Study Evaluating The Effects Of Bazedoxifene/Conjugated Estrogens On Endometrial Safety And Postmenopausal Osteoporosis

Study Overview
=================
Brief Summary
-----------------
The purpose of this research study is to evaluate the safety and effectiveness of this investigational drug for the treatment of menopausal symptoms while protecting the endometrium (uterine lining) and preventing postmenopausal osteoporosis. Subject participation will last approximately 14.5 months.

Official Title
-----------------
A Double-Blind, Randomized, Placebo And Active- Controlled Efficacy And Safety Study Of The Effects Of Bazedoxifene/Conjugated Estrogens Combinations On Endometrial Hyperplasia And Prevention Of Osteoporosis In Postmenopausal Women

Conditions
-----------------
Menopause, Osteoporosis

Intervention / Treatment
-----------------
* Drug: bazedoxifene 20 mg/ conjugated estrogens 0.45 mg
* Drug: bazedoxifene 20 mg/ conjugated estrogens 0.625 mg
* Drug: bazedoxifene 20 mg
* Drug: conjugated estrogens 0.45 mg/ medroxyprogesterone acetate 1.5 mg
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Generally healthy, postmenopausal women, aged 40 to 64 seeking treatment for menopausal symptoms At least 12 months of spontaneous amenorrhea, OR 6 months spontaneous amenorrhea with follicle-stimulating hormone (FSH) levels > 40 mIU/mL Intact Uterus Exclusion Criteria: Use of oral estrogen, progestin, androgen, or selective estrogen receptor modulator (SERM) containing drug products within 8 weeks before screening A history or active presence of clinically important medical disease: eg. cardiovascular disease (stroke, heart attack), chronic renal or liver disease, breast cancer, etc.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>bazedoxifene 20 mg/conjugated estrogens 0.45 mg | Drug: bazedoxifene 20 mg/ conjugated estrogens 0.45 mg<br>* One capsule, bazedoxifene 20 mg/conjugated estrogens 0.45 mg (over-encapsulated), once a day for one year.<br>|
| Experimental: 2<br>bazedoxifene 20 mg/conjugated estrogens 0.625 mg | Drug: bazedoxifene 20 mg/ conjugated estrogens 0.625 mg<br>* One capsule, bazedoxifene 20 mg/conjugated estrogens 0.625 mg (over-encapsulated), once a day for one year.<br>|
| Experimental: 3<br>bazedoxifene 20 mg | Drug: bazedoxifene 20 mg<br>* One capsule, bazedoxifene 20 mg (over-encapsulated), once a day for one year.<br>|
| Active Comparator: 4<br>Prempro | Drug: conjugated estrogens 0.45 mg/ medroxyprogesterone acetate 1.5 mg<br>* One capsule, conjugated estrogens 0.45 mg and medroxyprogesterone 1.5 mg (over-encapsulated), once a day for one year.<br>* Other names: Prempro;|
| Placebo Comparator: 5<br>Placebo | Drug: Placebo<br>* One capsule, placebo (over-encapsulated), once a day for one year.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Endometrial Hyperplasia at Month 12: Main Study | Endometrial hyperplasia was assessed by endometrial biopsies. All endometrial biopsies were read centrally by 2 primary pathologists. If both the pathologists disagreed on the presence of hyperplasia, a third pathologist was consulted. Results were summarized for two definitions of hyperplasia (simple hyperplasia with or without atypia or complex hyperplasia with or without atypia); definition 1: participants were considered to have a diagnosis of hyperplasia when the 3 pathologists disagreed but at least 1 pathologist determined hyperplasia; definition 2: participants were considered to have a diagnosis of hyperplasia if at least 2 of the 3 pathologists agreed on the diagnosis. | Month 12 | 
| Percent Change From Baseline in Bone Mineral Density (BMD) of Lumbar Spine at Month 12: Osteoporosis Sub-Study | BMD measurements of the anteroposterior lumbar spine were acquired by using dual-energy x-ray absorptiometry (DXA) scans, twice at Month 12 for a subset of participants who entered the osteoporosis substudy. The second scan was to be performed on the same day as the first; however, the participant was to be removed completely from the table after the first scan and repositioned for the second scan. Mean percentage change from baseline of the 2 readings were reported. | Baseline, Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Bone Mineral Density (BMD) of Lumbar Spine at Month 6: Osteoporosis Sub-Study | BMD measurements of the anteroposterior lumbar spine were acquired by using DXA scans, twice at Month 6 for a subset of participants who entered the osteoporosis substudy. The second scan was to be performed on the same day as the first; however, the participant was to be removed completely from the table after the first scan and repositioned for the second scan. Mean percentage change from baseline of the 2 readings were reported. | Baseline, Month 6 | 
| Percent Change From Baseline in Bone Mineral Density (BMD) of Total Hip at Month 6, 12: Osteoporosis Sub-Study | BMD measurements of the total hip were acquired by using DXA scans, twice at Month 6 and 12 for a subset of participants who entered the osteoporosis substudy. The second scan was to be performed on the same day as the first; however, the participant was to be removed completely from the table after the first scan and repositioned for the second scan. Mean percentage change from baseline of the 2 readings were reported. | Baseline, Month 6, Month 12 | 
