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Study was terminated due to patient feedback and need to redesign the delivery method.
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Curcumin Arm | Experimental | Participants in this arm will use 2000 mg of intravaginal curcumin once a week for 12 weeks. |
|
| Placebo Arm | Placebo Comparator | Participants in this arm will use 2000 mg of a placebo once a week for 12 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Curcumin | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Human Papillomavirus (HPV) Related Molecular Target HPV E6/E7 Messenger Ribonucleic Acid (mRNA) Expression Within HSIL Lesions of the Cervix | Vaginal samples were 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. | Baseline, Weeks 4, 8, 12, and 16 |
| Measure | Description | Time Frame |
|---|---|---|
| Curcumin Levels in Cervical Tissue | Vaginal sampling and colposcopy with targeted cervical biopsies will be examined to establish the level of curcumin penetration in cervical tissue, as well as the cumulative effect of daily curcumin over time. | Weeks 4, 8, 12, and 16 |
| Measure | Description | Time Frame |
|---|---|---|
| Explore the Association Between Curcumin and Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells (NF-κB) | 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. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Lisa Flowers, MD | Emory University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Grady Memorial Hospital | Atlanta | Georgia | 30303 | United States | ||
| Grady Hospital - Ponce De Leon Clinic |
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Participants were recruited from Grady Hospital Ponce De Leon Center in Atlanta Georgia, USA. Participant enrollment began November 20, 2017 and all follow-up assessments were completed by October 30, 2018. The study was suspended for several years due to participant feedback about using the suppository tablets and then the coronavirus disease 2019 (COVID-19) pandemic, and the study was ultimately terminated in April 2024.
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| ID | Title | Description |
|---|---|---|
| FG000 | Curcumin | Participants using 2000 mg of intravaginal curcumin capsules once a week for 12 weeks. |
| FG001 | Placebo | Participants using 2000 mg of intravaginal placebo capsules once a week for 12 weeks. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Curcumin | Participants using 2000 mg of intravaginal curcumin capsules once a week for 12 weeks. |
| BG001 | Placebo | Participants using 2000 mg of intravaginal placebo capsules once a week for 12 weeks. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Human Papillomavirus (HPV) Related Molecular Target HPV E6/E7 Messenger Ribonucleic Acid (mRNA) Expression Within HSIL Lesions of the Cervix | Vaginal samples were 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. | This analysis includes participants who attended the indicated study visit; some participants missed some visits. | Posted | Count of Participants | Participants | Baseline, Weeks 4, 8, 12, and 16 |
|
Information on adverse events was collected beginning at the time that participants gave consent to participant in the study continued through the final assessment at Week 16.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Curcumin | Participants using 2000 mg of intravaginal curcumin capsules once a week for 12 weeks. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Lisa Flowers | Emory University | 404-251-8931 | flowe2@emory.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 27, 2019 | Apr 17, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D009369 | Neoplasms |
| D003141 | Communicable Diseases |
| ID | Term |
|---|---|
| D007239 | Infections |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D003474 | Curcumin |
| ID | Term |
|---|---|
| D036381 | Diarylheptanoids |
| D006536 | Heptanes |
| D000473 | Alkanes |
| D006839 | Hydrocarbons, Acyclic |
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|
|
| Placebo | Drug | 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. |
|
| Baseline, Weeks 4, 8, 12, and 16 |
| Explore the Association Between Curcumin and p16INK4a | 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. | Baseline, Weeks 4, 8, 12, and 16 |
| Explore the Association Between Curcumin and Rb | 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. | Baseline, Weeks 4, 8, 12, and 16 |
| Explore the Association Between Curcumin and p53 | 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. | Baseline, Weeks 4, 8, 12, and 16 |
| Explore the Association Between Curcumin and Vascular Endothelial Growth Factor (VEGF) | 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. | Baseline, Weeks 4, 8, 12, and 16 |
| Atlanta |
| Georgia |
| 30308 |
| United States |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
Participants using 2000 mg of intravaginal curcumin capsules once a week for 12 weeks.
| OG001 | Placebo | Participants using 2000 mg of intravaginal placebo capsules once a week for 12 weeks. |
|
|
| Secondary | Curcumin Levels in Cervical Tissue | Vaginal sampling and colposcopy with targeted cervical biopsies will be examined to establish the level of curcumin penetration in cervical tissue, as well as the cumulative effect of daily curcumin over time. | Study enrollment stopped early and the focus of the study shifted to analysis of the primary outcome measure among current participants. Samples for analysis of curcumin in cervical tissue were not collected from any participants. | Posted | Weeks 4, 8, 12, and 16 |
|
|
| Other Pre-specified | Explore the Association Between Curcumin and Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells (NF-κB) | 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. | Not Posted | Baseline, Weeks 4, 8, 12, and 16 | Participants |
| Other Pre-specified | Explore the Association Between Curcumin and p16INK4a | 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. | Not Posted | Baseline, Weeks 4, 8, 12, and 16 | Participants |
| Other Pre-specified | Explore the Association Between Curcumin and Rb | 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. | Not Posted | Baseline, Weeks 4, 8, 12, and 16 | Participants |
| Other Pre-specified | Explore the Association Between Curcumin and p53 | 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. | Not Posted | Baseline, Weeks 4, 8, 12, and 16 | Participants |
| Other Pre-specified | Explore the Association Between Curcumin and Vascular Endothelial Growth Factor (VEGF) | 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. | Not Posted | Baseline, Weeks 4, 8, 12, and 16 | Participants |
| 0 |
| 4 |
| 0 |
| 4 |
| 0 |
| 4 |
| EG001 | Placebo | Participants using 2000 mg of intravaginal placebo capsules once a week for 12 weeks. | 0 | 3 | 0 | 3 | 0 | 3 |
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| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D002396 | Catechols |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |