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RANKL Inhibition and Mammographic Breast Density (TRIDENT)

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ClinicalTrials.gov Identifier: NCT04067726
Recruitment Status : Recruiting
First Posted : August 26, 2019
Last Update Posted : April 2, 2020
Sponsor:
Collaborator:
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:
Data supporting a role for RANKL signaling in mammographic density and breast cancer development has begun to emerge, but clinical trial data providing definitive evidence that would allow the adoption of RANKL inhibition in primary breast cancer prevention are not yet available. The hypothesis is that RANKL inhibition with denosumab will decrease mammographic density in high-risk premenopausal women with dense breasts. To address this, the investigators have developed this clinical trial to quantify the impact of RANKL inhibition on mammographic density in high-risk premenopausal women with dense breasts and to determine the effect of RANKL inhibition on markers of proliferation and biomarkers of breast cancer risk. Successful demonstration that RANKL inhibition reduces mammographic density could open up additional approaches to primary breast cancer prevention in high-risk premenopausal women, who do not have dominant genetic predisposition.

Condition or disease Intervention/treatment Phase
Dense Breasts Drug: Denosumab Drug: Placebo Drug: Calcium Drug: Vitamin D3 Procedure: Core needle biopsy Procedure: Blood draw Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Stratified permuted block randomized design will be used to generate the randomization table where permuted block randomization will be used for each stratum by age, with a varying block size of 4 and 6.
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Official Title: Randomized Clinical Trial of RANKL Inhibition With Denosumab on Mammographic Density in Premenopausal Women With Dense Breasts (TRIDENT)
Actual Study Start Date : August 27, 2019
Estimated Primary Completion Date : August 31, 2025
Estimated Study Completion Date : August 31, 2026

Resource links provided by the National Library of Medicine

Drug Information available for: Denosumab

Arm Intervention/treatment
Experimental: Denosumab
  • Subcutaneous injection of denosumab at a dose of 60 mg at two time points: baseline and 6 months
  • Participants will also be instructed to take calcium and vitamin D supplements daily for 12 months between baseline examination and 12-month mammographic breast density examination.
  • Mammographic breast density will be assessed at three time points in all participants: baseline, 12 months, and 24 months. A 36-month optional assessment may also occur.
  • Biopsies and blood draws will occur for research purposes at baseline and 12 months.
Drug: Denosumab
Denosumab is commercially available and will be provided at no cost to participants.
Other Name: Prolia

Drug: Calcium
-Participants will be instructed to take calcium (600 mg) daily for 12 months between baseline examination and 12- month mammographic breast density examination.

Drug: Vitamin D3
Participants will be instructed to take vitamin D3 (800 IU) supplements daily for 12 months between baseline examination and 12- month mammographic breast density examination.

Procedure: Core needle biopsy
Baseline and 12 months

Procedure: Blood draw
Baseline and 12 months

Placebo Comparator: Placebo
  • Subcutaneous injection of the placebo at a dose of 60 mg at two time points: baseline and 6 months
  • Participants will also be instructed to take calcium and vitamin D supplements daily for 12 months between baseline examination and 12 month mammographic breast density examination
  • Mammographic breast density will be assessed at three time points in all participants: baseline, 12 months, and 24 months. A 36 month optional assessment may also occur.
  • Biopsies and blood draws will occur for research purposes at baseline and 12 months.
Drug: Placebo
Placebo will be made available as 1 mL sterile, non-pyrogenic water solution in a single-use prefilled syringe.

Drug: Calcium
-Participants will be instructed to take calcium (600 mg) daily for 12 months between baseline examination and 12- month mammographic breast density examination.

Drug: Vitamin D3
Participants will be instructed to take vitamin D3 (800 IU) supplements daily for 12 months between baseline examination and 12- month mammographic breast density examination.

Procedure: Core needle biopsy
Baseline and 12 months

Procedure: Blood draw
Baseline and 12 months




Primary Outcome Measures :
  1. Change in mammographic breast density between the two arms as measured by volumetric percent density [ Time Frame: From baseline to 12 months ]
    -The investigators will use volumetric percent density (VPD) as the primary mammographic breast density measure.


