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Topical Curcumin for Precancer Cervical Lesions

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ClinicalTrials.gov Identifier: NCT02944578
Recruitment Status : Recruiting
First Posted : October 26, 2016
Last Update Posted : December 14, 2018
Sponsor:
Information provided by (Responsible Party):
Lisa Flowers, Emory University

Tracking Information
First Submitted Date  ICMJE October 24, 2016
First Posted Date  ICMJE October 26, 2016
Last Update Posted Date December 14, 2018
Actual Study Start Date  ICMJE November 20, 2017
Estimated Primary Completion Date August 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 24, 2016)
Change in human papillomavirus (HPV) related molecular target HPV E6/E7 messenger ribonucleic acid (mRNA) expression within HSIL lesions of the cervix [ Time Frame: Baseline, Weeks 4, 8, 12, and 16 ]
Vaginal sampling and colposcopy with targeted cervical biopsies will be performed at each study visit. These samples will be used to determine the association between intravaginal curcumin on known HPV-related molecular target HPV E6/E7 mRNA expression within high grade squamous intraepithelial (HSIL) lesions of the cervix in HIV- infected women. The APTIMA® HPV Assay that will be utilized detects full-length HPV E6/E7 mRNA for HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 and correlates very well with integrated HPV, which in turn correlates with full-length HPV E6/E7 protein levels.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02944578 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 24, 2016)
Quantify curcumin levels in cervical tissue [ Time Frame: Baseline, Weeks 4, 8, 12, and 16 ]
Vaginal sampling and colposcopy with targeted cervical biopsies will be performed at each study visit. These samples will be examined to establish the level of curcumin penetration in cervical tissue, as well as the cumulative effect of daily curcumin over time.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: October 24, 2016)
  • Explore the association between curcumin and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [ Time Frame: Baseline, Weeks 4, 8, 12, and 16 ]
    Vaginal samples and cervical biopsies, obtained at each study visit, will be used to determine the association between curcumin and known biomarkers of cervical disease. This exploratory aim seeks to use repeated-measures analyses, utilizing a linear mixed model for the curcumin group to assess the association between nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the concentration of curcumin at each time point. NF-κB upregulation is related to the grade of cervical intraepithelial neoplasia (CIN) although the significance of NF-κB activation per se to CIN lesion development and its prognostic value in cervical cancer have not been well defined. The analysis of NF-κB binding activity will provide a direct molecular benchmark for assessing curcumin treatment responses independent from its therapeutic effects.
  • Explore the association between curcumin and p16INK4a [ Time Frame: Baseline, Weeks 4, 8, 12, and 16 ]
    Vaginal samples and cervical biopsies, obtained at each study visit, will be used to determine the association between curcumin and known biomarkers of cervical disease. This exploratory aim seeks to use repeated-measures analyses, utilizing a linear mixed model for the curcumin group to assess the association between p16INK4a and the concentration of curcumin at each time point. p16INK4a (a tumor suppressor protein) is an indirect marker of cell cycle dysregulation and has been shown to be expressed in cervical dysplasias and carcinomas associated with high risk HPV infections.
  • Explore the association between curcumin and Rb [ Time Frame: Baseline, Weeks 4, 8, 12, and 16 ]
    Vaginal samples and cervical biopsies, obtained at each study visit, will be used to determine the association between curcumin and known biomarkers of cervical disease. This exploratory aim seeks to use repeated-measures analyses, utilizing a linear mixed model for the curcumin group to assess the association between Rb and the concentration of curcumin at each time point. Rb is an important cell cycle regulator protein in cervical carcinogenesis which is suppressed in most cervical cancer cells. Increased levels of this protein has been linked to regression of cervical cancer lesions.
  • Explore the association between curcumin and p53 [ Time Frame: Baseline, Weeks 4, 8, 12, and 16 ]
    Vaginal samples and cervical biopsies, obtained at each study visit, will be used to determine the association between curcumin and known biomarkers of cervical disease. This exploratory aim seeks to use repeated-measures analyses, utilizing a linear mixed model for the curcumin group to assess the association between p53 and the concentration of curcumin at each time point. p53 is an important cell cycle regulator protein in cervical carcinogenesis which is suppressed in most cervical cancer cells. Increased levels of this protein have been linked to regression of cervical cancer lesions.
  • Explore the association between curcumin and vascular endothelial growth factor (VEGF) [ Time Frame: Baseline, Weeks 4, 8, 12, and 16 ]
    Vaginal samples and cervical biopsies, obtained at each study visit, will be used to determine the association between curcumin and known biomarkers of cervical disease. This exploratory aim seeks to use repeated-measures analyses, utilizing a linear mixed model for the curcumin group to assess the association between vascular endothelial growth factor (VEGF) and the concentration of curcumin at each time point. VEGF expression has been shown to correlate with severity of cervical intraepithelial neoplasia (CIN) lesions and invasive disease.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Topical Curcumin for Precancer Cervical Lesions
Official Title  ICMJE Biomolecular Effects of Topical Curcumin in HSIL Cervical Neoplasia
Brief Summary The purpose of this study is to see if curcumin can reverse a cervical precancerous state by looking at people who have the condition and intervening with a study drug or placebo (an inactive drug), prior to planned therapeutic loop electrosurgical excision procedure (LEEP) which is a treatment procedure for removing cervical cancer. 40 women with high grade squamous intraepithelial lesion (HSIL) of the cervix will be enrolled to either insert 2000 mg capsule of curcumin or a placebo in their vagina daily for 12 weeks. After a 4 week long washout period the participants will then undergo removal of the precancerous cells as recommended standard of care. Participants will have regular monthly visits for the duration of the study.
Detailed Description

