Trial of Indole-3-Carbinol and Silibinin
- Registration Number
- NCT03687073
- Lead Sponsor
- Masonic Cancer Center, University of Minnesota
- Brief Summary
This is a non-therapeutic, Phase 1 clinical trial to examine the safety, pharmacokinetic (PK) characteristics, and pharmacodynamics (PD) effect of indole-3-carbinol (I3C) and silibinin (Sil) in healthy subjects.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 21
Inclusion Criteria
-
Adult ≥ 18 years old
-
Current smoker of ≥ 8 cigarettes per day for at least the last 6 months by self-report
-
Adequate blood counts, and adequate liver and kidney function defined as follows:
- Hemoglobin ≥ 9 g/dL for women, ≥ 10 g/dL for men
- Platelet count ≥ 100 x 10^9/L
- Total bilirubin ≤ Institutional upper limit of normal (≤ 1.3 mg/dL for UMMC)
- ALT ≤ 1.5 times institutional upper limit of normal
- Creatinine ≤ 1.4 g/dL and estimated GFR ≥ 80 mL/min/1.7m2
-
Able to understand the experimental nature of the study and provide informed written consent
Exclusion Criteria
- Chronic proton pump inhibitor, H2-blocker (i.e., ranitidine, famotidine), and/or calcium carbonate use
- History of gastric bypass surgery, gastric banding, bowel resection, malabsorption syndromes such as celiac sprue or pancreatic insufficiency, or other conditions that may affect gastric or intestinal absorption of nutrients
- Current use of tobacco products other than cigarettes (i.e. snuff, snuz, smokeless tobacco, cigars, pipes), or use of these products within 3 months of study registration
- Major or chronic medical disease, including heart disease, poorly controlled diabetes, etc., to be adjudicated by the principal investigator
- Known active malignancy
- History of aerodigestive malignancies
- Women who are pregnant, intend to become pregnant within 3 months of study registration, or who are lactating. Women of childbearing potential must have a negative urine pregnancy test within 14 days of starting the assigned intervention
- Antibiotic use within 2 months of study registration by self-report
- History of respiratory tract cancer
- Known allergy to I3C, Sil, or its components
- Psychiatric and/or social situations that would potentially limit compliance with study requirements
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Single-dose PK study Silibin Subjects will take the assigned dose of I3C, Sil, or I3C + Sil once at the study center. Ten mL of blood will be collected at the time points described in Section 9.14. Concurrently, urine will also be collected for 24 hours after the first dose of I3C, Sil or I3C + Sil, divided into the time intervals. Multi-dose PK Study Silibin Subjects will take the assigned dose of I3C, Sil, or I3C + Sil for 8 weeks. Ten mL of blood will be collected at the time points described in Section 9.14. Concurrently, urine will be collected for 24 hours after the first dose of I3C, Sil or I3C + Sil, divided into the time intervals. Safety Study Silibin Safety data will be generated during the multi-dose PK and PD study, as DLT is not anticipated in the single-dose PK study. Enrollment into dose cohorts 1 and 2 can occur on a continuous basis. Enrollment for dose cohorts 3 and 4 will be done sequentially using a modified 3+3 design (see Section 8.2). The first three subjects enrolled into a dose cohort must complete at least 21 days of the multi-dose PK/PD study without a DLT before the remaining 4 subjects in the cohort can be enrolled. Cohort 4 PD Study Silibin The effect of I3C, Sil, or I3C + Sil on the pharmacodynamic endpoints listed under the Secondary Objectives in Section 1.2 will be characterized. This PD study will be done concurrently with the multi-dose PK study. Subjects will take the assigned dose of I3C, Sil, or I3C + Sil for 8 weeks. Nasal epithelium, oral cavity cells, buccal cells, blood, and urine will be collected at the time points described in the study calendar in Section 4.0. Single-dose PK study Indole-3-Carbinol Subjects will take the assigned dose of I3C, Sil, or I3C + Sil once at the study center. Ten mL of blood will be collected at the time points described in Section 9.14. Concurrently, urine will also be collected for 24 hours after the first dose of I3C, Sil or I3C + Sil, divided into the time intervals. Multi-dose PK Study Indole-3-Carbinol Subjects will take the assigned dose of I3C, Sil, or I3C + Sil for 8 weeks. Ten mL of blood will be collected at the time points described in Section 9.14. Concurrently, urine will be collected for 24 hours after the first dose of I3C, Sil or I3C + Sil, divided into the time