Kronos Early Estrogen Prevention Study (KEEPS)

NCT00154180 | Unknown Phase 4 DMC

• 2 other identifiers: KLRI-04-1WIRB Protocol #20040792
• Study Type: interventional
• Target: 728
• Locations: 1 country
• Sites: 9

Brief Summary

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.

Conditions

Menopause; Arteriosclerosis

Keywords

Perimenopause; Coronary Disease; Estrogen Replacement Therapy; Hormone Replacement Therapy

Outcome Measures

Primary Outcomes (1)

• Rate of change of carotid intimal medial thickness by ultrasound

  Measured at screening, 12, 24, 36, and 48 months

Secondary Outcomes (7)

• 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

• 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

Study Arms (2)

Arm 1

ACTIVE COMPARATOR

CEE 0.45 mg w/ Prometrium 200 mg patch 0.05 mg w/ Prometrium 200 mg

Drug: Conjugated equine estrogens 0.45 mg/day; Drug: Transdermal estradiol, 50 mcg/day; Drug: Micronized progesterone, 200 mg/day x 12 d/month; Drug: CEE, progesterone, transdermal patch or the placebo

Arm 2

PLACEBO COMPARATOR

Placebo patch, placebo CEE, placebo Prometrium

Drug: CEE , progesterone, estradiol patch or placebo for each; Drug: CEE, progesterone, transdermal patch or the placebo

Interventions

Conjugated equine estrogens 0.45 mg/day DRUG

Pill, 1 pill taken daily each month for the study duration

Also known as: Premarin or placebo

Arm 1

Transdermal estradiol, 50 mcg/day DRUG

Patch; 1 patch is applied to the skin weekly. Patch site is rotated on a weekly basis.

Also known as: Climara 50 mcg/day or placebo

Arm 1

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

Also known as: Prometrium or placebo

Arm 1

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

Also known as: Premarin, Prometrium, Climara Patch

Arm 2

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

Also known as: Premarin, Prometrium, Climara

Arm 1; Arm 2

Eligibility Criteria

• Age: 42 Years - 58 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• menses absent for at least 6 months and no more than 36 months
• good general health
• plasma FSH level greater than or equal to 35 mIU/ml
• estradiol levels \< 40 pg/ml
• normal mammogram within 1 year of randomization

You may not qualify if:

• use of hormone replacement or supplement within 3 months of randomization
• endometrial thickness \>5 mm by vaginal ultrasound
• in utero exposure to diethylstilbestrol (DES)
• current smoking \> 10 cigarettes/day
• obesity-body mass index \> 35
• history of clinical cardiovascular disease
• history of cerebrovascular disease
• history of thromboembolic disease
• coronary calcium score ≥ 50 units
• dyslipidemia-LDL cholesterol \>190 mg/dl
• hypertriglyceridemia-triglycerides \>400 mg/dl
• lipid lowering medication (statin, fibrate,or \> 500 mg/day of niacin)
• nut allergy (Prometrium includes peanut oil)
• uncontrolled hypertension-systolic BP \>150 and/or diastolic BP \> 95
• hysterectomy

Sponsors & Collaborators

• Kronos Longevity Research Institute: lead
• Albert Einstein College of Medicine: collaborator
• Brigham and Women's Hospital: collaborator
• Columbia University: collaborator
• Mayo Clinic: collaborator
• University of California, San Francisco: collaborator
• University of Utah: collaborator
• University of Washington: collaborator
• Yale University: collaborator

Study Sites (9)

Kronos Longevity Research Institute

Phoenix, Arizona, 85016-3452, United States

Location

University of California, San Francisco

San Francisco, California, 94115, United States

Location

Yale University Medical Center

New Haven, Connecticut, 06519, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02215, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Columbia Presbyterian Hospital

New York, New York, 10032, United States

Location

Albert Einstein College of Medicine

The Bronx, New York, 10461, United States

Location

University of Utah

Salt Lake City, Utah, 84108, United States

Location

University of Washington/VA Puget Sound, HCS

Seattle/Tacoma, Washington, 98493, United States

Location

Related Publications (22)

• 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.

  PMID: 16024750 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.

  PMID: 15804727 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.

  PMID: 15542885 BACKGROUND

• 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.

  PMID: 39729067 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.

  PMID: 36395695 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.

  PMID: 32520900 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.

  PMID: 32015261 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.

  PMID: 31652073 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.

  PMID: 31078511 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.

  PMID: 28846767 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.

  PMID: 28364870 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.

  PMID: 27393520 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.

  PMID: 26035291 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.

  PMID: 25069991 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.

  PMID: 23874743 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.

  PMID: 23670850 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.

  PMID: 23322818 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.

  PMID: 23312232 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.

  PMID: 22587616 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.

  PMID: 22209479 DERIVED

• Henderson VW. Aging, estrogens, and episodic memory in women. Cogn Behav Neurol. 2009 Dec;22(4):205-14. doi: 10.1097/WNN.0b013e3181a74ce7.

  PMID: 19996872 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.

  PMID: 19657788 DERIVED

Related Links

• Information on hormone treatment and KEEPS rationale
• Information on sponsoring institution

MeSH Terms

Conditions

Arteriosclerosis; Coronary Disease

Interventions

Estrogens, Conjugated (USP); Estradiol; Progesterone; 2-chloroethyl ethyl sulfide; Transdermal Patch

Condition Hierarchy (Ancestors)

Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Myocardial Ischemia; Heart Diseases

Intervention Hierarchy (Ancestors)

Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Pregnenediones; Pregnenes; Pregnanes; Corpus Luteum Hormones; Progesterone Congeners; Equipment and Supplies

Study Officials

• 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

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: September 7, 2005
• First Posted: September 12, 2005
• Study Start: September 1, 2005
• Primary Completion: May 1, 2012
• Study Completion: July 1, 2012
• Last Updated: September 14, 2009

Record last verified: 2009-09

Locations

US (9)