Cervical cancer is the third most common cancer worldwide. The causative agent responsible for cervical cancer is the persistent infection with oncogenic Human Papillomavirus (HPV). Rates of cervical cancer and HPV infection are increased in HIV-infected women due to immunosuppression and cervical cancer is an AIDS-defining diagnosis. Despite the promise of HPV vaccine in the prevention of cervical cancer, the widespread availability of this vaccine is limited due to cost and accessibility. Therefore, prevention strategies to reduce cervical cancer after HPV exposure entail treatment at the most severe premalignant state (high grade squamous intraepithelial lesion or HSIL). As this procedure is expensive and not widely available in resource-limited areas there is a need for an inexpensive, non-invasive alternative method to treat these premalignant cervical lesions.

Curcumin, an extract from turmeric, a popular culinary spice, has been used in traditional Indian medicine for its anti-inflammatory and anti-infectious properties. Recent studies have shown the potential effect of curcumin to reduce tumors and precancerous lesions in animal and human cancer cells. It is postulated that curcumin achieves its effect on cancer cells by modulating different cellular pathways as well as altering HPV effect on tissue cells.

This study will explore the effect of curcumin as a potential medical treatment in HIV-infected women with HSIL lesions of the cervix. 40 women with high grade squamous intraepithelial lesion (HSIL) of the cervix will be enrolled to either insert 2000 mg capsule of curcumin or a placebo in their vagina daily for 12 weeks. After a 4 week long washout period the participants will then undergo removal of the precancerous cells as recommended standard of care. Participants will have regular monthly visits for the duration of the study.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Neoplasms
Intervention  ICMJE
  • Drug: Curcumin

    Curcumin (Curcumin C3 Complex®, prepared by Sabinsa Corporation), a constituent of the spice turmeric, is considered to be a low-toxicity, dietary-derived agent with chemopreventive and therapeutic benefits.

    Study participants will be instructed to insert four 500 mg (2000 mg total) curcumin capsules at bedtime every day (excluding days when they are on their menses). Participants will insert the capsules using the vaginal applicator while lying on their back with their knees bent. Participants will be instructed to gently insert the capsules into the vagina as far as they will go comfortably, similar to a tampon insertion or other common intravaginal drugs.

    Cervical cytology, colposcopies and biopsies will be performed at the Baseline, Week 4, 8, 12 and 16 visits to collect samples to analyze for the study outcomes.

    Other Name: Curcumin C3 Complex
  • Drug: Placebo

    Study participants randomized to the placebo arm will insert four 500 mg (2000 mg total) of the placebo (gelatin) capsules at bedtime every day (excluding days when they are on their menses). Participants will insert the capsules using the vaginal applicator while lying on their back with their knees bent. Participants will be instructed to gently insert the capsules into the vagina as far as they will go comfortably, similar to a tampon insertion or other common intravaginal drugs.

    Cervical cytology, colposcopies and biopsies will be performed at the Baseline, Week 4, 8, 12 and 16 visits to collect samples to analyze for the study outcomes.

Study Arms  ICMJE
  • Experimental: Curcumin Arm
    Participants in this arm will use 2000 mg of intravaginal curcumin daily for 12 weeks.
    Intervention: Drug: Curcumin
  • Placebo Comparator: Placebo Arm
    Participants in this arm will use 2000 mg of a placebo daily for 12 weeks.
    Intervention: Drug: Placebo
Publications * Not Provided

*   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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 24, 2016)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 2021
Estimated Primary Completion Date August 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • HIV positive women and HIV negative women
  • HSIL cytology with no invasive features identified on colposcopy or the baseline biopsy
  • Compliant on combined antiretrovirals (cART)
  • On continuous antiretrovirals with cluster of differentiation 4 (CD4) count >200 cells/ml with sustained undetectable viral load for at least 3 months
  • Patient on reliable birth control. Adequate birth control includes: Combined oral contraceptive pill (OCP), Long Lasting Reversible Contraceptive (LARCP), BiLateral Tubal Ligation (BLT) and DepoProvera Shot/Birth control shot.
  • Patient willing to conform to the study requirements
  • No risk factors for microinvasive disease (no colposcopic features of microinvasion, adequate colposcopy and negative endocervical curettage)

Exclusion Criteria:

  • Lactating and pregnant women
  • Patient with irregular cycles (more than once a month).
  • Previous hysterectomy and/or prior treatment for cervical precancer condition
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 21 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Rachael Abraham, PhD 4042518940 rfaraha@emory.edu
Contact: Ashley Urrutia 6504387736 ashley.n.urrutia@emory.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02944578
Other Study ID Numbers  ICMJE IRB00079183
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Lisa Flowers, Emory University
Study Sponsor  ICMJE Emory University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Lisa Flowers, MD Emory University
PRS Account Emory University
Verification Date December 2018

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