Conditions: Obesity Glucose Homeostasis Postmenopausal Symptoms
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 17
Healthy volunteers: no

Brief summary:
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.

Detailed description:

Arms:
arm 1: 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. arm 2: 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.

Interventions: intervention 1: Bazedoxifene/Conjugated Estrogens (BZA/CE) intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: Daily tablet containing conjugated estrogens 0.45 mg and bazedoxifene 20 mg. intervention 2: Daily placebo tablet

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
Bazedoxifene/Conjugated Estrogens (BZA/CE) 
Improvement of Metabolism  
 
NCT Number: NCT02237079 
 
Protocol Date: 7/26/2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version Date: _07/26/17___ 
Version Number: __9.0___ 
Page 2 of 17 
 
Bazedoxifene/Conjugated Estrogens (BZA/CE) Improvement of Metabolism 
  
1. Study aim, background, and design 
 
With the dramatic increase in life expectancy, many women will spend half of their lives in a post-
menopausal state of estrogen deficiency that increases risk for metabolic syndrome, type 2 diabetes 
(T2D) and non-alcoholic fatty liver diseases (NAFLD).1 Overall, the role of estrogen deficiency to the 
pathophysiology of chronic metabolic diseases in women is emerging as a novel therapeutic challenge. 
In 1995, approximately 38% of postmenopausal women in the U.S. used hormone therapy (HT), 
consisting of estrogen with or without progestin, to treat symptoms of menopause and to prevent 
chronic conditions such as cardiovascular disease (CVD) osteoporosis, and Alzheimer’s 2.  It was not 
until the Women’s Health Initiative (WHI) was abruptly halted in 2002 as a result of a link between HT 
and increased risk of coronary heart disease events, stroke and breast cancer that the health benefits 
of HT were seriously questioned.3 Results of the WHI led many women and their physicians to 
overestimate the individual-level risk associated with HT use. Fortunately, the period after 2010 saw a 
detailed analysis of the WHI and led to a stratification of the absolute risk of HT by age. Recently, the 
benefits of estrogen therapy have been reevaluated by international menopausal societies leading to a 
consensus on the benefits of HT pending that it is administered in early menopausal women and is not 
associated with a progestin.4 The most promising HT involves the use of tissue selective estrogen 
complexes (TSECs) combining a conjugated estrogen (CE) and the selective estrogen receptor 
modulator (SERM) bazedoxifene (BZA) in a single tablet. The major innovation of TSEC BZA/CE is 
that it provides all the advantages of CE treatment without the use and side effects of a progestin.5,6 
Another advantage is that it contains BZA, a SERM that has estrogen antagonistic activity in breast and 
uterus and estrogen agonistic activity in bone thus preventing osteoporosis while protecting the breast 
and uterus from estrogenic stimulation.6 BZA/CE (DUAVEE) is this novel menopausal therapy 
approved by the FDA for the treatment of postmenopausal symptoms and the prevention of 
menopausal osteoporosis. However, an important beneficial effect of estrogen is also to prevent 
postmenopausal metabolic disorders. 1,7,8 There is currently no information on the efficacy of BZA/CEin 
preventing postmenopausal metabolic disorders. Our recent preliminary data, derived from a mouse 
model of post-menopausal metabolic syndrome, demonstrate that the combination BZA/CE prevent 
estrogen deficiency-induced metabolic dysfunction-including obesity, T2D and NAFLD- and without 
uterus stimulation.9 Because SERMs like tamoxifen or Raloxifene have never shown such a 
beneficial metabolic effect in preclinical models and in humans,1 these data underscore the clinical 
significance of this line of investigation and they also provide a firm rationale for proposing a pilot 
study to assess the efficacy of BZA/CE  in preventing metabolic dysfunction in postmenopausal 
women. 
  
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 BZA/CE vs. placebo on glucose homeostasis and body 
composition in 30 post-menopausal women. The recruitment will be performed at Tulane Health 
Sciences Center. The following endpoint will be measured at the beginning of the study and after 3 
months of treatment. Patients will have a monthly visit with the clinical coordinator. 
 
a) Effect of DUAVEE™ on visceral adiposity. Rationale: Our preliminary data show that TSEC 
treatment prevents visceral fat accumulation in ovariectomized female mice with diet-induced 
metabolic dysfunction. 9 It also decreases hepatic and skeletal muscle triglyceride accumulation 9 in 
these ovariectomized mice.  Hypothesis: BZA/CE will improve visceral obesity in postmenopausal 
women. Design: We will determine the effect of a 3 month- treatment with DUAVEE on body mass 
index (BMI), waist to hip circumference (WHR)-a clinical index of visceral fat accumulation- and 


Version Date: _07/26/17___ 
Version Number: __9.0___ 
Page 3 of 17 
 
directly quantify abdominal fat by DEXA Scan. We expect that BZA/CE treatment will improve WHR 
and decrease abdominal fat in postmenopausal women. 
 
b) Effect of BZA/CE on glucose homeostasis. Rationale. Our preliminary data shows that TSEC 
treatment decreases fasting and fed blood glucose levels (as a result of improved insulin sensitivity) 
in ovariectomized female mice with diet-induced metabolic dysfunction. 9 Hypothesis: DUAVEE™ 
treatment will decrease glucose and insulin levels in postmenopausal women. Design: We will 
determine the effect of a 3 month- treatment with DUAVEE on fasting and fed glucose and insulin 
levels. We expect that BZA/CE treatment will decrease glucose and insulin levels in 
postmenopausal women. 
 
