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Chemoprevention of Prostate Cancer, HDAC Inhibition and DNA Methylation (PBroC)

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ClinicalTrials.gov Identifier: NCT01265953
Recruitment Status : Completed
First Posted : December 23, 2010
Results First Posted : July 14, 2017
Last Update Posted : May 1, 2019
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Oregon State University
OHSU Knight Cancer Institute
Information provided by (Responsible Party):
Jackilen Shannon, Portland VA Medical Center

Tracking Information
First Submitted Date  ICMJE December 16, 2010
First Posted Date  ICMJE December 23, 2010
Results First Submitted Date  ICMJE May 12, 2017
Results First Posted Date  ICMJE July 14, 2017
Last Update Posted Date May 1, 2019
Study Start Date  ICMJE July 2011
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 23, 2018)
  • Change of Total Urine SFN (Sulforaphane) Metabolites [ Time Frame: Baseline and 4-8 weeks following intervention ]
    Collection of blood and urine specimens occurred at pre-intervention and post-intervention. Change = post-intervention level minus pre-intervention level
  • Change of Total Plasma SFN (Sulforaphane) Metabolites Level [ Time Frame: Baseline and 4-8 weeks following intervention ]
    In subjects at risk for prostate cancer, presence of SFN was analyzed in plasma. Collection of blood specimens occurred at pre-intervention and post-intervention. The Change = post-intervention level minus pre-intervention level
  • Percentage of Ki67 Positive Cells up to 8 Weeks Post-randomization [ Time Frame: Baseline and 4-8 weeks following intervention; prostate biopsy were collected post-intervention when clinically-indicated ]
    Ki67 is a biomarker of disease progression. Immunohistochemical (IHC) analysis of Ki67 was performed using research only prostate biopsy specimens collected post-intervention at the time of the clinically-indicated prostate biopsy.
  • Expression of Histone Deacetylase 6 (HDAC6) [ Time Frame: Baseline and 4-8 weeks following intervention; prostate biopsy were collected post-intervention when clinically-indicated ]
    Immunohistochemical (IHC) analysis of HDAC6 expression using research-only prostate biopsy tissue collected post-intervention at the time of the clinically-indicated prostate biopsy. A modified Histo-score (H-score) was calculated, which involved semiquantitative assessment of both staining intensity (graded as 1-3 with 1 representing weak staining, 2 moderate, and 3 strong) and percentage of positive cells. H-score ranged from 0 to 300 with 300 the strongest expression.
Original Primary Outcome Measures  ICMJE
 (submitted: December 22, 2010)
  • Identify distribution of SFN (sulforaphane) and its metabolites and HDAC (histone deacetylase) inhibition following SFN supplementation [ Time Frame: minimum 4 to maximum 8 weeks ]
    In subjects at risk for prostate cancer by examining expression of acetylated H3 and H4, and absolute histone levels in peripheral blood and in prostate tissue. Presence of SFN and its metabolites (SFN-Cys, SFN-NAC) will be analyzed in plasma, urine and prostate tissue. Collection of blood and urine specimens will occur at pre-intervention and post-intervention; research only prostate biopsy specimens will be collected post-intervention at the time of the clinically-indicated prostate biopsy.
  • Investigate the effects (biomarkers of disease progression) of broccoli sprout supplementation on DNA methylation status and proliferation markers in a pre-biopsy setting. [ Time Frame: minimum 4 to maximum 8 weeks; prostate biopsy will be collected post-intervention when clinically-indicated. ]
    Prostate biopsy samples will be probed for 5-methyl cytosine staining by IHC; and serum and urinary DNA will undergo methyl-specific PCR for GSTp1, AR, sigma14-3-3 and P21. Cell proliferation (Ki-67 expression) and apoptosis (TUNEL expression) in SFN-supplemented and placebo prostate tissue specimens will be assessed. Collection of blood and urine specimens will occur pre-intervention and post-intervention; research only prostate biopsy specimens will be collected post-intervention at the time of the clinically-indicated prostate biopsy.
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Chemoprevention of Prostate Cancer, HDAC Inhibition and DNA Methylation
Official Title  ICMJE Chemoprevention of Prostate Cancer, HDAC Inhibition and DNA Methylation
Brief Summary

The objective of the study is to identify mechanisms by which compounds found in cruciferous vegetables alter gene expression via epigenetic modifications (changes in gene expression) and may prevent prostate cancer development.

The investigators have found that sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, inhibits histone deacetylase (HDAC) activity in human colorectal and prostate cancer cells.

Detailed Description

Prostate cancer is the most frequently diagnosed non-cutaneous cancer and is the second leading cause of cancer death in American men. The precise etiologic factors that initiate and enhance the progression of prostate cancer remain unknown, but epigenetic alterations and diet/lifestyle factors have come forth as significant contributing factors. Epidemiologic studies suggest that cruciferous vegetable intake decreases the risk for prostate cancer. The long-term goal of this proposal is to identify mechanisms by which dietary compounds, such as those found in cruciferous vegetables decrease prostate cancer risk. The objective of the study is to identify mechanisms by which compounds found in cruciferous vegetables alter gene expression via epigenetic modifications and may prevent prostate cancer development.

The investigators have found that SFN, an isothiocyanate found in cruciferous vegetables, inhibits HDAC activity in human colorectal and prostate cancer cells.

