| ID | Type | Description | Link |
|---|---|---|---|
| WIRB Protocol #20040792 |
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| Name | Class |
|---|---|
| Albert Einstein College of Medicine | OTHER |
| Brigham and Women's Hospital | OTHER |
| Columbia University | OTHER |
| Mayo Clinic |
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The study will examine the effects of estrogen and progesterone on the development of atherosclerosis in menopausal women when hormone treatment is initiated within 3 years of the menopausal transition.
The KEEPS is designed to explore the hypothesis that early initiation of hormone therapy, in women who are at the inception of their menopause, will decrease the rate of accumulation of atherosclerotic plaque, indicating a likely delay in the onset of clinical cardiovascular disease. The study is designed as a multicenter, 4 year randomized clinical trial. It will evaluate the effectiveness of of 0.45 mg/day of oral conjugated equine estrogens or 50 mcg/day of transdermal estradiol via skin patch changed weekly (each in combination with cyclic oral, micronized progesterone, 200 mg daily for 12 days per month), versus placebo in preventing progression of carotid intimal medial thickness by sonogram and the accrual of coronary calcium in women aged 42-58 who are within 36 months of their final menstrual period at initiation of treatment. A number of secondary endpoints including biochemical and genetic risk factors for cardiovascular and thrombotic disease, and effects on cognition will also be studied. The study will enroll a total of 720 women in 2005-6, with an anticipated completion of the trial in 2010.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm 1 | Active Comparator | CEE 0.45 mg w/ Prometrium 200 mg patch 0.05 mg w/ Prometrium 200 mg |
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| Arm 2 | Placebo Comparator | Placebo patch, placebo CEE, placebo Prometrium |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Conjugated equine estrogens 0.45 mg/day | Drug | Pill, 1 pill taken daily each month for the study duration |
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| Measure | Description | Time Frame |
|---|---|---|
| Rate of change of carotid intimal medial thickness by ultrasound | Measured at screening, 12, 24, 36, and 48 months |
| Measure | Description | Time Frame |
|---|---|---|
| Change in coronary calcium score by X-ray tomography | Meassured at screening and at 48 months | |
| Plasma lipid profiles | Samples taken at screening , 12, 36, and 48 months | |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| S Mitchell Harman, MD, PhD | Kronos Longevity Research Institute | Study Director |
| Frederick Naftolin, MD, PhD | Kronos Longevity Research Institute | Study Director |
| Michael Mendelsohn, MD | Tufts Medical Center | Principal Investigator |
| Howard Hodis, MD | University of Southern California | Principal Investigator |
| Matthew Budoff, MD | University of California, Los Angeles | Principal Investigator |
| Sanjay Asthana, MD | University of Wisconsin, Madison | Principal Investigator |
| Dennis M Black, PhD | University of California, San Francisco | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Kronos Longevity Research Institute | Phoenix | Arizona | 85016-3452 | United States | ||
| University of California, San Francisco |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 16024750 | Background | Harman SM, Naftolin F, Brinton EA, Judelson DR. Is the estrogen controversy over? Deconstructing the Women's Health Initiative study: a critical evaluation of the evidence. Ann N Y Acad Sci. 2005 Jun;1052:43-56. doi: 10.1196/annals.1347.004. | |
| 15804727 | Background | Harman SM, Brinton EA, Cedars M, Lobo R, Manson JE, Merriam GR, Miller VM, Naftolin F, Santoro N. KEEPS: The Kronos Early Estrogen Prevention Study. Climacteric. 2005 Mar;8(1):3-12. doi: 10.1080/13697130500042417. |
