Bazedoxifene/Conjugated Estrogens (BZA/CE) Improvement of Metabolism (BIM)

Study Overview
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Brief Summary
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The goal of this pilot clinical study is to perform a randomized placebo-controlled study to assess the beneficial effect of a 3 month-treatment with Bazedoxifene/Conjugated Estrogens (BZA/CE) vs. placebo on glucose homeostasis and body composition in 20 post-menopausal women. The recruitment will be performed at Tulane Health Sciences Center.

Official Title
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Bazedoxifene/Conjugated Estrogens (BZA/CE) Improvement of Metabolism (BIM)

Conditions
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Obesity, Glucose Homeostasis, Postmenopausal Symptoms

Intervention / Treatment
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* Drug: Bazedoxifene/Conjugated Estrogens (BZA/CE)
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Post-menopausal women (<5y since final menstrual period) with age between 50-60y Symptomatic (hot flashes, vaginal dryness) or asymptomatic BMI 26-45 kg/m2 (Overweight, Obesity I and Obesity II) Fasting glucose <125mg/dl Triglycerides <200mg/dl Normal mammogram within past 12 months Physician clearance Exclusion Criteria: Amenorrhea from other causes (Hyperandrogenemia and anovulation) type 2 and type 1 diabetes Medications: diabetes or diabetic drugs, dyslipidemia, estrogen/progestin therapy, antidepressants and antipsychotics, antiretroviral (HIV), oral steroids, weight loss drugs ≤ 3 month washout of birth control pill (often prescribed for postmenopausal symptoms) Hysterectomy (partial or complete) Contraindications to estrogen treatment (unusual vaginal bleeding, blot clots, hepatic disease, bleeding disorder, past/present history of breast or uterine cancer, pregnant, breastfeeding)

