period. Subjects' preferred method of administration was assessed 4 weeks after the last administration (day 56). RESULTS: No statistically significant difference in visual analogue scores and injection site reactions was detected between the two treatments. Treatment-emergent adverse events were mild, and there were no deaths or serious adverse events. Most subjects (61.5%) preferred the treatment when administered as a single 200 mg/2 mL subcutaneous injection rather than as two 100 mg/mL subcutaneous injections. CONCLUSIONS: Administration of 200 mg tildrakizumab as a single 2 mL subcutaneous injection was safe, well tolerated, and preferred over two separate 100 mg/1 mL subcutaneous injections by healthy subjects. Eudract No. 2020-000183-37.

A multicentre, randomised, parallel-group, double-blind, vehicle-controlled and open-label, active-controlled study (versus amorolfine 5%), to evaluate the efficacy and safety of terbinafine 10% nail lacquer in the treatment of onychomycosis.

BACKGROUND: Onychomycosis is a difficult-to-treat fungal nail infection whose treatment can involve systemic or topical antifungal approaches. OBJECTIVES: To assess the efficacy and safety of terbinafine 10% nail lacquer in distal-lateral subungual onychomycosis (DLSO). PATIENTS/METHODS: Patients with mild-to-moderate DLSO were randomised (3:3:1) to receive double-blind topical terbinafine 10% (n = 406) or its vehicle (n = 410) administered once daily for 4 weeks and then once weekly for 44 weeks, or open-label topical amorolfine 5% (n = 137) for 48 weeks, with a 12-week follow-up period. The primary efficacy endpoint, complete cure rate at Week 60, was a composite of negative potassium hydroxide (KOH) microscopy, negative culture for dermatophytes and no residual clinical involvement of the target big toenail. RESULTS: Complete cure rates at Week 60 in the terbinafine, vehicle and amorolfine groups were 5.67%, 2.20% and 2.92%, respectively (odds ratio (OR) vs vehicle = 2.68; 95% confidence intervals (CI): 1.22-5.86; p = .0138). Statistically significant differences in responder (negative KOH and negative culture and ≤10% residual clinical involvement) and mycological cure rates (negative KOH and negative culture) at Week 60 were obtained between terbinafine and vehicle. Terbinafine was well-tolerated with no systemic adverse reactions identified; the most common topical adverse reactions were erythema and skin irritation. CONCLUSIONS: Terbinafine 10% nail lacquer was an effective treatment for mild-to-moderate onychomycosis improving both clinical and mycological criteria compared with vehicle. Furthermore, there may be some benefits compared to the currently available topical agent, amorolfine 5%. Treatment was well-tolerated and safe.

Efficacy and Safety of 5-Fluorouracil 0.5%/Salicylic Acid 10% in the Field-Directed Treatment of Actinic Keratosis: A Phase III, Randomized, Double-Blind, Vehicle-Controlled Trial.

INTRODUCTION: Due to the high prevalence of actinic keratosis (AK) and potential for lesions to become cancerous, clinical guidelines recommend that all are treated. The objective of this study was to evaluate the efficacy and safety of 5-fluorouracil (5-FU) 0.5%/salicylic acid 10% as field-directed treatment of AK lesions. METHODS: This multicenter, double-blind, vehicle-controlled study (NCT02289768) randomized adults, with a 25 cm2 area of skin on their face, bald scalp, or forehead covering 4-10 clinically confirmed AK lesions (grade I/II), 2:1 to treatment or vehicle applied topically once daily for 12 weeks. The primary endpoint was the proportion of patients with complete clinical clearance (CCC) of lesions in the treatment field 8 weeks after the end of treatment. Secondary endpoints included partial clearance (PC; ≥75% reduction) of lesions. Safety outcomes were assessed. RESULTS: Of 166 patients randomized, 111 received 5-FU 0.5%/salicylic acid 10% and 55 received vehicle. At 8 weeks after the end of treatment, CCC was significantly higher with 5-FU 0.5%/salicylic acid 10% than with vehicle [49.5% vs. 18.2%, respectively; odds ratio (OR) 3.9 (95% CI) 1.7, 8.7; P = 0.0006]. Significantly more patients achieved PC of lesions with treatment than with vehicle [69.5% vs. 34.6%, respectively; OR 4.9 (95% CI 2.3, 10.5); P < 0.0001]. Treatment-emergent adverse events, predominantly related to application- and administration-site reactions, were more common with 5-FU 0.5%/salicylic acid 10% than with vehicle (99.1% vs. 83.6%). CONCLUSIONS: Compared with vehicle, field-directed treatment of AK lesions with 5-FU 0.5%/salicylic acid 10% was effective in terms of CCC. Safety outcomes were consistent with the known and predictable safety profile. TRIAL REGISTRATION: NCT02289768. FUNDING: Almirall S.A.