c) Clinical modelization of the impact of BZA/CE on glucose homeostasis. Rationale. Our 
preliminary data shows that TSEC treatment improves insulin resistance and glucose tolerance in 
ovariectomized female mice with diet-induced metabolic dysfunction. 9 Hypothesis: DUAVEE 
treatment will ameliorate insulin sensitivity and glucose tolerance in postmenopausal women. 
Design: We will determine the effect of a 3 month- treatment with DUAVEE™ on glucose 
homeostasis following an IV-Glucose Tolerance Test (IVGTT) which will be studied using the 
minimal model. In the minimal model, computer software is used to calculate insulin sensitivity and 
secretion from the glucose and insulin dynamics observed during the IVGTT. 10-12 Three major 
independent parameters can be derived: The insulin sensitivity index (SI) is the measure of the 
capability for insulin-stimulated glucose uptake; the acute insulin response to glucose (AIRg) which 
is the total insulin release during the first phase of insulin secretion and the disposition index (DI) 
which is the ability of an individual to control blood glucose taking into consideration insulin 
secretion in the face of the prevailing degree of insulin resistance.13 Therefore, the DI a major 
therapeutic index when assessing a new drug.  The IVGTT coupled to the minimal model is the gold 
standard and provides the most clinically relevant comprehensive metabolic portrait of an 
individual.10 We expect that BZA/CE treatment will enhance insulin sensitivity (SI) and the 
disposition index (DI) in postmenopausal women. 
 
d) Effect of DUAVEE™ on systemic inflammation. Rationale. Our preliminary data show that TSEC 
treatment improves systemic markers of inflammation and metabolic dysfunction in ovariectomized 
female mice with diet-induced metabolic dysfunction.  Metabolic dysfunction is characterized by 
recruitment and release of pro-inflammatory cytokines from WAT that cause insulin resistance and 
a general, low-grade systemic inflammatory state. Our preliminary data show that serum leptin 
levels and the leptin/adiponectin ratio — a marker of insulin resistance and atherogenesis — were 
markedly decreased by TSEC treatment in ovariectomized female mice fed a HFD. 9 In addition, 
TSEC treatment decreased serum levels of RBP4, an adipokine that is elevated in insulin 
resistance and type 2 diabetes.9 Further, TSEC treatment reduced serum levels of Lcn2,9 an 
adipokine that is also elevated in adipose tissue and in serum of obese and insulin resistant rodents 
and humans. Finally, serum levels of TBARS, a marker of oxidative stress and lipid peroxidation, 
were significantly decreased in OVX mice by TSEC treatment.9 Thus, in ovariectomized female 
mice fed a HFD, TSEC improves adipose dysfunction and systemic inflammation and protect 
against lipid peroxidation and oxidative stress. Hypothesis: BZA/CE treatment will improve 
systemic markers of inflammation in postmenopausal women. Design: We will determine the effect 
of a 3 month- treatment with DUAVEE on serum cytokines measurement (Leptin - Insulin – 
adiponectin – RBP4 - LCN2 – TNFα - IL6 – PAI-1 – FGF21). We expect that BZA/CE treatment will 
improve systemic markers of inflammation, lipid peroxidation and oxidative stress in 
postmenopausal women. 
 
 


Version Date: _07/26/17___ 
Version Number: __9.0___ 
Page 4 of 17 
 
Study Duration: Duration of the recruitment + treatment of patients: 1 year 
 
 
Target Start and End Dates: October, 2014 – September, 2015. 
 
Predicted outcome: We can foresee two possible outcomes. The most likely is that a 3 month- 
treatment with BZA/CE in postmenopausal women decreases visceral adiposity and markers of 
systemic inflammation and improves insulin resistance and glucose homeostasis. There are several 
reasons to anticipate these positive results. First, CE in already known to improve glucose and energy 
homeostasis in postmenopausal women1 and should continue to have the same activity in a TSEC. 
Second, an importantly SERMs like tamoxifen or raloxifene have never shown any beneficial 
metabolic effect in rodents and humans.1  Conversely, BZA exhibits a powerful metabolic effect in 
female mice and accordingly, we expect that it will translate to women. Finally, TSEC shows a 
beneficial effect on HFD-induced obesity, independently from estrogen deficiency in mice, suggesting 
that it may also improve obesity in women. For all these reasons, we are confident that BZA/CE anti-
diabetic and anti-obesity effects will translate to postmenopausal women. Acquisition of this information 
is critical to open novel avenues of therapies for postmenopausal women. The second possible 
outcome is that although our data generated in pre-clinical models are quite convincing and strongly 
suggests that BZA/CE will improve metabolic health in women, our hypothesis may not prove correct. 
This pilot study needs however to be performed because if successful, such preliminary data can lead 
to new therapeutic avenue for post-menopausal metabolic disturbances. 
 
