Kronos Early Estrogen Prevention Study (KEEPS) - Full Text View

Sponsor:	Kronos Longevity Research Institute
Collaborators:	Albert Einstein College of Medicine of Yeshiva University Brigham and Women's Hospital Columbia University Mayo Clinic University of California, San Francisco University of Utah University of Washington Yale University
Information provided by:	Kronos Longevity Research Institute
ClinicalTrials.gov Identifier:	NCT00154180

Purpose

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.

Condition	Intervention	Phase
Menopause Arteriosclerosis	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, estradiol patch or placebo for each Drug: CEE, progesterone, transdermal patch or the placebo	Phase IV

Study Type:	Interventional
Study Design:	Prevention, Randomized, Double Blind (Subject, Investigator), Dose Comparison, Parallel Assignment, Safety/Efficacy Study
Official Title:	Effects of Estrogen Replacement on Atherosclerosis Progression in Recently Menopausal Women

Resource links provided by NLM:

MedlinePlus related topics: Menopause

Drug Information available for: Estradiol Estradiol 3-benzoate Progesterone Estrogens, conjugated Polyestradiol phosphate Depogen Estradiol dipropionate Estradiol cypionate Estradiol valerate Estradiol acetate

U.S. FDA Resources

Further study details as provided by Kronos Longevity Research Institute:

Primary Outcome Measures:

Rate of change of carotid intimal medial thickness by ultrasound [ Time Frame: Measured at screening, 12, 24, 36, and 48 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Change in coronary calcium score by X-ray tomography [ Time Frame: Meassured at screening and at 48 months ] [ Designated as safety issue: No ]
Plasma lipid profiles [ Time Frame: Samples taken at screening , 12, 36, and 48 months ] [ Designated as safety issue: No ]
Blood clotting factors [ Time Frame: Samples taken at screening, 12, 36 and 48 months ] [ Designated as safety issue: No ]
Serum inflammatory factors [ Time Frame: Samples taken at screening, 12, 36 and 48 months ] [ Designated as safety issue: No ]
Hormone levels [ Time Frame: Samples taken at screening, 12, 36 and 48 months ] [ Designated as safety issue: No ]
Cognitive and Affective scores on standard psychometric tests [ Time Frame: Testing is conducted at Baseline, 18, 36 and 48 months ] [ Designated as safety issue: No ]
Quality of life [ Time Frame: Measured at Baseline, 18, 36 and 48 months ] [ Designated as safety issue: No ]

Estimated Enrollment:	728
Study Start Date:	September 2005
Estimated Study Completion Date:	July 2012
Estimated Primary Completion Date:	May 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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 Pill, 1 pill taken daily each month for the study duration Drug: Transdermal estradiol, 50 mcg/day Patch; 1 patch is applied to the skin weekly. Patch site is rotated on a weekly basis. Drug: Micronized progesterone, 200 mg/day x 12 d/month capsule, 1 capsule taken daily for the first 12 days of each month for the study duration Drug: CEE, progesterone, transdermal patch or the placebo 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
Arm 2: Placebo Comparator Placebo patch, placebo CEE, placebo Prometrium	Drug: CEE , progesterone, estradiol patch or placebo for each CEE 0.45mg 1 PO QD Progesterone 200 mg 1 PO HS first 12 days of the month estradiol patch use 1 per week Drug: CEE, progesterone, transdermal patch or the placebo 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

Arms

Assigned Interventions

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

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

Drug: Transdermal estradiol, 50 mcg/day

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

Drug: Micronized progesterone, 200 mg/day x 12 d/month

capsule, 1 capsule taken daily for the first 12 days of each month for the study duration

Drug: CEE, progesterone, transdermal patch or the placebo

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

Arm 2: Placebo Comparator

Placebo patch, placebo CEE, placebo Prometrium

Drug: CEE , progesterone, estradiol patch or placebo for each

CEE 0.45mg 1 PO QD Progesterone 200 mg 1 PO HS first 12 days of the month estradiol patch use 1 per week

Drug: CEE, progesterone, transdermal patch or the placebo

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

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

Ages Eligible for Study:	42 Years to 58 Years
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00154180

Locations

United States, Arizona
Kronos Longevity Research Institute
Phoenix, Arizona, United States, 85016-3452
United States, California
University of California, San Francisco
San Francisco, California, United States, 94115
United States, Connecticut
Yale University Medical Center
New Haven, Connecticut, United States, 06519
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02215
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, New York
Columbia Presbyterian Hospital
New York, New York, United States, 10032
Albert Einstein College of Medicine
Bronx, New York, United States, 10461
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84108
United States, Washington
University of Washington/VA Puget Sound, HCS
Seattle/Tacoma, Washington, United States, 98493

Sponsors and Collaborators

Kronos Longevity Research Institute

Albert Einstein College of Medicine of Yeshiva University

Brigham and Women's Hospital

Columbia University

Mayo Clinic

University of California, San Francisco

University of Utah

University of Washington

Yale University

Investigators

Study Director:	S Mitchell Harman, MD, PhD	Kronos Longevity Research Institute
Study Director:	Frederick Naftolin, MD, PhD	Kronos Longevity Research Institute
Principal Investigator:	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

More Information

Additional Information:

Information on hormone treatment and KEEPS rationale This link exits the ClinicalTrials.gov site

Information on sponsoring institution This link exits the ClinicalTrials.gov site

Publications:

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.

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.

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.

Additional publications automatically indexed to this study by National Clinical Trials Identifier (NCT ID):

Henderson VW. Aging, estrogens, and episodic memory in women. Cogn Behav Neurol. 2009 Dec;22(4):205-14.

Responsible Party:	Kronos Longevity Research Institute ( S. Mitchell Harman, MD, PhD/Director )
Study ID Numbers:	KLRI-04-1, WIRB Protocol #20040792
Study First Received:	September 7, 2005
Last Updated:	September 10, 2009
ClinicalTrials.gov Identifier:	NCT00154180 History of Changes
Health Authority:	United States: Institutional Review Board

Keywords provided by Kronos Longevity Research Institute:

Perimenopause
Coronary Disease
Estrogen Replacement Therapy
Hormone Replacement Therapy

Additional relevant MeSH terms:

Arterial Occlusive Diseases
Estrogens
Progesterone
Contraceptive Agents
Physiological Effects of Drugs
Estradiol valerate
Contraceptive Agents, Female
Hormones, Hormone Substitutes, and Hormone Antagonists
Vascular Diseases
Reproductive Control Agents
Arteriosclerosis

Estradiol 17 beta-cypionate
Hormones
Pharmacologic Actions
Estradiol
Estrogens, Conjugated (USP)
Progestins
Therapeutic Uses
Estradiol 3-benzoate
Cardiovascular Diseases
Polyestradiol phosphate

ClinicalTrials.gov processed this record on February 08, 2010