| Label | URL |
|---|---|
| Information on hormone treatment and KEEPS rationale | View source |
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| OTHER |
| University of California, San Francisco | OTHER |
| University of Utah | OTHER |
| University of Washington | OTHER |
| Yale University | OTHER |
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| Transdermal estradiol, 50 mcg/day | Drug | Patch; 1 patch is applied to the skin weekly. Patch site is rotated on a weekly basis. |
|
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| Micronized progesterone, 200 mg/day x 12 d/month | Drug | capsule, 1 capsule taken daily for the first 12 days of each month for the study duration |
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| CEE , progesterone, estradiol patch or placebo for each | Drug | CEE 0.45mg 1 PO QD Progesterone 200 mg 1 PO HS first 12 days of the month estradiol patch use 1 per week |
|
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| CEE, progesterone, transdermal patch or the placebo | Drug | CEE 0.45 mg 1 PO QD or placebo equivalent Prometrium 200 mg 1 PO qHS for first 12 dasy of each month or placebo equivalent transdermal patch 0.05 mg use 1 patch per week or placebo equivalent |
|
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| Blood clotting factors |
| Samples taken at screening, 12, 36 and 48 months |
| Serum inflammatory factors | Samples taken at screening, 12, 36 and 48 months |
| Hormone levels | Samples taken at screening, 12, 36 and 48 months |
| Cognitive and Affective scores on standard psychometric tests | Testing is conducted at Baseline, 18, 36 and 48 months |
| Quality of life | Measured at Baseline, 18, 36 and 48 months |
| San Francisco |
| California |
| 94115 |
| United States |
| Yale University Medical Center | New Haven | Connecticut | 06519 | United States |
| Brigham and Women's Hospital | Boston | Massachusetts | 02215 | United States |
| Mayo Clinic | Rochester | Minnesota | 55905 | United States |
| Columbia Presbyterian Hospital | New York | New York | 10032 | United States |
| Albert Einstein College of Medicine | The Bronx | New York | 10461 | United States |
| University of Utah | Salt Lake City | Utah | 84108 | United States |
| University of Washington/VA Puget Sound, HCS | Seattle/Tacoma | Washington | 98493 | United States |
| 15542885 | Background | Harman SM, Brinton EA, Clarkson T, Heward CB, Hecht HS, Karas RH, Judelson DR, Naftolin F. Is the WHI relevant to HRT started in the perimenopause? Endocrine. 2004 Aug;24(3):195-202. doi: 10.1385/ENDO:24:3:195. |
| 41618732 | Derived | Kantarci K, Kara F, Tosakulwong N, Fought AJ, Schwarz CG, Senjem ML, Kendall-Thomas J, Min P, Lowe VJ, Jack CR, Kapoor E, Fields JA, Bailey KR, James TT, Faubion L, Lobo RA, Manson JE, Pal L, Hammers DB, Brinton EA, Malek-Ahmadi M, Cedars MI, Naftolin FN, Santoro N, Miller VM, Harman SM, Dowling NM, Gleason CE. Long-term amyloid PET and MRI outcomes in a menopausal hormone therapy trial. Alzheimers Dement. 2026 Feb;22(2):e71067. doi: 10.1002/alz.71067. |
| 39729067 | Derived | Kara F, Tosakulwong N, Lesnick TG, Fought AJ, Kendell-Thomas J, Kapoor E, Faubion LL, Schwarz CG, Senjem ML, Fields JA, Min PH, Lowe VJ, Jack CR Jr, Bailey KR, James TT, Lobo RA, Manson JE, Pal L, Hammers DB, Malek-Ahmadi M, Cedars MI, Naftolin FN, Santoro N, Miller VM, Harman SM, Dowling NM, Gleason CE, Kantarci K. Associations of blood pressure with white matter hyperintensities later in life; influence of short-term menopausal hormone therapy. Menopause. 2025 Jan 1;32(1):12-22. doi: 10.1097/GME.0000000000002481. |