Statistical Methods: According to our preliminary data obtained in mice, 9 TSEC treatment increased 
whole body glucose disposal by 30% and enhanced hepatic insulin sensitivity by 75% compared to 
vehicle. Although a formal power analysis was not feasible in the pilot study, in light of the high 
precision that is achieved using the minimal model, we can expect similar improvements to be 
detectable with 30 patients for whole body insulin sensitivity (Si and DI) in this randomized trial. Our 
statistician will conduct our data analysis. Briefly, a mixed effects statistical model will be used to 
investigate the within subject differential response to BZA/CE compared to placebo. Statistical 
significance will be set at p<0.05. Analysis will be carried out using the software package SAS V 9.3, 
SAS Institute, Inc. Cary, NC.   
 
2. Subject Population 
 
We will recruit and screened participants with the aim of randomizing 30 women (10 per group). After 
referral and clearance (see below), the final assessment of eligibility will be performed during a 
screening visit (blood, medical history and physical examination, barriers to participation, 
questionnaires). Breast exam and/or mammography will be part of the screening to assess eligibility. 
 
Inclusion: 
• 
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 < 200 mg/dl 
• 
Normal mammogram within past 12 months 
• 
Physician clearance 
 


Version Date: _07/26/17___ 
Version Number: __9.0___ 
Page 5 of 17 
 
Exclusion: 
• 
Amenorrhea from other causes (Hyperandrogenemia and anovulation) 
• 
Type 2 and Type 1 diabetes 
• 
Medications: diabetes or diabetic drugs, 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) 
 
Screening paradigm: Subjects will be recruited through endocrine and other medicine clinics at 
Tulane University Hospital & Clinic, Tulane-Lakeside Hospital and through referral from the Department 
of Medicine at Tulane Hospital & Clinic. Importantly, our recruitment efforts will be done with the 
Section of Reproductive Endocrinology and Infertility in the Department of Obstetrics and Gynecology 
at Tulane University Health Science Center.  We will also use community advertisements and 
promotional materials (attached).  
 
3. Procedure 
 
Treatment plan: Subject will participate in a randomized scheme as follows: 
a) PLACEBO for 3 months (N=10 patients) 
b) BZA/CE for 3 months (N=10 patients) 
 
BZA/CE group: 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 14. 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. Pfizer will provide the medication.  
 
PLACEBO group:  In addition to receiving a placebo tablet (provided by Pfizer), participants assigned to 
the placebo group will be counseled on how to adapt to changes associated with menopause.  
 
DEXA scans: will be performed using a Hologic QDR 4500A whole-body scanner.  The scan takes 
about 5 – 15 minutes and the radiation dose is less than 1 mrem, equal to about 12-h of background 
radiation.  The scans are analyzed with the QDR for Windows V11.1 software.  In our hands, the SD is 
320 g (CVs of 0.6%) and 300 g (CVs of 1.1%) for FFM and FM, respectively.  We will also use the DXA 
data to estimate muscle mass. 
 
Glucose and insulin: Fasting glucose and insulin will be measured after the 12-h overnight fast. Insulin 
levels will be collected at each time point during the IVGTT which is described below.   
 
IV-Glucose Tolerance Test (IVGTT): The intravenous glucose tolerance test (IVGTT) interpreted with 
the minimal model provides individual indexes of insulin sensitivity (SI) and glucose effectiveness (SG). 


Version Date: _07/26/17___ 
Version Number: __9.0___ 
Page 6 of 17 
 
Patients will have intravenous catheters inserted in a vein in each arm. One will be used for blood 
samples and the other to administer the IVGTT required medications - glucose and insulin.  Baseline 
blood samples will be taken at -15, -10, and -1 min. before glucose is injected intravenously in the dose 
of 11.4 g/m2 body surface area over 1 min. beginning at time 0. Blood samples will then be taken at 
timed intervals to check glucose levels via the YSI glucose Analyzer   Insulin will be administered 
intravenously over 30 seconds in the dose of0.03 U/kg body weight twenty minutes after the glucose 
administration. Again, blood samples will be taken at timed intervals until the 3 hour IVGTT is 
completed.  A total of 33 blood samples will be collected for both glucose and insulin according to the 
chart below.  
 
Time 
(min) 
Glucose and Insulin  
 
-15 
X 
-5 
X 
-1 
X 
0 
Glucose IV over 60 seconds – 11.4 g/m2 body surface area 
+2 
X 
+3 
X 
+4 
X 
+5 
X 
+6 
X 
+8 
X 
+10 
X 
+12 
X 
+14 
X 
+16 
X 
+19 
X 
+20 
Insulin iv over 30 seconds - -0.03 U/kg body weight 
+22 
X 
+23 
X 


Version Date: _07/26/17___ 
Version Number: __9.0___ 
Page 7 of 17 
 
+24 
X 
+25 
X 
+27 
X 
+30 
X 
+35 
X 
+40 
X 
+50 
X 
+60 
X 
+70 
X 
+80 
X 
+90 
X 
+100 
X 
+120 
X 
+140 
X 
+160 
X 
+180 
X 
 
Biomarkers of Inflammation: We will measure serum cytokines (Leptin – Insulin – adiponectin – RBP4 - 
LCN2 – TNFa - IL6 – PAI-1 – FGF21) through high sensitivity ELISAs.  These biomarkers will be 
collected prior to any testing at Visits 2 and 5 after a 12 hour fast. 
 
Endothelial Function Test:  This test will be done at Visits 2 and 5 after a 12 hour fast. It is a non-
invasive test that uses Peripheral arterial tonometry (EndoPAT) to assess endothelial function. 
 
