Clinical trial NCT02274571
Conditions: Menopause
Sponsor: Pennington Biomedical Research Center
Start date: 2015-09-01; Completion date: 2017-04-11
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to find out if a novel drug approved by the Food and Drug Administration \[Duavee™, Pfizer, Inc\] for treatment of postmenopausal symptoms (vaginal dryness and hot flashes) and prevention of osteoporosis also improves insulin sensitivity by decreasing body fat especially in your liver.

DUAVEE™ (Conjugated Estrogens/Bazedoxifene) is a new prescription medicine that contains a mixture of estrogen (the main female hormone made by the ovaries) and bazedoxifene, which is FDA approved. For over 60 years, estrogens have been used as hormonal treatments to help manage hot flashes and help prevent postmenopausal bone loss. But in the treatment of postmenopausal women, the use of estrogens alone can increase the risk of developing cancer of the uterus. So estrogens have been traditionally paired with a progestin to decrease the risk of hyperplasia (the thickening of the lining of the uterus), which can be a precursor to cancer. DUAVEE™ uses bazedoxifene, a selective estrogen receptor modulator (SERM), in place of a progestin to help protect the uterus against thickening of the uterus that may result from estrogens alone.

In this study, you will get either DUAVEE™ or the placebo (a "dummy pill" that may look like medicine but contains no active medication) first and then switch to the other pill.

Detailed description:
This study involves a screening process to see if you are eligible to participate followed by two 8-week treatment periods separated by an 8-week washout period. The two 8-week treatments will be with:

1. 8 weeks of treatment with TSEC (Duavee™, combination of CE and BZA)
2. 8 weeks of treatment with a "dummy pill" (Placebo) The order of these 2 8-week treatment periods will be decided by chance (coin flip).

   STUDY VISITS (11 VISITS in total) If you participate in this study, after referral from the Baton Rouge General Obstetrics and Gynecology Physicians, you will complete 1 screening visit at Pennington Biomedical Research Center to determine your eligibility. If you are eligible and enrolled in the study, you will complete an additional 10 visits (8 brief visits and 2 overnight inpatient stays).

   Please note all times provided for procedures and the total times for each clinic visit are approximations and may vary depending on circumstances.

   SCREENING VISIT (1 visit, approximately 1.5 hours, fasting):

   Please do not drink any food or water for 10 hours before this appointment.

   Participants are asked to report to the Pennington clinic fasting. After a detailed explanation of the whole study by a coordinator, if you agree to the procedures by signing a consent form, you will have:
   1. Your height and body weight measured.
   2. You will then have an ECG (electrocardiogram) to measure your heart rate and rhythm.
   3. Your blood pressure will be measured.
   4. A blood sample (\<1 teaspoon) and urine will be collected to assess your general health.
   5. You will have a medical history and physical examination.

   If fully eligible according to the data collected during the screening visit, you will be called to set up a second visit to provide you with the medication or the dummy pill.

   VISIT 2 (30 minutes):

   You will come to the Pennington to pick up your drug supply (real medication or dummy pill) and meet with a nurse or a study coordinator to give you instructions on when and how to take your pill once a day.

   VISITS 3-5 (30 minutes each):

   At week 1, 3, and 5 of your 8-week treatment period, you will come to our outpatient clinic to measure your weight, blood pressure and pulse, collect some feedback on your health and check your medication compliance as well as distribute new medications.

   VISIT 6 (24 hours at our inpatient unit):

   You will be admitted to our inpatient unit at 4pm (not fasted) for measures of:
   1. Total body fat by DXA
   2. Abdominal visceral fat by Magnetic Resonance Imaging (MRI)
   3. Fat in your liver and muscle by Magnetic Resonance Spectroscopy (MRS) You will then receive a standard dinner at \~7pm and will be ask to switch off the light in your bedroom at \~10pm

   The next morning investigators will wake you up at \~4.45am to start an IV line and start a 8-hour procedure (Euglycemic Clamp) to measure how your body responds to insulin. You will be discharged from the inpatient unit between 2 and 3 pm after being fed a lunch.

   Visit 1 is Screening; Visit 2/7 is Wk0/17; Visit 3/8 is Wk1/18; Visit 4/9 is Wk3/20; Visit 5/10 is Wk5/22 and Visit 6/11 is Wk8/25

   ECG: Screening Vital Signs, Height, Weight, Waist \& Hip Measurements: Screening, Visit 3, Visit 4, Visit 5 \& Visit 6

   Fasting Blood \& Urine Sample: Screening and Visit 6

   Medical History \& Physical Exam + Questionnaire Barriers: Screening

   Pick up pills/receive instructions: Visit 2, Visit 3, Visit 4, \& Visit 5

   Health Status/Medication Compliance Visit 3, Visit 4 \& Visit 5

   Admittance to Inpatient Unit: Visit 6

   Body Composition (DXA): Visit 6

   Body Composition (MRI): Visit 6

   Liver/Muscle Fat (MRS): Visit 6

   Euglycemic Clamp with biopsies: Visit 6

   Eight weeks later (during which you will not take any pill), you will start the same sequence of visits (VISITS 7-11) as shown above for Visits 2-6 but this time with the other pill.

   DESCRIPTION OF PROCEDURES

   Euglycemic IV clamp (8 hours):

   This procedure measures how the body responds to insulin. Insulin is normally produced by your body during meals and helps your body use sugar. There will be 2 IV lines, one in your arm and one in your hand on the opposite side. Approximately 30 minutes after the IV lines are inserted; investigators will perform a fat biopsy to sample fat cells beneath the skin of your stomach area. Then, a muscle biopsy will be obtained to sample muscle cells beneath the skin of your thigh. Small amounts of glucose and insulin will be infused into your arm. Your blood sugar level will be checked every 5-10 minutes from the IV in your hand to determine how much glucose you should have to keep your blood sugar at a normal level. Your hand will be placed inside a warming box to increase skin temperature to about 105 degrees Fahrenheit. The temperature will be warm, but not uncomfortable. During your IV procedure, a small amount of your own blood (less than 1 teaspoon) will immediately be returned into your vein through the IV after each specimen is collected

   Three times during the 8-hour procedure, investigators will place a clear plastic hood, through which fresh air flows, over your head to measure how many calories your body burns. This measure will last 40 minutes each time. Your urine will be collected throughout the test in a urine jug (at the end of the test or in 2 collections if necessary).

   Fat biopsy (about 30 minutes):

   This procedure is used to sample fat cells from underneath the abdominal skin after cleansing the skin with iodine and using a local anesthetic. After cleansing the area, the doctor or Nurse Practitioner will make a small incision in the skin and introduce a needle under the skin to remove fat cells. About 1 gram (less than half a teaspoon size) of fat will be removed. After the biopsy is completed, the skin will be held closed with a sterile adhesive bandage; an antibiotic ointment will be applied.

   Risks: Fat Biopsy: Mild to severe pain, soreness, and bruising, and a small scar are common risks. There is a small risk of a hematoma (collection of blood in the tissue) or infection at the biopsy site. Sterile technique will be used to minimize these risks and the biopsy site will be monitored closely.

   Muscle Biopsy (about 30 minutes):

   This procedure is used to sample muscle cells from underneath the skin of the leg. After cleaning the skin with iodine and using a local anesthetic, the doctor or nurse practitioner will make a small incision in the skin and introduce a needle under the skin to remove muscle cells. About 200-750 milligrams (less than a teaspoon size) of muscle will be removed. After the biopsy is completed, the skin will be held closed with a sterile adhesive bandage and an antibiotic ointment will be applied.

   Risks: Muscle Biopsy: Mild to severe pain, soreness, bruising, and a small scar are common risks. A hematoma (collection of blood in the tissue) may occur. There is a slight risk that a superficial nerve may be cut; the nerve may heal, or it may result in a permanent loss of sensation in the skin at the biopsy site.

   DXA - Whole Body Scan (\~4 minutes):

   This scan measures the amount of bone, muscle, and fat in your body. The scan will be performed using a whole-body scanner. You will be required to wear a hospital gown, to remove all metal-containing objects from your body, and to lie down on the table. A scanner emitting low energy X-rays and a detector will pass along your body. You will be asked to remain completely still while the scan is in progress. The scan takes less than four minutes. This scan is for research purposes only and not for diagnostic treatment.

