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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, 2017
Sponsor:
Information provided by (Responsible Party):
Lisa Flowers, Emory University

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.

Condition or disease Intervention/treatment Phase
Neoplasms Drug: Curcumin Drug: Placebo Phase 2

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Biomolecular Effects of Topical Curcumin in HSIL Cervical Neoplasia
Actual Study Start Date : November 20, 2017
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : August 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Curcumin

Arm Intervention/treatment
Experimental: Curcumin Arm
Participants in this arm will use 2000 mg of intravaginal curcumin daily for 12 weeks.
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

Placebo Comparator: Placebo Arm
Participants in this arm will use 2000 mg of a placebo daily for 12 weeks.
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.





Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.


Other Outcome Measures:
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02944578


Contacts
Contact: Rachael Abraham, PhD 4042518940 rfaraha@emory.edu
Contact: Ashley Urrutia 6504387736 ashley.n.urrutia@emory.edu

Locations
United States, Georgia
Grady Memorial Hospital Recruiting
Atlanta, Georgia, United States, 30303
Contact: Rachael Farah-Abraham, PhD       rfarahabraham@emory.edu   
Grady Hospital - Ponce De Leon Clinic Recruiting
Atlanta, Georgia, United States, 30308
Contact: Rachael Farah-Abraham, PhD       rfarahabraham@emory.edu   
Sponsors and Collaborators
Emory University
Investigators
Principal Investigator: Lisa Flowers, MD Emory University

Responsible Party: Lisa Flowers, Professor, Emory University
ClinicalTrials.gov Identifier: NCT02944578     History of Changes
Other Study ID Numbers: IRB00079183
First Posted: October 26, 2016    Key Record Dates
Last Update Posted: December 14, 2017
Last Verified: December 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Lisa Flowers, Emory University:
Cancer
HIV
Oncology
Infectious Diseases
HPV
Preventive Medicine

Additional relevant MeSH terms:
Curcumin
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action