Trial of Indole-3-Carbinol and Silibinin

Study Overview
=================
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.

Official Title
-----------------
Trial of Indole-3-Carbinol & Silibinin

Conditions
-----------------
Smoking

Intervention / Treatment
-----------------
* Drug: Indole-3-Carbinol
* Drug: Silibinin
* Drug: Silibin


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single-dose PK study<br>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. | Drug: Indole-3-Carbinol<br>* Cohorts 2, 3, & 4: 400 mg PO BID<br>* Other names: 13C;Drug: Silibinin<br>* Cohorts 1 & 4: 720mg<br>* Other names: Sil;Drug: Silibin<br>* Cohort 3: 360mg<br>* Other names: Sil;|
| Experimental: Multi-dose PK Study<br>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. | Drug: Indole-3-Carbinol<br>* Cohorts 2, 3, & 4: 400 mg PO BID<br>* Other names: 13C;Drug: Silibinin<br>* Cohorts 1 & 4: 720mg<br>* Other names: Sil;Drug: Silibin<br>* Cohort 3: 360mg<br>* Other names: Sil;|
| Experimental: Safety Study<br>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. | Drug: Indole-3-Carbinol<br>* Cohorts 2, 3, & 4: 400 mg PO BID<br>* Other names: 13C;Drug: Silibinin<br>* Cohorts 1 & 4: 720mg<br>* Other names: Sil;Drug: Silibin<br>* Cohort 3: 360mg<br>* Other names: Sil;|
| Experimental: Cohort 4 PD Study<br>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. | Drug: Indole-3-Carbinol<br>* Cohorts 2, 3, & 4: 400 mg PO BID<br>* Other names: 13C;Drug: Silibinin<br>* Cohorts 1 & 4: 720mg<br>* Other names: Sil;Drug: Silibin<br>* Cohort 3: 360mg<br>* Other names: Sil;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of the combination of I3C + Sil | Incidence of Dose Limiting Toxicities (DLTs) | Week 8 | 
| Pharmacokinetic profile of I3C + Sil | AUC | Week 8 | 
| Pharmacokinetic profile of I3C + Sil | Cmax | Week 8 | 
| Pharmacokinetic profile of I3C + Sil | Half-life | Week 8 | 
| Pharmacokinetic profile of I3C + Sil | Elimination rate | Week 8 | 
| Pharmacokinetic profile of I3C + Sil | Plasma clearance | Week 8 | 
| Pharmacokinetic profile of I3C + Sil | Renal clearance | Week 8 | 
| Pharmacokinetic profile of I3C + Sil | Accumulation | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of I3C, Sil, or I3C + Sil on circulating inflammatory markers | Change in inflammatory markers IL-1B, TNF-a, IL-6, IL-8, Cox-2, prostaglandin E, and C-reactive protein | Week 8 | 
| Effect of I3C, Sil, or I3C + Sil on circulating immunophenotype | Change in circulating immunophenotype | Week 8 | 
| 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) | Change in protein expression of phosphorylated-Akt (pAkt), pERK, pSTAT3 and NF-kB from peripheral blood mononuclear cells (PBMC) | Week 8 | 
| Effect of I3C, Sil, or I3C + Sil on RNA sequencing from PBMC | Change in of I3C, Sil, or I3C + Sil on | Week 8 | 
| Effect of I3C, Sil, or I3C + Sil on PIK3CA pathway signaling in buccal cells | Change in PIK3CA pathway signaling in buccal cells | Week 8 | 
| Effect of I3C, Sil, or I3C + Sil on PIK3CA pathway signaling in oral cavity cells | Change in PIK3CA pathway signaling in oral cavity cells | Week 8 | 
| Effect of I3C, Sil, or I3C + Sil on PIK3CA pathway signaling in nasal mucosa | Change in PIK3CA pathway signaling in nasal mucosa | Week 8 | 
| Effect of I3C, Sil, or I3C + Sil on fasting glucose | Change in fasting glucose | Week 8 | 
| Effect of I3C, Sil, or I3C + Sil on fasting insulin | Change in fasting insulin | Week 8 | 
| Effect of I3C, Sil, or I3C + Sil on lipid profile | Change in lipid profile | Week 8 | 
| Effect of I3C, Sil, or I3C + Sil on leptin | Change in leptin | Week 8 | 
| Effect of I3C, Sil, or I3C + Sil on body weight | Change in body weight | Week 8 | 
| Effect of I3C, Sil, or I3C + Sil on waist circumference | Change in waist circumference | Week 8 |