Targeting the epigenome, including the use of HDAC and DNA methyltransferase (DNMT) inhibitors, is an evolving strategy for cancer chemoprevention and both have shown promise in cancer clinical trials.

This Randomized, Double Blind, Clinical Trial will address the following objectives:

  1. Identify distribution of SFN and its metabolites and HDAC inhibition following supplementation with an SFN-rich broccoli sprout extract in subjects at risk for prostate cancer (Primary Endpoints)
  2. Investigate the effects of supplementation with an SFN-rich broccoli sprout extract on DNA methylation status and proliferation markers in a pre-biopsy setting (secondary analysis)

The effects of short-term supplementation with an SFN-rich broccoli sprout extract on benign epithelial tissue will be studied in men characterized as being at risk for prostate cancer in a randomized, placebo-controlled trial. Men scheduled for prostate biopsy will be recruited into the trial.

Following successful completion of the consent, two 10 mL blood specimens for study analyses, a 4 mL specimen for total bilirubin assessment will be drawn and the subject will provide a urine sample. The study coordinator will explain the Diet History questionnaires (DHQ) and administer the risk factor and adverse event (AE) questionnaires in order to obtain data on potential confounding dietary variables and gain subjects' baseline symptoms.

The study coordinator will provide the subject with a month' supply of either an SFN-rich broccoli sprout extract (BSE) capsule which consist of 200µmol of sulforaphane (SFN) or matching placebo, as dispensed by the Research Pharmacy. The matching placebo for the BSE consists of a gelatin capsule containing microcrystalline cellulose.

Around every 2 weeks, study coordinator will call to complete AE reporting and any changes in medications or supplements and complete brief cruciferous vegetable intake checklist. Subjects will return any unused study "drug" to the study coordinator at the time of biopsy (or at the 4 week visit if subject's prostate biopsy is delayed).

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Condition  ICMJE Prostate Cancer Prevention
Intervention  ICMJE
  • Drug: SFN-rich broccoli sprout extract capsules
    Four weeks SFN-rich broccoli sprout extract (BSE) capsules: 200µmol of SFN, 2 capsules (1 capsule B.I.D.) daily
    Other Names:
    • BSE
    • SFN
    • Sulforaphane
  • Dietary Supplement: Gelatin capsule containing microcrystalline cellulose.
    Four weeks placebo capsules: 2 capsules (1 capsule B.I.D.) daily
Study Arms  ICMJE
  • Experimental: SFN-rich broccoli sprout extract capsules
    Four weeks SFN-rich broccoli sprout extract (BSE) capsules: 200µmol of sulforaphane (SFN) daily, 2 capsules (1 capsule B.I.D.) daily
    Intervention: Drug: SFN-rich broccoli sprout extract capsules
  • Placebo Comparator: Placebo capsules
    Four weeks placebo capsules: 2 capsules (1 capsule B.I.D.) daily
    Intervention: Dietary Supplement: Gelatin capsule containing microcrystalline cellulose.
Publications * Zhang Z, Garzotto M, Davis EW 2nd, Mori M, Stoller WA, Farris PE, Wong CP, Beaver LM, Thomas GV, Williams DE, Dashwood RH, Hendrix DA, Ho E, Shannon J. Sulforaphane Bioavailability and Chemopreventive Activity in Men Presenting for Biopsy of the Prostate Gland: A Randomized Controlled Trial. Nutr Cancer. 2020;72(1):74-87. doi: 10.1080/01635581.2019.1619783. Epub 2019 Jun 1.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 16, 2017)
98
Original Estimated Enrollment  ICMJE
 (submitted: December 22, 2010)
100
Actual Study Completion Date  ICMJE December 2015
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Men scheduled for a prostate biopsy
  • Age 21 years or older
  • Signed informed subject consent

Exclusion Criteria:

  • Definitive diagnosis with prostate cancer
  • Significant active medical illness which in the opinion of the investigator or clinician would preclude protocol treatment
  • Diagnosis of liver disease as noted on the patient problem list or baseline total bilirubin greater than institutional upper limit of normal
  • Subject reported allergy or sensitivity to cruciferous vegetables
  • Use of oral antibiotics, with the exception of doxycycline, within three months prior to randomization
  • Use of warfarin or need for therapeutic anticoagulation at time of biopsy or at anytime during the course of the trial.
  • Current oral steroid therapy
  • Current therapy with valproate or other pharmacological drugs associated with HDAC inhibition
  • Diagnosed dementia as noted on the patient problem list or other significant mental illness that may impact the subjects' ability to follow instructions or comply with the study protocol
  • Patient may not be a part of another flagged study
  • Patients already taking SFN dietary supplements
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 21 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01265953
Other Study ID Numbers  ICMJE Portland VA-09-0607
2096 ( Other Identifier: PVAMC IRB )
6232 ( Other Identifier: OHSU IRB )
2P01CA090890-06A2 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jackilen Shannon, Portland VA Medical Center
Study Sponsor  ICMJE Portland VA Medical Center
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Oregon State University
  • OHSU Knight Cancer Institute
Investigators  ICMJE
Principal Investigator: Jackilen Shannon, PhD Portland VA Medical Center
PRS Account Portland VA Medical Center
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP