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，有 仍有许多具有挑战性的需要了解，同时进一步调查 这一实体的病理生理学，它影响了美国1000万患者。全科医生患者表现出一系列 症状并不总是与我们诊断和评估所依赖的客观测试相关 他们对药物的临床反应。 根据RFA-DK-20-504，我们对NIDDK胃瘫联盟(U01)的回应有以下目标： 1)a)继续并完成GpCRC发起的已获批准的研究，这具体涉及 将符合条件的患者登记到胃瘫登记处3，并提供所有相关的临床和生物样本，包括 还有PBMC分离(外周血单核细胞)，以及完成丁螺环酮(BESST) 临床试验；B)继续采集胃窦和幽门平滑肌组织标本 进一步提高我们对胃轻瘫(PBG)的病理基础的认识。c) 调查胃瘫症状患者的幽门括约肌异常 EndoFlip评估协议。 B)我们对普通科医生登记处4(GPR4)的其他建议是：1)在GPR4的例行EGD期间和 可能的PSAGS研究，我们希望收集十二指肠和胃的微生物区系样本，通过获得 胃、十二指肠黏膜刷检；2)内窥镜下胃窦固有肌组织活检 上消化道内窥镜检查中的粘膜下剥离(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是否获得微生物区系 通过刷胃和十二指肠粘膜，会使特发性和十二指肠粘膜的成分有所不同 糖尿病全科医生和对照组。我们推测，上消化道微生物区系的失调可能对 GP患者的胃排空延迟和症状，特别是在我们的特发性亚组 一群人。 3)我们的临床试验方案是研究一种新的选择性5-HT4受体激动剂的治疗效果， 普鲁洛必利，用于改善特发性和糖尿病GP患者的症状和胃排空 同时拥有极佳的安全性能。多中心、双盲、随机、安慰剂- 将进行对照、平行研究，所有中心的所有GPR4患者将被邀请参加 用安慰剂或普鲁洛必利2 mg，qd，参加2个平行的为期4周的治疗周期。

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.