The Efficacy and Safety of Gefapixant in a Phase 3b Trial of Patients with Recent-Onset Chronic Cough.

PURPOSE: We evaluated gefapixant, a P2X3 receptor antagonist, in participants with recent-onset (≤ 12 months) refractory chronic cough (RCC) or unexplained chronic cough (UCC). METHODS: Participants (≥ 18 years of age; ≥ 40 mm on a 100-mm cough severity visual analog scale [VAS] at screening and randomization) with chronic cough for < 12 months were enrolled in this phase 3b, double-blind, placebo-controlled, parallel group, multicenter study (NCT04193202). Participants were randomized 1:1 to gefapixant 45 mg BID or placebo for 12 weeks with a 2-week follow-up. The primary efficacy endpoint was change from baseline at Week 12 in Leicester Cough Questionnaire (LCQ) total score. Adverse events were monitored and evaluated. RESULTS: There were 415 participants randomized and treated (mean age 52.5 years; median [range] duration 7.5 [1-12] months): 209 received placebo and 206 received gefapixant 45 mg BID. A statistically significant treatment difference of 0.75 (95% CI: 0.06, 1.44; p = 0.034) for gefapixant vs. placebo was observed for change from baseline in LCQ total score at Week 12. The most common AE was dysgeusia (32% gefapixant vs. 3% placebo participants); serious AEs were rare (1.5% gefapixant vs. 1.9% placebo participants). CONCLUSION: Gefapixant 45 mg BID demonstrated significantly greater improvement in cough-specific health status from baseline compared to placebo, in participants with recent-onset chronic cough. The most common AEs were related to taste and serious AEs were rare.

Treatment of Persistent Cough in Subjects with Idiopathic Pulmonary Fibrosis (IPF) with Gefapixant, a P2X3 Antagonist, in a Randomized, Placebo-Controlled Clinical Trial.

INTRODUCTION: Chronic cough is a highly problematic symptom for patients with idiopathic pulmonary fibrosis (IPF); limited therapeutic options are available. We evaluated gefapixant, a P2X3 receptor antagonist, for the treatment of chronic cough in IPF. METHODS: This randomized, double-blind, placebo-controlled, crossover study included subjects with IPF. Sequence A included gefapixant 50 mg BID (period 1; 14 days) followed by placebo (period 2; 14 days); sequence B had the opposite sequence of treatments. This regimen was specified in a protocol amendment that modified the original active treatment regimen of gefapixant 50 mg BID for 10 days and 150 mg BID for 4 days. Patients randomized to the original treatment regimen were excluded from efficacy analyses but included in safety assessments. The primary efficacy endpoint was change from baseline in awake cough frequency (coughs/hour) from periods 1 and 2 combined. Adverse events (AEs) were monitored throughout the study. RESULTS: A total of 51 subjects were randomized, 44 of whom were randomized to treatment sequences evaluated in the primary efficacy analysis (i.e., 22 subjects in sequence A and 22 subjects in sequence B); seven subjects received the treatment assigned before the protocol amendment and were excluded from efficacy analyses. The change from baseline in awake cough frequency from periods 1 and 2 combined (mixed model for repeated measures analysis) did not demonstrate a significant reduction versus placebo in cough at day 14 (p = 0.90); in a post hoc analysis of log-transformed data p value for reduction versus placebo at day 14 was 0.07. The most common AEs were related to taste (dysgeusia and ageusia). CONCLUSIONS: Gefapixant was generally well tolerated but was not associated with a significant improvement in chronic cough in subjects with IPF as defined by the primary endpoint in this study. TRIAL REGISTRATION: NCT02502097.

Pharmacokinetics and pharmacodynamics of aprepitant for the prevention of postoperative nausea and vomiting in pediatric subjects.

