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The overall hypothesis is that the combination of a low dose of the antiestrogen Raloxifene with omega-3 fatty acids will exert a synergistic breast cancer chemopreventive effect due to the crosstalk of their downstream cellular effects leading to decreased proliferation and increased apoptosis of premalignant mammary cells. Based on the investigators hypothesis that upregulation of functional estrogen receptors in the premalignant lesions is also responsible for the development of hormone independent tumors, the investigators postulate that the combination of antiestrogens and omega-3 fatty acids will reduce the development of both hormone-dependent and -independent tumors. At present, there are no known interventions able to decrease the development of hormone-independent tumors, which are more prevalent, more aggressive, leading to the patient's demise. In addition, the investigators postulate that this approach will be safe since it will combine a lower and hence a less toxic dose of Raloxifene with the administration of omega-3 fatty acids which are known to have health benefits, i.e., reduction in cardiovascular risk, beyond their possible chemo preventive effect in breast cancer.
The main objectives of this study are to determine the individual and combined effects of Raloxifene and omega-3 fatty acids on surrogate markers of breast cancer development in healthy, postmenopausal women. The primary endpoint will be mammographic density for which the study has been powered. Breast density is a major risk factor for breast cancer and hence it is chosen to evaluate the potential chemopreventive efficacy of our interventions. Secondary endpoints would include markers of oxidative stress, parameters of estrogen metabolism, markers of inflammation, and markers of IGF-I signaling, all of which have been shown in the literature to have an influence on mammary carcinogenesis.
Study Population: Healthy, postmenopausal women between the ages of 35-70 years, undergoing yearly mammograms as part of routine screening practice.
Method of Identification of Subjects/Samples/Medical Records: Women reporting for yearly mammograms will be considered for this protocol. They will be given first a screening questionnaire to rule out any co-existing medical condition that would predispose them to thromboembolic events.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group 1: Control | No Intervention | Control, no intervention | |
| Group 2: Raloxifene 60 Mg Oral Tablet | Experimental | Raloxifene 60 mg Orally Daily |
|
| Group 3: Raloxifene 30 Mg Oral Tablet | Experimental | Raloxifene 30 mg Orally Daily |
|
| Group 4: Lovaza 4 gm oral | Experimental | Lovaza 4 gm/day Orally with Meals |
|
| Group 5: Lovaza 4gm & Raloxifene 30mg | Experimental | Lovaza 4 gm/day oral capsule with meals plus Raloxifene 30 mg oral tablet daily |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Lovaza 4gm oral | Dietary Supplement | Dietary supplement; Take 4 mg oral capsules daily |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Absolute Breast Density | Change of absolute breast density as indicated by mammography from baseline to Year +1 and completion of study (Year +2). No other mammograms will be obtained or used for the purpose of this study. Absolute breast density volume is based on breast thickness and the x-ray attenuation at each pixel of the image. | 2 years |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Biomarkers for Oxidative Stress:Urinary 8-(Isoprostane) F-2α | Changes in biomarkers for oxidative stress. Specific time points for evaluation are baseline and Year +1 (only). Urinary 8-(isoprostane) F-2α as measured through urine analysis. | 1 year |
| Changes in Biomarkers for Oxidative Stress: Urinary 8-hydroxy-deoxyguansine |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Andrea Manni, MD | Penn State University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Penn State Hershey Medical Center | Hershey | Pennsylvania | 17033 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28145413 | Derived | Manni A, Richie JP, Schetter SE, Calcagnotto A, Trushin N, Aliaga C, El-Bayoumy K. Stearoyl-CoA desaturase-1, a novel target of omega-3 fatty acids for reducing breast cancer risk in obese postmenopausal women. Eur J Clin Nutr. 2017 Jun;71(6):762-765. doi: 10.1038/ejcn.2016.273. Epub 2017 Feb 1. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Group 1: Control | Control, no intervention |
| FG001 | Group 2: Raloxifene 60 mg | Raloxifene 60 mg Orally Daily |
| FG002 | Group 3: Raloxifene 30 mg | Raloxifene 30 mg Orally Daily |
| FG003 | Group 4: Lovaza 4 gm | Lovaza 4 gm/day Orally with Meals |
| FG004 | Group 5: Lovaza 4 gm and Raloxifene 30 mg | Lovaza 4 gm/day orally with meals plus Raloxifene 30 mg orally daily |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Group 1: Control | Control, no intervention |
| BG001 | Group 2: Raloxifene 60 mg | Raloxifene 60 mg Orally Daily |
| 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 | Change in Absolute Breast Density | Change of absolute breast density as indicated by mammography from baseline to Year +1 and completion of study (Year +2). No other mammograms will be obtained or used for the purpose of this study. Absolute breast density volume is based on breast thickness and the x-ray attenuation at each pixel of the image. | The decrease in the population groups is accounted for through subject withdrawals, subjects lost to follow-up, and other reasons for not completing study. | Posted | Mean | Standard Deviation | cm squared | 2 years |
|
Participants who did not meet an off study criterion were followed until 2 years post initiation of the study medication regimen.