   MRI Abdomen (30 minutes):

   This scan measures the amount of fat in your abdomen. You will change into a hospital gown and remove all objects containing metal from your body. You will lie on your back on the scanner table with your arms above your head. A large coil will be placed around your upper abdomen. You will then be moved into the magnet and will be instructed to hold your breath 4-5 times (once for six seconds, once for 13 seconds, and 2-3 times for about 18 seconds after the upper abdominal scans are completed, you will be moved up on the table, and the coil will be placed over your lower abdomen. The same scans will be acquired over this area with the same 4-5 breath holds. The total scan time for this procedure is approximately 30 minutes. During the scan, you will hear loud tapping noises. You will be given headphones for protection from the scanner noise and can listen to music during the scan if desired. You will also be given a call button should you need the MRI Technician during the exam. This scan is for research purposes only and not for diagnostic treatment.

   MRS IHL (Intrahepatic lipid) (20-30 minutes):

   This scan measures the amount of fat in your liver. You will change into a hospital gown and remove all objects containing metal from your body. You will be placed on the scanner table head first and on your stomach. The table will move you into the magnet where data will be obtained. The scan will last for approximately 20-30 minutes. During the scan, you will hear loud tapping noises. You will be given head phones for protection from the scanner noise and can listen to music during the scan if desired. You will also be given a call button should you need the MRI tech during the exam. This scan is for research purposes only and not for diagnostic treatment.

   MRS IMCL (Intramyocellular lipid) (60 minutes):

   This scan measures the amount of fat in your muscle fibers. You will change into a hospital gown and remove all objects containing metal from your body. You will lie on your back on the scanner table with the right leg in a special coil. The top part of the coil will then be placed over your calf. Cushions will be inserted around the calf to help keep the leg as still as possible. The table will then move you into the scanner where a series of several scans will be obtained. The entire procedure will last approximately 60 minutes. During the scan, you will hear loud tapping noises. You will be given head phones for protection from the scanner noise and can listen to music during the scan if desired. You will also be given a call button should you need the MRI tech during the exam. This scan is for research purposes only and not for diagnostic treatment.

Arms: arm 1: TSEC (Duavee™, combination of CE and BZA) arm 2: Non active comparator
Interventions: intervention 1: TSEC (Tissue-selective estrogen complexes) intervention 2: Placebo
Intervention descriptions: intervention 1: Duavee™, combination of CE(conjugated equine estrogens) and BZA (bazedoxifene) intervention 2: non active

Protocol documents:
Prot_SAP_000.pdf: 
1
March 18, 2020
PROTOCOL
Tissue selective estrogen complex to prevent metabolic 
dysfunction in women
(RISE)
Principal Investigator:
Eric Ravussin, Ph.D.
Medical Investigator:
Frank Greenway, M.D.
Version Number:
Eleven
Version Date:
March 18, 2020
Pennington Biomedical IRB FWA 00006218
Approved March 27, 2020


2
Table of Contents
BACKGROUND
3
STUDY DESIGN
4
STUDY OVERVIEW
4
HYPOTHESIS
4
POWER CALCULATION
4
TIMELINE
4
STUDY POPULATION
5
TARGET POPULATION
5
NUMBER OF PARTICIPANTS
5
INCLUSION CRITERIA
5
EXCLUSION CRITERIA
5
RECRUITMENT
5
STUDY DESCRIPTION
6
LOCATION
6
CONSENT PROCESS
6
SCREENING PROCESS
6
RANDOMIZATION
6
STUDY VISITS
6
STUDY PROCEDURES
7
DATA MANAGEMENT
8
DATA AND BIOSPECIMEN STORAGE
8
STATISTICAL ANALYSIS
9
CONFIDENTIALITY AND PRIVACY
9
BENEFITS, RISKS, AND SAFETY
9
POTENTIAL BENEFITS
9
RISKS
10
MONITORING SUBJECT SAFETY
12
COMPENSATION
12
WITHDRAWAL OF SUBJECTS
12
Pennington Biomedical IRB FWA 00006218
Approved March 27, 2020


3
BACKGROUND
With the dramatic increase in life expectancy, many women will spend a large part of their lives 
in a post-menopausal state. Apart from causing degeneration of the cardiovascular, skeletal and 
central nervous systems, estrogen deficiency also increases risk for metabolic syndrome, type 2 
diabetes (T2D) and non-alcoholic fatty liver diseases (NAFLD). Overall, the role of estrogen 
deficiency to the pathophysiology of chronic metabolic diseases in women is emerging as a 
novel therapeutic challenge that parallels the increased risk associated with conventional 
estrogen replacement protocols. It is against this backdrop that novel therapeutic strategies 
targeting estrogen receptor in non-reproductive tissues may offer therapeutic benefits that 
reduce metabolic dysfunction associated with both ovarian failure and estrogen deficiency.
Selective estrogen receptor modulators (SERMs) are compounds that exert tissue-selective 
estrogen receptor (ER) agonist or antagonist activity. For example, bazedoxifene (BZA) is a 
novel SERM that exhibits estrogen agonist activity in bone but estrogen antagonist activity in 
breast and uterus. Tissue-selective estrogen complexes (TSECs) are drugs in which a SERM 
and an estrogen are combined to produce mixed estrogen agonist and antagonist activity.7 The 
goal of a TSEC regimen containing BZA with conjugated equine estrogens (CE) is to provide 
the benefits of estrogen such as reducing hot flashes and vulvar–vaginal atrophy, preventing 
menopausal osteoporosis and promoting favourable effects on cardiovascular risk while 
simultaneously protecting the endometrium and breast from estrogen stimulation without the 
need for a progestin. The TSEC therapy combining CE and BZA was approved in September 
2013 by the Food and Drug Administration [Duavee™, Pfizer, Inc] for treatment of 
postmenopausal symptoms and prevention of osteoporosis.
Dr. Mauvais-Jarvis’ laboratory was a pioneer in demonstrating that estrogen protects pancreatic 
islet β-cell insulin secretion and synthesis, nutrient homeostasis, and survival via three estrogen 
receptors, ERα, ERβ and the G-protein coupled ER. They showed that ER actions were 
relevant to human islet function and survival, and had major clinical impacts in the diabetes field 
by enabling the design of a novel estrogenic peptide that targets β-cells without unfavorable 
gynecological effects in females. Most recent preliminary data, derived from a mouse model 
of post-menopausal metabolic syndrome, demonstrate that TSEC prevent estrogen 
deficiency-induced metabolic dysfunction – including obesity, T2D and NAFLD- as 
efficiently as CE alone and importantly, without causing endometrial hyperplasia. Because 
SERMs like Tamoxifen or Raloxifene have never shown such a beneficial metabolic effect in 
preclinical models and in humans, these data underscore the clinical significance of this line 
of investigation and they also provide a firm rationale for the next series of experiments that 
are proposed in this application. 
We propose to assess the therapeutic potential of TSEC in preventing metabolic dysfunction in 
postmenopausal women and to explore the hypothesis that the metabolic effect of TSEC relies 
on the activation of the production and sensitivity of the hepatic hormone fibroblast growth factor 
21 (FGF21). These findings will have a direct and immediate scientific impact that fits with the 
LACaTS Center theme. The knowledge that will be generated from this work will fill key gaps in 
our understanding of the mechanism of estrogen action on metabolic diseases that will be used 
for therapeutic purposes. Thus, there is direct, clinically relevant translational impact to the 
proposed work. As part of this LACaTS grant, Dr. Mauvais-Jarvis will continue to investigate the 
potential molecular mechanisms of TSEC on the metabolic syndrome in mice only. 
Pennington Biomedical IRB FWA 00006218
Approved March 27, 2020


