Trial Outcomes & Findings for Perimenopausal Estrogen Replacement Therapy Study (NCT NCT01308814)

Last Updated: 2017-08-22

Results Overview

Change from pre-trial (baseline) to post-trial (month 12) in the Center for Epidemiologic Studies Depression Scale (CES-D). The CES-D has a Range from 0-60, with higher scores indicating the presence of more symptomatology. A score of 16 or greater is indicative of clinically significant symptoms of depression.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

172 participants

Primary outcome timeframe

Baseline, month 12

Results posted on

2017-08-22

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Estradiol Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
Overall Study STARTED	86	86
Overall Study COMPLETED	69	63
Overall Study NOT COMPLETED	17	23

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Perimenopausal Estrogen Replacement Therapy Study

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=86 Participants Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Estradiol n=86 Participants Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.	Total n=172 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	86 Participants n=5 Participants	86 Participants n=7 Participants	172 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	50.5 years STANDARD_DEVIATION 3.0 • n=5 Participants	50.5 years STANDARD_DEVIATION 3.0 • n=7 Participants	50.5 years STANDARD_DEVIATION 3.0 • n=5 Participants
Sex: Female, Male Female	86 Participants n=5 Participants	86 Participants n=7 Participants	172 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	86 participants n=5 Participants	86 participants n=7 Participants	172 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, month 12

Population: The data presented here are based on individuals who completed the study and provided useable data for this particular measure at the time point reported.

Outcome measures

Outcome measures
Measure	Placebo n=69 Participants Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Estradiol n=63 Participants Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
Change in Depressive Symptoms as Indicated by The Center for Epidemiologic Studies Depression Scale (CES-D)	1.04 units on a scale Standard Deviation 7.56	-1.02 units on a scale Standard Deviation 4.89

PRIMARY outcome

Timeframe: Baseline and when prompted by CES-D score

Population: These data were not collected because this measure is no longer the preferred method for characterizing change in depression risk. The preferred method is now to measure depressive symptoms continuously, which was done. These continuous results can be found for the CESD score in this record.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Baseline, month 12

Population: The data presented here are based on individuals who completed the study and provided useable data for this particular measure at the time point reported.

Primary measures reflecting stress reactivity will consist of mean arterial pressure (MAP), vascular resistance index (VRI), plasma cortisol, and plasma IL-6. For each of these four measures, a delta score (change from rest to stress) will be calculated and then standardized as Z scores. The individual Z scores will then be averaged to yield a single Stress Reactivity profile measure (average z score) - a composite Z score reflecting magnitude of activation in the four primary stress-responsive pathways. This composite z score at baseline will be subtracted from the composite z score at 12 months to yield this outcome measure.

Outcome measures

Outcome measures
Measure	Placebo n=66 Participants Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Estradiol n=63 Participants Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
Change in Stress Reactivity During Laboratory Session Including Trier Social Stress Test	0.02 composite Z score Standard Deviation 0.67	-0.18 composite Z score Standard Deviation 0.54

SECONDARY outcome

Timeframe: Baseline, month 12

Population: The data presented here are based on individuals who completed the study and provided useable data for this particular measure at the time point reported.

The Medical Outcomes Study 36-item Short Form (SF-36) is a measure of functional well-being, including physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to emotional health problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. The range of this scale is 0-100, where higher scores indicates a more favorable health state.

Outcome measures

Outcome measures
Measure	Placebo n=67 Participants Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Estradiol n=59 Participants Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
Change in Functional Well-being as Assessed by the Medical Outcomes Study 36-item Short Form (SF-36)	0.94 units on a scale Standard Deviation 13.60	2.32 units on a scale Standard Deviation 11.32

SECONDARY outcome

Timeframe: Baseline, month 12

Population: The data presented here are based on individuals who completed the study and provided useable data for this particular measure at the time point reported.

Subjects will be classified as having metabolic risk if they either meet standard criteria for the metabolic syndrome (based on 3 of 5 risk factors: elevated blood pressure, fasting triglycerides, fasting glucose, waist circumference and low HDL-cholesterol) or they exhibit insulin resistance based on the homeostatic model assessment (HOMA) to derive HOMA-IR based on fasting insulin and glucose levels using the equation: HOMA-IR = fasting glucose (mmol/L) × fasting insulin (μU/mL)/22.5

Outcome measures

Outcome measures
Measure	Placebo n=86 Participants Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Estradiol n=86 Participants Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
Percentage Meeting Criteria for Metabolic Risk [Baseline and Month 12] baseline with metabolic risk	17 Participants	17 Participants
Percentage Meeting Criteria for Metabolic Risk [Baseline and Month 12] 12 month with metabolic risk	10 Participants	9 Participants

SECONDARY outcome

Timeframe: Baseline, month 12

Population: The data presented here are based on individuals who completed the study and provided useable data for this particular measure at the time point reported.