intervals. Single-dose PK study Silibinin Subjects will take the assigned dose of I3C, Sil, or I3C + Sil once at the study center. Ten mL of blood will be collected at the time points described in Section 9.14. Concurrently, urine will also be collected for 24 hours after the first dose of I3C, Sil or I3C + Sil, divided into the time intervals. Multi-dose PK Study Silibinin Subjects will take the assigned dose of I3C, Sil, or I3C + Sil for 8 weeks. Ten mL of blood will be collected at the time points described in Section 9.14. Concurrently, urine will be collected for 24 hours after the first dose of I3C, Sil or I3C + Sil, divided into the time intervals. Safety Study Indole-3-Carbinol Safety data will be generated during the multi-dose PK and PD study, as DLT is not anticipated in the single-dose PK study. Enrollment into dose cohorts 1 and 2 can occur on a continuous basis. Enrollment for dose cohorts 3 and 4 will be done sequentially using a modified 3+3 design (see Section 8.2). The first three subjects enrolled into a dose cohort must complete at least 21 days of the multi-dose PK/PD study without a DLT before the remaining 4 subjects in the cohort can be enrolled. Cohort 4 PD Study Indole-3-Carbinol The effect of I3C, Sil, or I3C + Sil on the pharmacodynamic endpoints listed under the Secondary Objectives in Section 1.2 will be characterized. This PD study will be done concurrently with the multi-dose PK study. Subjects will take the assigned dose of I3C, Sil, or I3C + Sil for 8 weeks. Nasal epithelium, oral cavity cells, buccal cells, blood, and urine will be collected at the time points described in the study calendar in Section 4.0. Safety Study Silibinin Safety data will be generated during the multi-dose PK and PD study, as DLT is not anticipated in the single-dose PK study. Enrollment into dose cohorts 1 and 2 can occur on a continuous basis. Enrollment for dose cohorts 3 and 4 will be done sequentially using a modified 3+3 design (see Section 8.2). The first three subjects enrolled into a dose cohort must complete at least 21 days of the multi-dose PK/PD study without a DLT before the remaining 4 subjects in the cohort can be enrolled. Cohort 4 PD Study Silibinin The effect of I3C, Sil, or I3C + Sil on the pharmacodynamic endpoints listed under the Secondary Objectives in Section 1.2 will be characterized. This PD study will be done concurrently with the multi-dose PK study. Subjects will take the assigned dose of I3C, Sil, or I3C + Sil for 8 weeks. Nasal epithelium, oral cavity cells, buccal cells, blood, and urine will be collected at the time points described in the study calendar in Section 4.0.
- Primary Outcome Measures
Name Time Method Safety of the combination of I3C + Sil Week 8 Incidence of Dose Limiting Toxicities (DLTs)
Pharmacokinetic profile of I3C + Sil Week 8 Accumulation
- Secondary Outcome Measures
Name Time Method Effect of I3C, Sil, or I3C + Sil on RNA sequencing from PBMC Week 8 Change in of I3C, Sil, or I3C + Sil on
Effect of I3C, Sil, or I3C + Sil on circulating inflammatory markers Week 8 Change in inflammatory markers IL-1B, TNF-a, IL-6, IL-8, Cox-2, prostaglandin E, and C-reactive protein
Effect of I3C, Sil, or I3C + Sil on protein expression of phosphorylated-Akt (pAkt), pERK, pSTAT3 and NF-kB from peripheral blood mononuclear cells (PBMC) Week 8 Change in protein expression of phosphorylated-Akt (pAkt), pERK, pSTAT3 and NF-kB from peripheral blood mononuclear cells (PBMC)
Effect of I3C, Sil, or I3C + Sil on waist circumference Week 8 Change in waist circumference
Effect of I3C, Sil, or I3C + Sil on circulating immunophenotype Week 8 Change in circulating immunophenotype
Effect of I3C, Sil, or I3C + Sil on fasting glucose Week 8 Change in fasting glucose
Effect of I3C, Sil, or I3C + Sil on fasting insulin Week 8 Change in fasting insulin
Effect of I3C, Sil, or I3C + Sil on lipid profile Week 8 Change in lipid profile
Effect of I3C, Sil, or I3C + Sil on leptin Week 8 Change in leptin
Effect of I3C, Sil, or I3C + Sil on body weight Week 8 Change in body weight
Effect of I3C, Sil, or I3C + Sil on PIK3CA pathway signaling in buccal cells Week 8 Change in PIK3CA pathway signaling in buccal cells
Effect of I3C, Sil, or I3C + Sil on PIK3CA pathway signaling in oral cavity cells Week 8 Change in PIK3CA pathway signaling in oral cavity cells
Effect of I3C, Sil, or I3C + Sil on PIK3CA pathway signaling in nasal mucosa Week 8 Change in PIK3CA pathway signaling in nasal mucosa
Trial Locations
- Locations (1)
Masonic Cancer Center at University of Minnesota
🇺🇸Minneapolis, Minnesota, United States