Raising Insulin Sensitivity in Post Menopause
Condition: Menopause
Study type: Interventional
Phase: Early Phase 1

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.
    

Intervention name(s): TSEC (Tissue-selective estrogen complexes); Placebo
Intervention type(s): Drug; Other
Intervention description(s): Duavee™, combination of CE(conjugated equine estrogens) and BZA (bazedoxifene); non active
Other intervention name(s): Duavee™
Intervention MeSH terms: Estrogens
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention