Patient-reported well-being in value-based care using tildrakizumab in a real-world setting: protocol of a multinational, phase IV, 1-cohort prospective observational study (the POSITIVE study).

INTRODUCTION: Psoriasis is a chronic inflammatory skin disease that negatively impacts the quality of life of patients and their families. However, the most commonly used decision-making tools in psoriasis, Psoriasis Area and Severity Index (PASI), Physician Global Assessment (PGA) and Dermatology Life Quality Index (DLQI), do not fully capture the impact of psoriasis on patients' lives. In contrast, the well-established 5-item WHO Well-being Index (WHO-5) assesses the subjective psychological well-being of patients. Moreover, while drug innovations became available for psoriasis, data on the impact of these therapies on patients' lives and their closest environment (family, physicians) are limited. This study will assess the effect of tildrakizumab, an interleukin-23p19 inhibitor, on the overall well-being of patients with moderate-to-severe psoriasis. Moreover, the long-term benefit of tildrakizumab on physicians' satisfaction and partners' lives of patients with psoriasis will be evaluated. METHODS AND ANALYSIS: This non-interventional, prospective, observational, real-world evidence study will involve multiple sites in Europe and approximately 500 adults with moderate-to-severe psoriasis treated with tildrakizumab. Each patient will be followed for 24 months. The primary endpoint is well-being measured by the WHO-5 questionnaire. Key secondary endpoints include Physician's Satisfaction and partner's quality of life (FamilyPso). Other endpoints will evaluate skin-generic quality of life (DLQI-R), Treatment Satisfaction Questionnaire for Medication (TSQM-9), Treatment-related Patient Benefit Index 'Standard', 10 items (PBI-S-10) and work productivity and activity impairment due to psoriasis (WPAI:PSO). Statistical analyses will be based on observed cases. Multiple imputations will be performed as a sensitivity analysis, and adverse events will be reported. ETHICS AND DISSEMINATION: The study will be conducted according to the protocol, which received ethics committee approval and applicable regulatory requirements of each participating country. The results will be disseminated through scientific publications and congress presentations. TRAIL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT04823247 (Pre-results).

Efficacy, safety, and tolerability of once-daily abediterol in patients with stable, persistent asthma: a Phase II, randomized, 7-day, crossover study.

Abediterol is a once-daily, long-acting ß2 -adrenergic agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. We assessed the efficacy, safety, and tolerability of three dose levels of abediterol, given once daily for 7 days in patients with stable, persistent asthma. This was an ascending-dose, three-period incomplete crossover study design investigating three dose levels of abediterol versus placebo (EudraCT No. 2008-003732-38). Twenty-eight male patients (25-59 years) were randomized to one of four treatment sequences (1:1:1:1). Follow-up was 7 days after final treatment. Spirometry was performed regularly up to 24 h postdose Day 1, up to 36 h postdose Day 7, and at follow-up. Vital signs, 12-lead electrocardiogram, and clinical laboratory tests were recorded throughout. Abediterol 2.5, 5, and 10 µg provided clinically and statistically significant improvements from baseline (predose, Day 1) in trough forced expiratory volume in 1 sec (FEV1 ) versus placebo on Day 7 (primary endpoint) of 334, 365, and 294 mL, respectively (all P < 0.01), and peak FEV1 versus placebo on Day 7 of 364 (P < 0.001), 403 (P < 0.001), and 375 mL (P < 0.01), respectively. Days 1 and 7 area under the curve (AUC) parameters within each abediterol group were similar for AUC0-6 , AUC0-12 , AUC0-24 , and AUC12-24 , with dose-dependent effects observed on Day 1. Abediterol (2.5-10 µg) demonstrated a good safety and tolerability profile. Abediterol 2.5, 5, and 10 µg once daily achieved statistically and clinically significant improvements in pulmonary function versus placebo over 7 days and demonstrated a safety and tolerability profile comparable with placebo.

Abediterol, a novel long-acting ß2-agonist: bronchodilation, safety, tolerability and pharmacokinetic results from a single-dose, dose-ranging, active-comparator study in patients with COPD.

