A Study of Pharmacokinetic/Pharmacodynamic Profile of Orally Administered Leuprolide in Healthy Female Volunteers
Condition: Endometriosis
MeSH terms: Endometriosis
Intervention: Leuprolide Oral Tablet 4-mg QD; Leuprolide Oral Tablet 4-mg BID; Leuprolide Depot; Leuprolide Oral Tablet 10-mg BID
Intervention description: 4-mg Leuprolide oral tablet once daily for 28 consecutive days.; 4-mg Leuprolide oral tablet twice daily for 28 consecutive days.; 3.75 mg intramuscular depot injection; 10-mg Leuprolide oral tablet twice daily for 28 consecutive days.
Intervention MeSH terms: Leuprolide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 35.0
Sex: Female
Minimum age: 18 Years
Maximum age: 49 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: endometriosis; gonadotropin-releasing hormone agonist; healthy volunteers; leuprolide oral tablet

Summary:

      This Phase 2a, pharmacokinetic/pharmacodynamic study will determine the safety and provide
      evaluation of the PK/PD metrics of three different oral doses selected upon the results of
      the study LOPDT-PH1-01 - 4 mg oral tablets administered over 28 days as QD and BID regimens
      and 10 mg oral tablets administered over 28 days as a BID regimen. The PK/PD profiles of the
      study drug will be compared to the leuprolide formulation approved for the treatment of
      endometriosis (a monthly intramuscular injection, Lupron Depot 3.75 mg). Major PK (e.g., a
      total exposure to leuprolide) and PD parameters (e.g., rates of the estradiol suppression and
      cessation of the menstrual period) will also be evaluated against the Lupron Depot historical
      data.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Healthy premenopausal female volunteers, aged 18 to 49 years;

          2. Body mass index (BMI) ≥ 18 and ≤ 32 kg/m2, and weight ≥ 110 lb (approximately 50 kg);

          3. Regular menstrual cycles with a usual length ranging from 21 days to 35 days. If
             subject had recently used hormonal birth control, historical data prior to use were
             used to determine qualification and must also meet this criterion;

          4. If of childbearing potential and sexually active with a risk of pregnancy, willing to
             use one of the following acceptable methods of contraception throughout the study and
             for at least 30 days after the last drug administration:

               1. intrauterine contraceptive device (IUD) without hormone release system placed at
                  least 4 weeks prior to the first study drug administration with simultaneous use
                  of condom for the male partner;

               2. simultaneous use of diaphragm with intravaginally applied spermicide and condom
                  for the male partner starting at least 14 days prior to drug administration;

               3. sterile male partner (vasectomized for at least 6 months); Note: Surgically
                  sterile subjects who have had a tubal ligation were considered of
                  non-childbearing potential and were not required to use contraception;

          5. Willing to refrain from excessive use of alcohol during the entire study and willing
             to refrain from use of alcohol 24 hours prior to any PK blood draw taken during the
             study;

          6. Willing to refrain from use of prescription medications, over-the-counter medications,
             and natural health products during the entire study;

          7. Willing and capable to give informed consent to participate in study.

        Exclusion Criteria:

          1. Hypersensitivity to GnRH, GnRH agonist analogs, similar nonapeptides, or any of the
             excipients in Lupron Depot®. Note: This was a contraindication from the Lupron Depot®
             label;

          2. Undiagnosed abnormal vaginal bleeding. Note: This was a contraindication from the
             Lupron Depot® label;

          3. Known or suspected pregnancy, or subjects who were considered to become pregnant prior
             to the conclusion of this study. Note: Lupron Depot® was contraindicated in women who
             were or may become pregnant while receiving the drug. Lupron Depot® could cause fetal
             harm when administered to a pregnant woman. If this drug was used during pregnancy, or
             if the patient becomes pregnant while taking this drug, the patient should be apprised
             of the potential hazard to the fetus;

          4. Breastfeeding or within 2 months after stopping breastfeeding (relative to the
             Screening visit). Note: Use of Lupron Depot® was contraindicated in women who were
             breastfeeding;