| Percentage of Participants With Cumulative Amenorrhea: Main Study | Cumulative amenorrhea was defined as the absence of any bleeding or spotting for cumulative 4-week periods throughout 1-year study. | Day 1 up to Day 364 | 
| Percent Change From Baseline in Breast Density at Month 12: Breast Density Sub-Study | Breast density was assessed by digitalized mammograms which were centrally read by a single radiologist using specifically-developed software. Breast density was assessed for subset of participants who entered the breast density sub-study | Baseline, Month 12 | 
| Percent Change From Baseline in Bone Turnover Markers (BTMs) at Month 6 and Month 12: Osteoporosis Sub-Study | Bone turnover is the removal of old bone from the body and its replacement by new bone. Bone turnover markers included serum osteocalcin, C-telopeptide, and procollagen type 1 N-propeptide (P1NP), were measured at Month 6 and Month 12 for a subset of participants who entered the osteoporosis substudy. Blood samples were collected to evaluate bone turnover markers levels. | Baseline, Month 6, 12 | 
| Medical Outcomes Study (MOS) Sleep Scale at Baseline: Sleep Sub-Study | Participant-rated questionnaire to assess sleep quality and quantity. Consists of 12-item questionnaires answered on a range of 1 to 6 for questions (Q) 3 to 12, 1 to 5 for Q1 (some questions are reversed so that a high score reflects more of the attributes); and Q2 answered on 0 to 24. Scores are transformed (actual raw score minus lowest possible score divided by possible raw score range* 100); total score range: 0 to 100; higher score = greater intensity of attribute. The items contribute to each scale and are averaged to create the 7 scale scores and a sleep quantity scale. Scales with at least one item answered was used to generate a scale score. Scales include; sleep disturbance (SD), snoring, awaken short of breath (ASoB) or with a headache (H), somnolence, sleep adequacy (SA), sleep problem index (SPI) I and II (range: 0-100) and sleep quantity (SQ [range 0 to 24]). Except for sleep quantity, higher scores=greater impairment. | Baseline | 
| Change From Baseline in Medical Outcomes Study (MOS) Sleep Scale at Month 3: Sleep Sub-Study | Participant-rated questionnaire to assess sleep quality and quantity. Consists of 12-item questionnaires answered on a range of 1 to 6 for questions (Q) 3 to 12, 1 to 5 for Q1 (some questions are reversed so that a high score reflects more of the attributes); and Q2 answered on 0 to 24. Scores are transformed (actual raw score minus lowest possible score divided by possible raw score range* 100); total score range: 0 to 100; higher score = greater intensity of attribute. The items contribute to each scale and are averaged to create the 7 scale scores and a sleep quantity scale. Scales with at least one item answered was used to generate a scale score. Scales include; sleep disturbance (SD), snoring, awaken short of breath (ASoB) or with a headache (H), somnolence, sleep adequacy (SA), sleep problem index (SPI) I and II (range: 0-100) and sleep quantity (SQ [range 0 to 24]). Except for sleep quantity, higher scores=greater impairment. | Baseline, Month 3 | 
| Menopause-Specific Quality of Life (MENQOL) Score at Baseline: Sleep Sub-Study | MENQOL questionnaire assessed how bothered participants were due to menopause. It consists of 29 items divided into 4 domains: vasomotor function (3 items), psychosocial function (7 items), physical function (16 items), and sexual function (3 items). Each item scores a range from 1 to 8, with 1 indicating that the participant did not experience the symptom or problem, 8 indicating that the participant was extremely bothered by the symptom or problem. The total score for each domain is the average of item scores and ranged from 1 to 8 with higher score indicating worsening of symptoms. The MENQOL total score is the mean of these 4 domain scores and ranged from 1 to 8 with higher score indicating worsening of symptoms. | Baseline | 
| Change From Baseline in Menopause-Specific Quality of Life (MENQOL) Score at Month 3: Sleep Sub-Study | MENQOL questionnaire assessed how bothered participants were due to menopause. It consists of 29 items divided into 4 domains: vasomotor function (3 items), psychosocial function (7 items), physical function (16 items), and sexual function (3 items). Each item scores a range from 1 to 8, with 1 indicating that the participant did not experience the symptom or problem, 8 indicating that the participant was extremely bothered by the symptom or problem. The total score for each domain is the average of item scores and ranged from 1 to 8 with higher score indicating worsening of symptoms. The MENQOL total score is the mean of these 4 domain scores and ranged from 1 to 8 with higher score indicating worsening of symptoms. | Baseline, Month 3 | 
| Percentage of Participants With Uterine Bleeding | Percentage of participants with uterine bleeding were calculated for each 4-week period for 1-year on therapy. | Week 1-4, 5-8, 9-12, 13-16, 17-20, 21-24, 25-28, 29-32, 33-36, 37-40, 41-44, 45-48, 49-52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Postmenopausal Women, Bazedoxifene/Conjugated Estrogens