4
There are several innovative features to our proposed study. First, a novel feature of our 
approach is that translational studies of TSEC action in preventing metabolic dysfunction in 
postmenopausal women have never been performed. A second, innovation is to propose a 
novel paradigm in which the metabolic actions of TSEC are mediated via a stimulation of FGF21 
production and action.
STUDY DESIGN
Study Overview
The goal of this pilot clinical study is to perform a randomized crossover study to test the 
beneficial effect of 8 weeks of treatment with TSEC or BZA/CE/(a clinical image of Duavee™) 
vs. placebo on insulin sensitivity and energy metabolism in eight post-menopausal women. 
There will be a two-month washout period in-between the 2 treatments (TSEC vs. Placebo). The 
recruitment will be performed at the Pennington Biomedical Research Center with the help in 
recruiting from the Baton Rouge General Obstetrics and Gynecology Physicians (see below). 
The drugs will be provided by Pfizer, Inc. without charge.
Objective:  Assess the therapeutic potential of TSEC in preventing metabolic dysfunction in 
postmenopausal women.
Primary Endpoint:  Insulin sensitivity by a 2-step hyperinsulinemic euglycemic clamp
Secondary Endpoints:   a) Resting metabolic rate by a metabolic cart (Deltatrac) and;
      b) Body composition by DXA and MRS
Exploratory Endpoints:  Molecular work (at Tulane) in animal model only.
Hypothesis
TSEC treatment will improve both whole body insulin sensitivity (high insulin dose) and liver 
insulin sensitivity (suppression of HGP) in postmenopausal women.
Power Calculation
Although a formal power analysis was not feasible in this pilot study, in light of the high 
precision that is achieved using the clamp, we can expect similar improvements to be 
detectable with up to 10 or less completers for whole body and hepatic insulin sensitivity 
respectively in this randomized crossover trial. 
Timeline
After passing the screening process, the expected duration of an individual subject’s 
participation in the study is about 26 weeks.
We anticipate that it will take up to 6 months to complete enrollment for the study.  
Pennington Biomedical IRB FWA 00006218
Approved March 27, 2020


5
STUDY POPULATION
Target Population
Post-menopausal women (<5y post last period) aged 50-60 years old 
Number of Participants
We expect up to 10 post-menopausal women to complete this study.
Inclusion/Exclusion Criteria
Inclusion Criteria
Exclusion Criteria.
Post-menopausal women (<5y post last 
period)
Amenorrhea other causes (excess 
androgen)
Age between 50-60y
Diabetes mellitus
Symptomatic (hot flashes, vaginal 
dryness) or asymptomatic
Medications: (diabetes, antipsychotics, oral 
steroids, weight loss drugs†)
History of major depressive episodes 
requiring treatment
Tricyclic antidepressants (TCAs)
Current smokers, or having smoked within 
last 3 months
BMI 30-40 kg/m2
≤ 3 month washout of birth control pill, 
estrogen, and/or progestin
Hysterectomy (total and partial)
Normal mammogram past 12 months
Contraindications to estrogen treatment ††
Physician clearance (Ob/Gyn, Baton 
Rouge General Physician Primary Care 
Network, or PBRC)
Be willing to accept own blood during IV 
procedure
Unable or unwilling to do an MRS
Additional exclusion for optional BIA 
procedure only:

Medications: Diuretics, glitazones

Congestive heart failure

Chronic kidney disease

Pacemaker or other metal implants
† other chronic medications are acceptable as long as stable for 2 months, and may need MI 
approval before screening.
†† for unusual vaginal bleeding, blood clots, hepatic disease, bleeding disorder, past/present 
history of breast or uterine cancer, pregnant, breastfeeding 
Recruitment
Baton Rouge General Obstetrics and Gynecology Physicians will be the primary site for 
recruiting patients for the study. Gynecology and the Baton Rouge General Physician Primary 
Care Network will also be asked to provide additional recruits through a series of educational 
Pennington Biomedical IRB FWA 00006218
Approved March 27, 2020


6
presentations by Dr. Evelyn K. Hayes, MD, FACOG, NCMP. At these clinics, patients are seen 
for routine wellness exams in addition to problem visits. Women in the target population for 
recruitment frequently present with symptoms of estrogen deficiency. Over the past 12 months, 
the Baton Rouge General Obstetrics and Gynecology practice has seen over 800 women aged 
50-60 with a BMI between 30 and 40 and with menopause according to the definition adopted in 
this study. Further delineation of such group can identify those women who are naïve to 
estrogen and symptomatic with hot flashes and/or vaginal dryness. After an explanation of the 
study by Dr. Hayes or her staff, interested participants who meet initial screening criteria (date 
of final menstrual period, last mammogram, confirmation of medication use, age, BMI,) will be 
cleared by the primary-care Obstetrician-Gynecologist and a referral form will be sent by 
REDCap to PBRC. All this information will be transferred to a study coordinator at PBRC in 
accordance with HIPAA and eligible patients will be contacted to schedule a screening visit at 
PBRC. 
Additionally, PBRC will be a secondary site for recruitment. Participants will be recruited 
continuously by our recruitment core via media advertising, listserv, health promotion events, 
databases, and referral sources. Similarly, once potential participants are identified via PBRC 
recruitment methods and recorded in PBRC tracking databases, PBRC staff will schedule a 
screening visit at PBRC. We anticipate no problem in rapidly recruiting the 8 women needed to 
complete the study.
STUDY DESCRIPTION
Location
After referral of potential participants from Dr. Hayes (and her staff) or participant recruitment via 
PBRC, the screening visit will be conducted in the Outpatient Unit at PBRC.  
The Insulin sensitivity testing (clamp), energy expenditure testing, blood drawing will be 
performed in the Inpatient Unit at PBRC. 
Consent Process
The informed consent process will be conducted in the Outpatient Unit at PBRC during the  
screening visit and will be conducted primarily by the study coordinator, but also on occasion by 
the study PI or by a trained staff member of the Outpatient Clinic. Written informed consent will 
be obtained before any procedures are performed. Potential subjects will be given ample time to 
read the Informed Consent and to ask questions during the screening visit.
Screening Process
Prospective volunteers will be both referred from Dr. Evelyn Hayes or via PBRC recruitment 
efforts (see above) and invited to the Center for a complete screening visit conducted in the 
morning after an overnight fast. Height, metabolic weight, waist and hip circumference as well 
as blood pressure will be measured. This will be followed by a complete medical history 
including reproductive function and medications, a physical exam, and an ECG. If eligible, a 
blood sample (CBC, chemistry panel with electrolytes, total testosterone, estradiol and FSH) 
Pennington Biomedical IRB FWA 00006218
Approved March 27, 2020


7
and a urine sample (urine analysis for general health) will be collected. Potential participants will 
then be interviewed by trained staff that is overseen by a licensed Clinical Psychologist to 
identify potential barriers to adherence and study completion. We will work with potential 
participants to determine if the study is consistent with their lifestyle/time demands and if 
adhering to and completing the study is feasible. The final enrollment will then be determined on 
the basis of the laboratory results (blood and urine).
Randomization 
Participants will be randomized to the order in which they complete the two parts of the study 
(Active drug (TSEC) and placebo). 
Study Visits
The study visits are described in this section, while the study procedures that will be performed 
during these visits are detailed in the latter section “Study Procedures”.
This study involves is a randomized crossover study with two 8-week treatment period 
separated by an 8-week washout period. Each participant will participate in this randomized 
scheme with two evaluation periods (see Figure 1)
a) End of 8 weeks of treatment with PLACEBO or TSEC
b) End of 8 weeks of treatment with TSEC or PLACEBO
Figure 1.  TSEC Experimental Protocol
Screening
8 week
washout
1 2
1 2
1 2
1 2
8 week 
treatment
TSEC
TSEC
Placebo
Placebo
8 week 
treatment
Randomization
Pennington Biomedical IRB FWA 00006218
Approved March 27, 2020


