A Safety and Efficacy Study of the Combination Estradiol and Progesterone to Treat Vasomotor Symptoms
Condition: Menopause
Intervention: Estradiol; Progesterone; Placebo
Intervention MeSH terms: Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Estradiol; Polyestradiol phosphate; Progesterone
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 1845.0
Sex: Female
Minimum age: 40 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Vasomotor symptoms; Hot flashes; Endometrial protection

Summary:

      This study will be a prospective, randomized, double-blind, placebo-controlled, parallel
      group, multicenter trial of postmenopausal subjects with an intact uterus.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Be a female between the ages of 40 and 65 years (at the time of randomization) who is
             willing to participate in the study, as documented by signing the informed consent
             form.

          2. Be a postmenopausal woman with an intact uterus and a Screening serum estradiol level
             of ≤50 pg/mL. Postmenopausal is defined herein as:

               1. ≥ 12 months of spontaneous amenorrhea, or

               2. at least 6 months of spontaneous amenorrhea with a Screening serum FSH level of
                  >40 mIU/ml, or

               3. ≥ 6 weeks postsurgical bilateral oophorectomy.

          3. Be seeking treatment or relief for vasomotor symptoms associated with menopause.

          4. To participate in the VMS Substudy, a subject must also report ≥7 moderate to severe
             hot flushes per day, or ≥50 per week, at the baseline assessment during Screening
             (subjects whose hot flushes are less frequent may still participate as non-Substudy
             subjects.

             Note: A minimum of 14 consecutive days of complete hot flush diary data are required
             during the baseline assessment at Screening, and these consecutive days must occur
             within the last 14 days prior to the Randomization visit (not counting the
             Randomization visit day itself). The most recent 7 consecutive days of data prior to
             randomization (Day -7 to Day -1) will be used to determine the baseline number of
             mild, moderate and severe hot flushes for each subject.

          5. Have a Body Mass Index (BMI) less than or equal to 34 kg/mP2P. (BMI values should be
             rounded to the nearest integer [e.g., 34.4 rounds down to 34, while 26.5 rounds up to
             27]).

          6. Be willing to abstain from using products (other than study medication) that contain
             estrogen, progestin, or progesterone throughout study participation.

          7. Be judged by the principal or sub-investigator physician as being in otherwise
             generally good health based on a medical evaluation performed during the Screening
             period prior to the initial dose of study medication. The medical evaluation findings
             must include:

               1. a normal or non-clinically significant physical examination, including vital
                  signs (sitting blood pressure, heart rate, respiratory rate and temperature).
                  Sitting systolic blood pressure is ≤140 mmHg and diastolic blood pressure ≤90
                  mmHg at Screening. A subject may be taking up to two antihypertensive
                  medications.

               2. a normal or non-clinically significant pelvic examination.

               3. a mammogram that shows no sign of significant disease (can be performed within
                  previous 6 months prior to initial dose of study medication). Subjects must have
                  a BI-RADS 1 or 2 to enroll in the study. An incomplete mammogram result, i.e.
                  BI-RADS 0, is not acceptable. The site must obtain a copy of the official report
                  for the subject's study file, and it must be verified that the mammogram itself
                  is available if needed for additional assessment.

               4. a normal or non-clinically significant clinical breast examination. An acceptable
                  breast examination is defined as no masses or other findings identified that are
                  suspicious of malignancy.

               5. a normal Screening Papanicolaou ("Pap") smear. (Subjects with findings of
                  atypical glandular cells [AGC], AGUS, ASCUS with high risk HPV type upon reflex
                  testing, LSIL, ASC-H, HSIL, dysplastic cells, or malignant cells must be excluded
                  from randomization.)

               6. an acceptable result from an evaluable Screening endometrial biopsy. The
                  endometrial biopsy reports by the two central pathologists at Screening must each
                  specify one of the following: proliferative endometrium; weakly proliferative
                  endometrium; disordered proliferative pattern; secretory endometrium; endometrial
                  tissue other (including benign, inactive or atrophic fragments of endometrial
                  epithelium, glands, stroma, etc); endometrial tissue insufficient for diagnosis;
                  no endometrium identified; or no tissue identified. However, at least one
                  pathologist must identify sufficient tissue to evaluate the biopsy. Additionally,
                  the endometrial biopsy reports by the two central pathologists of Other Findings
                  at Screening must each specify one of the following: endometrial polyp not
                  present; benign endometrial polyp; or polyp other. (See Exclusion criterion #27)

               7. a normal or non-clinically significant 12-lead ECG.

        Exclusion Criteria:

          -  To participate in the study, a subject must NOT:

               1. Be currently hospitalized.

               2. Have a history of thrombosis of deep veins or arteries or a thromboembolic
                  disorder.

               3. Have a history of coronary artery or cerebrovascular disease (e.g., myocardial
                  infarction, angina, stroke, TIA).

               4. Have a history of a chronic liver or kidney dysfunction/disorder (e.g., Hepatitis
                  C or chronic renal failure).

               5. Have a history of a malabsorption disorder (e.g., gastric bypass, Crohn's
                  disease).

               6. Have a history of gallbladder dysfunction/disorders (e.g., cholangitis,
                  cholecystitis), unless gallbladder has been removed.

