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A Study of Pharmacokinetic/Pharmacodynamic Profile of Orally Administered Leuprolide in Healthy Female Volunteers

This study is currently recruiting participants.
Verified July 2017 by Enteris BioPharma Inc.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02807363
First Posted: June 21, 2016
Last Update Posted: July 21, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Enteris BioPharma Inc.
  Purpose
This Phase 2a, pharmacokinetic/pharmacodynamic study will determine the safety and provide evaluation of the PK/PD metrics of two 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. 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.

Condition Intervention Phase
Endometriosis Drug: Leuprolide Oral Tablet QD Drug: Leuprolide Oral Tablet BID Drug: Leuprolide Depot Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Open-label, Parallel-group, Active-control PK/PD Study of Two Doses of Leuprolide Oral Tablets in Comparison to an IM Dose of Leuprolide in Healthy Female Volunteers

Resource links provided by NLM:


Further study details as provided by Enteris BioPharma Inc.:

Primary Outcome Measures:
  • Adequacy of suppression of estradiol (E2) as assessed by the subject incidence of estradiol level below 40 pg/mL [ Time Frame: Treatment day 22 to day 29 ]

Secondary Outcome Measures:
  • Adequacy of suppression of estradiol (E2) as assessed by the subject incidence of estradiol level below 40 pg/mL [ Time Frame: Treatment Day 1 to Day 15; Post-Dosing Day 7 to Day 28 ]
  • Adequacy of suppression of estradiol (E2) as assessed by the subject incidence of estradiol level below 20 pg/mL [ Time Frame: Treatment Day 1 to Day 29; Post-Dosing Day 7 to Day 28 ]
  • Adequacy of suppression of ovulation as assessed by the subject incidence of progesterone level below 3 ng /mL [ Time Frame: Treatment Day 1 to Day 29; Post-Dosing Day 7 to Day 28 ]
  • Adequacy of suppression of menstrual periods as assessed by the number of vaginal (menstrual) bleeding days [ Time Frame: : Treatment Day 1 to Day 29; Post-Dosing Day 7 to Day 28 ]
  • Serum concentration, AUC (area under curve) of Leuprolide [ Time Frame: Treatment Days 1 and 28 ]
  • Serum concentration, Css (steady state levels) of Leuprolide [ Time Frame: Treatment Days 28-29 for oral groups; Treatment Days 22-29 for Lupron Depot group ]
  • Number of patients with adverse events [ Time Frame: Treatment Day 1 to Day 29; Post-Dosing Day 1 to Day 28 ]

Estimated Enrollment: 32
Anticipated Study Start Date: July 2017
Estimated Study Completion Date: October 2017
Estimated Primary Completion Date: October 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Leuprolide Oral Tablet, 4 mg QD
Leuprolide Oral Tablet QD: 4 mg for 28 consecutive days.
Drug: Leuprolide Oral Tablet QD
4-mg oral tablet once daily for 28 consecutive days.
Experimental: Leuprolide Oral Tablet, 4 mg BID
Leuprolide Oral Tablet BID: 4 mg, 12 hours apart for 28 consecutive days.
Drug: Leuprolide Oral Tablet BID
4-mg oral tablet twice daily for 28 consecutive days.
Active Comparator: Leuprolide 1 month depot
Leuprolide Depot : intramuscular (IM) 3.75 mg depot injection administered for one month of therapy
Drug: Leuprolide Depot
3.75 mg intramuscular depot injection
Other Name: Lupron

Detailed Description:

This study will evaluate the safety, pharmacokinetic profile and pharmacodynamic effects of the two Leuprolide Oral Tablet dosing regimens: Leuprolide Oral Tablet, 4 mg, administered QD for 28 consecutive days and Leuprolide Oral Tablet, 4 mg, administered BID for 28 consecutive days in comparison to leuprolide administered intramuscularly, Lupron Depot 3.75 mg.

The study is designed as a randomized, open-label, parallel-group active-control trial. Up to thirty-two (32) subjects (12 subjects in each Leuprolide Oral Tablet treatment group and 8 subjects in the Lupron Depot group) will be randomly assigned to the study drug in a ratio of 3:3:2. The randomization schedule will be balanced by using permuted blocks. The randomization schedule may be further stratified by the study site, if necessary.

The study consists of two major periods: approximately one month of dosing (either 28 consecutive days of daily oral dosing, or a single intramuscular injection on Treatment Day 1) and approximately 1 month (28 days) of post-dosing PK/PD evaluations. The total study duration, from screening to the final study visit will be up to approximately 3.5 months.

After the 28-day dosing period, four follow-up visits will be scheduled at 7, 14, 21 and 28 days after the last dose. During each follow-up visit, serum samples will be drawn to assess leuprolide (via a single blood draw) and LH, FSH, E2, and progesterone concentrations. During each follow-up visit, subjects will be asked about onset (or absence) of menstrual period.