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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 | Group 1: Control | Control, no intervention |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Endometrial Cancer | Reproductive system and breast disorders | NCI CTC V 3.0 | Systematic Assessment | Endometrial Cancer (unlikely a secondary malignancy- likely new primary) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hot flashes | Endocrine disorders | NCI CTC V 3.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Andrea Manni | Milton S. Hershey Medical Center | 717-531-8395 | amanni@pennstatehealth.psu.edu |
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| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
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| ID | Term |
|---|---|
| D020849 | Raloxifene Hydrochloride |
| D013607 | Tablets |
| ID | Term |
|---|---|
| D013629 | Tamoxifen |
| D013267 | Stilbenes |
| D001597 | Benzylidene Compounds |
| D001555 | Benzene Derivatives |
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| Raloxifene 60 Mg Oral Tablet | Drug | 60 mg orally every day for two years |
|
|
| Raloxifene 30 Mg Oral Tablet | Drug | 30 mg orally daily for two years |
|
|
| Lovaza 4gm & Raloxifene 30mg | Drug | Lovaza 4gm and Raloxifene 30 Mg orally once per day for 2 years |
|
|
Changes in biomarkers for oxidative stress. Specific time points for evaluation are baseline and Year +1 (only). Urinary 8-hydroxy-deoxyguansine as measured through urinary analysis. |
| 1 year |
| Changes in Biomarkers for Estrogen Metabolism: 2-hydroxy Estrone (Urinary 2-OHE1) and 16-α-hydroxy Estrone (16α-OHE1) | Changes in biomarkers for estrogen metabolism: 2-hydroxy estrone (Urinary 2-OHE1) and 16-α-hydroxy estrone (16α-OHE1) as measured by urinary analysis. Specific time points for evaluation are baseline and Year +1 (only). | 1 year |
| Changes in Serum Biomarkers for Inflammation From Levels of High Sensitivity C-reactive Protein (hsCRP) and Interleukin 6 (IL-6) | Changes in serum biomarkers for inflammation including highly sensitive C-reactive protein and IL-6 obtained through a blood draw. Specific time points for evaluation are baseline and Year +1 (only). | 1 Year |
| Changes in Insulin-like Growth Factor-1 (IGF-1) and Insulin-like Growth Factor-1 Binding Protein-3 (IGFBP-3) | Changes in insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-1 binding protein-3 (IGFBP-3) obtained through blood sample. Specific time points for evaluation are baseline and Year +1 (only). | 1 year |
| Changes in Serum Lipid Levels | Changes in serum lipid levels as measured through total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Specific time points for evaluation are baseline, Year +1, and Year 2. | 2 years |
| Changes in Complete Blood Count: Red Blood Cells | Changes in complete blood count levels as measured through red blood cells (RBC). Specific time points for evaluation are baseline, Year +1, and Year 2. | 2 years |
| Changes in Complete Blood Count: Hemoglobin | Changes in complete blood count levels as measured through hemoglobin. Specific time points for evaluation are baseline, Year +1, and Year 2. | 2 years |
| Changes in Complete Blood Count: Hematocrit | Changes in complete blood count levels as measured through hematocrit percentage. Specific time points for evaluation are baseline, Year +1, and Year 2. | 2 years |
| Changes in Complete Blood Count: White Blood Cells and Platelets | Changes in complete blood count levels as measured through white blood cells (WBC) and platelets. Specific time points for evaluation are baseline, Year +1, and Year 2. | 2 years |
| Protocol Violation |
|
| Physician Decision |
|
| Adverse Event |
|
| Lost to Follow-up |
|
| BG002 |
| Group 3: Raloxifene 30 mg |
Raloxifene 30 mg Orally Daily |
| BG003 | Group 4: Lovaza 4 gm | Lovaza 4 gm/day Orally with Meals |
| BG004 | Group 5: Lovaza 4 gm and Raloxifene 30 mg | Lovaza 4 gm/day orally with meals plus Raloxifene 30 mg orally daily |