| 36395695 | Derived | Kling JM, Dowling NM, Bimonte-Nelson H, Gleason CE, Kantarci K, Stonnington CM, Harman SM, Naftolin F, Pal L, Cedars M, Manson JE, James TT, Brinton EA, Miller VM. Associations between pituitary-ovarian hormones and cognition in recently menopausal women independent of type of hormone therapy. Maturitas. 2023 Jan;167:113-122. doi: 10.1016/j.maturitas.2022.10.002. Epub 2022 Oct 27. |
| 32520900 | Derived | Kling JM, Miller VM, Tosakulwong N, Lesnick T, Kantarci K. Associations of pituitary-ovarian hormones and white matter hyperintensities in recently menopausal women using hormone therapy. Menopause. 2020 Aug;27(8):872-878. doi: 10.1097/GME.0000000000001557. |
| 32015261 | Derived | El Khoudary SR, Venugopal V, Manson JE, Brooks MM, Santoro N, Black DM, Harman M, Naftolin F, Hodis HN, Brinton EA, Miller VM, Taylor HS, Budoff MJ. Heart fat and carotid artery atherosclerosis progression in recently menopausal women: impact of menopausal hormone therapy: The KEEPS trial. Menopause. 2020 Mar;27(3):255-262. doi: 10.1097/GME.0000000000001472. |
| 31652073 | Derived | El Khoudary SR, Zhao Q, Venugopal V, Manson JE, Brooks MM, Santoro N, Black DM, Harman SM, Cedars MI, Hopkins PN, Kearns AE, Miller VM, Taylor HS, Budoff MJ. Effects of Hormone Therapy on Heart Fat and Coronary Artery Calcification Progression: Secondary Analysis From the KEEPS Trial. J Am Heart Assoc. 2019 Aug 6;8(15):e012763. doi: 10.1161/JAHA.119.012763. Epub 2019 Aug 1. |
| 31078511 | Derived | Jayawardena E, Li D, Nakanishi R, Dey D, Dailing C, Qureshi A, Dickens B, Hathiramani N, Kim M, Flores F, Kearns AE, Lui LY, Black D, Budoff MJ. Non-contrast cardiac CT-based quantitative evaluation of epicardial and intra-thoracic fat in healthy, recently menopausal women: Reproducibility data from the Kronos Early Estrogen Prevention Study. J Cardiovasc Comput Tomogr. 2020 Jan-Feb;14(1):55-59. doi: 10.1016/j.jcct.2019.05.004. Epub 2019 May 4. |
| 28846767 | Derived | Taylor HS, Tal A, Pal L, Li F, Black DM, Brinton EA, Budoff MJ, Cedars MI, Du W, Hodis HN, Lobo RA, Manson JE, Merriam GR, Miller VM, Naftolin F, Neal-Perry G, Santoro NF, Harman SM. Effects of Oral vs Transdermal Estrogen Therapy on Sexual Function in Early Postmenopause: Ancillary Study of the Kronos Early Estrogen Prevention Study (KEEPS). JAMA Intern Med. 2017 Oct 1;177(10):1471-1479. doi: 10.1001/jamainternmed.2017.3877. |
| 28364870 | Derived | Cintron D, Beckman JP, Bailey KR, Lahr BD, Jayachandran M, Miller VM. Plasma orexin A levels in recently menopausal women during and 3 years following use of hormone therapy. Maturitas. 2017 May;99:59-65. doi: 10.1016/j.maturitas.2017.01.016. Epub 2017 Feb 17. |
| 27393520 | Derived | Owen CM, Pal L, Mumford SL, Freeman R, Isaac B, McDonald L, Santoro N, Taylor HS, Wolff EF. Effects of hormones on skin wrinkles and rigidity vary by race/ethnicity: four-year follow-up from the ancillary skin study of the Kronos Early Estrogen Prevention Study. Fertil Steril. 2016 Oct;106(5):1170-1175.e3. doi: 10.1016/j.fertnstert.2016.06.023. Epub 2016 Jul 5. |
| 26035291 | Derived | Gleason CE, Dowling NM, Wharton W, Manson JE, Miller VM, Atwood CS, Brinton EA, Cedars MI, Lobo RA, Merriam GR, Neal-Perry G, Santoro NF, Taylor HS, Black DM, Budoff MJ, Hodis HN, Naftolin F, Harman SM, Asthana S. Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Med. 2015 Jun 2;12(6):e1001833; discussion e1001833. doi: 10.1371/journal.pmed.1001833. eCollection 2015 Jun. |
| 25069991 | Derived | Harman SM, Black DM, Naftolin F, Brinton EA, Budoff MJ, Cedars MI, Hopkins PN, Lobo RA, Manson JE, Merriam GR, Miller VM, Neal-Perry G, Santoro N, Taylor HS, Vittinghoff E, Yan M, Hodis HN. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med. 2014 Aug 19;161(4):249-60. doi: 10.7326/M14-0353. |
