Trial of Indole-3-Carbinol and Silibinin

Overview

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.

Full Title of Study: “Trial of Indole-3-Carbinol & Silibinin”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: May 7, 2021

Interventions

  • Drug: Indole-3-Carbinol
    • Cohorts 2, 3, & 4: 400 mg PO BID
  • Drug: Silibinin
    • Cohorts 1 & 4: 720mg
  • Drug: Silibin
    • Cohort 3: 360mg

Arms, Groups and Cohorts

  • 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.
  • 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.
  • 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.
  • 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.

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

  • Effect of I3C, Sil, or I3C + Sil on circulating inflammatory markers
    • Time Frame: 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 circulating immunophenotype
    • Time Frame: Week 8
    • Change in circulating immunophenotype
  • 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)
    • Time Frame: 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 RNA sequencing from PBMC
    • Time Frame: Week 8
    • Change in of I3C, Sil, or I3C + Sil on
  • Effect of I3C, Sil, or I3C + Sil on PIK3CA pathway signaling in buccal cells
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: Week 8
    • Change in PIK3CA pathway signaling in nasal mucosa
  • Effect of I3C, Sil, or I3C + Sil on fasting glucose
    • Time Frame: Week 8
    • Change in fasting glucose
  • Effect of I3C, Sil, or I3C + Sil on fasting insulin
    • Time Frame: Week 8
    • Change in fasting insulin
  • Effect of I3C, Sil, or I3C + Sil on lipid profile
    • Time Frame: Week 8
    • Change in lipid profile
  • Effect of I3C, Sil, or I3C + Sil on leptin
    • Time Frame: Week 8
    • Change in leptin
  • Effect of I3C, Sil, or I3C + Sil on body weight
    • Time Frame: Week 8
    • Change in body weight
  • Effect of I3C, Sil, or I3C + Sil on waist circumference
    • Time Frame: Week 8
    • Change in waist circumference

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Masonic Cancer Center, University of Minnesota
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Naomi Fujioka, MD, Principal Investigator, Division of Hematology, Oncology and Transplantation, University of Minnesota

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