Cost-effectiveness of linaclotide compared to antidepressants in the treatment of irritable bowel syndrome with constipation in Scotland.

Presently, linaclotide is the only EMA-approved therapy indicated for the treatment of irritable bowel syndrome with constipation (IBS-C). This study sought to determine the cost-effectiveness of linaclotide compared to antidepressants for the treatment of adults with moderate to severe IBS-C who have previously received antispasmodics and/or laxatives. A Markov model was created to estimate costs and QALYs over a 5-year time horizon from the perspective of NHS Scotland. Health states were based on treatment satisfaction (satisfied, moderately satisfied, not satisfied) and mortality. Transition probabilities were based on satisfaction data from the linaclotide pivotal studies and Scottish general all-cause mortality statistics. Treatment costs were calculated from the British National Formulary. NHS resource use and disease-related costs for each health state were estimated from Scottish clinician interviews in combination with NHS Reference costs. Quality of life was based on EQ-5D data collected from the pivotal studies. Costs and QALYs were discounted at 3.5 % per annum. Uncertainty was explored through extensive deterministic and probabilistic sensitivity analyses. Over a 5-year time horizon, the additional costs and QALYs generated with linaclotide were £659 and 0.089, resulting in an incremental cost-effectiveness ratio of £7370 per QALY versus antidepressants. Based on the probabilistic sensitivity analysis, the likelihood that linaclotide was cost-effective at a willingness to pay of £20,000 per QALY was 73 %. Linaclotide can be a cost-effective treatment for adults with moderate-to-severe IBS-C who have previously received antispasmodics and/or laxatives in Scotland.

Efficacy of aclidinium bromide 400 µg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD.

BACKGROUND: The efficacy and safety of aclidinium bromide bid, a novel, long-acting, muscarinic antagonist, was assessed in patients with moderate to severe COPD. METHODS: In this phase IIa randomized, double-blind, double-dummy, crossover trial, patients with moderate to severe COPD received aclidinium 400 µg bid, tiotropium 8 µg once daily, and placebo for 15 days, with a 9- to 15-day washout between treatment periods. Treatments were administered through the Genuair or HandiHaler dry powder inhalers. The primary end point was mean change from baseline in FEV(1) AUC(0-12/12h) (area under the curve where the numbers represent the time period for which data were collected divided by the number of hours over which the data are averaged [eg, 0-12 h postdose divided by 12 h]) on day 15. Secondary end points were changes from baseline in FEV(1) AUC(12-24/12h), FEV(1) AUC(0-24/24h), morning predose FEV(1), peak FEV(1), and COPD symptom scores. RESULTS: Thirty patients with COPD were randomized, and 27 completed the study. Mean change from baseline in FEV(1) AUC(0-12/12h) at day 15 was significantly greater for aclidinium and tiotropium over placebo (P < .0001). Mean changes from baseline in FEV(1) AUC(12-24/12h), FEV(1) AUC(0-24/24h), morning predose FEV(1), and peak FEV(1) at day 15 were significantly greater for aclidinium and tiotropium over placebo (P < .0001 for all except P < .001 for FEV(1) AUC(12-24/12h) tiotropium vs placebo). Improvements were significantly greater with aclidinium vs tiotropium on day 1 for all of the normalized AUC values of FEV(1) as well as on day 15 for FEV(1) AUC(12-24/12h) (P < .05 for all). COPD symptoms were significantly improved from baseline with aclidinium vs placebo (P < .05) but not with tiotropium. CONCLUSIONS: In patients with COPD, aclidinium 400 µg bid compared with placebo provided clinically meaningful improvements in 24-h bronchodilation that generally were comparable to tiotropium 18 µg daily but with significant differences in favor of aclidinium observed in the average nighttime period. Larger studies with longer treatment duration are ongoing to confirm the efficacy of aclidinium 400 µg bid on bronchodilation and COPD symptoms. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00868231; URL: www.clinicaltrials.gov.

