Hormone Replacement Therapy for Use in Postmenopausal Women for Relief of Hot Flushes and Urogenital Symptoms.

Study Overview
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Brief Summary
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Multicenter, double-blind, controlled, parallel group, randomized study to compare the clinical benefit of Estradiol acetate tablets, estradiol tablets and conjugated equine estrogen tablets, each administered orally, once daily, to postmenopausal women.

Official Title
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A Multicenter, Double-Blind, Controlled, Randomized Study to Compare the Efficacy in Relief of Hot Flushes in Women Receiving Oral Estradiol Acetate Tablets, Oral Estradiol Tablets or Oral Conjugated Equine Estrogens

Conditions
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Hormone Replacement Therapy

Intervention / Treatment
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* Drug: Estradiol acetate
* Drug: Estradiol
* Drug: Conjugated equine estrogens


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 40 years of age; bilateral oophorectomy ≥ 35 years of age. Non-hysterectomized women: Amenorrhea for ≥ 12 months or Amenorrhea for ≤ 12 months, but longer than 6 months, and serum FSH (follicle stimulating hormone) levels > 40 units/L and serum estradiol levels < 20 pg /mL, Hysterectomized women: Bilateral oophorectomy - subjects may enter the study 6 weeks after surgery or History of removal of ovaries may be confirmed by - serum FSH levels > 40 units/L and serum estradiol levels < 20 pg/mL or via surgical report / ultrasound. Seven or more moderate or severe hot flushes daily for 1 week or 60 or more moderate or severe flushes in 1 week during the 2 week screening period prior to study entry. Exclusion Criteria: Hormone therapy administered via the following routes and during the specified timeframes: oral within 8 weeks, vaginal (rings, creams, gels) within 1 week, transdermal within 4 weeks, intramuscular within 6 weeks, progestational implants, estrogen or estrogen/progestational injectable drug therapy within 3 months, estrogen pellet or progestational injectable within 6 months. Abnormal Pap smear suggestive of low grade squamous intraepithelial lesion (LGSIL) or worse. Enrollment of subjects with an ASCUS (atypical squamous cells of undetermined significance) interpretation must be discussed with the sponsor prior to randomization. Urinary tract infection Congestive heart failure Uncontrolled hypertension; sitting systolic BP ≥ 160 mmHg or diastolic ≥ 95 mmHg History of stroke or transient ischemic attacks Treatment with anticoagulants (heparin or warfarin). Uncontrolled thyroid disorders. Insulin-dependent diabetes mellitus. Increase frequency or severity of headaches including migraines during previous estrogen therapy.

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Estradiol acetate (E3A)<br> | Drug: Estradiol acetate<br>* Tablet containing 0.9 mg E3A, daily oral administration.<br>|
| Active Comparator: Estradiol<br> | Drug: Estradiol<br>* Tablet containing 1 mg estradiol, daily oral administration.<br>* Other names: Estrace;|
| Active Comparator: Conjugated equine estrogens (CEE):<br> | Drug: Conjugated equine estrogens<br>* Tablet containing 0.625 mg CEE, daily oral administration.<br>* Other names: Premarin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the Number of Moderate to Severe Hot Flushes, Week 4, ITT (Intention to Treat) Population | Severity of hot flush definitions: mild - sensation of heat without perspiration, moderate - sensation of heat with perspiration, able to continue activity, severe - sensation of heat with perspiration, causing the subject to stop activity or awaken from sleep | Baseline to Week 4 | 
| Mean Change From Baseline in the Number of Moderate to Severe Hot Flushes, Week 12, ITT Population | Severity of hot flush definitions: mild - sensation of heat without perspiration, moderate - sensation of heat with perspiration, able to continue activity, severe - sensation of heat with perspiration, causing the subject to stop activity or awaken from sleep | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the Severity of Moderate to Severe Hot Flushes, Week 4, ITT Population | Patient self-reported outcome. Severity of hot flush definitions: mild (1) - sensation of heat without perspiration, moderate (2) - sensation of heat with perspiration, able to continue activity, severe (3) - sensation of heat with perspiration, causing the subject to stop activity or awaken from sleep. Minimum 0/no hot flushes, Maximum 3/all severe hot flushes. Lower the score the greater the improvement in reducing hot flushes. | Baseline to Week 4 | 
| Mean Change From Baseline in the Severity of Moderate to Severe Hot Flushes, Week 12, ITT Population | Patient self-reported outcome. Severity of hot flush definitions: mild (1) - sensation of heat without perspiration, moderate (2) - sensation of heat with perspiration, able to continue activity, severe (3) - sensation of heat with perspiration, causing the subject to stop activity or awaken from sleep. Minimum 0/no hot flushes, Maximum 3/all severe hot flushes. Lower the score the greater the improvement in reducing hot flushes. | Baseline to Week 12 | 
| Mean Change From Baseline in Total Urogenital Symptom Score, Week 4, ITT Population | Urogenital Symptom Severity scored none=0, mild=1, moderate=2, severe=3. | Baseline to Week 4 | 
| Change From Baseline in Total Urogenital Symptom Score, Week 8, ITT Population | Urogenital Symptom Severity scored none=0, mild=1, moderate=2, severe=3. | Baseline to Week 8 | 
| Change From Baseline in Total Urogenital Symptom Score, Week 12, ITT Population | Urogenital Symptom Severity scored none=0, mild=1, moderate=2, severe=3. | Baseline to Week 12 |