8
After screening, enrollment and 
randomization (Week 0) , participants will 
come for a brief (<1 hour) clinic visit after 1, 
3 and 5 weeks (± 3 days) into the first 
treatment phase (TSEC or Placebo) to get 
their pills, record weight, waist and hip, and 
vital signs and collect adverse events. 
During the eight week (Day 53 & 54 ± 2 
days), participants will be admitted to our 
inpatient unit at ~4pm for measures of total 
body fat (DXA) and ectopic fat (intra-hepatic 
and intra-myocellular fat) by 1H Magnetic 
Resonance Spectroscopy (1H –MRS) as 
well as visceral fat (VAT by MRI). These 
measures will be followed by a standard 
dinner (see Study procedures below) at ~7pm. The following morning at ~4.45am, an IV infusion 
of D2-glucose will be started to measure splanchnic glucose output (SGO) over 3 hours 
followed by a 150 min low dose insulin clamp followed by a 2-hour high dose insulin clamp 
(Figure 2). Also, at this time metabolic weight, blood pressure, and pulse will be collected. At 
around 6am, during the baseline of the clamp procedure, an adipose and skeletal muscle biopsy 
will be collected. Additionally, an optional Bioelectrical Impedance Analysis procedure will be 
offered and, if consent is given, will be completed following voiding and metabolic weight. 
Participants will be discharged ~2 hours after the end of the clamp procedure.
After an 8 week washout period, the exact same 8-week treatment and clinic visit protocol will 
be repeated, this time with the opposite treatment (Placebo or TSEC).
Study Procedures
Body Composition and Ectopic Fat
DXA scans will be performed using a GE Lunar iDXA whole-body scanner. The scan takes 
about 10 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. We 
will also use the DXA data to estimate muscle mass. 
Visceral (VAT) and subcutaneous (SAT) adipose tissue (MRI):  Determination of body fat, 
visceral fat (intraperitoneal and retroperitoneal fat), and subcutaneous fat will be obtained using 
a 3T GE Signa magnet with measurements from a series of 8 T1-weighted MRI slices 
positioned axially across the abdomen. Measuring VAT and SAT from only 8 non-contiguous 
slices has been shown in our hands to be as accurate as measuring it from a much larger 
number of contiguous slices  
Intrahepatic and intramyocellular lipid by 1H –MRS: The magnetic resonance scans will be 
performed at the Imaging Facility of the Center (part of the NORC, NIDDK funded Center Grant; 
PI Ravussin). The subject will be asked to lie supine on the patient table of the 3.0 T magnet for 
approximately 20 min.  A 1H body coil will be used to measure intrahepatic fat stores. A single 
PRESS box (30 x 30 x 30 mm) will be collected in an area of the liver that is free from heavy 
vascularization. Similar measures will be acquired from 3 voxels in the soleus muscle. Data are 
analyzed using the jMRUi software package.
2-Step Hyperinsulinemic (20 & 120 mU.m-2.min-1) Clamp at 90 mg/dl Glucose with RMR
Pennington Biomedical IRB FWA 00006218
Approved March 27, 2020


9
The glucose clamp will be performed at the end of the two 8-week treatment periods as shown 
in Figure 2. At approximately 7pm the night before, participants will eat a standard meal (30% of 
energy requirements calculated on the basis of their (Harris-Benedict predicted RMR x 1.4; 50% 
CHO, 30% fat, and 20% protein). Between 4am and 7am, a catheter will be inserted into a hand 
vein heated at 56oC to obtain arterialized blood samples and into an antecubital vein of the 
contralateral arm for infusion of labeled glucose. Approximately 30 minutes after inserting the IV 
lines, a skeletal muscle biopsy and an abdominal adipose tissue biopsy will be collected. After 
baseline blood samples are obtained, [6,6-2H2]glucose (22 µmol/kg prime and 0.22 µmol.kg-
1.min-1 constant infusion basal) will be started between 4am and 7am. Three hours later, the 2-
step euglycemic (20 and 120 mU m-2 min-1) hyperinsulinemic clamp is initiated and continued for 
5 hours. Euglycemia (90 mg/dl) is achieved by a variable infusion of 20% dextrose enriched to 
approximately 2.0% with [6,6-2H2]-glucose to minimize changes in glucose isotopic enrichment. 
The plasma insulin concentrations achieved with these insulin infusion rates provide optimal 
ranges for evaluating insulin’s effect on hepatic glucose production (HGP) (20 mU m-2 min-1) and 
glucose uptake by skeletal muscle (120 mU m-2 min-1). The infusion of [2H2]-glucose will be 
decreased by 50% (0.11 µmol.kg-1.min-1) of basal during stage 1 and completely during stage 2 
(full suppression of HGP). Three blood samples will be taken during the last 30 min of each step 
and at each step including baseline, a blood sample will be drawn to be archived (20 ml at 
baseline and 10 ml at steps 1 and 2).  
Calculations.  At low dose insulin infusion, plasma insulin levels are expected to increase to ~50 
U/ml, and HGP is expected to be ~50% suppressed in these participants. During this steady 
state (Rd), peripheral glucose uptake equals the glucose infusion rate (GINF) plus the 
measured residual HGP (Rd = St-state GINF + residual HGP).  At 120 mU m-2 min-1 of insulin, 
HGP will probably be totally suppressed, and Rd = Steady State GINF. At each step, insulin 
sensitivity (SI) will be calculated using the formula: SI = Rd / (St-state insulin level - basal insulin 
level).
Resting metabolic rate (RMR) will be measured 3 times during the clamp procedure. At each 
step, O2 consumption and CO2 production will be measured by indirect calorimetry for 40 min 
(last 30 min will be used for calculations) using a metabolic cart (DeltaTrac, SensorMedics, 
Yorba Linda, CA). Patients will void before the test, and urine will be collected to determine 
urinary nitrogen and substrate oxidation.
Fat and muscle biopsy
Fat biopsy will be collected during the baseline of the clamp for cell sizing and 
numbering using osmium fixation, and to extract DNA and RNA for future work. The biopsy will 
be obtained as follows: After cleansing the skin on the right side of the abdomen with povidone-
iodine solution, and placing a sterile drape, topical anesthesia will be administered with a 
mixture containing 50%/50% lidocaine 2% and bupivacaine 0.5%. A 0.75-cm incision will be 
made in the skin and a Bergstrom needle inserted to collect, under aspiration, approximately 
500-750 mg of adipose tissue. The sample will be washed in sterile PBS and 75% of it snap 
frozen in liquid nitrogen, the remaining placed in osmium tetra oxide. Upon completion of the 
biopsy, the incision will be closed with a sterile bandage, and antibiotic ointment / sterile 
dressing applied.  
Muscle biopsy.  Similarly, after the adipose tissue biopsy, a Vastus Lateralis muscle 
biopsy will be performed using the technique of Bergstrom in order to measure the impact of 
treatment on insulin signaling pathway gene expression, measure in vitro the impact on glucose 
uptake, and to look at skeletal muscle morphology after TSEC vs. placebo treatment. After 
cleansing the skin with povidone-iodine solution, the skin, adipose tissue and skeletal muscle 
Pennington Biomedical IRB FWA 00006218
Approved March 27, 2020


10
fascia of the right leg will be anesthetized using a 50%/50% mixture of bupivicaine 0.5% and 
lidocaine 2%. The skin will be incised (0.75cm) with a #11 scalpel. The fascia fibers are 
separated with the blunt edge of the scalpel and the Bergstrom needle inserted into the vastus 
lateralis. After suction is applied, approximately 100 mg of tissue is cut and removed.  Several 
passes will be used to obtain at least 250mg of muscle.  Pressure is applied and the skin is 
closed with sterile tape. After cleaning the sample, the muscle will be snap frozen in liquid 
nitrogen and stored for subsequent analysis.  
Bioelectrical Impedance Device (BIA) (optional procedure)
Participants should remain resting in the supine position for 10 minutes prior to testing, after 
voiding, in the fasting state. Once a participant’s Subject ID, date of birth, age, sex, height, and 
weight are entered into the device, the procedure can be conducted. The BIA device 
automatically tests and analyzes with imbedded software. BIA will be performed according to 
the recommendations (ESPEN Guidelines, Kyle et al. Clin Nutr 2004). Two disposable 
BioTekna electrodes will be applied to the dorsal surface of the right hand: the first (injector 
electrode) on the distal end of the third metacarpal bone between the 2nd and 3rd finger 
(metacarpophalangeal joint), and the second (sensor electrode) between the distal prominences 
of the radius and ulna of the wrist (radio-ulnar joint). Another couple of electrodes will be placed 
on the dorsal surface of the right foot: the first electrode on the distal end of the third metatarsal 
bone between the 2nd and 3rd toe (metatarsophalangeal joint), and the second electrode) 
between the medial and lateral malleolus of the ankle (tibiotarsal joint).
The distance between the electrodes is 5 cm. Two pairs of cables will be connected to the right 
hand (it is irrelevant which of the two pairs of cables). Similarly, the other pair of cables will be 
connected to the right foot. The red alligator clip shall be connected to the injector electrode 
(metatarsophalangeal joint and metacarpophalangeal joint), while the black clip to the sensor 
electrode (tibiotarsal joint and radio-ulnar joint). Note: the two pairs of cables should not touch or 
cross each other, or touch the floor. Failure to observe these precautions may distort the test 
results.
DATA MANAGEMENT
Data and Biospecimen Storage
Electronic data will be stored securely on computers at PBRC. Paper forms will be kept securely 
in locked storage at PBRC. Blood samples will be stored in the Clinical Chemistry Core at 
PBRC. Specimens will be labeled with a unique de-identification code if transported outside of 
Pennington Biomedical.  
Statistical Analysis
Using SAS Version 9.4 and/or other statistical software, the data will be analyzed using mixed 
model or other appropriate statistical approaches and using post-hoc comparison adjustments for 
multi-testing. Descriptive analysis will also be performed. Statistical significance is set at α=0.05.
Confidentiality and Privacy
Pennington Biomedical IRB FWA 00006218
Approved March 27, 2020