Secondary Outcome Measures :
  1. Change in mammographic breast density between the two arms as measured by volumetric percent density [ Time Frame: From baseline to 24 months ]
  2. Change in mammographic breast density between the two arms as measured by volumetric percent density [ Time Frame: From 12 months to 24 months ]

Other Outcome Measures:
  1. Change in expression of RANKL pathway genes compared between the two arms [ Time Frame: Baseline and 12 months ]
  2. Change in expression of progesterone receptor and progesterone-regulated pathway genes compared between the two arms [ Time Frame: Baseline and 12 months ]
  3. Change in expression of markers of epithelial proliferation compared between the two arms [ Time Frame: Baseline and 12 months ]
  4. Change in expression of markers of stromal proliferation and growth factors compared between the two arms [ Time Frame: Baseline and 12 months ]
  5. Change in expression of immune markers compared between the two arms [ Time Frame: Baseline and 12 months ]
  6. Change in expression of inflammatory markers compared between the two arms [ Time Frame: Baseline and 12 months ]
  7. Correlations between gene expression within the breast tissue and within the blood [ Time Frame: Baseline ]


Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Female.
  • Premenopausal (when menopausal status is uncertain, the investigators will measure follicle-stimulating hormone and estradiol to ascertain that a partcipant is premenopausal)
  • At least 40 years of age.
  • Dense breasts on routine mammogram (BI-RADS Category C and D, i.e. volumetric percent density ≥ 7.5% on Volpara)
  • May be at increased risk for breast cancer using one of the following:

    • Positive family history of breast cancer in a first-degree relative
    • Presence of non-BRCA susceptibility genes
    • Biopsy confirmed benign breast disease
    • Age at menarche <12 years
    • Age at first birth >30 years
    • Nulliparity
    • Rosner-Colditz risk prediction models
  • Able to understand and willing to sign an IRB-approved written informed consent document.

Exclusion Criteria:

  • History of ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), invasive breast cancer, or other cancer (except non-melanoma skin cancer).
  • Known BRCA mutation(s).
  • Current use of tamoxifen, aromatase inhibitors, or bisphosphonates, or RANKL inhibitors
  • Concurrent participation in another cancer chemoprevention trial (unless no longer receiving the intervention).
  • Pregnant or lactating, or planning to get pregnant while the trial is ongoing.
  • Recent history of invasive dental procedure (e.g. tooth extraction, dental implant, oral surgery).
  • Unhealed and/or planned dental/oral surgery.
  • History of osteonecrosis/osteomyelitis of the jaw.
  • History of osteoporosis or severe osteopenia.

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): NCT04067726


Contacts
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Contact: Adetunji T Toriola, M.D., Ph.D. MPH 314-286-2668 a.toriola@wustl.edu
Contact: Ava Weibman 314-747-9992 a.weibman@wustl.edu

Locations
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United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Adetunji T Toriola, M.D., Ph.D., MPH    314-286-2668    a.toriola@wustl.edu   
Contact: Ava Weibman    314-747-9992    a.weibman@wustl.edu   
Principal Investigator: Adetunji T Toriola, M.D., Ph.D., MPH         
Sub-Investigator: Cheryl Herman, M.D.         
Sub-Investigator: Graham Colditz, M.D., D. PH         
Sub-Investigator: Ian Hagemann, M.D.         
Sub-Investigator: Jingqin (Rosy) Luo, Ph.D.         
Sub-Investigator: Christopher Maher, Ph.D.         
Sub-Investigator: Julie Margenthaler, M.D.         
Sub-Investigator: Katherine Weilbaecher, M.D.         
Sub-Investigator: Lindsay Peterson, M.D.         
Sponsors and Collaborators
Washington University School of Medicine
National Institutes of Health (NIH)
Investigators
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Principal Investigator: Adetunji T Toriola, M.D., Ph.D. Washington University School of Medicine
Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT04067726    
Other Study ID Numbers: 201907039
First Posted: August 26, 2019    Key Record Dates
Last Update Posted: April 2, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified participant data used in generating tables and figures in published manuscripts.
Time Frame: IPD will be shared beginning 12 months, and ending 24 months following article publication.
Access Criteria: IPD will be shared with investigators who propose a methodologically sound proposal. These proposals should have been reviewed and approved by independent review committees, including institutional review boards. Proposals should be directed to the Principal Investigator, who will review the request with other co-Investigators. Proposals may also be subject to further review by the Protocol Review Monitoring Committee and Institutional Review Board at Principal Investigator's institution. Requestors will need to sign an institutional data access agreement to gain access to the data.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Washington University School of Medicine:
Mammographic density
Breast cancer
RANKL
Denosumab
Prevention
Premenopausal
Additional relevant MeSH terms:
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Vitamin D
Cholecalciferol
Denosumab
Calcium
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Calcium-Regulating Hormones and Agents
Bone Density Conservation Agents