Effect of Estradiol+Drospirenone Versus Estradiol+MPA on Endothelial Function

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01109979
• Collaborator: Bayer (Industry)
• Enrollment: 24
• Location: 1
• Arms: 2
• Duration (Months): 78
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study compares the effects of two common hormone medications on the heart and blood vessels of healthy post-menopausal women over the age of 45.

The study will take place over the course of about 5 months. Each subject will take two different medications over two six-week periods. They will be randomized at the beginning of the study to either estradiol+medroxyprogesterone acetate or estradiol+drospirenone for the first period, and will receive the other medication the second six-weeks of the study. At the very beginning of the study and at the end of each six-week treatment period, subjects will come to the hospital various tests including non-invasive blood vessel imaging tests, blood draws to test the levels of certain hormones in the body, an oral glucose tolerance test, a test to monitor renal blood flow, and 24-hour blood pressure monitoring. Between treatment periods, there will be a four-week medication-free washout period.

Condition or Disease	Intervention/Treatment	Phase
Cardiovascular Diseases	Drug: Estradiol+MPA; Drug: Estradiol+Drospirenone	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: Effect of Combined Estradiol and Drospirenone Treatment Versus Combined Estradiol and Medroxyprogesterone Acetate Treatment on Endothelial Function: A Crossover Study
• Study Start Date: Dec 1, 2009
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Estradiol+MPA	Drug: Estradiol+MPA; 1 single pill dose daily containing estradiol 1 mg + medroxyprogesterone acetate 2.5 mg; Other Names: Estradiol+medroxyprogesterone acetate
Active Comparator: Estradiol+DRSP	Drug: Estradiol+Drospirenone; 1 single pill dose daily containing estradiol 1mg + drospirenone 0.5 mg; Other Names: Angeliq

Outcome Measures

Primary Outcome Measures

1. Brachial Artery Reactivity % Flow Mediated Dilation (BAR %FMD) [%FMD after 6 weeks of treatment]

   This crossover study examined the effects of E+MPA versus E+DRSP on brachial artery reactivity (BAR) assessed after six weeks of treatment. BAR is a noninvasive measure of endothelium-dependent flow-mediated vasodilation (FMD) of the brachial artery. With this technique, inflation of an arm blood pressure cuff to suprasystolic blood pressure causes relative ischemia downstream to the cuff. Upon deflation, a brief state of increased blood flow occurs (reactive hyperemia), and the resulting increase in shear stress causes nitric oxide release and resulting vasodilation of the brachial artery (flow-mediated vasodilation). The flow-mediated changes in brachial artery diameter can be imaged by ultrasound and measured as an index of peripheral vasomotor function. BAR correlates with invasive assessments of coronary endothelial function as well as multiple cardiovascular risk factors.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 75 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Healthy female postmenopausal volunteers, as defined by absence of menses for at least 12 months and follicle stimulating hormone (FSH) 30 IU/L;

2. Age 45 to 75 years;

3. Systolic blood pressure <140 and >90 mmHg and diastolic blood pressure <90 and >60 mmHg at the screening visit;

4. No personal history of diabetes;

5. Body mass index < 30 kg/m2;

6. No clinically significant abnormalities on screening tests (complete blood count, serum electrolytes, liver enzymes, thyroid stimulating hormone, urinalysis, and electrocardiogram).

Exclusion Criteria:

1. Current smoking, defined as smoking within the 12 months before the screening visit;

2. Alcohol intake >1 beverage per night or history of alcohol abuse;

3. Current or past recreational drug use;

4. Personal history of hypertension, cardiovascular disease (coronary artery disease, congestive heart failure, valvular heart disease, stroke, transient ischemic attack, or intermittent claudication), hyperlipidemia, diabetes (defined as a fasting glucose ≥126 mg/dL), kidney disease, liver disease, venous or arterial thromboembolic disease, adrenal insufficiency, depression, or illness requiring overnight hospitalization in the past 6 months;

5. Risk factors for arterial or venous thromboembolism;

6. Personal history of breast cancer or any other type of cancer;

7. Personal history of endometrial hyperplasia, endometrial cancer, or unexplained vaginal bleeding;

8. History of cervical cancer or abnormal pap smear

9. Prescription or herbal medication use, excluding thyroid hormone supplementation;

10. Ischemic changes on resting electrocardiogram;

11. Serum creatinine ≥ 1.3 mg/dL.

12. Serum potassium level > 5.0 mmol/L;

13. Known hypersensitivity to any of the study drugs;

14. Other active medical problems detected by examination or laboratory testing, except for treated hypothyroidism.

15. Pregnancy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Brigham and Women's Hospital
• Bayer

Investigators

• Principal Investigator: Ellen Seely, MD, Brigham and Women's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ellen W. Seely, M.D., Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT01109979
• Other Study ID Numbers: 2006p002137
• First Posted: Apr 23, 2010
• Last Update Posted: Jul 12, 2016
• Last Verified: Jun 1, 2016