| 23874743 | Derived | Dowling NM, Gleason CE, Manson JE, Hodis HN, Miller VM, Brinton EA, Neal-Perry G, Santoro MN, Cedars M, Lobo R, Merriam GR, Wharton W, Naftolin F, Taylor H, Harman SM, Asthana S. Characterization of vascular disease risk in postmenopausal women and its association with cognitive performance. PLoS One. 2013 Jul 17;8(7):e68741. doi: 10.1371/journal.pone.0068741. Print 2013. |
| 23670850 | Derived | Ogorodnikova AD, Khan UI, McGinn AP, Zeb I, Budoff MJ, Harman SM, Miller VM, Brinton EA, Manson JE, Hodis HN, Merriam GR, Cedars MI, Taylor HS, Naftolin F, Lobo RA, Santoro N, Wildman RP. Ectopic fat and adipokines in metabolically benign overweight/obese women: the Kronos Early Estrogen Prevention Study. Obesity (Silver Spring). 2013 Aug;21(8):1726-33. doi: 10.1002/oby.20200. Epub 2013 May 13. |
| 23322818 | Derived | Farr JN, Khosla S, Miyabara Y, Miller VM, Kearns AE. Effects of estrogen with micronized progesterone on cortical and trabecular bone mass and microstructure in recently postmenopausal women. J Clin Endocrinol Metab. 2013 Feb;98(2):E249-57. doi: 10.1210/jc.2012-3406. Epub 2013 Jan 15. |
| 23312232 | Derived | Wolff EF, He Y, Black DM, Brinton EA, Budoff MJ, Cedars MI, Hodis HN, Lobo RA, Manson JE, Merriam GR, Miller VM, Naftolin F, Pal L, Santoro N, Zhang H, Harman SM, Taylor HS. Self-reported menopausal symptoms, coronary artery calcification, and carotid intima-media thickness in recently menopausal women screened for the Kronos early estrogen prevention study (KEEPS). Fertil Steril. 2013 Apr;99(5):1385-91. doi: 10.1016/j.fertnstert.2012.11.053. Epub 2013 Jan 8. |
| 22587616 | Derived | Huang G, Wang D, Khan UI, Zeb I, Manson JE, Miller V, Hodis HN, Budoff MJ, Merriam GR, Harman MS, Brinton EA, Cedars MI, Su Y, Lobo RA, Naftolin F, Santoro N, Taylor HS, Wildman RP. Associations between retinol-binding protein 4 and cardiometabolic risk factors and subclinical atherosclerosis in recently postmenopausal women: cross-sectional analyses from the KEEPS study. Cardiovasc Diabetol. 2012 May 15;11:52. doi: 10.1186/1475-2840-11-52. |
| 22209479 | Derived | Huang G, Wang D, Zeb I, Budoff MJ, Harman SM, Miller V, Brinton EA, El Khoudary SR, Manson JE, Sowers MR, Hodis HN, Merriam GR, Cedars MI, Taylor HS, Naftolin F, Lobo RA, Santoro N, Wildman RP. Intra-thoracic fat, cardiometabolic risk factors, and subclinical cardiovascular disease in healthy, recently menopausal women screened for the Kronos Early Estrogen Prevention Study (KEEPS). Atherosclerosis. 2012 Mar;221(1):198-205. doi: 10.1016/j.atherosclerosis.2011.12.004. Epub 2011 Dec 9. |
| 19996872 | Derived | Henderson VW. Aging, estrogens, and episodic memory in women. Cogn Behav Neurol. 2009 Dec;22(4):205-14. doi: 10.1097/WNN.0b013e3181a74ce7. |
| 19657788 | Derived | Mulvagh SL, Behrenbeck T, Lahr BA, Bailey KR, Zais TG, Araoz PA, Miller VM. Endothelial function and cardiovascular risk stratification in menopausal women. Climacteric. 2010 Feb;13(1):45-54. doi: 10.3109/13697130902943287. |
| Information on sponsoring institution | View source |
| ID | Term |
|---|---|
| D001161 | Arteriosclerosis |
| D003327 | Coronary Disease |
| ID | Term |
|---|---|
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D017202 | Myocardial Ischemia |
| D006331 | Heart Diseases |
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| ID | Term |
|---|---|
| D004966 | Estrogens, Conjugated (USP) |
| D004958 | Estradiol |
| D011374 | Progesterone |
| C031278 | 2-chloroethyl ethyl sulfide |
| D057968 | Transdermal Patch |
| ID | Term |
|---|---|
| D045166 | Estradiol Congeners |
| D012739 | Gonadal Steroid Hormones |
| D042341 | Gonadal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D004963 | Estrenes |
| D004962 | Estranes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D003339 | Corpus Luteum Hormones |
| D045167 | Progesterone Congeners |
| D004864 | Equipment and Supplies |
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