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 60 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bazedoxifene/Conjugated Estrogens (BZA/CE)<br>Participants assigned to BZA/CE will receive a daily tablet containing conjugated estrogens 0.45 mg and bazedoxifene 20 mg. BZA/CE (bazedoxifene/conjugated estrogens) tablets, 0.45 mg/20 mg are oval, biconvex, pink tablets, branded with 0.45/20 in black ink on one side. The recommended and only FDA approved dosage is one BZA/CE tablet daily, taken without regard to meals. Tablets should be swallowed whole. If a dose of BZA/CE is missed, participants will be instructed to take it as soon as remembered unless it is almost time for the next scheduled dose. They should not take two doses at the same time. The dose is one tablet per day independent of weight and fat mass. Participants will be provided with information about BZA/CE and its potential side effects and contraindications. | Drug: Bazedoxifene/Conjugated Estrogens (BZA/CE)<br>* Daily tablet containing conjugated estrogens 0.45 mg and bazedoxifene 20 mg.<br>* Other names: DUAVEE;|
| Placebo Comparator: Placebo<br>Participants assigned to placebo will receive a daily tablet that matches the BZA/CE to maintain the blind. Placebo tablets, 0.45 mg/20 mg are oval, biconvex, pink tablets, branded with 0.45/20 in black ink on one side. Also to assure the blind is maintain, participants in the placebo group will be given the same instructions for taking the study medication.Tablets should be swallowed whole. If a dose, participants will be instructed to take it as soon as remembered unless it is almost time for the next scheduled dose. They should not take two doses at the same time. The dose is one tablet per day independent of weight and fat mass. Participants will be provided with information about BZA/CE and its potential side effects and contraindications, again to maintain the blind. | Drug: Placebo Oral Tablet<br>* Daily placebo tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Mass Index | Body composition will be assessed through change in body mass index at baseline and at 3 months post-treatment. | Change at 3 months from baseline | 
| Effect of CE/BZA on Body Composition Using Waist-to-hip Ratio | Body composition will be assessed through change in waist-to-hip ratio at baseline and at 3 months post-treatment. | Change at 3 months from baseline | 
| Change in Body Composition Using Dual-energy X-ray Absorptiometry (DXA) | Dual-Energy X-ray Absorptiometry was used to assess body composition. DXA uses an x-ray technique to look at the density of the body and can then estimate the amount of lean muscle mass and fat tissue. Body composition will be assessed through change in DXA body composition at baseline and at 3 months post-treatment. | Change at 3 months from baseline | 
| Change in Acute Insulin Response to Glucose (AIRg) | This will be assessed through an IV Glucose Tolerance Test (IVGTT) conducted at baseline and 3 months to measure the change in acute insulin response to glucose. IVGTT data derived by MINMOD Millennium software. MINMOD: a computer program to calculate insulin sensitivity and pancreatic responsivity from the frequently sampled intravenous glucose tolerance test. Acute Insulin Response (AIRg) to Intravenous Glucose is based on glucose and insulin levels obtained during the frequently sampled intravenous glucose tolerance test and calculated using a mathematical model. AIRg is measured as the magnitude of the insulin response to an intravenous glucose injection following glucose administration. A low AIRg indicates decreased ability of the pancreas to secrete insulin. | Change at 3 months from baseline | 
| Change in Basal Glucose Concentration (Gb) | This will be assessed through an IV Glucose Tolerance Test (IVGTT) conducted at baseline and 3 months to measure the change in basal glucose concentration. IVGTT data derived by MINMOD Millennium software. | Change at 3 months from baseline | 
| Change in Disposition Index (DI) | Disposition index (DI) is the product of insulin sensitivity times the amount of insulin secreted in response to blood glucose levels. DI is commonly used as a measure of β-cell function. This will be assessed through an IV Glucose Tolerance Test (IVGTT) conducted at baseline and 3 months to measure the change in disposition index (DI). IVGTT data derived by MINMOD Millennium software. DI is based on glucose and insulin levels obtained during the frequently sampled intravenous glucose tolerance test and calculated using a mathematical model. DI is the product of insulin sensitivity and the amount of insulin secreted in response to blood glucose levels. Disposition index is used as a measure of beta cell function and the ability of the body to dispose of a glucose load. A low DI is indicative of a higher risk of developing diabetes. | Change at 3 months from baseline | 
| Change in Insulin Sensitivity (SI) Index | SI indicates the net capacity for insulin to promote the disposal of glucose and to inhibit the endogenous production of glucose. This will be assessed through an IV Glucose Tolerance Test (IVGTT) conducted at baseline and 3 months to measure the change in insulin sensitivity (SI) index. IVGTT data derived by MINMOD Millennium software. SI is based on glucose and insulin levels obtained during the frequently sampled intravenous glucose tolerance test and calculated using a mathematical model. SI is a measure of tissue response to circulating insulin in the blood following glucose injection. A low SI signifies low insulin sensitivity and high SI represents high insulin sensitivity. | Change at 3 months from baseline | 
| Change in Homeostatic Model Assessment (HOMA) β-cell Function | The homeostasis model assessment of β-cell function (HOMA-β) is an index of insulin secretory function derived from fasting plasma glucose and insulin concentrations. This will be assessed at baseline and 3 months to measure the change in Homeostatic model assessment (HOMA) β-cell function. (HOMA) β-cell function is a method used to quantify beta-cell function from fasting blood samples of insulin and glucose. Normal levels for (HOMA) β-cell function is 107 or more. Lower numbers mean higher risk of developing diabetes. | Change at 3 months from baseline | 
| Change in Homeostatic Model Assessment (HOMA) Insulin Resistance (IR) | Homeostatic model assessment (HOMA) is a method for assessing β-cell function and insulin resistance (IR) from basal (fasting) glucose and insulin or C-peptide concentrations. This will be assessed at baseline and 3 months to measure the change in Homeostatic model assessment (HOMA) insulin resistance. HOMA IR is a method used to quantify insulin resistance from fasting blood samples of insulin and glucose. Normal levels for HOMA-IR is less than 2.0. Higher levels mean higher risk for developing diabetes. | Change at 3 months from baseline | 
| Change in Fasting Insulin Clearance (FIC) | This will be assessed at baseline and 3 months to measure the change in fasting insulin clearance (FIC). FIC derived from fasting C-peptide to insulin ratio. | Change at 3 months from baseline | 
| Change in Glucose-stimulated Insulin Clearance (GSIC) | This will be assessed through an IV Glucose Tolerance Test (IVGTT) conducted at baseline and 3 months to measure the change in glucose-stimulated insulin clearance (GSIC). GSIC derived from molar ratio of C-peptide to insulin area under curve (AUC) over first 20 min of IVGTT. | Change at 3 months from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure Change in Serum Biomarkers Panel 1 | Systematic inflammation will be measured through change in serum biomarkers (Leptin, Lipocalin 2 (LCN2), plasminogen activator inhibitor-1 (PAI-1), Intact OCN) taken at baseline and 3 months. | Change at 3 months from baseline | 
| Measure Change in Serum Biomarkers Panel 2 | Systematic inflammation will be measured through change in serum biomarkers (Adiponectin, RBP4) taken at baseline and 3 months. | Change at 3 months from baseline | 
| Measure Change in Leptin:Adiponectin Ratio (LAR) | Systematic inflammation will be measured through change in leptin:adiponectin ratio (LAR) taken at baseline and 3 months. | Change at 3 months from baseline | 
| Measure Change in Fibroblast Growth Factor-21 (FGF-21) | Systematic inflammation will be measured through change in Fibroblast growth factor-21 (FGF-21) taken at baseline and 3 months. | Change at 3 months from baseline | 
| Measure Change in C-Reactive Protein (CRP) | Systematic inflammation will be measured through change in C-Reactive Protein (CRP) taken at baseline and 3 months. | Change at 3 months from baseline | 
| Measure Change in Thiobarbituric Acid Reactive Substance (TBARS) | Systematic inflammation will be measured through change in Thiobarbituric acid reactive substance (TBARS) taken at baseline and 3 months. | Change at 3 months from baseline |