Specifics of this Endothelial Function Test can be found in the “Addendum to BIM Study” document that 
is attached to this protocol.  
 
4. Risks 
 
Risks to Subjects:  This Human Subjects Research meets the definition of a Clinical Trial.  
 
 
 


Version Date: _07/26/17___ 
Version Number: __9.0___ 
Page 8 of 17 
 
Sources of Materials 
 
All data and specimens will be obtained solely for research purposes. These will include 1) detailed 
medical history, 2) physical exam including BMI and WHR measurement, 3) multiple blood samples to 
assess complete blood count, complete metabolic panel, lipid profile; glucose and insulin blood 
samples from IV-GTT testing, and cytokines(biomarkers of inflammation), 4) body composition 
measures by DXA (for details see section 3c. Approach), Endothelial Testing using the EndoPAT 
machine and  5) stored blood specimens used to study metabolic health and inflammation. All data 
from individual subjects will be maintained for confidentiality and names and identities will not be 
disclosed in any published document. 
 
This study does not involve major risk to screeners and trial participants.  To minimize the potential 
risks of the assessment methods and outcome variables, investigators will frequently monitor the study 
to assure that no volunteer suffers any adverse effects from participating in the research.  Risks of 
complications will be reduced by carefully selecting participants for enrollment as per our 
inclusion/exclusion criteria.  Other than participants being Overweight, with Obesity I and Obesity II at 
the time of enrollment, the inclusion and exclusion criteria were created to ensure women with low risk 
for bone fractures, have no diabetes and are not on medications such as diabetic drugs, dyslipidemia, 
estrogen/progestin therapy, antidepressants and antipsychotics. The Principal Investigator or its 
representative(s) will obtain medical clearance prior to each participant’s enrollment.  
Potential risks associated with the study procedures include: 
 
a) Analysis of archived of blood specimens:  There is no risk for participants to have their blood 
collected and stored for future use pertaining to metabolic health and inflammation.  All 
specimens will be de-identified and kept in a secure location.   
b) Blood pressure testing: Participants may experience temporary discomfort during blood 
pressure recordings due to the pressure of the cuff inflating on their arm. 
c) Blood draw: There is the possibility of pain and bruising at the vein on your arm where the 
needle is inserted. Multiple sticks may be necessary if there is difficulty in drawing participants 
blood. Aseptic (sterile) technique and trained personnel minimize these risks. 
d) Body composition assessment: The DXA scan involves extremely low levels radiation exposure. 
This technique has been demonstrated to be safe and approved for children. There are no 
known risks of the body scan 
e)   IV Glucose Tolerance Test: The IV glucose tolerance test is the gold standard for assessing 
insulin sensitivity and secretion from the glucose and insulin dynamics observed during the 
IVGTT which are computerized as a minimal model using software. Some people feel 
nauseated or sweaty after receiving the glucose. Some people develop hypoglycemia. The IV(s) 
may be associated with pain or bruising where the needle(s) are inserted and the development 
of a bruise at these sites with a minimal possibility of infection.  Trained personnel and aseptic 
(sterile) techniques are used to minimize these risks. The intended sites of catheterization will 
be cleaned thoroughly with an antiseptic and, after insertion; the area will be dressed so that it is 
not in contact with the outer environment. Also, the subject will be supervised, and all sites will 
be monitored for any signs of infection (increase in body temperature, swelling, redness, etc., 
around the insertion sites), upon which the catheter(s) will be removed immediately. Trained, 
credentialed personnel under the supervision of PIs will perform all procedures.  
f) Endothelial Function Test: The EndoPAT is performed with the participant in a lying or sitting 
position for approximately 15 minutes.  The subject may become uncomfortable for that length 
of time.  Finger probes are placed on each index finger and minimally inflated which may pose 
some discomfort to their fingertips.  The finger probes are deflated after the testing is 


Version Date: _07/26/17___ 
Version Number: __9.0___ 
Page 9 of 17 
 
completed.  A cuff is placed on their non-dominant arm and inflated for about 5 minutes during 
the testing period.  This may cause some discomfort and/or tingling in there arm, however it is 
considered very safe and should pass with the release of the cuff.  Only Trained personnel will 
be performing this test. 
 
Protection against Risks 
 
Confidentiality 
 
The study investigators will treat participant identity with professional standards of confidentiality.  Each 
participant will be assigned an identification number and all participant protected health 
information/records/questionnaires/data will be coded and identified using these numbers rather than 
participant names.  The coded participant list identifying participants by name will be stored separately 
from the number coded records/questionnaires/data.  All participant records/data will be stored in 
locked file cabinets.  Study results will be reported as group data and/or by participant identification 
number only.  Study results may be presented in publications or at meetings/conferences, however 
participant identity will not be disclosed.   A participant may request their personal health information or 
their personal study data/results at any time during the study and will be given copies. 
 
All volunteers are assured of their confidentiality both verbally and in the informed consent form.  The 
clinical facilities are strictly limited to the staff of the research institution and to research volunteers.  
This is accomplished by a variety of stringent security measures.  All medical records are stored in 
locked areas.  Access to these areas is limited to the clinical support staff, director of the clinical 
facilities, and the PIs. Electronic data storage is similarly restricted with only the PIs and authorized 
persons having access to databases containing confidential clinical records, i.e. those containing name 
OR other identifying information.  
 