Change (from Baseline-to-12 Month) in flow mediated dilatation (FMD) test of the brachial artery, dilatation occurs following an acute increase in blood flow, induced by via circulatory arrest in the arm for a period of time. Measured using high resolution ultrasound, yielding a measure of endothelial-dependent vasodilatation. The increase in brachial arterial diameter as a consequence of reactive hyperemia is compared to the baseline diameter of the artery and expressed as a percentage of the baseline diameter (% FMD). Flow-mediated vasodilatation at each time point was calculated as diameter of the brachial artery under reactive hyperemia minus baseline diameter of the brachial artery. The change presented here is calculated as 12 month %FMD minus baseline month %FMD.

Outcome measures

Outcome measures
Measure	Placebo n=86 Participants Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Estradiol n=85 Participants Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
Change in Percentage of Brachial Artery Diameter	-0.65 percent flow mediated dilatation Standard Deviation 4.75	0.56 percent flow mediated dilatation Standard Deviation 4.91

SECONDARY outcome

Timeframe: Baseline, month 12

Population: The data presented here are based on individuals who completed the study and provided useable data for this particular measure at the time point reported.

A finometer noninvasive blood pressure devise (FMS) was used to collect a 10 minute recording of beat-to-beat blood pressure and pulse rate during spontaneous breathing under quiet recumbent conditions. baroreflex sensitivity was computed from the most stable 5-minute segment of this 10-minute period. Cross-spectral analysis was used to estimate the average transfer function modulus (i.e., gain) between systemic blood pressure oscillations and R-R interval oscillations in the frequency range of 0.07-0.14 Hz, also known as the low frequency band. The units of this baroreflex sensitivity (BRS) were msec/mmHg. The outcome presented here is the 12 month BRS minus baseline BRS.

Outcome measures

Outcome measures
Measure	Placebo n=85 Participants Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Estradiol n=85 Participants Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
Change in Baroreceptor Sensitivity	0.19 msec/mmHg Standard Deviation 2.74	0.43 msec/mmHg Standard Deviation 2.52

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 81 other events

Deaths: 0 deaths

Estradiol

Serious events: 0 serious events

Other events: 83 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Placebo n=86 participants at risk Placebo patches for 12 months and placebo pills for 12 days every 2 months. Placebo: Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.	Estradiol n=86 participants at risk Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. Estradiol: Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.
Vascular disorders Stage 1 hypertension	11.6% 10/86	4.7% 4/86
Psychiatric disorders High CES-D depression scale score without major or minor depression	27.9% 24/86	15.1% 13/86
Infections and infestations Bacterial or viral infection	26.7% 23/86	32.6% 28/86
Blood and lymphatic system disorders Bleeding changes, heavy bleeding	12.8% 11/86	37.2% 32/86
Blood and lymphatic system disorders Bleeding changes, prolonged bleeding	1.2% 1/86	15.1% 13/86
Musculoskeletal and connective tissue disorders Musculoskeletal pain	29.1% 25/86	34.9% 30/86
Skin and subcutaneous tissue disorders Skin irritation	36.0% 31/86	37.2% 32/86
Respiratory, thoracic and mediastinal disorders Shortness of breath or chest pain	11.6% 10/86	17.4% 15/86
Psychiatric disorders Anxiety	5.8% 5/86	2.3% 2/86
Psychiatric disorders Irritability	16.3% 14/86	17.4% 15/86
Psychiatric disorders Negative mood changes	29.1% 25/86	23.3% 20/86
Reproductive system and breast disorders Bleeding changes, spotting	33.7% 29/86	64.0% 55/86
Reproductive system and breast disorders Bleeding changes, mild or moderate bleeding	44.2% 38/86	80.2% 69/86
Gastrointestinal disorders Bloating	2.3% 2/86	9.3% 8/86
Reproductive system and breast disorders Breast tenderness	38.4% 33/86	53.5% 46/86
General disorders Fatigue	5.8% 5/86	14.0% 12/86
Gastrointestinal disorders GI Symptoms	26.7% 23/86	20.9% 18/86
General disorders Headache, not migraine	67.4% 58/86	60.5% 52/86
General disorders Headache, migraine with no aura	10.5% 9/86	10.5% 9/86
Reproductive system and breast disorders Hot flushes	17.4% 15/86	4.7% 4/86
Musculoskeletal and connective tissue disorders Leg or calf discomfort, swelling, or pain	44.2% 38/86	48.8% 42/86
General disorders Sleep issues	14.0% 12/86	10.5% 9/86
Eye disorders Vision changes or issues	32.6% 28/86	30.2% 26/86
General disorders Weight gain	61.6% 53/86	58.1% 50/86
General disorders Other	55.8% 48/86	50.0% 43/86

Additional Information

Susan S. Girdler, Ph.D.

University of North Carolina at Chapel Hill

Phone: 919-966-2179

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place