11
Records that identify study participants will be kept confidential as required by law, and every 
effort will be made to maintain the confidentiality of participants’ study records. Except when 
required by law, study participants will not be identified by name, social security number, 
address, telephone number, or any other direct personal identifier in records disclosed outside 
of Pennington Biomedical Research Center.  
All biological specimens will be stored and analyzed at Pennington by the Clinical Chemistry 
Core, and will be labeled with a unique code number (“A number”). Some samples may be 
analyzed by outside labs or outside personnel. All samples analyzed externally from Pennington 
Biomedical will be sent with no identifying information and in compliance with Pennington 
Biomedical policies and procedures.  
To protect subjects’ privacy interests and to make subjects feel at ease, all participants will be 
assured of their anonymity and confidentially. In addition, the amount of personal information 
collected by the study will be minimized and limited to the study’s endpoints; all data will be 
used only for research purposes.  
Access to participants’ data and biological specimens will be limited only to the study’s 
investigators, including investigators external to Pennington Biomedical, to clinical support staff 
for this study, and to the overseers of clinical facilities at Pennington. This will be ensured 
through stringent security measures (assured by the Research Computing Core), including the 
use of subject ID numbers, storage of medical records in locked areas, and electronic security 
systems required by HIPAA.
BENEFITS, RISKS, AND SAFETY
Potential Benefits
Given the short duration of the study, we do not promise any benefits to participants from 
participating in this study. Possible benefits to participants include learning about their current 
health status.  
Risks
This study involves the following risks to subjects:

Risks associated with TSEC (Bazedoxifene/Conjugated Estrogens (BZA/CE): The most 
common side effects reported in at least 1 out of 100 postmenopausal women receiving 
BZA/CE include abdominal (stomach) pain, vaginal discharge, vaginal yeast infection, and 
leg cramps. Other adverse events reported in less than 1 out of 100 subjects were gall 
bladder disease and increase in liver function tests. More serious but rare side effects 
associated with the use of BZA/CE included venous thromboembolic events (blood clot in a 
vein of the legs or lungs), reported in less than 1 out of 100 subjects. If you experience 
sudden pain in legs or difficulty breathing, notify the Medical Investigator immediately.
Precautions
You may be allergic to conjugated estrogens or bazedoxifene. If you experience allergy 
symptoms such as rash, hives, or itching, notify your study doctor immediately.
     All estrogens and SERMS should be stopped prior to and during prolonged
Pennington Biomedical IRB FWA 00006218
Approved March 27, 2020


12
immobilization (such as bed rest, surgery or long-distance travel). It is recommended that 
study drug be discontinued four to six weeks prior to prolonged immobilization.
     You may not use hormone products during the study; including any oral, transdermal, 
vaginal or other products containing estrogens, progestins, androgens, testosterone, DHEA 
or SERMs.

Blood Draws:  There is the possibility of discomfort, pain, and bruising at the arm vein or 
site where the needle is inserted. There is also a small risk of bleeding and a very small risk 
of infection at the site of the blood draw. Aseptic (sterile) technique and trained personnel 
minimize these risks.
 

DXA: 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.

MRI & MRS: There are no known serious risks associated with MR studies provided that 
prescreening is performed to exclude individuals with internal ferromagnetic foreign bodies. 
MR prescreening will be performed according to PBRC policy and procedure and as part of 
the inclusion exclusion criteria. PBRC policy includes informed consent prescreening, a pre-
screen by the study coordinator, a screening questionnaire reviewed by the MR technologist 
with the participant, and a hand wand search for ferromagnetic bodies where necessary by 
procedure. Claustrophobia is a potential non-serious adverse event. The proposed RF 
energy deposition is within limits set forth by the FDA [calculated on the MR instrument as 
SAR].

Two-Step Clamp Procedure: The use of sterile procedures and good technique will 
minimize the risks. The intended site 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. There has been no incidence of catheter infection in any of the hundreds 
of experiments we have already performed using this technique. A risk during the 
measurement of insulin sensitivity is hypoglycemia (low blood sugar) which will be 
minimized by: 1) constant supervision by a qualified physician at all times during the 
procedure; 2) constant monitoring of blood glucose during the procedure (every 5 min) and 
after (every 15 min for 2 hr); and 3) immediate availability of corrective measures (IV 50% 
dextrose). There is no risk to the measurement of RMR by indirect calorimetry during the 
different steps of the clamp.

Fat biopsy: There is a small risk of infection, bleeding, and scarring of the skin at the site of 
the biopsy.  Our inpatient medical team has performed more than 500 subcutaneous 
adipose biopsies.

Muscle biopsy: Muscle biopsy risks include: pain from the injecting local anesthesia and 
cramping during the biopsy, bleeding, scarring of the skin at the site of the biopsy, 
cutaneous anesthesia from cutting a subcutaneous sensory nerve (1 in 70), the latter is 
almost always temporary but occasionally can become permanent.  Our inpatient team has 
performed more than 1,000 muscle biopsies with no serious complications.
Pennington Biomedical IRB FWA 00006218
Approved March 27, 2020


13

Bioelectrical Impedance Analysis (BIA): There is no risk associated with the BIA 
measurement provided that prescreening is performed to exclude individuals with medical 
implants such as pacemakers or metal joint replacements. Measurements will not be 
performed on any subject who is pregnant, and all females should inform the technologist if 
there is any possibility that they are pregnant.
In addition to the risks listed above, participants may experience a previously unknown risk or 
side effect.
Monitoring Subject Safety
Participants will be asked about any adverse events following each stay in the respiratory 
chamber. Any instances adverse events and safety concerns will be documented and reported 
to the PBRC IRB per standard procedures.  
Once every 4 months, the PI will review the progress and safety of the study with the MI, and 
write a summary of the results of those discussions as applicable.
Compensation
Participants will be compensated $1000 if they complete the entire study. $350 of the 
compensation will be paid at the end of their first phase treatment and the remaining $650 at the 
end of the study. There is no compensation available for research-related injury.
Withdrawal of Subjects
There is no risk associated with withdrawal from TSEC. Participants may be withdrawn from the 
study if either the PI or MI feels that their continued participation would jeopardize either the 
subject’s health or the results of the study.
Pennington Biomedical IRB FWA 00006218
Approved March 27, 2020

ICF_001.pdf: 
#PBRC 2014-039                                                                .                              
Page 1 of 12
Version Date:   10.5.2016
Volunteer’s Initials ___________
                             
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
FOR AN ADULT
INFORMED CONSENT - PART I
Title of Study:
Tissue selective estrogen complex to prevent metabolic 
dysfunction in women (RISE)
What you should know about a research study

We give you this consent form so that you may read about the purpose, risks and 
benefits of this research study.

The main goal of research studies is to gain knowledge that may help future 
participants.

You have the right to refuse to take part, or agree to take part now and change your 
mind later on.

Please review this consent form carefully and ask any questions before you make a 
decision.

Your participation is voluntary.

By signing this consent form, you agree to participate in the study as it is described.
1- Who is doing the study?
     Investigator Information:
      Principal Investigator:     Eric Ravussin, Ph.D.
    225-763-3186
      Co-Principal Investigator:  Franck Mauvais-Jarvis, M.D., Ph.D.
     504-988-5990
      Medical Investigators:      Frank Greenway, M.D.
     225-763-2576
     24-hr. Emergency Phone Nos.:
     225-763-2500 (Weekdays 7:00 a.m.-4:30 p.m.)
     225-765-4644 (After 4:30 p.m. and Weekends)
Dr. Eric Ravussin directs this study, which is under the medical supervision of Dr. Frank 
Greenway. We expect up to 10 post-menopausal women to complete this study at the 
Pennington Biomedical Research Center. The study will take place over a period of 
about 1-2 years. Your expected time in this study will be about 26 weeks (2-week 
screening period followed by two 8-week treatment periods with 8 weeks in between).   
2- Where is the study being conducted? 
This study takes place at Pennington Biomedical Research Center.
Pennington Biomedical IRB FWA 00006218
Approved 10/06/2016


#PBRC 2014-039                                                                .                              
Page 2 of 12
Version Date:   10.5.2016
Volunteer’s Initials ___________
                             