• Keywords provided by Ellen W. Seely, M.D., Brigham and Women's Hospital: Cardiovascular, vascular
• Additional relevant MeSH terms: Cardiovascular Diseases; Medroxyprogesterone Acetate; Drospirenone; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Medroxyprogesterone; Drospirenone and ethinyl estradiol combination; Estradiol; Polyestradiol phosphate

Study Results

Participant Flow

Recruitment Details	Postmenopausal women ages 45 and 75 were recruited 2009- 2011 via flyers, newspaper advertisements, Craigslist, RSVP for Health, and websites.
Pre-assignment Detail	Subjects were excluded after screening procedures due to history of hypertension, cardiovascular disease, hyperlipidemia, diabetes, liver disease, cancer, elevated creatinine/potassium levels, abnormal thyroid function, and evidence that menopause was not completed.

Arm/Group Title	E+MPA, Then E+DRSP	E+DRSP, Then E+MPA
Arm/Group Description	Estradiol (E) 1 mg orally per day + medroxyprogesterone acetate (MPA) 2.5 mg orally per day for 6 weeks, then 4 week washout before Estradiol (E) 1 mg orally per day + Drospirenone (DRSP) 0.5 mg orally per day for 6 weeks	Estradiol (E) 1 mg orally per day + Drospirenone (DRSP) 0.5 mg orally per day for 6 weeks, then 4 week washout before Estradiol (E) 1 mg orally per day + medroxyprogesterone acetate (MPA) 2.5 mg orally per day for 6 weeks
Period Title: Overall Study
STARTED	12	12
COMPLETED	10	11
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	E+MPA, Then E+DRSP	E+DRSP, Then E+MPA	Total
Arm/Group Description	Estradiol (E) 1 mg orally per day + medroxyprogesterone acetate (MPA) 2.5 mg orally per day for 6 weeks, then 4 week washout before Estradiol (E) 1 mg orally per day + Drospirenone (DRSP) 0.5 mg orally per day for 6 weeks	Estradiol (E) 1 mg orally per day + Drospirenone (DRSP) 0.5 mg orally per day for 6 weeks, then 4 week washout before Estradiol (E) 1 mg orally per day + medroxyprogesterone acetate (MPA) 2.5 mg orally per day for 6 weeks	Total of all reporting groups
Overall Participants	12	12	24
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	8 66.7%	10 83.3%	18 75%
>=65 years	4 33.3%	2 16.7%	6 25%
Sex: Female, Male (Count of Participants)
Female	12 100%	12 100%	24 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	12 100%	12 100%	24 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 8.3%	1 4.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 8.3%	1 8.3%	2 8.3%
White	11 91.7%	10 83.3%	21 87.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Brachial Artery Reactivity % Flow Mediated Dilation (BAR %FMD)
Description	This crossover study examined the effects of E+MPA versus E+DRSP on brachial artery reactivity (BAR) assessed after six weeks of treatment. BAR is a noninvasive measure of endothelium-dependent flow-mediated vasodilation (FMD) of the brachial artery. With this technique, inflation of an arm blood pressure cuff to suprasystolic blood pressure causes relative ischemia downstream to the cuff. Upon deflation, a brief state of increased blood flow occurs (reactive hyperemia), and the resulting increase in shear stress causes nitric oxide release and resulting vasodilation of the brachial artery (flow-mediated vasodilation). The flow-mediated changes in brachial artery diameter can be imaged by ultrasound and measured as an index of peripheral vasomotor function. BAR correlates with invasive assessments of coronary endothelial function as well as multiple cardiovascular risk factors.
Time Frame	%FMD after 6 weeks of treatment

Outcome Measure Data

Analysis Population Description

The number of participants for analysis includes only the participants that completed a baseline assessment and at least one of the treatment arms.

Arm/Group Title	E+MPA	E+DRSP
Arm/Group Description	Estradiol (E) 1 mg orally per day + medroxyprogesterone acetate (MPA) 2.5 mg orally per day for 6 weeks	Estradiol (E) 1 mg orally per day + Drospirenone (DRSP) 0.5 mg orally per day for 6 weeks
Measure Participants	21	21
Mean (Standard Deviation) [% FMD after 6 weeks of treatment]	5.49 (3.32)	3.39 (3.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E+MPA, E+DRSP
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Arm/Group Title	E+MPA		E+DRSP
Arm/Group Description	Estradiol (E) 1 mg orally per day + medroxyprogesterone acetate (MPA) 2.5 mg orally per day for 6 weeks		Estradiol (E) 1 mg orally per day + Drospirenone (DRSP) 0.5 mg orally per day for 6 weeks
All Cause Mortality
	E+MPA		E+DRSP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	E+MPA		E+DRSP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	E+MPA		E+DRSP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/24 (0%)

Limitations/Caveats

There may have been an order effect of E+DRSP on FMD. For this, however, we would expect %FMD to be lower in the 2nd treatment period, regardless of specific treatment. It is unclear whether this was true cross-over effect or due to the study size.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.