Study to Evaluate the Pharmacodynamics and Efficacy of Leuprolide Tablets (Ovarest®) in Women With Endometriosis

Study Overview
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Brief Summary
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The pharmacodynamic endpoint of percentage of subjects with suppressed estradiol level (less than 20 pg/mL) on cycle day 29 is the primary endpoint of the study.

Detailed Description
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Objectives of this study: To determine efficacy and pharmacodynamic effects of various dosing regimens of Ovarest® (within the 60-mg - 120 mg daily dosing range) in women with endometriosis. To determine a minimally effective daily dosing regimen of Ovarest® with pharmacodynamic effects at least comparable to the historical data for marketed Lupron Depot formulations and for GnRH antagonists indicated for the treatment of endometriosis. To evaluate safety and tolerability of the long-term administration of leuprolide within the targeted daily dosing range in women with endometriosis. The most important goal of this study is to provide adequate dose-response data for the suppression of estradiol (E2) levels below the menopausal threshold of 20 pg/mL. Results of this study in conjunction of Enteris proprietary PK data will support further development of Leuprolide Acetate Oral Tablet for the treatment of reproductive disorders, particularly endometriosis. Another reason for this trial is to support a comparative evaluation of the PD effects across the QD and BID regimens delivering the same overall dose of Ovarest

Official Title
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An Open-label Dose-finding Study to Evaluate the Pharmacodynamic (PD) Profiles and Efficacy of Different Dosing Regimens of Leuprolide Oral Tablets (Ovarest®) in Women With Endometriosis

Conditions
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Endometriosis

Intervention / Treatment
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* Drug: Leuprolide Oral Tablet - 120 mg - QD- Treatment A
* Drug: Leuprolide Oral Tablet - 80 mg - QD - Treatment B
* Drug: Leuprolide Oral Tablet - 60 mg - QD - Treatment C
* Drug: Leuprolide Oral Tablet - 60 mg - BID - Treatment D
* Drug: Leuprolide Oral Tablet - 40 mg - BID - Treatment E


