Efficacy Study of Progesterone Tablet in Post-menopausal Women

Effect of Progesterone 5, 10, and 20 mg Tablets Compared To Progesterone 100 mg Capsules on the Endometrial Thickness of Post-Menopausal Women Under Hormone Therapy - A Prospective, Open-Label, Randomized, Four-Arm, Parallel-Group, Phase II Clinical Trial

This is a phase II study intended to determine the effect of progesterone 5, 10 and 20 mg tablets compared to progesterone 100 mg capsules on the endometrial thickness of post-menopausal women under hormone therapy with estradiol.

Inclusion Criteria:

1. Availability for the entire study period

2. Post-menopausal female defined as:

   • at least 12 consecutive months of spontaneous amenorrhea and
   • less than 10 years of spontaneous amenorrhea, and
   • Follicle-stimulating hormone (FSH) levels > 40 milli International Units/ml

3. Females with an intact uterus

4. Moderate to severe climacteric vasomotor symptoms

5. Aged of at least 40 years but not older than 65 years

6. Body mass index (BMI) greater than or equal to 18.00 kg/m2 and below 30.00 kg/m2

7. Non- or ex-smoker;

8. Endometrium thickness ≤4 mm on ultrasonography at screening

9. Negative mammogram (dated < 2 years)

10. Negative Pap smear test (dated < 1 year)

11. Normal clinical breast examination

12. Normal pelvic examination

13. Have no clinically significant diseases captured in the medical history or evidence of clinically significant findings on physical examination, as determined by the medical investigator

14. Willingness to adhere to the protocol requirements as evidenced by the informed consent form (ICF) duly read, signed and dated by the subject

Exclusion Criteria:

1. Use of any estrogen, progestin, or estrogen/progestin drug products, androgens, selective estrogen receptor modulators (SERMs), phytoestrogen supplements or natural products (soy, black cohosh, dong quai) during the past 3 months before the screening visit

2. Use of any estrogen, progestin or androgen pellet or injectable therapy during the past 6 months before the screening visit

3. Contraindications to hormone therapy:

   • Active liver dysfunction or disease or history of severe liver disease
   • Known, suspected or past history of hepatic tumors (benign or malign)
   • Active or past history of arterial thromboembolic disease (e.g. angina, myocardial infarction, stroke, coronary heart disease, transient ischemic attack)
   • Active or past history of venous thromboembolism (e.g. deep venous thrombosis, pulmonary embolism) or active thrombophlebitis
   • Known, suspected or past history of breast cancer
   • Known, suspected or past history of estrogen-dependent or progestin-dependent malignant neoplasia (e.g. endometrial cancer)
   • Endometrial hyperplasia
   • Porphyria cutanea tarda
   • Genital bleeding
   • Untreated hypertension
   • Classical migraine
   • Partial or complete loss of vision or diplopia due to ophthalmic vascular disease

4. Presence of clinically significant screening ECG abnormalities as defined by medical judgment

5. Presence of polyps

6. Presence of uterine fibroids or other abnormalities affecting endometrial thickness measurement or precluding estrogen therapy

7. Known hypersensitivity to the active substances or to any of the excipients contained in the drug products in particular to soya or peanut, as well as hereditary problems of fructose intolerance or phenylketonuria

8. Participation in a concurrent clinical trial or another trial within the past 2 months

9. Use of any enzyme-modifying drugs, including strong inhibitors of cytochrome P450 (CYP) enzymes (such as cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem and HIV antivirals) and strong inducers of CYP enzymes (such as barbiturates, carbamazepine, glucocorticoids, phenytoin, rifampin and St John's Wort), in the previous 28 days before day 1 of this study

10. Maintenance therapy with any drug or significant history of drug dependency, drug abuse or alcohol abuse within the last 2 years

11. Presence of any medical condition or other circumstances which would significantly decrease the chance of obtaining reliable data, achieving study objectives or completing the study

12. Serious psychiatric problems (whether or not receiving treatment) or in any case such as to compromise the patient's reliability

13. Any clinically significant illness in the previous 28 days before day 1 of this study

14. Any history of tuberculosis and/or prophylaxis for tuberculosis

15. Positive screening of alcohol and/or drugs of abuse

16. Positive results to HIV Ag/Ab combo, hepatitis B surface antigen or hepatitis C virus tests

17. Females who are pregnant according to a positive serum pregnancy test

18. Presumption of subject's poor reliability/cooperation

19. Any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study