3- What is the purpose of this study?
The purpose of this study is to find out if a novel drug approved by the Food and Drug 
Administration [Duavee™, Pfizer, Inc.] for treatment of postmenopausal symptoms 
(vaginal dryness and hot flashes) and prevention of osteoporosis also improves insulin 
sensitivity by decreasing body fat especially in your liver. You will be receiving a clinical 
image of the commercial drug, made specifically for this study, TSEC or a placebo.
The TSEC (Conjugated Estrogens/Bazedoxifene) is a new prescription medicine that 
contains a mixture of estrogen (the main female hormone made by the ovaries) and 
bazedoxifene, which is FDA approved. For over 60 years, estrogens have been used as 
hormonal treatments to help manage hot flashes and help prevent postmenopausal 
bone loss. But in the treatment of postmenopausal women, the use of estrogens alone 
can increase the risk of developing cancer of the uterus. So estrogens have been 
traditionally paired with a progestin to decrease the risk of hyperplasia (the thickening of 
the lining of the uterus), which can be a precursor to cancer. A TSEC drug uses 
bazedoxifene, a selective estrogen receptor modulator (SERM), in place of a progestin 
to help protect the uterus against thickening of the uterus that may result from estrogens 
alone. 
In this study, you will get either a TSEC or the placebo (a “dummy pill” that may look like 
medicine but contains no active medication) first and then switch to the other pill.
4- Who is eligible to participate in the study?  
Inclusion Criteria
Exclusion Criteria.
Post-menopausal women but less 
than 5 years since last period
50-60 years of age
Symptomatic (hot flashes, vaginal 
dryness) or asymptomatic for 
menopause
BMI 30-40 kg/m2
Normal mammogram past 12 months
Physician clearance (Ob/Gyn, Baton 
Rouge General Physician Primary 
Care Network or PBRC)
Be willing to accept your own blood 
during an IV procedure
Amenorrhea other causes (excess 
androgen)
Diabetes mellitus
Medications: (diabetes, antipsychotics, 
oral steroids, weight loss drugs†)
History of major depressive episodes 
requiring treatment
Tricyclic antidepressants (TCAs)
Current smokers, or having smoked 
within last 3 months
≤ 3 month washout of birth control pill, 
estrogen, and/or progestin
Hysterectomy (total and partial)
Contraindications to estrogen treatment†† 
Unable or unwilling to do an MRS
Additional exclusion for optional BIA 
procedure only:
o
Medications: Diuretics, glitazones
o
Congestive heart failure
o
Chronic kidney disease
Pennington Biomedical IRB FWA 00006218
Approved 10/06/2016


#PBRC 2014-039                                                                .                              
Page 3 of 12
Version Date:   10.5.2016
Volunteer’s Initials ___________
                             
o
Pacemaker or other metal implants
†other chronic medications are acceptable as long as stable for 2 months, and may need MI 
approval before screening.†† for unusual vaginal bleeding, blood clots, hepatic disease, 
bleeding disorder, past/present history of breast or uterine cancer, pregnant, breastfeeding
5- What will happen to you if you take part in the study?
Summary
This study involves a screening process to see if you are eligible to participate followed 
by two 8-week treatment periods separated by an 8-week washout period. The two 8-
week treatments will be with:
a) 8 weeks of treatment with TSEC (combination of CE and BZA) 8 weeks of 
treatment with a “dummy pill” (Placebo)
The order of these 2 8-week treatment periods will be decided by chance (coin flip).
STUDY VISITS (11 VISITS in total) 
If you participate in this study, you will complete 1 screening visit at Pennington 
Biomedical Research Center to determine your eligibility. If you are eligible and enrolled 
in the study, you will complete an additional 10 visits (8 brief visits and 2 overnight 
inpatient stays).
Please note all times provided for procedures and the total times for each clinic visit are 
approximations and may vary depending on circumstances.
SCREENING VISIT (1 visit, approximately 2.5 hour) – FASTING Visit: Please do 
not drink any food or water for 10 hours before this appointment 
We ask you to report to the Pennington clinic fasting. After a detailed explanation of the 
whole study by a coordinator, if you agree to the procedures by signing a consent form, 
you will have:
1) Your height and body weight measured.
2) You will then have an ECG (electrocardiogram) to measure your heart rate and 
rhythm.
3) Your blood pressure will be measured.
4) A blood sample (~ 2 teaspoons) and urine will be collected to assess your 
general health.
5) You will have a medical history and physical examination.
If fully eligible according to the data collected during the screening visit, you will be 
called to set up a second visit to provide you with the medication or the dummy pill.
VISIT 2 and 7 (30 minutes) – NON-FASTING
You will come to Pennington to pick up your drug supply (real medication or dummy pill) 
and meet with a nurse or a study coordinator to give you instructions on when and how 
to take your pill once a day.
Pennington Biomedical IRB FWA 00006218
Approved 10/06/2016


#PBRC 2014-039                                                                .                              
Page 4 of 12
Version Date:   10.5.2016
Volunteer’s Initials ___________
                             
VISITS 3-5 and 8-10 (30 minutes each) – NON-FASTING
At week 1, 3 and 5 of your 8-week treatment period, you will come to our outpatient 
clinic to measure your weight, blood pressure and pulse, collect some feedback on your 
health and check your medication compliance as well as distribute new medications.
VISIT 6 and 11 (24 hours at our inpatient unit)
You will be admitted to our inpatient unit at 4pm (not fasted) for measures of:
1) Total body fat by dual-enegy X-ray absorptiometry (DXA)
2) Abdominal visceral fat by Magnetic Resonance Imaging (MRI)
3) Fat in your liver and muscle by Magnetic Resonance Spectroscopy (MRS)
You will then receive a standard dinner at ~7pm and will be ask to switch off the light in 
your bedroom at ~10pm.
The next morning we will wake you up at ~4.45am to be weighed and to start an IV line 
and start an 8-hour procedure (Euglycemic Clamp) to measure how your body responds 
to insulin. Also during this procedure, you will have muscle and fat biopsies, as well as 
possibly have bioelectrical impedance analysis (BIA) performed to assess body fluid 
volumes and body composition (optional procedure). You will be discharged from the 
inpatient unit between 2pm and 3pm after being fed a lunch.
Visits
1
2 & 7
3 & 8
4 & 9
5 & 10
6 & 11
Procedure
Screening
Wk0 & 17
Wk1 & 18
Wk3 & 20
Wk5 & 22
Wk8 & 25
ECG
X
Vital Signs, Height1, Weight, 
Waist & Hip Measurements
X
X
X
X
X
Fasting Blood & Urine Sample
X
X
Medical History & Physical 
Exam + Questionnaire Barriers
X
Pick up pills/receive instructions
X
X
X
X
Health Status/Medication 
Compliance
X
X
X
X
Admittance to Inpatient Unit
X
Body Composition (DXA)
X
Body Composition (MRI)
X
Liver/Muscle Fat (MRS)
X
Euglycemic Clamp w/ RMR
X
Muscle and Fat biopsies
X
Bioelectrical Impedance 
Analysis (BIA) (optional)
X
1: Height will only be measured at Screening (Visit 1).
Eight weeks later (during which you will not take any pill), you will start the same 
sequence of visits (VISITS 7-11) as shown above for Visits 2-6 but this time with the 
other pill.
Pennington Biomedical IRB FWA 00006218
Approved 10/06/2016


#PBRC 2014-039                                                                .                              
Page 5 of 12
Version Date:   10.5.2016
Volunteer’s Initials ___________
                             