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Women diagnosed with endometriosis and having pelvic pain, both treatment naive or previously treated with GnRH agonists or antagonists with improvement Premenopausal females in general good health, including absence of current COVID infection (positive test or presence of symptoms), aged 18 to 49 years BMI ≥18 and ≤35 kg/m2, and weight ≥110 lb. (≈50 kg). A documented estradiol level ≥ 40 pg/mL at screening or on retest 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. If of childbearing potential and sexually active with a risk of pregnancy, willing to use acceptable methods of contraception (Note: acceptable methods of contraception are specified in Section 8.1) 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 the use of any hormone-containing or hormone-altering substances during the study. Willing and able to adhere to medication schedule and to utilize the AiCure medication adherence monitoring platform correctly with the administration of each dose of medication throughout the duration of the 3 treatment cycles comprising this study Willing and capable to give informed consent to participate in study Exclusion Criteria: Subjects to whom any of the following applies will be excluded from the study: Hypersensitivity to GnRH, GnRH agonist analogs, similar nonapeptides, or any of the excipients in LUPRON DEPOT. Note: This is a contraindication from the Lupron Depot label. Undiagnosed abnormal vaginal bleeding. Note: This is a contraindication from the Lupron Depot label. 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. Breastfeeding or within 2 months after stopping breastfeeding (relative to the screening visit). Note: Use of LUPRON DEPOT is contraindicated in women who are 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 is 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 coadministration of norethindrone acetate is 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 coadministration of norethindrone acetate is contraindicated in women with known or suspected carcinoma of the breast. Status postpartum or postabortion within a period of 2 months prior to the screening visit History of significant alcohol or drug abuse within one year prior to the screening visit Clinically significant vital sign abnormalities (systolic blood pressure lower than 90 or over 140 mm Hg, diastolic blood pressure lower than 50 or over 90 mm Hg, or heart rate less than 50 or over 100 bpm) at screening (following recheck after five minutes at rest) Any clinically significant history or presence of neurologic, endocrinologic, pulmonary, hematologic, immunologic, or metabolic disease History of severe respiratory depression or pulmonary insufficiency Diabetes mellitus requiring insulin History of headaches with focal neurological symptoms Uncontrolled thyroid disorder Sickle cell anemia Current or history of clinically significant depression in the last year Known disturbance of lipid metabolism Hepatic adenoma or carcinoma Known or suspected endometrial carcinoma or estrogen-dependent neoplasia Clinically significant history or presence of any gastrointestinal pathology (e.g., chronic diarrhea, inflammatory bowel diseases, history of cholecystectomy), 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 Difficulty in swallowing study medication Any food allergy, intolerance, restriction or special diet that, in the opinion of the Investigator, could contraindicate the subject's participation in this study Positive test for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) at screening Administration of any investigational drug and/or experimental device within 30 days prior to the screening visit Administration of any biologics within 30 days prior to the screening visit. Note: The Covid-19 vaccine is not included in this prohibition. Clinically significant finding on the ECG suggesting participation in the study could pose a risk to the subject A depot injection or an implant of any drug within 1 month prior to the screening visit Use of oral contraceptives or other sex steroid hormones within 1 month prior to the screening visit. Note: A 1-month drug holiday period is mandatory for potential subjects receiving GnRH agonists and GnRH antagonists. Any clinically significant physical or gynecological abnormality at the screening visit Any clinically significant abnormal laboratory test result at the screening visit Hemoglobin <11.5 g/dL and/or hematocrit <32% Use of over-the-counter products containing any substances which could have the propensity to impact either estradiol or gonadotropin level 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 History of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors 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 Participation in another drug research within 1 month prior to screening Deemed by the Investigator to have questionable ability to comply with the study protocol, including inadequate adherence to both dosing and use of the AiCure medication adherence monitoring platform during the Run-in Period or during the three Treatment Cycles Current use of any prescription medication known to cause delayed gastric emptying (e.g. glucagon-like peptide-1 receptor agonists)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A: Leuprolide Oral Tablet, 120 mg QD<br>Leuprolide Oral Tablet (Ovarest), 120 mg (2 x 60 mg tablets), administered once daily (QD), for up to 35 consecutive days with food-intake restrictions. | Drug: Leuprolide Oral Tablet - 120 mg - QD- Treatment A<br>* If the subject during Treatment A meets the pharmacodynamic success criterion (estradiol level <20 pg/mL on Treatment Day 29 of the First Treatment Cycle), in the Second Treatment Cycle, she will be assigned Treatment B - 80 mg (2 x 40 mg tablets) (QD), with food-intake restrictions. If the subject during Treatment A fails to meet the pharmacodynamic success criterion (i.e., if estradiol level ≥20 pg/mL on Treatment Day 29 of the First Treatment Cycle), then she will be switched to the Second Treatment Cycle with Treatment D - 60 mg (BID) with food intake restrictions.<br>* Other names: Ovarest® 60 mg;|