Onset of effect of aclidinium, a novel, long-acting muscarinic antagonist, in patients with COPD.

ABSTRACT Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). The aim of this study was to assess the rate of onset of bronchodilation with aclidinium compared with placebo and tiotropium. This was a double-blind, double-dummy, multicenter, crossover study in COPD patients with a post-bronchodilator forced expiratory volume in 1 second (FEV(1)) ≥30% and <60% predicted. On study days, patients received single doses of aclidinium 200 µg, tiotropium 18 µg, or placebo. Serial spirometry was conducted from 10 minutes to 3 hours post-dose. The primary variable was the percentage of patients with an increase in FEV(1) of ≥10% above baseline at 30 minutes post-dose. Other assessments included change from baseline in FEV(1) and dyspnea over 3 hours post-dose. A total of 115 patients entered the study. Significantly more patients had an increase in FEV(1) of ≥10% above baseline at 30 minutes with aclidinium and tiotropium versus placebo (49.5% and 51.8% versus 13.8%; p < 0.0001). At 30 minutes, the relative increase from baseline in FEV(1) was significantly higher for aclidinium and tiotropium versus placebo (12% and 11% versus 3%; p < 0.0001). Aclidinium and tiotropium also significantly increased FEV(1) (p < 0.01) and improved the perception of dyspnea compared with placebo at all measured time points from 10 minutes to 3 hours post-dose. In conclusion, aclidinium provided effective bronchodilation, similar to that seen with tiotropium, with significant improvements compared with placebo observed from 10 minutes post-dose.

Meta-analysis of the efficacy of ebastine 20 mg compared to loratadine 10 mg and placebo in the symptomatic treatment of seasonal allergic rhinitis.

BACKGROUND: Few randomized studies have compared the efficacy of ebastine and loratadine in the symptomatic treatment of seasonal allergic rhinitis (SAR). METHODS: A meta-analysis was performed on data from four randomized, double-blind, placebo-controlled, parallel-group clinical trials comparing the efficacy of ebastine 20 mg once daily versus loratadine 10 mg once daily in the symptomatic treatment of SAR symptoms. Primary efficacy variable was the mean change in the overall mean daily reflective total symptom score (TSS), i.e. the sum of five rhinitis symptom scores: nasal discharge, nasal congestion, nasal itching, sneezing and total eye symptoms (itchy/watery eyes) over the first 2 weeks of treatment compared to baseline. RESULTS: There were 2,089 patients in the population analyzed: 749, 739 and 601 patients in the ebastine 20 mg, loratadine 10 mg and placebo groups, respectively. Compared to baseline, overall mean daily reflective TSS over the first 2 weeks of treatment was -3.61 (35.4% reduction from baseline) in the ebastine group, -3.05 (29.0% reduction) in the loratadine group and -2.30 (22.7% reduction) in the placebo group. Statistically significant differences in the mean change from baseline were found when comparing ebastine and loratadine (p<0.001), ebastine and placebo (p<0.0001), and loratadine and placebo (p<0.0001). The global effect (i.e. the difference in overall mean daily reflective TSS over the first 2 weeks of treatment) of ebastine compared with loratadine over the first 2 weeks of treatment was -0.56 (95% confidence interval, CI, -0.86 to -0.26), and it was sustained during the whole (4-week) period studied. The global effects of ebastine and loratadine compared with placebo were -1.30 (95% CI, -1.61 to -0.99) and -0.74 (95% CI, -1.05 to -0.43), respectively. Secondary variables (reflective and snapshot individual symptom scores) showed the same trend. CONCLUSIONS: This meta-analysis confirms that ebastine 20 mg has a good efficacy profile, inducing a greater decrease from baseline in mean rhinitis symptom scores than loratadine 10 mg or placebo.