E4/DRSP Ovarian Function Inhibition Study

Study Overview
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Brief Summary
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A combined oral contraceptive (COC) containing 15 mg E4 and 3 mg DRSP administered for 24 days followed by 4 placebo tablets, is being evaluated for further development. This study will investigate the effect of this COC on ovarian function inhibition, levels of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2) and progesterone during 3 treatment cycles in comparison with the reference COC 20 mcg EE/3 mg DRSP.

Official Title
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A Single-center, Randomized, Open-label, Two-arm Study to Evaluate the Ovarian Function Inhibition of a Monophasic Combined Oral Contraceptive (COC) Containing 15 mg Estetrol (E4) and 3 mg Drospirenone (DRSP) and a Monophasic COC Containing 20mcg Ethinylestradiol (EE)/3 mg DRSP (YAZ®), Administered Orally Once Daily in a 24/4 Day Regimen for Three Consecutive Cycles

Conditions
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Prevention of Pregnancy

Intervention / Treatment
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* Drug: 15 mg E4/3 mg DRSP
* Drug: 20 mcg EE/3 mg DRSP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Overtly healthy female subjects, as determined by medical history, physical examination including breast examination, gynecological examination (including cervical smear [Pap smear]), vital signs, ECG, echocardiogram, and laboratory tests. Negative pregnancy test at subject screening. Women who ovulate in the Pre-Treatment Cycle. Willing to use a non-hormonal method of contraception (e.g. condom) during the wash-out period, Pre-Treatment Cycle and Post-Treatment Cycle. BMI between 18.0 and 35.0 kg/m², inclusive, at time of Screening. Able to fulfill the requirements of the protocol and have indicated a willingness to participate in the study by providing written informed consent form (ICF). Exclusion Criteria: Irregular menstrual cycle. Amenorrhea or abnormal uterine bleeding. Clinically relevant abnormal laboratory result at Screening. Clinically significant abnormalities of the uterus and/or ovaries detected by examination and/or ultrasound. Known hypersensitivity to any of the investigational or reference product ingredients. Intention to become pregnant during the course of the study. Pregnancy during accurate hormonal contraceptive use in the past. Dyslipoproteinemia requiring active treatment with antilipidemic agent. Diabetes mellitus with vascular involvement (nephropathy, retinopathy, neuropathy, other) or diabetes mellitus of more than 20-year duration. Any arterial hypertension. Any condition associated with an increased risk of venous thromboembolism and/or arterial thromboembolism. Complicated valvular heart disease. History of pregnancy-related cardiomyopathy or moderately or severely impaired cardiac function. Systemic lupus erythematosus. Presence or history of migraine with aura. Abnormal Papanicolaou (PAP) smear result. Presence of an undiagnosed breast mass. Current symptomatic gallbladder disease. History of COC-related cholestasis. Presence or history of severe hepatic disease. Presence or history of pancreatitis if associated with hypertriglyceridemia. Porphyria. Presence or history of hepatocellular adenoma or malignant liver tumors. Renal impairment. Hyperkaliemia or presence of conditions that predispose to hyperkaliemia. Presence or history of hormone-related malignancy. History of non-hormone-related malignancy within 5 years before Screening. Subjects with a non-melanoma skin cancer are allowed in the study. Use of drugs potentially triggering interactions with COCs. History of alcohol or drug abuse. Any prior procedure, disease or condition that could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the investigational product. Uncontrolled thyroid disorders. Have received an investigational drug within the last 2 cycles prior to start of Pre-Treatment Cycle. Subjects who participated in an oral contraceptive clinical study, using Food and Drug Administration (FDA)/European Union (EU) approved active ingredients, may start the Pre-Treatment Cycle one cycle after last medication intake of the preceding study. Sponsor, contract research organization (CRO) or PI's site personnel directly affiliated with this study. Is judged by the PI to be unsuitable for any reason.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 15 mg E4/3 mg DRSP<br>15 mg E4 combined with 3 mg DRSP administered in a 24/4-day regimen. One tablet per day orally for 3 treatment cycles. | Drug: 15 mg E4/3 mg DRSP<br>* 15 mg E4/3 mg DRSP combined tablets will be administered orally once daily in a 24/4 day regimen for three consecutive cycles<br>* Other names: 15 mg estetrol combined with 3 mg drospirenone;|