BACKGROUND: Abediterol is a novel, once-daily long-acting ß2-agonist in development for the treatment of chronic obstructive pulmonary disease (COPD) and asthma in combination with an anti-inflammatory agent. This Phase IIa, randomised, double-blind, crossover study investigated the bronchodilation, safety, tolerability and pharmacokinetics of abediterol in patients with moderate to severe COPD. METHODS: Seventy patients (aged ≥40 years, Global initiative for chronic Obstructive Lung Disease Stage II/III) were randomised (1:1:1:1:1:1) to single doses of abediterol 0.625, 2.5, 5 or 10 µg, indacaterol 150 µg or placebo. Spirometry was performed up to 36 h post-dose. Pharmacokinetics were assessed in a subset of patients (N = 20). Safety and tolerability were evaluated throughout the study. RESULTS: Abediterol (all doses) significantly improved change from baseline in trough forced expiratory volume in 1 s (FEV1) compared with placebo (0.102, 0.203, 0.233 and 0.259 L for abediterol 0.625, 2.5, 5 and 10 µg, respectively; all p < 0.0001; primary endpoint). Abediterol 2.5, 5 and 10 µg significantly improved trough FEV1 compared with indacaterol 150 µg (0.092, 0.122 and 0.148 L, respectively; all p < 0.0001). Improvements in bronchodilation were maintained at all time points post-dose versus placebo (all abediterol doses) and from 15 or 30 min post-dose versus indacaterol 150 µg with abediterol 2.5, 5 and 10 µg (all p < 0.05). Abediterol had low systemic exposure; incidence of treatment-emergent adverse events was similar between treatment groups. CONCLUSIONS: All doses of abediterol (0.625-10 µg) provided clinically and statistically significant, dose-dependent improvements in bronchodilation versus placebo, and abediterol 2.5, 5 and 10 µg gave significant improvements versus indacaterol. All doses of abediterol were safe and well tolerated in patients with COPD. TRIAL REGISTRATION: Clinicaltrials.gov NCT01425814 . Registered 29 August 2011.

A dose-ranging study of the bronchodilator effects of abediterol (LAS100977), a long-acting ß2-adrenergic agonist, in asthma; a Phase II, randomized study.

BACKGROUND: Long-acting ß2-adrenergic agonists (LABAs) are recommended in combination with inhaled corticosteroids (ICSs) for asthma management. Abediterol is a novel, selective, potent, once-daily LABA in development for treatment of asthma and chronic obstructive pulmonary disease. This study aimed to determine abediterol doses with similar peak bronchodilatory effect to salbutamol 400 µg, and duration of action compatible with once-daily dosing in patients with persistent, stable asthma. METHODS: This was a Phase II, randomized, double-blind, double-dummy, crossover, placebo-controlled, dose-ranging study (ClinicalTrials.gov NCT01425801) in 62 patients with mild-to-moderate asthma who were also receiving an ICS. Patients received single doses of abediterol 0.313, 0.625, 1.25, or 2.5 µg, salbutamol 400 µg, or placebo in the morning. Spirometry was performed up to 36 h post-dose; safety and tolerability were assessed throughout the study. The primary endpoint was change from baseline in peak forced expiratory volume in 1 s (FEV1). Additional endpoints included trough FEV1, normalized area under the FEV1 curve (FEV1 AUC) up to 24 h post-dose, and peak and trough forced vital capacity (FVC). RESULTS: Abediterol produced dose-dependent improvements in peak FEV1 from baseline compared with placebo, from 0.274 (95% CI 0.221, 0.327) to 0.405 L (95% CI 0.353, 0.458) for abediterol 0.313 to 2.5 µg, respectively (p < 0.0001 all doses). Abediterol 0.625, 1.25, and 2.5 µg had similar magnitude of peak FEV1 effect to salbutamol. Dose-dependent changes from baseline in trough FEV1 versus placebo were 0.219 (95% CI 0.136, 0.302) to 0.400 L (95% CI 0.317, 0.483) for abediterol 0.313 to 2.5 µg, respectively (p < 0.0001). All abediterol doses achieved significant improvements versus placebo in FEV1 AUC 0-6, 0-12, and 0-24 h, and peak and trough FVC (p < 0.05). Less than 10% of patients experienced treatment-related adverse events for each dose of abediterol; most were mild to moderate in intensity and the most common were headache and nasopharyngitis. There were no clinically relevant changes in heart rate. CONCLUSIONS: Abediterol 0.625-2.5 µg provided dose-dependent, clinically and statistically significant bronchodilation versus placebo in patients with asthma, with a peak effect similar to salbutamol and duration of action compatible with once-daily dosing. All doses of abediterol were well tolerated.

First-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of abediterol (LAS100977), a novel long-acting Β2 -agonist.

Here we report the results of a first-in-human study to evaluate the safety, tolerability pharmacokinetics, and pharmacodynamics of abediterol, a new ß2 -adrenergic agonist. Forty-eight healthy males aged 18-45 years received abediterol doses of 5, 10, 25, or 50 µg, or placebo. Safety and tolerability assessments included adverse event reporting, pulse and blood pressure monitoring, 12-lead electrocardiograms, laboratory tests, and physical examination. Pharmacodynamic assessments included whole body plethysmography to determine the bronchodilatory effect by means of airway conductance and resistance. Blood and urine samples were obtained for pharmacokinetic analyses. Abediterol showed an overall good safety and tolerability profile in the dose range tested, consistent with the expected characteristics of a ß2 -adrenergic agonist. A dose-dependent increase of systemic treatment-emergent adverse events was observed, the most frequent being palpitations, tremor, nausea, and asthenia; most were mild in intensity and resolved without the need for intervention. Improvements in airway conductance (increase) and resistance (decrease) were greater for all doses of abediterol tested compared with placebo at all time-points up to 36 hours. This first-in-human study suggests a potent, rapid, and sustained bronchodilatory effect of abediterol in healthy male subjects. Lower doses are currently under investigation in patients with asthma and in patients with COPD.