A multicenter, double-blind, randomized, placebo- controlled, parallel study to assess the efficacy of 5- HT4 agonist prucalopride for the treatment of diabetic and idiopathic gastroparesis

摘要 在诊断和治疗胃轻瘫（GP）症状谱的临床世界中， 仍然有许多具有挑战性的需求需要了解，同时进一步调查 该实体的病理生理学，其在美国影响> 1000万患者。GP患者表现出一系列 这些症状并不总是与我们所依赖的诊断和评估的客观测试相关 他们对药物的临床反应。 我们根据RFA-DK-20-504对NIDDK胃轻瘫联盟（U 01）的回应有以下目的： 1)A）继续并完成GpCRC发起的已批准的研究，具体包括： 将合格患者纳入胃轻瘫登记研究3，并提供所有相关临床和生物样本，包括 还有PBMC分离（外周血单核细胞），以及完成丁螺环酮（BEST） 临床试验; B）在以下时间点继续获得胃窦和幽门平滑肌组织样品： 手术，以进一步提高我们的胃轻瘫（PBG协议的病理基础的知识。C）、 研究胃轻瘫症状患者的幽门括约肌功能（PSAGS） EndoFlip评估方案。 B）我们对GP登记4（GpR 4）的其他建议是：1）在GpR 4的常规EGD期间， 可能的PSAGS研究，我们想收集十二指肠和胃微生物群的样本，通过获得 胃和十二指肠粘膜刷; 2）使用内窥镜活检胃窦固有肌层组织 上消化道内镜检查期间的粘膜下剥离（ESD）方法。 2)作为一种新的研究策略，我们建议调查在内窥镜检查时获得的微生物群是否 通过刷胃和十二指肠的粘膜，在特发性和 糖尿病GP和对照组。我们假设上消化道微生物群的生态失调可能有助于 GP患者的胃排空延迟和症状，特别是我们的特发性亚组， 队列。 3)我们的临床试验计划是研究一种新的选择性5-HT 4受体激动剂的治疗效果， 普芦必利，改善特发性和糖尿病GP患者的症状和胃排空， 同时具有优异的安全特性。一项多中心、双盲、随机、安慰剂- 将进行对照、平行研究，邀请所有中心的所有GpR 4患者参加 入组2个平行的4周安慰剂或普芦必利2 mg QD治疗期试验。

Abstract In the clinical world of diagnosis and treatment options for the spectrum of gastroparesis (GP) symptoms, there are still numerous and challenging needs to understand, while at the same time further investigating the pathophysiology of this entity, which affects > 10 million of patients in the US. GP patients exhibit a range of symptoms which do not always correlate with the objective tests we rely on for diagnosis, as well as for assessing their clinical reactions to pharmacological agents. Our response to the NIDDK Gastroparesis Consortium (U01) under RFA-DK-20-504 has the following aims: 1) A) Continue and complete already approved studies initiated by the GpCRC, which specifically entails enrolling qualified patients to Gastroparesis Registry 3, with all relevant clinical and bio-samples, including also PBMC isolation (peripheral blood mononuclear cells), as well as completing the Buspirone (BESST) clinical trial; B) Continue obtaining gastric antral and pyloric smooth muscle tissue samples at the time of surgeries to further advance our knowledge of pathological basis of gastroparesis (PBG) protocol. C) Investigate Pyloric Sphincter Abnormalities in Patients with Gastroparesis Symptoms (PSAGS) per the EndoFlip assessment protocol. B) Our additional proposals for the GP Registry 4 (GpR4) are: 1) During the routine EGD for GpR4 and possible PSAGS studies, we would like to collect samples of duodenal and gastric microbiota by obtaining brushings of gastric and duodenal mucosa; 2) biopsy antral muscularis propria tissue using Endoscopic Submucosal Dissection (ESD) methodology during upper GI endoscopy . 2) As a new research strategy, we propose to investigate whether microbiota obtained at the time of endoscopy by brushing the mucosa of the stomach and duodenum, will differ in their composition in idiopathic and diabetic GP and control patients. We hypothesize that dysbiosis of the upper GI microbiota may contribute to the delayed gastric emptying and symptoms in GP patients, particularly in the idiopathic subgroup of our cohort. 3) Our clinical trial proposal is to investigate the therapeutic efficacy of a new selective 5-HT4 receptor agonist, Pruclalopride, to improve the symptoms and gastric emptying in idiopathic and diabetic GP patients while at the same time having an excellent safety profile. A multicenter, double blind, randomized, placebo- controlled, parallel study, will be conducted were all GpR4 patients from all centers will be invited to be enroll into 2 parallel 4-week treatment periods with placebo or pruclalopride 2mg QD trial.