HIPPA Compliance 
 
Tulane University Health Sciences Center complies with the federal 1996 Health Insurance Portability 
and Accountability Act (HIPPA). Specifically, Tulane University Health Sciences Center protects the 
privacy and confidentiality of medical records and information contained in medical records of persons 
who are subjects of research projects, including all Protected Health Information (PHI) as defined by 
the HIPAA Privacy Regulations. PHI of research subjects and the use or disclosure of such information 
is governed by PBRC research policies, as well as Common Rule, FDA regulations and other 
applicable laws. 
 
Tulane University Health Sciences Center and the Principal Investigators (the persons chiefly 
responsible for the record) protect the privacy of research subjects and their PHI collected during a 
research project. Tulane University Health Sciences Center will not use or disclose existing PHI or PHI 
created during a research project, unless: 
 
• 
The subject signs both (a) a HIPAA Authorization for use and disclosure of PHI using an 
approved Authorization Form or other form containing all the elements of legally effective HIPAA 
authorization and (b) the informed consent to participate in research form approved by the 
Institutional Review Board (IRB), or 
• 
The IRB grants a waiver to the requirement of obtaining a signed HIPAA Authorization Form, or 
• 
The IRB-approved protocol uses properly de-identified PHI 


Version Date: _07/26/17___ 
Version Number: __9.0___ 
Page 10 of 17 
 
• 
The IRB-approved protocol uses the limited data set and the Principal Investigator signs a 
limited data use agreement with the entity that maintains the designated record set. 
 
5. Benefits 
 
We cannot promise benefits from participating in this study but we expect clear improvements of 
metabolic health for all the women randomized to pharmacological interventions. The results of the 
study will provide important information about pharmacological intervention with BZA/CE that may help 
in controlling weight/fat gain in women during early post menopause.  This information can contribute to 
the development of evidence-based recommendations to help manage weight during menopause.  
 
6. Remuneration 
Subjects will receive compensation for their time and travel in the form of a Clincard.  They will receive 
$25.00 for study visits 1, 3, and 4 and $50.00 for study visits 2 and 5. The Clincard is a reloadable 
debit/credit card that will be given to each subject upon completion of their first visit. After each 
completed study visit thereafter, the card will be uploaded with the amount allowed for that visit.  The 
subject will received compensation for each completed study visit. If they complete all study visits, they 
will receive up to a total of $175.00. If a subject is withdrawn from the study by either the investigator or 
sponsor, or withdraws voluntarily, the subject will be compensated only for the study visits they 
complete. 
 
Tulane University is required to report payments of $600 or more to the Internal Revenue Service (IRS).  
This means that if you receive $600 or more from Tulane during the calendar year, your compensation 
will be reported to the IRS and you will receive an IRS 1099 Form. 
 
7. Costs 
 
There will be no costs to the subject for participating in this research study. 
 
8. Alternatives 
 
The alternative is that the subjects do not have to participate in the research. 
 
9. Consent process and documentation 
 
The objectives of the project, all experimental procedures, all requirements for participation, and any 
possible discomforts, risks, and benefits of participation will be clearly explained in writing and orally, in 
lay terms, to the subject by the study coordinator, the Principal Investigator or its representatives. 
Subjects will be informed orally and in writing that they are free to withdraw from the study at any time 
for any reason without bias or prejudice. After all questions have been answered and the subject 
agrees to participate in the study as described, he/she will sign a written informed consent document. 
   
10. Qualifications of the investigators 
 
We have assembled a synergic team.  
 
The Principal Investigator, Dr. Mauvais-Jarvis, MD, PhD is a physician scientist who received his 
medical degree from the University of Paris School of Medicine in France and completed clinical 


Version Date: _07/26/17___ 
Version Number: __9.0___ 
Page 11 of 17 
 
training in endocrinology in Paris teaching hospitals. He is a world-renowned expert in the action of 
estrogen on metabolism with 15 years experience in the conduct of metabolic studies in preclinical 
models. Dr. Mauvais-Jarvis also has extensive experience in clinical studies in patients with diabetes 
with over 15 publications involving human subjects.  
 
The Co-Investigator, Dr. Vivian A. Fonseca, MD, is the Chief of the Section of Endocrinology. He is a 
world-renowned expert in the conduct of clinical investigation of novel diabetes drugs in obese and 
diabetic human subjects and has been conducting such studies at Tulane Health Science Center for 
the past 20 years 
 
Roberta McDuffie, MSN, ACNS-BC, BSBA, ADN, CDE, Instructor in Medicine, is the principal research 
coordinator for endocrine research at Tulane University. She will be involved in overseeing patient 
recruitment. 
 
Tina Thethi, MD, MPH is an Associate Professor and attending physician is the Department of 
Medicine, Section of Endocrinology at Tulane University Health Sciences Center. She is currently the 
principal investigator of the LEADER study, a multicenter study examining the effects of liraglutide 
versus placebo on cardiovascular events and will be involved in patient recruitment. 
 
Dragana Lovre, MD is an Assistant Professor of Medicine in the Department of Medicine, Section of 
Endocrinology at Tulane University Health Sciences Center, and will be involved in patient recruitment. 
 
