Clinical trial NCT00154180: Kronos Early Estrogen Prevention Study (KEEPS)
Official title: Effects of Estrogen Replacement on Atherosclerosis Progression in Recently Menopausal Women
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Menopause
Arteriosclerosis
Keywords: Perimenopause
Coronary Disease
Estrogen Replacement Therapy
Hormone Replacement Therapy
Lead sponsor: Kronos Longevity Research Institute
Sponsor class: OTHER
Collaborators: name: Albert Einstein College of Medicine
name: Brigham and Women's Hospital
name: Columbia University
name: Mayo Clinic
name: University of California, San Francisco
name: University of Utah
name: University of Washington
name: Yale University
First posted: 2005-09-12
Enrollment: 728
Sex: FEMALE
Minimum age (years): 42
Maximum age (years): 58
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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
* history of, or prevalent, chronic diseases including any cancer (other than basal cell skin cancers), renal failure, cirrhosis, diabetes mellitus, and endocrinopathies other than adequately treated thyroid disease
* known HIV infection and/or medications for HIV infection
* results of any safety laboratory test chemistries, (TSH, CBC, U/A) more than 20% abnormal

Primary outcomes:
measure: Rate of change of carotid intimal medial thickness by ultrasound
timeFrame: Measured at screening, 12, 24, 36, and 48 months
Secondary outcomes:
measure: Change in coronary calcium score by X-ray tomography
timeFrame: Meassured at screening and at 48 months
measure: Plasma lipid profiles
timeFrame: Samples taken at screening , 12, 36, and 48 months
measure: Blood clotting factors
timeFrame: Samples taken at screening, 12, 36 and 48 months
measure: Serum inflammatory factors
timeFrame: Samples taken at screening, 12, 36 and 48 months
measure: Hormone levels
timeFrame: Samples taken at screening, 12, 36 and 48 months
measure: Cognitive and Affective scores on standard psychometric tests
timeFrame: Testing is conducted at Baseline, 18, 36 and 48 months
measure: Quality of life
timeFrame: Measured at Baseline, 18, 36 and 48 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Kronos Longevity Research Institute
state: Arizona
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: New Haven
country: United States
facility: Yale University Medical Center
state: Connecticut
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Bronx
country: United States
facility: Albert Einstein College of Medicine
state: New York
city: New York
country: United States
facility: Columbia Presbyterian Hospital
state: New York
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle/Tacoma
country: United States
facility: University of Washington/VA Puget Sound, HCS
state: Washington
Study officials:
affiliation: Kronos Longevity Research Institute
name: S Mitchell Harman, MD, PhD
role: STUDY_DIRECTOR
affiliation: Kronos Longevity Research Institute
name: Frederick Naftolin, MD, PhD
role: STUDY_DIRECTOR
affiliation: Tufts Medical Center
name: Michael Mendelsohn, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Southern California
name: Howard Hodis, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles
name: Matthew Budoff, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Wisconsin, Madison
name: Sanjay Asthana, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Dennis M Black, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
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citation: 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.