          5. Thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or a past history of
             these conditions. Note: Per the Lupron Depot® label, a possible coadministration of
             norethindrone acetate was contraindicated in women with thrombophlebitis,
             thromboembolic disorders, cerebral apoplexy, or a past history of these conditions

          6. Markedly impaired liver function or liver disease. Note: Per the Lupron Depot® label,
             a possible co-administration of norethindrone acetate was contraindicated in women
             with markedly impaired liver function or liver disease;

          7. Known or suspected carcinoma of the breast. Note: Per the Lupron Depot® label, a
             possible co-administration of norethindrone acetate was contraindicated in women with
             known or suspected carcinoma of the breast;

          8. Status postpartum or post-abortion within a period of 2 months prior to the Screening
             visit;

          9. A cervical cytology smear of Papanicolaou (Pap) Class III or greater or a Bethesda
             System report of low grade squamous intraepithelial lesions (SIL) or greater (Pap
             smear results within last 12 months were acceptable if properly documented);

         10. Use of any tobacco products (including electronic cigarettes) in the 3 months
             preceding the Screening visit or positive urine cotinine test at Screening;

         11. History of significant alcohol or drug abuse within 1 year prior to the Screening
             visit;

         12. Clinically significant (CS) vital sign abnormalities (systolic blood pressure [BP]
             lower than 90 or over 140 mm Hg, diastolic BP lower than 50 or over 90 mm Hg, or heart
             rate less than 50 or over 100 bpm) at Screening;

         13. Any CS history or presence of neurologic, endocrinologic, pulmonary, hematologic,
             immunologic, or metabolic disease;

         14. History of severe respiratory depression or pulmonary insufficiency;

         15. Diabetes mellitus requiring insulin;

         16. History of headaches with focal neurological symptoms;

         17. Uncontrolled thyroid disorder;

         18. Sickle cell anemia;

         19. Current or history of CS depression in the last year;

         20. Known disturbance of lipid metabolism;

         21. Hepatic adenoma or carcinoma;

         22. Known or suspected endometrial carcinoma or estrogen-dependent neoplasia;

         23. Clinically significant history or presence of any gastrointestinal pathology (e.g.,
             chronic diarrhea, inflammatory bowel diseases), unresolved gastrointestinal symptoms
             (e.g., diarrhea, vomiting) or kidney disease, or other conditions known to interfere
             with the absorption, distribution, metabolism, or excretion of the drug;

         24. Difficulty in swallowing study medication;

         25. Any food allergy, intolerance, restriction or special diet that, in the opinion of the
             Investigator, could contraindicate the subject's participation in this study;

         26. Positive test for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) at
             Screening;

         27. Administration of any investigational drug and/or experimental device within 30 days
             prior to the Screening visit;

         28. Administration of any biologics within 90 days prior to the Screening visit;

         29. Clinically significant finding on the electrocardiogram (ECG) suggesting participation
             in the study could pose a risk to the subject;

         30. A depot injection or an implant of any drug within 6 months prior to the Screening
             visit;

         31. Use of oral contraceptives or other sex steroid hormones within 3 months prior to the
             Screening visit;

         32. Any CS physical or gynecological abnormality at the Screening visit;

         33. Any CS abnormal laboratory test result at the Screening visit;

         34. Hemoglobin < 115 g/L and/or hematocrit < 0.32 L/L;

         35. Use of prescription medication within 14 days prior to the first administration of
             study medication or over-the-counter (OTC) products (including natural health
             products; e.g., food supplements, vitamins, herbal supplements) within 7 days prior to
             the first administration of study medication, except for topical products without
             significant systemic absorption;

         36. Donation of plasma within 7 days prior to dosing. Donation or loss of blood (excluding
             volume drawn at Screening) of 50 mL to 499 mL of blood within 30 days, or more than
             499 mL within 56 days prior to the first dosing;

         37. Deemed by the Investigator to have questionable ability to comply with the study
             protocol;

         38. History of seizures, epilepsy, cerebrovascular disorders, central nervous system (CNS)
             anomalies or tumors;

         39. Significant risk factors for decreased bone mineral content and/or bone mass, such as
             family history (in a first degree relative) of osteoporosis, personal history of
             chronic use of corticosteroids or anticonvulsants.