 
 


Version Date: _07/26/17___ 
Version Number: __9.0___ 
Page 12 of 17 
 
 
11. References 
 
1. 
Mauvais-Jarvis, F., Clegg, D.J. & Hevener, A.L. The role of estrogens in control of energy 
balance and glucose homeostasis. Endocr Rev 34, 309-338 (2013). 
2. 
Keating, N.L., Cleary, P.D., Rossi, A.S., Zaslavsky, A.M. & Ayanian, J.Z. Use of hormone 
replacement therapy by postmenopausal women in the United States. Ann Intern Med 130, 545-
553 (1999). 
3. 
Rossouw, J.E., Anderson, G.L., Prentice, R.L., LaCroix, A.Z., Kooperberg, C., Stefanick, M.L., 
Jackson, R.D., Beresford, S.A., Howard, B.V., Johnson, K.C., Kotchen, J.M., Ockene, J. & 
Writing Group for the Women's Health Initiative, I. Risks and benefits of estrogen plus progestin 
in healthy postmenopausal women: principal results From the Women's Health Initiative 
randomized controlled trial. JAMA 288, 321-333 (2002). 
4. 
de Villiers, T.J., Gass, M.L., Haines, C.J., Hall, J.E., Lobo, R.A., Pierroz, D.D. & Rees, M. Global 
consensus statement on menopausal hormone therapy. Climacteric 16, 203-204 (2013). 
5. 
Santen, R.J., Kagan, R., Altomare, C.J., Komm, B., Mirkin, S. & Taylor, H.S. Current and 
evolving approaches to individualizing estrogen receptor-based therapy for menopausal women. 
J Clin Endocrinol Metab 99, 733-747 (2014). 
6. 
Komm, B.S. & Mirkin, S. Evolution of the tissue selective estrogen complex (TSEC). J Cell 
Physiol 228, 1423-1427 (2013). 
7. 
Margolis, K.L., Bonds, D.E., Rodabough, R.J., Tinker, L., Phillips, L.S., Allen, C., Bassford, T., 
Burke, G., Torrens, J., Howard, B.V. & Women's Health Initiative, I. Effect of oestrogen plus 
progestin on the incidence of diabetes in postmenopausal women: results from the Women's 
Health Initiative Hormone Trial. Diabetologia 47, 1175-1187 (2004). 
8. 
Kanaya, A.M., Herrington, D., Vittinghoff, E., Lin, F., Grady, D., Bittner, V., Cauley, J.A., Barrett-
Connor, E., Heart & Estrogen/progestin Replacement, S. Glycemic effects of postmenopausal 
hormone therapy: the Heart and Estrogen/progestin Replacement Study. A randomized, double-
blind, placebo-controlled trial. Ann Intern Med 138, 1-9 (2003). 
9. 
Kim, J.H., Meyers, M.S., Khuder, S.S., Abdallah, S.L., Muturi, H.T., Russo, L., Tate, C.R., 
Hevener, A.L., Najjar, S.M., Leloup, C. & Mauvais-Jarvis, F. Tissue-selective estrogen 
complexes with bazedoxifene prevent metabolic dysfunction in female mice. Mol Metab 3, 177-
190 (2014). 
10. 
Bergman, R.N. Lilly lecture 1989. Toward physiological understanding of glucose tolerance. 
Minimal-model approach. Diabetes 38, 1512-1527 (1989). 
11. 
Bergman, R.N., Ider, Y.Z., Bowden, C.R. & Cobelli, C. Quantitative estimation of insulin 
sensitivity. Am J Physiol 236, E667-677 (1979). 
12. 
Pacini, G. & Bergman, R.N. MINMOD: a computer program to calculate insulin sensitivity and 
pancreatic responsivity from the frequently sampled intravenous glucose tolerance test. Comput 
Methods Programs Biomed 23, 113-122 (1986). 
13. 
Kahn, S.E., Prigeon, R.L., McCulloch, D.K., Boyko, E.J., Bergman, R.N., Schwartz, M.W., 
Neifing, J.L., Ward, W.K., Beard, J.C., Palmer, J.P. & et al. Quantification of the relationship 
between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic 
function. Diabetes 42, 1663-1672 (1993). 
14. 
Pfizer. DOF.DuaveeUSPISeptember. (2013). 


Version Date: _07/26/17___ 
Version Number: __9.0___ 
Page 13 of 17 
 
Addendum to the Bazedoxifene/Conjugated Estrogens (BZA/CE) Improvement of Metabolism 
Study 
 
