gsk1325756 and Pulmonary-Disease--Chronic-Obstructive

This study aimed to illustrate how a new methodology to assess clinical trial outcome measures using a longitudinal item response theory-based model (IRM) could serve as an alternative to mixed model repeated measures (MMRM). Data from the EXACT (Exacerbation of chronic pulmonary disease tool) which is used to capture frequency, severity, and duration of exacerbations in COPD were analyzed using an IRM. The IRM included a graded response model characterizing item parameters and functions describing symptom-time course. Total scores were simulated (month 12) using uncertainty in parameter estimates. The 50th (2.5th, 97.5th) percentiles of the resulting simulated differences in average total score (drug minus placebo) represented the estimated drug effect (95%CI), which was compared with published MMRM results. Furthermore, differences in sample size, sensitivity, specificity, and type I and II errors between approaches were explored. Patients received either oral danirixin 75 mg twice daily (n = 45) or placebo (n = 48) on top of standard of care over 52 weeks. A step function best described the COPD symptoms-time course in both trial arms. The IRM improved precision of the estimated drug effect compared to MMRM, resulting in a sample size of 2.5 times larger for the MMRM analysis to achieve the IRM precision. The IRM showed a higher probability of a positive predictive value (34%) than MMRM (22%). An item model-based analysis data gave more precise estimates of drug effect than MMRM analysis for the same endpoint in this one case study.

Topics: Administration, Oral; Aged; Data Interpretation, Statistical; Female; Humans; Male; Middle Aged; Models, Biological; Piperidines; Placebos; Pulmonary Disease, Chronic Obstructive; Research Design; Sample Size; Severity of Illness Index; Sulfones; Symptom Flare Up; Treatment Outcome

Oral CXC chemokine receptor 2 (CXCR2) antagonists have been shown to inhibit neutrophil migration and activation in the lung in preclinical and human models of neutrophilic airway inflammation. A previous study with danirixin, a reversible CXCR2 antagonist, demonstrated a trend for improved respiratory symptoms and health status in patients with COPD.. This 26-week, randomised, double-blind, placebo-controlled phase IIb study enrolled symptomatic patients with mild-to-moderate COPD at risk for exacerbations. Patients received danirixin 5, 10, 25, 35 or 50 mg twice daily or placebo in addition to standard of care. Primary end-points were the dose response of danirixin compared with placebo on the incidence and severity of respiratory symptoms (Evaluating Respiratory Symptoms in COPD [E-RS:COPD] scores) and safety. Secondary end-points included the incidence of moderate-severe exacerbations, health status (COPD Assessment test, CAT) and health-related quality of life HRQoL (St. George Respiratory Questionnaire-COPD, SGRQ-C).. A total of 614 participants were randomized to treatment. There were no improvements in E-RS:COPD, CAT or SGRQ-C scores in participants treated with any dose of danirixin compared to placebo; a larger than expected placebo effect was observed. There was an increased incidence of exacerbation in the danirixin-treated groups and an increased number of pneumonias in participants treated with danirixin 50 mg.. The robust placebo and study effects prohibited any conclusions on the efficacy of danirixin. However, the absence of a clear efficacy benefit and the observed increase in exacerbations in danirixin-treated groups suggests an unfavorable benefit-risk profile in patients with COPD.. This study was registered with clinicaltrials.gov, NCT03034967.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Mucus; Piperidines; Pulmonary Disease, Chronic Obstructive; Receptors, Interleukin-8B; Retrospective Studies; Sulfones; Surveys and Questionnaires; Young Adult

Danirixin is a selective and reversible CXC chemokine receptor 2 antagonist that may be useful for the treatment of respiratory diseases such as chronic obstructive pulmonary disease. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of danirixin after administration of single oral doses of 10, 50, and 100 mg danirixin hydrobromide (HBr) tablets in the fed state (high-fat meal) (part 1) and to evaluate the food effect (low-fat meal) on the pharmacokinetics of danirixin after administration of a single oral dose of 50 mg danirixin HBr tablets (part 2). A total of 34 Japanese healthy elderly male participants were enrolled; 18 participants were included in part 1, and 16 in part 2. The systemic exposure to danirixin (maximum blood concentration [C

Topics: Administration, Oral; Aged; Area Under Curve; Cross-Over Studies; Dietary Fats; Dose-Response Relationship, Drug; Double-Blind Method; Food-Drug Interactions; Healthy Volunteers; Humans; Japan; Male; Piperidines; Pulmonary Disease, Chronic Obstructive; Receptors, Interleukin-8B; Sulfones; Tablets

Topics: Administration, Oral; Aged; Female; Health Status; Humans; Male; Middle Aged; Omeprazole; Piperidines; Pulmonary Disease, Chronic Obstructive; Receptors, Interleukin-8B; Sulfones; Treatment Outcome