BACKGROUND/PURPOSE: This multicenter, randomized, partially-blinded phase IIb study evaluated the pharmacokinetics (PK)/pharmacodynamics, safety, and tolerability of aprepitant in pediatric subjects for the prevention of postoperative nausea and vomiting (PONV). METHODS: Subjects aged birth to 17 years scheduled to undergo surgery and receive general anesthesia with ≥1 risk factor for PONV were randomly assigned to 1 of 3 aprepitant dose regimens (a single oral dose of aprepitant equivalent to adult doses of 10 mg, 40 mg, or 125 mg), or a control regimen of ondansetron before anesthesia. Assessments included PK, safety, and exploratory efficacy (complete response [CR; no emesis, retching, or dry heaves and no rescue therapy within 0-24 h following surgery] and no vomiting [NV; no emesis, retching, or dry heaves within 0-24 h following surgery]). RESULTS: Of 220 randomized and treated subjects, 119 receiving a single aprepitant dose were sampled for PK analysis and had evaluable aprepitant plasma concentrations. A dose-dependent relationship in exposure (AUC0-8 h and Cmax) was observed. Aprepitant was generally well tolerated, and the CR and NV rates were high (>80%) across treatment groups. CONCLUSIONS: PK, safety, and preliminary efficacy analyses support further clinical evaluation of aprepitant for PONV prophylaxis in pediatric patients. CLINICALTRIALS. GOV ID: NCT01732458 LEVEL OF EVIDENCE: Therapeutic, Level I.

The Relationship between Obesity and Cognitive Performance in Children: A Longitudinal Study.

BACKGROUND: The relationship between obesity and academic outcomes remains unclear. We evaluated the association between obesity and cognitive performance in US children. METHODS: We analyzed two nationally representative prospective cohorts of children in the 1979 National Longitudinal Survey of Youth, ages 2 through 8 at baseline and followed for 6 years, from 1988 to 1994 (cohort 1, n=2672) and 1994 to 2000 (cohort 2, n=1991). The main exposure variable was obesity (defined as never obese, became obese, always obese, and became nonobese). The main outcomes were standardized scores on four cognitive assessments. Univariate regression analyses of test scores on obesity were performed. Fixed-effects regression models, controlling for measured and unmeasured time-invariant confounders, were additionally adjusted for time-variant confounders to analyze the impact of change in obesity status on change in test scores. RESULTS: Unadjusted analyses revealed a significant association between obesity and Peabody Individual Achievement Test (PIAT) scores. In cohort 1, always obese children had lower PIAT math scores than never obese children (ß=-7.48; p<0.05). Always obese boys had lower PIAT math scores than those who were never obese (ß=-16.45; p<0.01). In cohort 2, PIAT math scores were lower in the became obese category than the never obese category (ß=-4.10; p<0.05). Always obese girls had lower PIAT reading scores than those who were never obese (ß=-11.28; p<0.01). Fixed-effects models additionally adjusted for Home Observation Measurement of the Environment, Short Form score and height percentile showed no significant relationship between obesity and test scores in either cohort. CONCLUSION: Childhood obesity is unlikely to be causally related to cognitive performance.

Three Interventions That Reduce Childhood Obesity Are Projected To Save More Than They Cost To Implement.

Policy makers seeking to reduce childhood obesity must prioritize investment in treatment and primary prevention. We estimated the cost-effectiveness of seven interventions high on the obesity policy agenda: a sugar-sweetened beverage excise tax; elimination of the tax subsidy for advertising unhealthy food to children; restaurant menu calorie labeling; nutrition standards for school meals; nutrition standards for all other food and beverages sold in schools; improved early care and education; and increased access to adolescent bariatric surgery. We used systematic reviews and a microsimulation model of national implementation of the interventions over the period 2015-25 to estimate their impact on obesity prevalence and their cost-effectiveness for reducing the body mass index of individuals. In our model, three of the seven interventions--excise tax, elimination of the tax deduction, and nutrition standards for food and beverages sold in schools outside of meals--saved more in health care costs than they cost to implement. Each of the three interventions prevented 129,000-576,000 cases of childhood obesity in 2025. Adolescent bariatric surgery had a negligible impact on obesity prevalence. Our results highlight the importance of primary prevention for policy makers aiming to reduce childhood obesity.