| BG005 | 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 |
|
Raloxifene 60 mg Orally Daily
| OG002 | Group 3: Raloxifene 30 mg | Raloxifene 30 mg Orally Daily |
| OG003 | Group 4: Lovaza 4 gm | Lovaza 4 gm/day Orally with Meals |
| OG004 | Group 5: Lovaza 4 gm and Raloxifene 30 mg | Lovaza 4 gm/day orally with meals plus Raloxifene 30 mg orally daily |
|
|
| Secondary | Changes in Biomarkers for Oxidative Stress:Urinary 8-(Isoprostane) F-2α | Changes in biomarkers for oxidative stress. Specific time points for evaluation are baseline and Year +1 (only). Urinary 8-(isoprostane) F-2α as measured through urine analysis. | Biomarker measurements were not taken for the entire population of the study due to non-significant trends for treatment effects found in this population (n = 47). | Posted | Mean | Standard Error | pg/mg creatinine | 1 year |
|
|
|
| Secondary | Changes in Biomarkers for Oxidative Stress: Urinary 8-hydroxy-deoxyguansine | Changes in biomarkers for oxidative stress. Specific time points for evaluation are baseline and Year +1 (only). Urinary 8-hydroxy-deoxyguansine as measured through urinary analysis. | Biomarker measurements were not taken for the entire population of the study due to non-significant trends for treatment effects found in this population (n = 47). | Posted | Mean | Standard Error | ng/mg creatinine | 1 year |
|
|
|
| Secondary | Changes in Biomarkers for Estrogen Metabolism: 2-hydroxy Estrone (Urinary 2-OHE1) and 16-α-hydroxy Estrone (16α-OHE1) | Changes in biomarkers for estrogen metabolism: 2-hydroxy estrone (Urinary 2-OHE1) and 16-α-hydroxy estrone (16α-OHE1) as measured by urinary analysis. Specific time points for evaluation are baseline and Year +1 (only). | Biomarker measurements were not taken for the entire population of the study due to non-significant trends for treatment effects found in this population (n = 47). | Posted | Mean | Standard Deviation | ng/mg creatinine | 1 year |
|
|
|
| Secondary | Changes in Serum Biomarkers for Inflammation From Levels of High Sensitivity C-reactive Protein (hsCRP) and Interleukin 6 (IL-6) | Changes in serum biomarkers for inflammation including highly sensitive C-reactive protein and IL-6 obtained through a blood draw. Specific time points for evaluation are baseline and Year +1 (only). | Biomarker measurements were not taken for the entire population of the study (N = 266) due to non-significant trends for treatment effects found in this initial population (n = 89). | Posted | Mean | Standard Deviation | pg/ml | 1 Year |
|
|
|
| Secondary | Changes in Insulin-like Growth Factor-1 (IGF-1) and Insulin-like Growth Factor-1 Binding Protein-3 (IGFBP-3) | Changes in insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-1 binding protein-3 (IGFBP-3) obtained through blood sample. Specific time points for evaluation are baseline and Year +1 (only). | Measurements were not taken for the entire population of the study due to non-significant trends for treatment effects found in this population (n = 46). | Posted | Mean | Standard Deviation | ng/mL | 1 year |
|
|
|
| Secondary | Changes in Serum Lipid Levels | Changes in serum lipid levels as measured through total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Specific time points for evaluation are baseline, Year +1, and Year 2. | The decrease in the population groups is accounted for through subject withdrawals, subjects lost to follow-up, and other reasons for not completing study. | Posted | Mean | Standard Deviation | mg/dL | 2 years |
|
|
|
| Secondary | Changes in Complete Blood Count: Red Blood Cells | Changes in complete blood count levels as measured through red blood cells (RBC). Specific time points for evaluation are baseline, Year +1, and Year 2. | The decrease in the population groups is accounted for through subject withdrawals, subjects lost to follow-up, and other reasons for not completing study. | Posted | Mean | Standard Deviation | millions of cells per microliter | 2 years |
|
|
|
