Topical Curcumin for Precancer Cervical Lesions

Sponsor

Emory University (Other)

Overall Status

Suspended

CT.gov ID

NCT02944578

Collaborator

(none)

Enrollment

Locations

Arms

58.3

Anticipated Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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 once a week 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 once a week 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 Design

Study Type:

Interventional

Anticipated 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 :

Nov 20, 2017

Anticipated Primary Completion Date :

Oct 1, 2022

Anticipated Study Completion Date :

Oct 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Curcumin Arm Participants in this arm will use 2000 mg of intravaginal curcumin once a week 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 once a week (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 Names: Curcumin C3 Complex
Placebo Comparator: Placebo Arm Participants in this arm will use 2000 mg of a placebo once a week 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 once a week (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.

Arm

Intervention/Treatment

Experimental: Curcumin Arm

Participants in this arm will use 2000 mg of intravaginal curcumin once a week 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 once a week (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 Names:

Curcumin C3 Complex

Placebo Comparator: Placebo Arm

Participants in this arm will use 2000 mg of a placebo once a week 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 once a week (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.

Outcome Measures

Primary Outcome Measures

Change in human papillomavirus (HPV) related molecular target HPV E6/E7 messenger ribonucleic acid (mRNA) expression within HSIL lesions of the cervix [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

Quantify curcumin levels in cervical tissue [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

Explore the association between curcumin and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [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 [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 [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 [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) [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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)