Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 3 Study Safety and Efficacy Study of the Combination Estradiol and Progesterone to Treat Vasomotor Symptoms in Postmenopausal Women With an Intact Uterus
Brief Summary: This study will be a prospective, randomized, double-blind, placebo-controlled, parallel group, multicenter trial of postmenopausal subjects with an intact uterus.


Options:
A: Inclusion Criteria

* Females aged 45-70 years
* 2 or more years since last natural menstrual period, or surgical menopause (bilateral oophorectomy)
* At least 1 vaginal symptom (inside or outside the vagina) reported from the following list, experienced in the past 30 days which is moderate or severe:

  * Dryness at least once a week
  * Itching at least once a week
  * Irritation at least once a week
  * Soreness/Pain at least once a week
  * Pain associated with sexual activity at least once
* Signed informed consent

Exclusion Criteria

* Current unexplained abnormal genital bleeding (or any unevaluated bleeding since menopause)
* Currently pregnant, attempting pregnancy or breast feeding
* Current acute vaginal infection (as indicated by wet mount at V1)
* Pelvic or vaginal surgery in prior 60 days
* Antibiotic use in the past 30 days
* Women under age 55 with endometrial ablation
* Women under age 55 with hysterectomy and at least one ovary
* Current cancer treatment (exception basal or squamous skin cell cancers)
* Current or past thromboembolic disease (pulmonary embolus or deep vein thrombosis, not including thrombophlebitis), myocardial infarction or stroke
* Current severe liver disease
* Current or past breast or endometrial cancer or pre-cancer
* Blood clotting disorder (e.g., Factor V Leiden, prothrombin mutation, protein C, protein or antithrombin deficiency)
* Porphyria
* Current or past lichen sclerosus or lichen planus
* History of adverse reaction to vaginal estrogen or Replens
* Use of any systemic reproductive hormones (hormonal contraception, postmenopausal hormone therapies, SERMS) in the past 2 months
* Use of hormonal contraception in the past year
* Use of any type of vaginal estrogen product (however interested women will be allowed to join the study if they abstain from use during the month preceding enrollment)
* Use of any type of vaginal moisturizer, douche, vaginal prebiotic or probiotic, or soap in the vagina in the past month (however interested women will be allowed to join the study if they abstain from use during the month preceding enrollment)
* Unwilling to abstain from use of any non-study vaginal moisturizer, vaginal estrogen, douche, or soap in the vagina throughout the trial
* Unable to follow instructions, complete questionnaires, or physically unable to place product in the vagina
* Current participation in another drug trial or intervention study
* Chronic vulvo-vaginal symptoms in the 5 years before menopause (defined as a vaginal or vulvar condition requiring more than 4 visits to a health care provider in a given year)
B: Inclusion Criteria:

* Naturally or surgically menopausal
* Minimum 7 daily or 50 weekly moderate-to-severe hot flashes

Exclusion Criteria:

* Any contraindication to hormone therapy
C: 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.
D: Inclusion Criteria:

* Histologically confirmed and surgically treated invasive breast carcinoma (T1/2/3 N0/1/2 M0), irrespective of hormonal (estrogen/progestogen) receptor status.
* Last menstrual bleeding at least 12 months before the start of the study or ovariectomized or hysterectomized or currently being treated with gonadotropin releasing hormone analogs.
* Vasomotor symptoms whether related to natural menopause, ovariectomy, or to breast cancer therapy (chemotherapy, tamoxifen, aromatase inhibitors or other anticancer therapy).
* In subjects with an intact uterus, a 'normal' endometrium, defined as:

  1. in tamoxifen users: absence of endometrial polyps
  2. in non-tamoxifen users: double layer endometrial thickness \<=4 mm as assessed by TVUS or double layer endometrial thickness \>4 mm and \<=8 mm as assessed by TVUS plus an endometrial biopsy result of inactive/atrophic.
* Voluntary written informed consent and willing and able to make reasonable efforts to meet all clinical trial requirements.

Exclusion Criteria:

* Age \>75 years at baseline.
* Ductal carcinoma in situ (DCIS) of the breast without the existence of invasive breast carcinoma.
* Invasive breast carcinoma having a tumor of any size with direct extension to chest wall or skin (T4) and/or having metastasis to ipsilateral mammary lymph node(s) (N3) and/or having presence of distant metastasis (M1).
* Surgical treatment of the primary breast cancer \>5 years ago.
* History or presence of residual or recurrent breast cancer.
* History or presence of endometrial cancer.
* History or presence of any other malignancy (besides breast cancer and endometrial cancer) within the past 5 years, except for adequately treated basal cell carcinoma of the skin.
* Diagnostic findings suspicious for any malignancy.
* Double layer endometrial thickness \>8 mm as assessed by TVUS in subjects not being treated with tamoxifen.
* Final diagnosis of endometrial biopsy different from inactive/atrophic
* Existence of endometrial polyps as demonstrated by TVUS.
* Undiagnosed vaginal bleeding.
* Abnormal cervical smear (corresponding to PAP IIb or higher)
* Any previous or current unopposed estrogen administration in women with an intact uterus (occasional use of estrogen-containing vaginal cream was allowed after an appropriate washout period - see below).
* Use of systemic estrogens and/or progestogens (including intra-uterine progestogen therapy) and/or tibolone and/or phytoestrogens within 8 weeks prior to baseline; use of transdermal hormone therapy and/or local estrogen applications and/or non-hormonal medication for vasomotor symptoms within 4 weeks prior to baseline.
* Use of progestogen implants or injections and/or estrogen/progestogen injectable therapy within the past 6 months.
* Use of estrogen implants or injections within the past 5 years.
* Use of raloxifene hydrochloride and/or any non-registered investigational drug within the last 8 weeks.
* Active deep vein thrombosis, thromboembolic disorders, or a documented history of these conditions.
* Severe liver disorders.
* Abnormal laboratory values considered to be clinically relevant by the investigator.
* Any disease or condition that is clinically relevant and which, in the opinion of the investigator, would jeopardize the subject's well-being during the course of the trial.
* Known hypersensitivity to tibolone or any of its components
* Known or suspected pregnancy
* Age \<40 years at baseline and planned breast cancer therapy \<2 years after baseline

Answer: C