DESCRIPTION OF PROCEDURES
 
Euglycemic IV clamp: 8 hours    
This procedure measures how the body responds to insulin. Insulin is normally 
produced by your body during meals and helps your body use sugar. During the 
procedure about 4 tablespoons of blood will be collected. There will be 2 IV lines, one in 
your arm and one in your hand on the opposite side. Approximately 30 minutes after the 
IV lines are inserted, we will perform a fat biopsy to sample fat cells beneath the skin of 
your stomach area. Then, a muscle biopsy will be obtained to sample muscle cells 
beneath the skin of your thigh. Small amounts of glucose and insulin will be infused into 
your arm. Your blood sugar level will be checked every 5-10 minutes from the IV in your 
hand to determine how much glucose you should have to keep your blood sugar at a 
normal level. Your hand will be placed inside a warming box to increase skin 
temperature to about 105 degrees Fahrenheit. The temperature will be warm, but not 
uncomfortable. During your IV procedure, a small amount of your own blood (less 
than 1 teaspoon) will immediately be returned into your vein through the IV after 
each specimen is collected. 
RMR (Resting Metabolic Rate)
Three times during the 8-hour procedure described above, we will place a clear plastic 
hood, through which fresh air flows, over your head to measure how many calories your 
body burns. This measure will last 40 minutes each time. Your urine will be collected 
throughout the test in a urine jug (at the end of the test or in 2 collections if necessary).
Fat biopsy:  about 30 minutes    Fast for 10 hours before the test  
This procedure is used to sample fat cells from underneath the abdominal skin after 
cleansing the skin with iodine and using a local anesthetic. After cleansing the area, the 
doctor, nurse practitioner, or Physician Assistant will make a small incision in the skin 
and introduce a needle under the skin to remove fat cells. About 1 gram (less than half 
a teaspoon size) of fat will be removed. After the biopsy is completed, the skin will be 
held closed with a sterile adhesive bandage; an antibiotic ointment will be applied.
Muscle Biopsy:  about 30 minutes   Fast for 10 hours before the test
This procedure is used to sample muscle cells from underneath the skin of the leg.  
After cleaning the skin with iodine and using a local anesthetic, the doctor, Nurse 
Practitioner, Physician Assistant will make a small incision in the skin and introduce a 
needle under the skin to remove muscle cells. About 200-750 milligrams (less than a 
teaspoon size) of muscle will be removed. After the biopsy is completed, the skin will be 
held closed with a sterile adhesive bandage and an antibiotic ointment will be applied.
Bioelectrical Impedance Analysis (BIA) Measurements: about 10 minutes – 
Optional Procedure
This procedure is used to sample body fluid volumes and body composition. You will be 
asked to change into a gown and to remove all footwear and socks/stockings. Once 
changed and barefoot, you will be asked to empty your bladder and to have your weight 
measured. Then, you will be asked to lie down for 10 minutes. Your skin will be cleaned 
Pennington Biomedical IRB FWA 00006218
Approved 10/06/2016


#PBRC 2014-039                                                                .                              
Page 6 of 12
Version Date:   10.5.2016
Volunteer’s Initials ___________
                             
with disinfectant wipes, and two pairs of disposable electrodes will be placed on your 
right hand and your right foot where the skin was disinfected. Two cables will be 
connected to the electrodes, and the bioelectrical impedance analysis will be performed.
DXA - Whole Body Scan: ~10 minutes
This scan measures the amount of bone, muscle, and fat in your body. The scan will be 
performed using a whole-body scanner. You will be required to wear a hospital gown, to 
remove all metal-containing objects from your body, and to lie down on the table. A 
scanner emitting low energy X-rays and a detector will pass along your body. You will 
be asked to remain completely still while the scan is in progress. The scan takes less 
than four minutes. This scan is for research purposes only and not for diagnostic 
treatment.
MRI Abdomen: 30 minutes
This scan measures the amount of fat in your abdomen. You will change into a hospital 
gown and remove all objects containing metal from your body. You will lie on your back 
on the scanner table with your arms above your head. A large coil will be placed around 
your upper abdomen. You will then be moved into the magnet and will be instructed to 
hold your breath 4-5 times (once for six seconds, once for 13 seconds, and 2-3 times for 
about 18 seconds After the upper abdominal scans are completed, you will be moved 
up on the table, and the coil will be placed over your lower abdomen. The same scans 
will be acquired over this area with the same 4-5 breath holds. The total scan time for 
this procedure is approximately 30 minutes. During the scan, you will hear loud tapping 
noises. You will be given headphones for protection from the scanner noise and can 
listen to music during the scan if desired. You will also be given a call button should you 
need the MRI Technician during the exam. This scan is for research purposes only and 
not for diagnostic treatment.
MRS IHL (Intrahepatic lipid): 20-30 minutes
This scan measures the amount of fat in your liver. You will change into a hospital gown 
and remove all objects containing metal from your body. You will be placed on the 
scanner table head first and on your stomach. The table will move you into the magnet 
where data will be obtained. The scan will last for approximately 20-30 minutes. During 
the scan, you will hear loud tapping noises. You will be given head phones for 
protection from the scanner noise and can listen to music during the scan if desired. 
You will also be given a call button should you need the MRI tech during the exam. This 
scan is for research purposes only and not for diagnostic treatment.
MRS IMCL (Intramyocellular lipid): 60 minutes   
This scan measures the amount of fat in your muscle fibers. You will change into a 
hospital gown and remove all objects containing metal from your body. You will lie on 
your back on the scanner table with the right leg in a special coil. The top part of the coil 
will then be placed over your calf. Cushions will be inserted around the calf to help keep 
the leg as still as possible. The table will then move you into the scanner where a series 
of several scans will be obtained. The entire procedure will last approximately 60 
minutes. During the scan, you will hear loud tapping noises. You will be given head 
Pennington Biomedical IRB FWA 00006218
Approved 10/06/2016


#PBRC 2014-039                                                                .                              
Page 7 of 12
Version Date:   10.5.2016
Volunteer’s Initials ___________
                             
phones for protection from the scanner noise and can listen to music during the scan if 
desired. You will also be given a call button should you need the MRI tech during the 
exam. This scan is for research purposes only and not for diagnostic treatment.
6- What are the possible risks and discomforts?

Risks associated with a TSEC (Bazedoxifene/Conjugated Estrogens (BZA/CE). The 
most common side effects reported in at least 1 out of 100 postmenopausal women 
receiving BZA/CE include abdominal (stomach) pain, vaginal discharge, vaginal 
yeast infection, and leg cramps. Other adverse events reported in less than 1 out of 
100 subjects were gall bladder disease and increase in liver function tests. More 
serious but rare side effects associated with the use of BZA/CE included venous 
thromboembolic events (blood clot in a vein of the legs or lungs), reported in less 
than 1 out of 100 subjects. If you experience sudden pain in legs or difficulty 
breathing, notify the Medical Investigator immediately.
Precautions
You may be allergic to conjugated estrogens or bazedoxifene. If you experience allergy 
symptoms such as rash, hives, or itching, notify your study doctor immediately.
     
All estrogens and SERMS should be stopped prior to and during prolonged 
immobilization (such as bed rest, surgery or long-distance travel). It is recommended 
that study drug be discontinued 1 week prior to prolonged immobilization (orthopedic 
surgeries or flights > 8 hours. As with any planned discontinuation of medications, 
please contact the study investigator or coordinator prior to any surgeries or 
extended flights.
     
You may not use hormone products during the study; including any oral, 
transdermal, vaginal or other products containing estrogens, progestins, 
androgens, testosterone, DHEA or SERMs.

Blood Draws: There is the possibility of infection and/or pain and bruising at the site 
where the needle is inserted. Aseptic (sterile) technique and trained personnel 
minimize these risks. 

DXA: The amount of radiation used for this procedure is very small. The radiation 
dose for a DXA scan is equivalent to the radiation you are naturally exposed to in the 
environment in less than one day. 

MRI & MRS: There is a small chance of claustrophobia or muscle-skeletal 
discomfort from lying partially in the magnet. During the imaging measurement, the 
noise may be somewhat unpleasant, but your headphones will help with this.  
Although the long-term risk of exposure to a magnetic field is not known, the 
possibility of any long-term risk is extremely low from the information accumulated 
over the past ten years.
Pennington Biomedical IRB FWA 00006218
Approved 10/06/2016


#PBRC 2014-039                                                                .                              
Page 8 of 12
Version Date:   10.5.2016
Volunteer’s Initials ___________
                             
MRI/MRS Warning: Certain implants, devices, or foreign objects implanted in 
the human body may interfere with the MR procedure. Volunteers who have 
undergone specific prior surgeries (i.e. heart, brain, gastric bypass, breast 
augmentation, etc.) and/or have implants of specific types may be required to 
provide their IMPLANT CARD in order to determine implant 
safety/compatibility with the magnet before a scan is performed. 

Two-Step Clamp Procedure: There is a possibility of pain, bruising, or infection at 
the site of the needle insertion for the IV line. Trained personnel minimize this risk.  
There is a small risk of developing low blood sugar. If this happens it can make you 
feel hungry and your heart may beat faster. If not treated, low blood sugar can cause 
coma, seizures, and even death. Precautions are taken to avoid low blood sugar: A 
doctor will be present on site and a registered nurse will be available at all times 
during the clamp. Your blood sugar will be measured every 5-10 minutes, and 
dextrose (a sugar) will be administered intravenously as needed to prevent a drop in 
blood sugar levels. If your blood sugar drops to a level considered unsafe, the 
procedure will be stopped immediately and dextrose will be given through the 
IV line.