We will add two markers to the labs that we are drawing at visit 2 and 5:  
A. Osteocalcin (Total Active and Inactive) 
This will be in collaboration with Dr. Gerard Karsenty at Columbia University, New York as that is the 
only location where the assay is available. Samples will be processed in the Department of Genetics 
and Development at Columbia University.  
We are interested in Osteoacalcin as a recent study uncovered that a novel pathway taking place in 
osteoblasts which results in secreting a hormone Osteocalcin which improves glucose homeostasis, 
this adds more confidence to support the concept of bone and energy metabolism regulate one 
another. [1] The regulation of bone remodeling by an adipocyte-derived hormone implies that bone may 
exert a feedback control of energy homeostasis.[1] One of the features of Osteocalcin especially 
relevant to our study is that it possibly mediates the metabolic function (observed in study with mice) 
and it may be responsible for changes in visceral fat, beta cell proliferation, insulin secretion, and 
insulin sensitivity. [1] Given that out study will be looking at DUAVEE effect on glucose homeostasis, 
visceral adiposity and estrogens’ key role in regulation of bone mass and strength (by controlling 
activity of bone-forming osteoblasts and bone-resorbing osteoclasts ) it would be very important to see 
what happens to the osteocalcin during Estrogen therapy in postmenopausal women. 
Therefore, this marker for bone (Osteocalcin) is particularly of interest to us and our study as we are 
conducting a study that is giving conjugated estrogen and bazedoxifene in postmenopausal women 
when they are losing bone.  
B.  Telomere Length  
This will be in collaboration with Dr. Stacey Drury at Tulane University Behavioral and 
Neurodevelopmental Genetics Laboratory. Samples will be processed in the Genetics Laboratory at 
Tulane.  
This Telomere length represents a novel biomarker that may represent one mechanism linking 
environmental stress exposure and biological outcomes at the cellular level.  One retrospective study 
showed telomere lengths were longer in postmenopausal women who had a history of long-term HT 
than in postmenopausal women without HT. [2] With the dramatic increase in life expectancy, many 
women will spend a large part of their lives in a post-menopausal state[3] and apart from causing 
degeneration of the cardiovascular, skeletal and central nervous systems[3-5] estrogen deficiency also 
increases risk for metabolic syndrome and type 2 diabetes.[3] Overall, the role of estrogen deficiency to 
the pathophysiology of chronic diseases in women is emerging as a novel therapeutic challenge 
therefore; we would like to examine the effect of short-term hormone therapy on telomere length in 
postmenopausal women. We are interested the effect of conjugated estrogen and bazedoxifene on 
telomere length in our study with postmenopausal women.   


Version Date: _07/26/17___ 
Version Number: __9.0___ 
Page 14 of 17 
 
References: 
1. Lee, N.K., et al., Endocrine regulation of energy metabolism by the skeleton. Cell, 2007. 130(3): p. 
456-69. 
2. Lee, D.C., et al., Effect of long-term hormone therapy on telomere length in postmenopausal 
women. Yonsei Med J, 2005. 46(4): p. 471-9. 
3. Mauvais-Jarvis, F., D.J. Clegg, and A.L. Hevener, The role of estrogens in control of energy 
balance and glucose homeostasis. Endocr Rev, 2013. 34(3): p. 309-38. 
4. Carr, M.C., The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab, 
2003. 88(6): p. 2404-11. 
5. Rossouw, J.E., et al., Risks and benefits of estrogen plus progestin in healthy postmenopausal 
women: principal results From the Women's Health Initiative randomized controlled trial. Jama, 
2002. 288(3): p. 321-33. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version Date: _07/26/17___ 
Version Number: __9.0___ 
Page 15 of 17 
 
Addendum to BIM study  
 
1. Addition of a noninvasive endothelial function assessment using Peripheral arterial tonometry 
(EndoPAT) as a part of Visit 2 and visit 5 assessments. 
 
EndoPAT is FDA cleared non-invasive test which evaluates the level of Endothelial Function.  
The test will take approximately 15 minutes. During the test patient should be lying or sitting in a 
relaxed position and recording will be taken from both index fingers via thimble-like sensors that are 
non invasive and positioned on patient’s fingertips. After 5 minutes, a blood pressure cuff will be inflated 
on non-dominant arm for 5 minutes; this might be associated with some discomfort and/or tingling in the 
arm, however it is considered very safe and should pass with the release of the cuff. Recording of the 
arterial tone will continue for 5 more minutes after the cuff is released. 
 
To prepare for the test patients will be asked to avoid the following actions at least 3 hours prior to the 
test: Eating (anything), Drinking coffee, tea, sodas, juice, alcohol (water is the only drink allowed), 
Smoking (including any cigarette/nicotine replacements such as electronic cigarettes).  
 
Recommendation on the day of visit: to wear loose clothing around the arms.  To remove all jewelry 
such as a watch, bracelets and rings as these might interfere with blood circulation during the test.  
Trim nails of index fingers on both hands - we will place thimble-like sensors on index fingers during the 
test. Long nails might damage the sensor and affect measurements. 
 
EndoPAT assesses digital flow mediated dilation during reactive hyperemia using measurements from 
both arms – occluded side and control side. 
 
Normal Endothelial Function means that arteries function well, and this has been shown to protect 
blood vessels from atherosclerosis (hardening of the arteries) and plaque buildup. Results of the 
Endothelial Function test are automatically calculated and EndoScore is generated, which indicates the 
present state of arterial health, or how well arteries dilate in response to increased need for blood.  
 