| Experimental: Treatment B: Leuprolide Oral Tablet, 80 mg QD<br>Leuprolide Oral Tablet (Ovarest), 80 mg (2 x 40 mg tablets), administered once daily (QD) for up to 35 consecutive days with food-intake restrictions. | Drug: Leuprolide Oral Tablet - 80 mg - QD - Treatment B<br>* If the subject on Treatment B meets the pharmacodynamic success criterion (estradiol level <20 pg/mL on Treatment Day 29 of the Second Treatment Cycle), then she will be switched to the Third Treatment Cycle with Treatment C - 60 mg (QD) with food-intake restrictions. If the subject on Treatment B does not meet the pharmacodynamic success criterion (i.e., if estradiol level ≥20 pg/mL on Treatment Day 29 of the Second Treatment Cycle), then she will be switched to the Third Treatment Cycle with Treatment E - 40 mg (BID) with food intake restrictions.<br>* Other names: Ovarest® 40 mg;|
| Experimental: Treatment C: Leuprolide Oral Tablet, 60 mg QD<br>Leuprolide Oral Tablet (Ovarest), 60 mg, administered once daily (QD) for up to 29 consecutive days with food-intake restrictions. | Drug: Leuprolide Oral Tablet - 60 mg - QD - Treatment C<br>* For up to 29 consecutive days with food-intake restrictions<br>* Other names: Ovarest® 60 mg;|
| Experimental: Treatment D: Leuprolide Oral Tablet, 60 mg BID<br>Leuprolide Oral Tablet (Ovarest), 60 mg, administered twice daily (BID), 12 hours apart for up to 35 consecutive days with food-intake restrictions. | Drug: Leuprolide Oral Tablet - 60 mg - BID - Treatment D<br>* If the subject on Treatment D fails to meet the pharmacodynamic success criterion (i.e., if estradiol level ≥20 pg/mL on Treatment Day 29 of the Second Treatment Cycle), she will be discontinued from the study following completion of the Second Treatment Cycle. If the subject during Treatment D meets the pharmacodynamic success criterion (estradiol level <20 pg/mL on Treatment Day 29 of her Second Treatment Cycle), then she will be switched to the Third Treatment Cycle with Treatment E - 40 mg (BID) with food intake restrictions.<br>* Other names: Ovarest® 60 mg;|
| Experimental: Treatment E:Leuprolide Oral Tablet (Ovarest), 40 mg BID<br>Leuprolide Oral Tablet (Ovarest), 40 mg, administered twice daily (BID), 12 hours apart for up to 29 consecutive days with food-intake restrictions. | Drug: Leuprolide Oral Tablet - 40 mg - BID - Treatment E<br>* For up to 29 consecutive days with food-intake restrictions<br>* Other names: Ovarest® 40 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adequacy of suppression of estradiol (E2) as assessed by the subject incidence of estradiol level below 20 pg/mL | The primary PD metric - suppression of E2 level (E2 <20 pg/mL) - will be assessed at each on-treatment evaluation timepoint. E2 below 20 pg/mL at Day 29 is a primary endpoint for a given Treatment Cycle. | Treatment cycle: Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Suppression of ovulation (as evidenced by progesterone levels <3 ng/mL) | It will be evaluated with Treatment Cycle Day 22 and Treatment Cycle Day 29 (separately and combined) positioned as most important timepoints for this analyte. | Treatment cycle: Day 22 and 29 | 
| Number of vaginal (menstrual) bleeding days | The onset of menstrual period is defined as at least three consecutive bleeding/spotting days during the 14-day postdosing period. | 28 days of therapy and 14 days post study follow up | 
| Composite Pelvic Signs and Symptoms (CPSS) scores | CPSS scores (composite and for the individual items) and changes from the pre-dosing baseline will be summarized by treatment received. CPSSS values are derived from the Biberoglu and Behrman scale, with 5 components addressing dysmenorrhea (0-none and 3-severe), dyspareunia (0-none and 3-severe), non-menstrual pelvic pain (0-none and 3-severe), pelvic tenderness (0-none and 3-severe), and pelvic induration (0-none and 3-severe). In composite score (total symptom and sign severity score) 0 being none and 11-15 being very severe. | Treatment day 29 | 
| (Pre-dose leuprolide level) Subject incidence of Leuprolide below detectable level | The summaries will be provided for each PK evaluation timepoint and across the entire treatment cycle | Treatment Cycle: Days 1, 8, 15, 22 and 29 days | 
| Luteinizing hormone (LH) levels | Serum concentration measured immediately prior to dosing | Treatment days: 1,8, 15, 22 and 29; Post dosing day 14 | 
| Follicle Stimulating Hormone (FSH) levels | Serum concentration measured immediately prior to dosing | Treatment days: 1,8, 15, 22 and 29; Post dosing day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leuprolide oral tablets, Endometriosis, pharmacodynamic