Back to resultsKronos Early Estrogen Prevention Study (KEEPS)
Primary Purpose
Menopause, Arteriosclerosis
Status
Unknown status
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Conjugated equine estrogens 0.45 mg/day
Transdermal estradiol, 50 mcg/day
Micronized progesterone, 200 mg/day x 12 d/month
CEE , progesterone, estradiol patch or placebo for each
CEE, progesterone, transdermal patch or the placebo
Sponsored by
About this trial
This is an interventional prevention trial for Menopause focused on measuring Perimenopause, Coronary Disease, Estrogen Replacement Therapy, Hormone Replacement Therapy
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
Sites / Locations
- Kronos Longevity Research Institute
- University of California, San Francisco
- Yale University Medical Center
- Brigham and Women's Hospital
- Mayo Clinic
- Albert Einstein College of Medicine
- Columbia Presbyterian Hospital
- University of Utah
- University of Washington/VA Puget Sound, HCS
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Arm 1
Arm 2
Arm Description
CEE 0.45 mg w/ Prometrium 200 mg patch 0.05 mg w/ Prometrium 200 mg
Placebo patch, placebo CEE, placebo Prometrium
Outcomes
Primary Outcome Measures
Rate of change of carotid intimal medial thickness by ultrasound
Secondary Outcome Measures
Change in coronary calcium score by X-ray tomography
Plasma lipid profiles
Blood clotting factors
Serum inflammatory factors
Hormone levels
Cognitive and Affective scores on standard psychometric tests
Quality of life
Full Information
NCT ID
NCT00154180
First Posted
September 7, 2005
Last Updated
September 10, 2009
Sponsor
Kronos Longevity Research Institute
Collaborators
Albert Einstein College of Medicine, Brigham and Women's Hospital, Columbia University, Mayo Clinic, University of California, San Francisco, University of Utah, University of Washington, Yale University
1. Study Identification
Unique Protocol Identification Number
NCT00154180
Brief Title
Kronos Early Estrogen Prevention Study (KEEPS)
Official Title
Effects of Estrogen Replacement on Atherosclerosis Progression in Recently Menopausal Women
Study Type
Interventional
2. Study Status
Record Verification Date
September 2009
Overall Recruitment Status
Unknown status
Study Start Date
September 2005 (undefined)
Primary Completion Date
May 2012 (Anticipated)
Study Completion Date
July 2012 (Anticipated)
3. Sponsor/Collaborators
Name of the Sponsor
Kronos Longevity Research Institute
Collaborators
Albert Einstein College of Medicine, Brigham and Women's Hospital, Columbia University, Mayo Clinic, University of California, San Francisco, University of Utah, University of Washington, Yale University
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Menopause, Arteriosclerosis
Keywords
Perimenopause, Coronary Disease, Estrogen Replacement Therapy, Hormone Replacement Therapy
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
728 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Arm 1
Arm Type
Active Comparator
Arm Description
CEE 0.45 mg w/ Prometrium 200 mg patch 0.05 mg w/ Prometrium 200 mg
Arm Title
Arm 2
Arm Type
Placebo Comparator
Arm Description
Placebo patch, placebo CEE, placebo Prometrium
Intervention Type
Drug
Intervention Name(s)
Conjugated equine estrogens 0.45 mg/day
Other Intervention Name(s)
Premarin or placebo
Intervention Description
Pill, 1 pill taken daily each month for the study duration
Intervention Type
Drug
Intervention Name(s)
Transdermal estradiol, 50 mcg/day
Other Intervention Name(s)
Climara 50 mcg/day or placebo
Intervention Description
Patch; 1 patch is applied to the skin weekly. Patch site is rotated on a weekly basis.
Intervention Type
Drug
Intervention Name(s)
Micronized progesterone, 200 mg/day x 12 d/month
Other Intervention Name(s)
Prometrium or placebo
Intervention Description
capsule, 1 capsule taken daily for the first 12 days of each month for the study duration
Intervention Type
Drug
Intervention Name(s)
CEE , progesterone, estradiol patch or placebo for each
Other Intervention Name(s)
Premarin, Prometrium, Climara Patch
Intervention Description
CEE 0.45mg 1 PO QD Progesterone 200 mg 1 PO HS first 12 days of the month estradiol patch use 1 per week
Intervention Type
Drug
Intervention Name(s)
CEE, progesterone, transdermal patch or the placebo
Other Intervention Name(s)
Premarin, Prometrium, Climara
Intervention Description
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
Primary Outcome Measure Information:
Title
Rate of change of carotid intimal medial thickness by ultrasound
Time Frame
Measured at screening, 12, 24, 36, and 48 months
Secondary Outcome Measure Information:
Title
Change in coronary calcium score by X-ray tomography
Time Frame
Meassured at screening and at 48 months
Title
Plasma lipid profiles
Time Frame
Samples taken at screening , 12, 36, and 48 months
Title
Blood clotting factors
Time Frame
Samples taken at screening, 12, 36 and 48 months
Title
Serum inflammatory factors
Time Frame
Samples taken at screening, 12, 36 and 48 months
Title
Hormone levels
Time Frame
Samples taken at screening, 12, 36 and 48 months
Title
Cognitive and Affective scores on standard psychometric tests
Time Frame
Testing is conducted at Baseline, 18, 36 and 48 months
Title
Quality of life
Time Frame
Measured at Baseline, 18, 36 and 48 months
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
42 Years
Maximum Age & Unit of Time
58 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
S Mitchell Harman, MD, PhD
Organizational Affiliation
Kronos Longevity Research Institute
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Frederick Naftolin, MD, PhD
Organizational Affiliation
Kronos Longevity Research Institute
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Michael Mendelsohn, MD
Organizational Affiliation
Tufts Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Howard Hodis, MD
Organizational Affiliation
University of Southern California
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Matthew Budoff, MD
Organizational Affiliation
University of California, Los Angeles
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Sanjay Asthana, MD
Organizational Affiliation
University of Wisconsin, Madison
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Dennis M Black, PhD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
Kronos Longevity Research Institute
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85016-3452
Country
United States
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Yale University Medical Center
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06519
Country
United States
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Albert Einstein College of Medicine
City
Bronx
State/Province
New York
ZIP/Postal Code
10461
Country
United States
Facility Name
Columbia Presbyterian Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84108
Country
United States
Facility Name
University of Washington/VA Puget Sound, HCS
City
Seattle/Tacoma
State/Province
Washington
ZIP/Postal Code
98493
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
16024750
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.
Results Reference
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PubMed Identifier
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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.
Results Reference
background
PubMed Identifier
15542885
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.
Results Reference
background
PubMed Identifier
36395695
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.
Results Reference
derived
PubMed Identifier
32520900
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.
Results Reference
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PubMed Identifier
32015261
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.
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PubMed Identifier
31652073
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.
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PubMed Identifier
31078511
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.
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PubMed Identifier
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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.
Results Reference
derived
PubMed Identifier
28364870
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.
Results Reference
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PubMed Identifier
27393520
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.
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PubMed Identifier
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Results Reference
derived
Links:
URL
http://www.kronosinstitute.org
Description
Information on sponsoring institution
Learn more about this trial
Kronos Early Estrogen Prevention Study (KEEPS)
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