Trial of Indole-3-Carbinol and Silibinin

Trial of Indole-3-Carbinol & Silibinin

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.

Study Overview

• Status: Completed
• Conditions: Smoking
• Intervention / Treatment: Drug: Indole-3-Carbinol; Drug: Silibinin; Drug: Silibin

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center at University of Minnesota

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single-dose PK study; 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; Cohorts 2, 3, & 4: 400 mg PO BID; Other Names: 13C; Drug: Silibinin; Cohorts 1 & 4: 720mg; Other Names: Sil; Drug: Silibin; Cohort 3: 360mg; Other Names: Sil
Experimental: Multi-dose PK Study; 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; Cohorts 2, 3, & 4: 400 mg PO BID; Other Names: 13C; Drug: Silibinin; Cohorts 1 & 4: 720mg; Other Names: Sil; Drug: Silibin; Cohort 3: 360mg; Other Names: Sil
Experimental: Safety Study; 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; Cohorts 2, 3, & 4: 400 mg PO BID; Other Names: 13C; Drug: Silibinin; Cohorts 1 & 4: 720mg; Other Names: Sil; Drug: Silibin; Cohort 3: 360mg; Other Names: Sil
Experimental: Cohort 4 PD Study; 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; Cohorts 2, 3, & 4: 400 mg PO BID; Other Names: 13C; Drug: Silibinin; Cohorts 1 & 4: 720mg; Other Names: Sil; Drug: Silibin; Cohort 3: 360mg; 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

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Investigators: Principal Investigator: Naomi Fujioka, MD, Division of Hematology, Oncology and Transplantation, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): November 29, 2018
• Primary Completion (Actual): May 7, 2021
• Study Completion (Actual): May 7, 2021

Study Registration Dates

• First Submitted: September 14, 2018
• First Submitted That Met QC Criteria: September 25, 2018
• First Posted (Actual): September 27, 2018

Study Record Updates

• Last Update Posted (Actual): August 11, 2021
• Last Update Submitted That Met QC Criteria: August 10, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antineoplastic Agents; Protective Agents; Antineoplastic Agents, Phytogenic; Anticarcinogenic Agents; Silybin; Indole-3-carbinol
• Other Study ID Numbers: 2017LS075

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No