               7. Have a history of diabetes, thyroid disease or any other endocrinological
                  disease. (Subjects with diet-controlled diabetes or controlled hypothyroid
                  disease at Screening are not excluded.)

               8. Have a history of estrogen-dependent neoplasia.

               9. Have a history of atypical ductal hyperplasia of the breast.

              10. Have a finding of clinically significant uterine fibroids at Screening.

              11. Have had a uterine ablation.

              12. Have a history of undiagnosed vaginal bleeding.

              13. Have any history of endometrial hyperplasia, melanoma, or uterine/endometrial,
                  breast or ovarian cancer.

              14. Have any history of other malignancy within the last 5 years, with the exception
                  of basal cell (excluded if within 1 year) or non-invasive squamous cell (excluded
                  if within 1 year) carcinoma of the skin.

              15. Have a history of any other cardiovascular, hepatic, renal, pulmonary,
                  hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic,
                  psychological (e.g., bipolar disorder, schizophrenia, major depressive disorder),
                  or musculoskeletal disease or disorder that is clinically significant in the
                  opinion of the Principal Investigator or Medical Sub-Investigator.

              16. Have any of the following clinical laboratory values at Screening:

                    1. fasting triglyceride of ≥300 mg/dL and/or total cholesterol of ≥300mg/dL

                    2. positive laboratory finding for Factor V Leiden mutation

                    3. AST or ALT ≥1.5 times the upper limit of normal (ULN)

                    4. fasting glucose >125 mg/dL

              17. Be known to be pregnant or have a positive urine pregnancy test. (Note: A
                  pregnancy test is not required for subjects who have had bilateral tubal
                  ligation, bilateral oophorectomy, or are 55 years old or greater and have
                  experienced cessation of menses for at least 1 year.)

              18. Have contraindication to estrogen and/or progestin therapy or allergy to the use
                  of estradiol and/or progesterone or any components of the investigational drugs.

              19. Use 15 or more cigarettes per day or currently use any electronic cigarettes.

              20. Have a history of drug and/or alcohol abuse within one year of start of study.

              21. Have used, within 28 days prior to the initial dose of study medication at Visit
                  1, any medication known to induce or inhibit CYP3A4 enzyme activity that may
                  affect estrogen and/or progestin drug metabolism. (See 48TUSection 4.3U48T)

              22. Have used, within 28 days prior to Screening, or plan to use during the study,
                  any prescription or over-the-counter (OTC) medications (including herbal
                  products, such as St. John's Wort) that would be expected to alter progesterone
                  or estrogen activity or is being used to treat vasomotor symptoms. (See Section
                  4.3U48T)

              23. Have used estrogen alone or estrogen/progestin, SERM (selective estrogen receptor
                  modulator), testosterone, or estrogen/testosterone for any of the following time
                  periods:

                    1. Vaginal nonsystemic hormonal products (rings, creams, gels) within 7 days
                       prior to Screening, or vaginal systemic products (e.g., FemRing) within 28
                       days prior to Screening.

                    2. Transdermal estrogen alone or estrogen/progestin products within 8 weeks
                       prior to Screening.

                    3. Oral estrogen and/or progestin and/or SERM therapy within 8 weeks prior to
                       Screening.

                    4. Progestational implants, estrogen or estrogen/progestational injectable drug
                       therapy within 3 months prior to Screening.

                    5. Estrogen pellet therapy or progestational injectable drug therapy within 6
                       months prior to Screening.

                    6. Percutaneous estrogen lotions/gels within 8 weeks prior to Screening.

                    7. Oral, topical, vaginal, patch, implantable or injectable androgen therapy
                       within 8 weeks prior to Screening.

              24. Have used an intrauterine device (IUD) within the 12 weeks prior to Screening.

              25. For subjects in the VMS Substudy only: use of medication that may affect the
                  outcome of the vasomotor symptom endpoints within 28 days prior to Screening
                  (e.g. SSRIs [selective serotonin reuptake inhibitors], SNRIs [serotonin and
                  norepinephrine reuptake inhibitors], aldomet, dopaminergic or antidopaminergic
                  drugs, gabapentin, clonidine, or bellergal.)

              26. Have any reason which, in the opinion of the Principal Investigator or Medical
                  Sub-Investigator, would prevent the subject from safely participating in the
                  study or complying with protocol requirements.

              27. Have a Screening endometrial biopsy sample that is found by both primary
                  pathologists to have endometrial tissue insufficient for diagnosis, no
                  endometrium identified, or no tissue identified. (With the approval of the
                  Medical Monitor, the Screening endometrial biopsy may be repeated once.)

              28. Endometrial polyps with atypical nuclei reported by at least 1 central
                  pathologist.

              29. Have contraindication to any planned study assessments (e.g., endometrial
                  biopsy).

              30. Have participated in another clinical trial within 30 days prior to Screening,
                  have received an investigational drug within the three months prior to the
                  initial dose of study medication, or be likely to participate in a clinical trial
                  or receive another investigational medication during the study.

              31. Currently use marijuana.