| Secondary | Changes in Complete Blood Count: Hemoglobin | Changes in complete blood count levels as measured through hemoglobin. Specific time points for evaluation are baseline, Year +1, and Year 2. | The decrease in the population groups is accounted for through subject withdrawals, subjects lost to follow-up, and other reasons for not completing study. | Posted | Mean | Standard Deviation | g/dL | 2 years |
|
|
|
| Secondary | Changes in Complete Blood Count: Hematocrit | Changes in complete blood count levels as measured through hematocrit percentage. Specific time points for evaluation are baseline, Year +1, and Year 2. | The decrease in the population groups is accounted for through subject withdrawals, subjects lost to follow-up, and other reasons for not completing study. | Posted | Mean | Standard Deviation | volume percentage | 2 years |
|
|
|
| Secondary | Changes in Complete Blood Count: White Blood Cells and Platelets | Changes in complete blood count levels as measured through white blood cells (WBC) and platelets. Specific time points for evaluation are baseline, Year +1, and Year 2. | The decrease in the population groups is accounted for through subject withdrawals, subjects lost to follow-up, and other reasons for not completing study. | Posted | Mean | Standard Deviation | thousand cells/mL | 2 years |
|
|
|
| 0 |
| 53 |
| 1 |
| 53 |
| EG001 | Group 2: Raloxifene 60 mg | Raloxifene 60 mg Orally Daily | 1 | 53 | 10 | 53 |
| EG002 | Group 3: Raloxifene 30 mg | Raloxifene 30 mg Orally Daily | 0 | 53 | 7 | 53 |
| EG003 | Group 4: Lovaza 4 gm | Lovaza 4 gm/day Orally with Meals | 0 | 54 | 0 | 54 |
| EG004 | Group 5: Lovaza 4 gm and Raloxifene 30 mg | Lovaza 4 gm/day orally with meals plus Raloxifene 30 mg orally daily | 0 | 53 | 6 | 53 |
|
| Night Sweating (diaphoresis) | General disorders | NCI CTC V 3.0 | Systematic Assessment |
|
| Rosacea | Skin and subcutaneous tissue disorders | NCI CTC V 3.0 | Systematic Assessment |
|
| Vaginal Spotting | Reproductive system and breast disorders | NCI CTC V 3.0 | Systematic Assessment |
|
| Leg cramping | General disorders | NCI CTC V 3.0 | Systematic Assessment |
|
| Headache | Nervous system disorders | NCI CTC V 3.0 | Systematic Assessment |
|
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| D017437 |
| Skin and Connective Tissue Diseases |
| D006841 |
| Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
|
|
| 1 year |
|
| 1 year |
|
| 1 year: Urinary 2-OHE1 |
|
| Baseline: 16α-OHE1 |
|
| 1 year: 16α-OHE1 |
|
|
| 1 year: Serum hsCRP |
|
|
| Baseline: Serum IL-6 |
|
|
| 1 year: Serum IL-6 |
|
|
| 1 year: IGF-1 |
|
| Baseline: IGFBP-3 |
|
| 1 year: IGFBP-3 |
|
|
| 1 year: Total Cholestrol |
|
|
| 2 year: Total Cholesterol |
|
|
| Baseline: LDL Cholesterol |
|
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| 1 year: LDL Cholesterol |
|
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| 2 year: LDL Cholesterol |
|
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| Baseline: HDL Cholesterol |
|
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| 1 year: HDL Cholesterol |
|
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| 2 year: HDL Cholestrol |
|
|
| Baseline: Triglycerides |
|
|
| 1 year: Triglycerides |
|
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| 2 year: Triglycerides |
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| 1 year: RBC |
|
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| 2 year: RBC |
|
|
|
| 1 year: Hemoglobin |
|
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| 2 year: Hemoglobin |
|
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| 1 year: Hematocrit |
|
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| 2 year: Hematocrit |
|
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| 1 year: WBC |
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| 2 year: WBC |
|
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| Baseline: Platelets |
|
|
| 1 year: Platelets |
|
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| 2 year: Platelets |
|
|