RMR: There is no known risk in having a RMR (resting metabolic rate). If you are 
claustrophobic, it may be uncomfortable to have the plastic hood over your upper 
body.

Fat Biopsy: Mild to severe pain, soreness, and bruising, and a small scar are 
common risks.  There is a small risk of a hematoma (collection of blood in the tissue) 
or infection at the biopsy site. Sterile technique will be used to minimize these risks 
and the biopsy site will be monitored closely.

Muscle Biopsy: Mild to severe pain, soreness, bruising, and a small scar are 
common risks. A hematoma (collection of blood in the tissue) may occur. There is a 
slight risk that a superficial nerve may be cut; the nerve may heal, or it may result in 
a permanent loss of sensation in the skin at the biopsy site.

Bioelectrical Impedance Analysis (BIA): Measurements will not be performed 
on any subject who is pregnant, and all females should inform the 
technologist if there is any possibility that they are pregnant. There is no risk 
associated with the BIA measurement. However, subjects with medical implants 
such as a pacemaker or metal joint replacements cannot be measured on the 
machine.
In addition to the risks listed above, you may experience a previously unknown risk or 
side effect.  
7- What are the possible benefits?
We cannot promise any benefits from your being in the study. However, possible 
benefits include learning about your health.  
Pennington Biomedical IRB FWA 00006218
Approved 10/06/2016


#PBRC 2014-039                                                                .                              
Page 9 of 12
Version Date:   10.5.2016
Volunteer’s Initials ___________
                             
8- If you do not want to take part in the study, are there other 
choices? 
You have the choice at any time not to participate in this research study. If you choose 
not to participate, any health benefits to which you are entitled will not be affected in any 
way.
9- If you have any questions or problems, whom can you call?
If you have any questions about your rights as a research volunteer, you should call the 
Institutional Review Board Office at 225-763-2693 or the Executive Director of 
Pennington Biomedical at 225-763-2513. If you have any questions about the research 
study, contact Dr. Eric Ravussin at 225-763-3186. If you think you have a research-
related injury or medical illness, you should call Dr. Frank Greenway at 225-763-2576 
during regular working hours. After working hours and on weekends you should call the 
answering service at 225-765-4644. The on-call physician will respond to your call.
10- What information will be kept private?
Every effort will be made to maintain the confidentiality of your study records. However, 
someone from Pennington Biomedical Research Center or Tulane University may 
inspect and/or copy the medical records related to the study. Results of the study may 
be published; however, we will keep your name and other identifying information 
private. Other than as set forth above, your identity will remain confidential unless 
disclosure is required by law.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This web site will not include information that can identify you. At 
most, the web site will include a summary of the results. You can search this web site at 
any time.
11- Can your taking part in the study end early?
Dr. Eric Ravussin, Dr. Frank Greenway, or the study sponsor can withdraw you from the 
study for any reason or for no reason. You may withdraw from the study at any time 
without penalty; however, all data Pennington Biomedical has previously collected 
cannot be removed from the study. Possible reasons for withdrawal include not 
following the study requirements. The sponsor of the study may end the study early.  
12- What if information becomes available that might affect your 
decision to stay in the study?
During the course of this study there may be new findings from this or other research 
which may affect your willingness to continue participation. Information concerning any 
such new findings will be provided to you.
13- What charges will you have to pay? None.
14- What payment will you receive?
Pennington Biomedical IRB FWA 00006218
Approved 10/06/2016


#PBRC 2014-039                                                                .                              
Page 10 of 12
Version Date:   10.5.2016
Volunteer’s Initials ___________
                             
If you agree to take part, we will pay you $1000 if you complete the entire study. A first 
check of $350 will be requested from the LSU payroll department after completing the 
first 8-week treatment period and a second check of $650 will be requested when you 
complete the study. It usually takes about 3-4 weeks for it to arrive at Pennington 
Biomedical Research Center.
15- Will you be compensated for a study-related injury or medical 
illness?
No form of compensation for medical treatment or for other damages (i.e., lost wages, 
time lost from work, etc.) is available from the Pennington Biomedical Research Center.  
In the event of injury or medical illness resulting from the research procedures in which 
you participate, you will be referred to a treatment facility. Medical treatment may be 
provided at your expense or at the expense of your health care insurer (e.g., Medicare, 
Medicaid, Blue Cross-Blue Shield, Dental Insurer, etc.) which may or may not provide 
coverage. The Pennington Biomedical Research Center is a research facility and 
provides medical treatment only as part of research protocols. Should you require 
ongoing medical treatments, they must be provided by community physicians and 
hospitals. 
16- Storage of Blood for Future Research or Use
Biospecimens for future research: 
You are being asked to allow some of your blood to be stored and used for research at 
a later time. These bodily materials are called biospecimens. The donation of 
biospecimens in this study is optional. No matter what you decide to do, it will not affect 
your study participation. You will still be allowed to take part in the study even if you 
don't want your specimens to be collected and used for future research. Some 
biospecimen samples will be stored and used for the study and other biospecimen 
samples will be stored for future studies. The collection of samples may give scientists 
valuable research material that can help them to develop new diagnostic tests, new 
treatments, and new ways to prevent diseases. If you agree to have your samples 
stored, you can change your mind later.
 
The samples will be stored indefinitely. If you agree to donate your samples, they may 
be given to other investigators for future research as well. The future research may take 
place at Pennington Biomedical and may involve Pennington Biomedical Researchers 
in this study. The future research may not take place at Pennington Biomedical 
Research Center and may not be reviewed by Pennington Biomedical Research 
Center’s Institutional Review Board. For privacy and confidentiality, your biospecimens 
will be labeled with a unique series of letters and numbers. Pennington Biomedical will 
store your biospecimens with this unique identifier and the minimum number of personal 
identifiers to meet laboratory standards. The research done with your specimens may 
help to develop new products in the future, or may be used to establish a cell line or test 
that could be patented or licensed. You will not receive any financial compensation for 
any patents, inventions or licenses developed from this research.
Pennington Biomedical IRB FWA 00006218
Approved 10/06/2016


#PBRC 2014-039                                                                .                              
Page 11 of 12
Version Date:   10.5.2016
Volunteer’s Initials ___________
                             
Making your choice about future research:
Please read about each biospecimen below. It is your choice which samples will be 
collected, stored and used for future research for this study or future studies. After 
reading about each below, sign next to “Yes” or “No” to show your choice about the 
collections for this research study and for future research studies.  
Blood
If you give permission, approximately 6 tablespoons of blood will be collected and 
stored by this study. Your stored samples may be tested at Pennington Biomedical 
Research Center or other locations used in future research. Do you give permission for 
your blood to be collected and used in future research by this study?
Yes, I give permission _____________________________________
 
Signature
Date
No, I do not give permission _________________________________
Signature
Date
Tissue
If you give permission, your left over tissue, tissue not be used for the purposes of the 
current study will be collected and stored by this study. Your stored samples may be 
tested at Pennington Biomedical Research Center or other locations used in future 
research. Do you give permission for your tissue to be collected and used for future 
research?
Yes, I give permission _____________________________________
 
Signature
Date
No, I do not give permission _________________________________
Signature
Date
Making your choice about additional procedures:
BIA
If you give permission, the data collected from the BIA procedure will be used in future 
research. Do you give permission for your data to be collected and used for future 
research?
Yes, I give permission _____________________________________
 
Signature
Date
No, I do not give permission _________________________________
Signature
Date
Pennington Biomedical IRB FWA 00006218
Approved 10/06/2016


#PBRC 2014-039                                                                .                              
Page 12 of 12
Version Date:   10.5.2016
Volunteer’s Initials ___________
                             
17- Signatures  
The study has been discussed with me and all my questions have been answered. I 
understand that additional questions regarding the study should be directed to the study 
investigators. I agree with the terms above and acknowledge that I have been given a 
copy of the signed consent form.
With my signature, I also acknowledge that I have been given either today or in the past 
a copy of the Notice of Privacy Practices for Protected Health Information.
        
Printed Name of Volunteer
                
Signature of Volunteer
    
Date
                                                              
Date of Birth of Volunteer
Signature of Person Administering Informed Consent              
Date                                               
Eric Ravussin, Ph.D.                            
Principal Investigator
Frank Greenway, M.D.                                          
Medical Investigator
Pennington Biomedical IRB FWA 00006218
Approved 10/06/2016