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

NCT02807363 | Completed Phase 2 Results FDA Drug

• 1 other identifier: LOPDT-ENDO-01
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Endometriosis

Keywords

endometriosis; gonadotropin-releasing hormone agonist; healthy volunteers; leuprolide oral tablet

Outcome Measures

Primary Outcomes (5)

• Number of Participants With Adequacy of Suppression of Estradiol (E2) as Assessed by Estradiol Level Below 40 pg/mL

  Criterion: E2 level is considered suppressed during the evaluation period if a value below pre-specified threshold was reported at least once during that period. The days in the row title indicate the evaluation interval.

  Dosing Period: Day 8 to 28, Post-dosing: Day 1 to day 28 of post dosing period; Day 29 is the post dosing day 1

• Ovulation Rate - Measured by Number of Subjects With Progesterone Levels Not Less Than 3000 pg/mL

  Progesterone level is considered suppressed during the evaluation period if a value below pre-specified threshold (3000 pg/mL) was reported at least once during that period. The days in row title indicate the evaluation interval.

  Dosing period: Day 1 to Day 28 and 28 day Post-Dosing Period; 29 day is post dosing day 1

• Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAE) Excluding Menstrual Disorders

  The participant incidence of TEAEs was generally comparable during the dosing period across the treatment groups. Treatment C is a depot formulation established to release the drug over a period of 1 month. The data for adverse event was collected for day 1 to 28 of the dosing period.

  Dosing Period: Day 1 to day 28

• Number of Subjects Who Experienced Treatment-Emergent Adverse Events (TEAEs), Excluding Menstrual Disorders

  Treatment C is a depot formulation established to release the drug over a period of 1 month. The data for post dosing adverse event was collected starting from day 1 to 28 post the 28th day of dosing.

  Post dosing period (starting day 1 to day 28 post dosing period)

• Steady State Concentration Level, (Css) of Leuprolide

  Treatment A and B: Steady state concentration level calculated for oral tablets at the end of the fourth treatment week (Treatment Day 28) as the 24-hour AUCs divided by the duration of the dosing interval i.e. 24 hours. Treatment C: Steady state concentration level calculated for IM injection at the fourth treatment week (a mean of leuprolide levels on Days 22 and 29).

  Treatment Day 28 for oral groups; Treatment Days 22-29 for Lupron Depot group

Study Arms (4)

Treatment A: Leuprolide Oral Tablet, 4 mg QD

EXPERIMENTAL

Leuprolide Oral Tablet QD: 4 mg for 28 consecutive days.

Drug: Leuprolide Oral Tablet 4-mg QD

Treatment B: Leuprolide Oral Tablet, 4 mg BID

EXPERIMENTAL

Leuprolide Oral Tablet BID: 4 mg, 12 hours apart for 28 consecutive days.

Drug: Leuprolide Oral Tablet 4-mg BID

Treatment C: Leuprolide 1 month depot

ACTIVE COMPARATOR

Leuprolide Depot : intramuscular (IM) 3.75 mg depot injection administered for one month of therapy

Drug: Leuprolide Depot

Treatment D: Leuprolide Oral Tablet, 10 mg BID

EXPERIMENTAL

Leuprolide Oral Tablet BID: 10 mg, 12 hours apart for 28 consecutive days

Drug: Leuprolide Oral Tablet 10-mg BID

Interventions

Leuprolide Oral Tablet 4-mg QD DRUG

4-mg Leuprolide oral tablet once daily for 28 consecutive days.

Also known as: Ovarest™ 4.0 mg

Treatment A: Leuprolide Oral Tablet, 4 mg QD

Leuprolide Oral Tablet 4-mg BID DRUG

4-mg Leuprolide oral tablet twice daily for 28 consecutive days.

Also known as: Ovarest™ 4.0 mg

Treatment B: Leuprolide Oral Tablet, 4 mg BID

Leuprolide Depot DRUG

3.75 mg intramuscular depot injection

Also known as: Lupron Depot® 3.75 mg

Treatment C: Leuprolide 1 month depot

Leuprolide Oral Tablet 10-mg BID DRUG

10-mg Leuprolide oral tablet twice daily for 28 consecutive days.

Also known as: Ovarest™ 10.0 mg

Treatment D: Leuprolide Oral Tablet, 10 mg BID

Eligibility Criteria

• Age: 18 Years - 49 Years
• Gender Eligibility Details: Pre-menopausal female volunteers
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy premenopausal female volunteers, aged 18 to 49 years;
• Body mass index (BMI) ≥ 18 and ≤ 32 kg/m2, and weight ≥ 110 lb (approximately 50 kg);
• 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;
• 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:
• 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;
• simultaneous use of diaphragm with intravaginally applied spermicide and condom for the male partner starting at least 14 days prior to drug administration;
• 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;
• 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;
• Willing to refrain from use of prescription medications, over-the-counter medications, and natural health products during the entire study;
• Willing and capable to give informed consent to participate in study.

You may not qualify if:

• 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;
• Undiagnosed abnormal vaginal bleeding. Note: This was a contraindication from the Lupron Depot® label;
• 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;
• 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;
• 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
• 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;
• 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;
• Status postpartum or post-abortion within a period of 2 months prior to the Screening visit;
• 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);
• Use of any tobacco products (including electronic cigarettes) in the 3 months preceding the Screening visit or positive urine cotinine test at Screening;
• History of significant alcohol or drug abuse within 1 year prior to the Screening visit;
• 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;
• Any CS history or presence of neurologic, endocrinologic, pulmonary, hematologic, immunologic, or metabolic disease;
• History of severe respiratory depression or pulmonary insufficiency;
• Diabetes mellitus requiring insulin;

Sponsors & Collaborators

• Enteris BioPharma Inc.: lead
• Syneos Health: collaborator

Study Sites (1)

inVentiv Health Clinique, Inc.

Québec, Quebec, G1P 0A2, Canada

Location

MeSH Terms

Conditions

Endometriosis

Interventions

Leuprolide; BID protein, human

Condition Hierarchy (Ancestors)

Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Results Point of Contact

• Title: Paul Shields, Ph.D
• Organization: Enteris Biopharma Inc.

pshields@enterisbiopharma.com

9734533520

Study Officials

• Gary Shangold, MD

  Enteris BioPharma Inc.

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 14, 2016
• First Posted: June 21, 2016
• Study Start: August 23, 2017
• Primary Completion: June 27, 2018
• Study Completion: June 27, 2018
• Last Updated: February 11, 2022
• Results First Posted: February 11, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)