The primary statistical analyses of PK data will be conducted on the population of subjects completing 28 days of dosing. Supporting evaluations will be performed for the cohort of subjects who received at least one dose of study medication and provided any pharmacokinetic data.

Similarly, the primary statistical analyses of PD data will be conducted on the population of subjects completing 28 days of dosing. Supporting evaluations will be performed for the cohort of subjects who received at least one dose of study medication and provided any pharmacodynamic data.

The safety analysis will be performed on all subjects who received at least one dose of study medication.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 49 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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 lbs. (≈50 kg).
  3. Regular menstrual cycles with a usual length ranging from 21 days to 35 days. If subject has recently used hormonal birth control, historical data prior to use will be 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. intra-uterine contraceptive device 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
    3. sterile male partner (vasectomized for at least 6 months);
  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

Exclusion Criteria:

  1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in LUPRON DEPOT - Note: This is a contraindication from the Lupron Depot label
  2. Undiagnosed abnormal vaginal bleeding. Note: This is a contraindication from the Lupron Depot label
  3. Known or suspected pregnancy, or subjects who are considering becoming pregnant prior to the conclusion of this study Note: LUPRON DEPOT is contraindicated in women who are or may become pregnant while receiving the drug. LUPRON DEPOT may cause fetal harm when administered to a pregnant woman…. If this drug is 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 This is a contraindication from the Lupron Depot label
  4. Breast-feeding or within 2 months after stopping breast-feeding (relative to the screening visit) Note: Use of LUPRON DEPOT is contraindicated in women who are breast-feeding.
  5. Thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or a past history of these conditions. Note: Per the LUPRON DEPOT label, a possible co-administration of Norethindrone acetate is 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 is contraindicated in women with markedly impaired liver function or liver disease.
  7. Known or suspected carcinoma of the breast. Per the LUPRON DEPOT label, a possible co-administration of Norethindrone acetate is contraindicated in women with known or suspected carcinoma of the breast.
  8. Status post-partum 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 are 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 one year prior to the screening visit.
  12. Clinically significant vital sign abnormalities (systolic blood pressure lower than 90 or over 140 mmHg, diastolic blood pressure lower than 50 or over 90 mmHg, or heart rate less than 50 or over 100 bpm) at screening.
  13. Any clinically significant 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 clinically significant depression in the last year
  20. Known disturbance of lipid metabolism
  21. Hepatic adenoma or carcinoma
  22. Undiagnosed abnormal genital bleeding
  23. Known or suspected endometrial carcinoma, or estrogen-dependent neoplasia
  24. History of sensitivity to leuprolide acetate or other GnRH agonists
  25. 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.
  26. Difficulty in swallowing study medication
  27. Any food allergy, intolerance, restriction or special diet that, in the opinion of the Investigator, could contraindicate the subject's participation in this study
  28. Positive test for hepatitis B, hepatitis C, or HIV at screening
  29. Administration of any investigational drug and/or experimental device within 30 days prior to the screening visit
  30. Administration of any biologics within 90 days prior to the screening visit
  31. Clinically significant finding on the ECG suggesting participation in the study could pose a risk to the subject
  32. A depot injection or an implant of any drug within 6 months prior to the screening visit
  33. Use of oral contraceptives or other sex steroid hormones within 3 months prior to the screening visit
  34. Any clinically significant physical or gynecological abnormality at the screening visit
  35. Any clinically significant abnormal laboratory test result at the screening visit
  36. Hemoglobin <115 g/L and/or hematocrit < 0.32 L/L
  37. Use of prescription medication within 14 days prior to the first administration of study medication or over-the-counter 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
  38. 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
  39. Deemed by the Investigator to have questionable ability to comply with the study protocol
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02807363


Contacts
Contact: Paul Shields, Ph.D. 9734533530 pshields@enterisbiopharma.com
Contact: Amos Sanchez, MBA asanchez@enterisbiopharma.com

Locations
Canada, Quebec
inVentiv Health clinique Recruiting
Quebec City, Quebec, Canada, G1P 0A2
Contact: Marie Lagace, M.Sc.         
Sponsors and Collaborators
Enteris BioPharma Inc.
  More Information

Responsible Party: Enteris BioPharma Inc.
ClinicalTrials.gov Identifier: NCT02807363     History of Changes
Other Study ID Numbers: LOPDT-ENDO-01
First Submitted: June 14, 2016
First Posted: June 21, 2016
Last Update Posted: July 21, 2017
Last Verified: July 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Enteris BioPharma Inc.:
endometriosis
gonadotropin-releasing hormone agonist
healthy volunteers
leuprolide oral tablet

Additional relevant MeSH terms:
Endometriosis
Genital Diseases, Female
Leuprolide
Fertility Agents, Female
Fertility Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents