Abstract：
BACKGROUND: Neurokinin receptor 1 antagonists are effective in reducing nausea and vomiting in chemotherapy-induced emesis. We investigated the safety and efficacy of tradipitant, a neurokinin receptor 1 antagonist, in patients with idiopathic and diabetic gastroparesis.
METHODS: A total of 201 adults with gastroparesis were randomly assigned to oral tradipitant 85 mg (n = 102) or placebo (n = 99) twice daily for 12 weeks. Symptoms were assessed by a daily symptom dairy, Gastroparesis Cardinal Symptom Index scores, and other patient-reported questionnaires. Blood levels were monitored for an exposure-response analysis. The primary outcome was change from baseline to week 12 in average nausea severity, measured by daily symptom diary.
RESULTS: The intention-to-treat (ITT) population did not meet the prespecified primary endpoint at week 12 (difference in nausea severity change drug vs placebo; P = .741) or prespecified secondary endpoints. Post hoc analyses were performed to control for drug exposure, rescue medications, and baseline severity inflation. Subjects with high blood levels of tradipitant significantly improved average nausea severity beginning at early time points (weeks 2-4). In post hoc sensitivity analyses, tradipitant treatment demonstrated strengthened effects, with statistically significant improvements in nausea at week 12.
CONCLUSIONS: Although tradipitant did not reach significance in the ITT population, a pharmacokinetic exposure-response analysis demonstrated significant effects with adequate tradipitant exposure. When accounting for confounding factors such as baseline severity inflation and rescue medication, a statistically significant effect was also observed. These findings suggest that tradipitant has potential as a treatment for the symptom of nausea in gastroparesis. (ClincialTrials.gov, Number: NCT04028492).
METHODS: A total of 201 adults with gastroparesis were randomly assigned to oral tradipitant 85 mg (n = 102) or placebo (n = 99) twice daily for 12 weeks. Symptoms were assessed by a daily symptom dairy, Gastroparesis Cardinal Symptom Index scores, and other patient-reported questionnaires. Blood levels were monitored for an exposure-response analysis. The primary outcome was change from baseline to week 12 in average nausea severity, measured by daily symptom diary.
RESULTS: The intention-to-treat (ITT) population did not meet the prespecified primary endpoint at week 12 (difference in nausea severity change drug vs placebo; P = .741) or prespecified secondary endpoints. Post hoc analyses were performed to control for drug exposure, rescue medications, and baseline severity inflation. Subjects with high blood levels of tradipitant significantly improved average nausea severity beginning at early time points (weeks 2-4). In post hoc sensitivity analyses, tradipitant treatment demonstrated strengthened effects, with statistically significant improvements in nausea at week 12.
CONCLUSIONS: Although tradipitant did not reach significance in the ITT population, a pharmacokinetic exposure-response analysis demonstrated significant effects with adequate tradipitant exposure. When accounting for confounding factors such as baseline severity inflation and rescue medication, a statistically significant effect was also observed. These findings suggest that tradipitant has potential as a treatment for the symptom of nausea in gastroparesis. (ClincialTrials.gov, Number: NCT04028492).
摘要：
背景：神经激肽受体1（NK1R）拮抗剂可有效减少化疗引起的呕吐中的恶心和呕吐。我们调查了传统匹坦的安全性和有效性，NK1R拮抗剂,特发性和糖尿病性胃轻瘫患者。
方法：201例成人胃轻瘫患者被随机分配到口服85mg（n=102）或安慰剂（n=99），每天两次，持续12周。通过每日症状乳制品评估症状，胃轻瘫的症状指数评分，和其他患者报告的问卷。监测血液水平以进行暴露-反应分析。主要结果是平均恶心严重程度从基线到第12周的变化，通过每日症状日记测量。
结果：ITT人群在第12周未达到预定的主要终点（恶心严重程度变化药物与安慰剂,P=.741)或预先指定的次要端点。进行事后分析以控制药物暴露，救护药物,和基线严重通货膨胀。具有高血液水平的传统匹坦的受试者在第2周至第4周的早期时间点开始显著改善平均恶心严重程度。在事后敏感性分析中，传统的pitant治疗表现出增强的效果，在第12周，恶心有统计学意义的改善。
结论：尽管traditipitant在ITT人群中没有达到显著性，药代动力学暴露-反应分析显示,适当的tradicpitant暴露有显著影响.在考虑混杂因素时，如基线严重程度通胀和救援药物，还观察到统计学上显著的效果。这些发现表明，tradicpitant具有治疗胃轻瘫恶心症状的潜力。[ClincialTrials.gov编号，NCT04028492].
方法：201例成人胃轻瘫患者被随机分配到口服85mg（n=102）或安慰剂（n=99），每天两次，持续12周。通过每日症状乳制品评估症状，胃轻瘫的症状指数评分，和其他患者报告的问卷。监测血液水平以进行暴露-反应分析。主要结果是平均恶心严重程度从基线到第12周的变化，通过每日症状日记测量。
结果：ITT人群在第12周未达到预定的主要终点（恶心严重程度变化药物与安慰剂,P=.741)或预先指定的次要端点。进行事后分析以控制药物暴露，救护药物,和基线严重通货膨胀。具有高血液水平的传统匹坦的受试者在第2周至第4周的早期时间点开始显著改善平均恶心严重程度。在事后敏感性分析中，传统的pitant治疗表现出增强的效果，在第12周，恶心有统计学意义的改善。
结论：尽管traditipitant在ITT人群中没有达到显著性，药代动力学暴露-反应分析显示,适当的tradicpitant暴露有显著影响.在考虑混杂因素时，如基线严重程度通胀和救援药物，还观察到统计学上显著的效果。这些发现表明，tradicpitant具有治疗胃轻瘫恶心症状的潜力。[ClincialTrials.gov编号，NCT04028492].
