DELTA F508 CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这是一项I期、开放标签、安全性和剂量发现的研究，目的是提高口服姜黄素类药物的剂量，用于囊性纤维化的成年受试者，这些受试者是？F508 CFTR突变纯合子。这项研究的主要目的是评估连续14天口服提前剂量的姜黄素类药物在囊性纤维化(CF)成人受试者中的安全性，这些患者是？F508CFTR纯合子。本研究的次要目的是：1)获得口服姜黄素在慢性阻塞性肺疾病患者中的药代动力学数据，2)通过测量鼻电位差(NPD)来评估姜黄素改变呼吸道上皮离子转运的有效性，以及3)通过测量汗液氯浓度来初步评估姜黄素改变汗管上皮离子转运的潜在疗效。这项研究是非随机开放标签，没有安慰剂对照。它将包括一个14天的剂量队列，其中初始剂量水平将持续7天，然后是更高的剂量水平，持续7天。将有大约10名受试者加入队列，以达到总共8个可评价的受试者。这项研究将涉及两(2)个地点。受试者将接受1.5克研究药物(TID)，每天三次(剂量级别1)，连续7天，随后接受3克研究药物TID(剂量级别2)，连续7天。每个受试者参加研究的时间约为34天，包括5次研究访问，定义为：访问1(筛查，第14天至第10天，其中第1天是受试者将获得第一剂研究药物的当天)、访问2(基线测量和开始研究药物的第1天)、访问3(开始更大剂量的研究药物，第8天)、访问4(最后剂量的研究药物，第15天)和访问5(后续，第22天)。研究药物将首先在下午的第一天(第二天)就诊时按初始剂量水平给予。受试者将于第一天晚上在家服用学习药物，第二天至第七天每天三次，上午、下午和晚上。最后一剂初始剂量的学习药物将在第三次访问的上午(第八天)服用。研究药物将在下午的较高剂量水平下在第三次就诊时(第8天)给予。受试者将在第8天晚上在家中服用较高剂量的研究药物，并在第9至14天每天三次。最后一次较高剂量的药物将在上午访问第4次(第15天)。受试者将被允许在第三次和第四次访问之前选择在GCRC工地过夜，以便在这两个上午的适当时间(上午8点)开始访问程序。这项研究将评估在筛查(访问1)、第8天(访问3，在初始剂量水平的最终剂量之后)和第15天(访问4，在研究药物的最后剂量之后)就诊时安全参数的变化以及鼻部电位差(NPD)测量的变化。基线氯化汗量将在第1次就诊(筛查)，或服药前第2次就诊，或第1次就诊和第2次就诊之间的任何一天进行。在最后一次研究药物剂量后，第4次就诊时将进行氯化汗量测量。在第一次服用研究药物前的第2天(第1天)，将采集血浆进行基线药代动力学(PK)分析。在访问第2天第一剂研究药物、在访问3(第8天)以初始剂量水平最后一次给药、在访问4(第15天)最后一次以较高剂量给药之后，将获得连续的PK采集。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a Phase I, open label, safety and dose finding study of advancing doses of orally administered curcuminoids in adult subjects with cystic fibrosis who are homozygous for ?F508 CFTR mutation. The primary objective of this study is to assess the safety of advancing doses of curcuminoids administered orally for fourteen consecutive days in adult subjects with cystic fibrosis (CF) who are homozygous for ?F508 CFTR. The secondary objectives of this study are: 1) to obtain pharmacokinetic data for oral curcuminoids in CF subjects, 2) to assess the efficacy of curcuminoids to alter ion transport across respiratory epithelia by measurement of nasal potential difference (NPD), and 3) to make a preliminary assessment of the potential efficacy of curcuminoids to alter ion transport across sweat duct epithelia by measurement of sweat chloride concentrations. The study is non-randomized and open label with no placebo control. It will consist of a single 14-day dosing cohort in which an initial dose level will be administered for 7 days, followed by a higher dose level administered for 7 days. Approximately 10 subjects will be enrolled in the cohort in order to achieve a total of 8 evaluable subjects. Two (2) sites will be involved in the study. Subjects will receive 1.5 grams of study drug three times per day (TID) (Dose Level 1) for 7 consecutive days, followed by 3 grams of study drug TID (Dose Level 2) for 7 consecutive days. The length of study participation for each subject will be approximately 34 days and consist of 5 study Visits defined as: Visit 1 (Screening, Day -14 to -10 where Day 1 is that day on which the subject will receive their first dose of study drug), Visit 2 (Baseline measurements and initiation of study drug, Day 1), Visit 3 (Initiation of higher dose, Day 8), Visit 4 (final dose of study drug, Day 15), and Visit 5 (Follow-up, Day 22). Study drug will first be administered at the initial dose level in the afternoon at Visit 2 (Day 1). The subject will take study drug at home on the evening of Day 1 and three times a day, morning, afternoon and evening, on Days 2 through 7. The final dose of study drug at the initial dose level will be administered on the morning of Visit 3 (Day 8). Study drug will be administered at the higher dose level in the afternoon at Visit 3 (Day 8). The subject will take study drug at the higher dose level at home on the evening of Day 8 and three times a day on Days 9 through 14. The final dose at the higher dose level will be administered in the morning at Visit 4 (Day 15). Subjects will be allowed the option of staying in the site GCRC overnight prior to Visits 3 and 4 to allow the Visit procedures to begin at an appropriate time on those mornings (@ 8am). The study will assess changes in safety parameters, and changes in Nasal Potential Difference (NPD) measurements between Visits at screening (Visit 1), Day 8 (Visit 3, after final dose at initial dose level) and Day 15 (Visit 4, after the final dose of study drug). A baseline sweat chloride measurement will be obtained at Visit 1 (screening), or at Visit 2 prior to dosing, or any day between Visits 1 and 2. A post-treatment sweat chloride measurement will be performed on Visit 4 following the final dose of study drug. A plasma collection will be obtained for baseline pharmacokinetic (PK) analysis at Visit 2 (Day 1) prior to the first dose of study drug. Sequential PK collections will be obtained following the first dose of study drug on Visit 2, following the last administration of study drug at the initial dose level on Visit 3 (Day 8), and following the last administration of study drug at the higher dose level on Visit 4 (Day 15).