Significance of adding EndoPAT to our study  
The disparity between the incidence of cardiovascular disease among pre- and postmenopausal 
women has been ascribed to the actions of endogenous estrogen on the cardiovascular system and 
particularly on the vascular endothelium.[1]  
 
As cardiovascular disease remains the leading cause of death in the 21st century,[2] endothelial 
vascular dysfunction has become suspected as being associated with cardiovascular disease at its very 
beginning stages.[3]  Recent studies have shown that peripheral vascular endothelial function testing in 
the ambulatory setting correlates with the extent of CAD risk and the presence or absence of CAD, [4, 
5] and that recent data suggest that peripheral vascular endothelial function testing is feasible in 
ambulatory patients, and plays important next step in bringing this technology to clinical applicability.[5] 
The main actions exerted by the endothelium are selective permeability, maintenance of balance 
between thrombosis and fibrinolysis, inhibition of cell proliferation of vascular smooth muscles, active 
participation of immune response through the release of factors leading to active contractions, and 
modulation of vascular tonus through the production of vasoactive substances.[1] In women, the 
processes involved in vascular damage are thought to be slowed by the presence of estrogen.[6]  
There is currently no information on the efficacy of CE/BZA in preventing postmenopausal metabolic 
disorders. Available data on the effects of estrogens on inflammatory process are fairly contradictory, 
with both anti-inflammatory,[7, 8] and proinflammatory[9] effects reported. The pre-clinical study from 
Mauvais-Jarvis’ lab in a mouse model of post-menopausal metabolic syndrome, demonstrates that the 


Version Date: _07/26/17___ 
Version Number: __9.0___ 
Page 16 of 17 
 
combination CE/BZA prevents estrogen deficiency-induced metabolic dysfunction-including obesity, 
T2DM and NAFLD- and without uterus stimulation.[10] 
 
Given the fundamental role of endothelial dysfunction in the genesis of atherosclerosis and other 
chronic disorders, such as diabetes mellitus and hypertension,[1] the significance of preventing initial 
disturbance of metabolic syndrome through decreasing inflammation and coagulation pathways as well 
as vascular tone regulation may have an impact on morbidity and mortality in postmenopausal women . 
Recently, the benefits of estrogen therapy have been reevaluated by international menopausal 
societies leading to a consensus on the benefits of HRT pending that it is administered in early 
menopausal women and is not associated with a progestin.[11] The most promising HRT involves the 
use of tissue selective estrogen complexes (TSECs) combining a conjugated estrogen (CE) and the 
selective estrogen receptor modulator (SERM) bazedoxifene (BZA) in a single tablet. The major 
innovation of TSEC BZA/CE is that it provides all the advantages of CE treatment without the use and 
side effects of a progestin.[12, 13] Another advantage is that it contains BZA, a SERM that has 
estrogen antagonistic activity in breast and uterus and estrogen agonistic activity in bone thus 
preventing osteoporosis while protecting the breast and uterus from estrogenic stimulation.[13] 
DUAVEE (BZA/CE) is this novel menopausal therapy approved by the FDA for the treatment of 
postmenopausal symptoms and the prevention of menopausal osteoporosis. An important beneficial 
effect of estrogen is also to prevent postmenopausal metabolic disorders which may be associated with 
vascular tone regulation and may have an impact on morbidity and mortality in postmenopausal 
women.  
 


Version Date: _07/26/17___ 
Version Number: __9.0___ 
Page 17 of 17 
 
References: 
 
1. 
Maturana, M.A., M.C. Irigoyen, and P.M. Spritzer, Menopause, estrogens, and endothelial 
dysfunction: current concepts. Clinics (Sao Paulo), 2007. 62(1): p. 77-86. 
2. 
Murray, C.J. and A.D. Lopez, Global burden of disease. Vol. 1. 1996: Harvard University Press 
Cambridge, MA. 
3. 
Fonseca, V., et al., Nontraditional risk factors for cardiovascular disease in diabetes. Endocr 
Rev, 2004. 25(1): p. 153-75. 
4. 
Kuvin, J.T., et al., Assessment of peripheral vascular endothelial function in the ambulatory 
setting. Vasc Med, 2007. 12(1): p. 13-6. 
5. 
Hamburg, N.M., et al., Cross-sectional relations of digital vascular function to cardiovascular risk 
factors in the Framingham Heart Study. Circulation, 2008. 117(19): p. 2467-74. 
6. 
Granger, D.N., T. Vowinkel, and T. Petnehazy, Modulation of the inflammatory response in 
cardiovascular disease. Hypertension, 2004. 43(5): p. 924-31. 
7. 
Straub, R.H., The complex role of estrogens in inflammation. Endocr Rev, 2007. 28(5): p. 521-
74. 
8. 
Stork, S., et al., Estrogen, inflammation and cardiovascular risk in women: a critical appraisal. 
Trends Endocrinol Metab, 2004. 15(2): p. 66-72. 
9. 
Cutolo, M., et al., Estrogens and autoimmune diseases. Ann N Y Acad Sci, 2006. 1089: p. 538-
47. 
10. 
Kim, J.H., et al., Tissue-selective estrogen complexes with bazedoxifene prevent metabolic 
dysfunction in female mice. Mol Metab, 2014. 3(2): p. 177-90. 
11. 
de Villiers, T.J., et al., Global consensus statement on menopausal hormone therapy. 
Climacteric, 2013. 16(2): p. 203-4. 
12. 
Santen, R.J., et al., Current and evolving approaches to individualizing estrogen receptor-based 
therapy for menopausal women. J Clin Endocrinol Metab, 2014. 99(3): p. 733-47. 
13. 
Komm, B.S. and S. Mirkin, Evolution of the tissue selective estrogen complex (TSEC). J Cell 
Physiol, 2013. 228(7): p. 1423-7.