DELTA F508 CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

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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).