| Active Comparator: 20 mcg EE/3 mg DRSP<br>20 mcg EE combined with 3 mg DRSP administered in a 24/4-day regimen. One tablet per day orally for 3 treatment cycles. | Drug: 20 mcg EE/3 mg DRSP<br>* 20 mcg EE/3 mg DRSP combined tablets will be administered orally once daily in a 24/4 day regimen for three consecutive cycles<br>* Other names: 20 mcg ethinylestradiol combined with 3 mg drospirenone (Yaz);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with ovarian inhibition at treatment Cycle 1 | Ovarian inhibition will be assessed by rating the suppression of ovaries using the Hoogland score. This score is based on: the follicular size assessed by transvaginal ultrasound (TVUS) endogenous hormone levels: serum E2, and serum progesterone. | All assessments will be performed once every 3 days starting treatment Cycle 1 Day 3 (± 1 day) until Day 27 (± 1 day) (one treatment cycle = 28 days). | 
| Proportion of subjects with ovarian inhibition at treatment Cycle 3 | Ovarian inhibition will be assessed by rating the suppression of ovaries using the Hoogland score. This score is based on: the follicular size assessed by TVUS endogenous hormone levels: serum E2, and serum progesterone. | All assessments will be performed once every 3 days starting treatment Cycle 3 Day 3 (± 1 day) until Day 27 (± 1 day) (one treatment cycle = 28 days). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum level of luteinizing hormone (LH) | Blood samples will be taken at regular time points defined in the time frame. | On cycle Day 3, 6, 9, 12, 15, 18, 21, 24, 27 at treatment Cycle 1 and treatment Cycle 3 and on cycle Day 3 of the Treatment Cycle 2 (each treatment cycle = 28 days) | 
| Serum level of follicle stimulating hormone (FSH) | Blood samples will be taken at regular time points defined in the time frame. | On cycle Day 3, 6, 9, 12, 15, 18, 21, 24, 27 at treatment Cycle 1 and treatment Cycle 3 and on cycle Day 3 of the Treatment Cycle 2 (each treatment cycle = 28 days) | 
| Serum level of estradiol (E2) | Blood samples will be taken at regular time points defined in the time frame. | On cycle Day 3, 6, 9, 12, 15, 18, 21, 24, 27 at treatment Cycle 1 and treatment Cycle 3 and on cycle Day 3 of the Treatment Cycle 2 (each treatment cycle = 28 days) | 
| Serum level of progesterone (P) | Blood samples will be taken at regular time points defined in the time frame. | On cycle Day 3, 6, 9, 12, 15, 18, 21, 24, 27 at treatment Cycle 1 and treatment Cycle 3 and on cycle Day 3 of the Treatment Cycle 2 (each treatment cycle = 28 days) | 
| Maximum endometrial thickness | Endometrial thickness will be measured using transvaginal ultrasound (TVUS). Maximum endometrial thickness was defined as the largest endometrial thickness during a cycle. | From Baseline (study day 1), through 3 treatment cycles and up to Cycle Day 36 (±1) of the Post-Treatment Cycle (study day 120 (±1)) (each treatment cycle = 28 days) | 
| Mean diameter of the largest follicle | Follicular size will be measured using TVUS. | Day 3 to Day 24 of Post-Treatment Cycle | 
| Number of participants who experience at least one Treatment-Emergent Adverse Event (TEAE) |  | Day 1 to Follow-Up Visit (+ 30 days) | 
| Number of participants who experience pregnancy during treatment |  | Cycle 1 Day 1 to Follow-Up Visit (+ 30 days) (each treatment cycle = 28 days) | 
| Number of participants who experience a clinically significant change in physical examination results |  | Day 1 to End of Follow-Up Visit (+ 30 Days) | 
| Number of participants who experience a clinically significant change in gynecological examination results |  | Day 1 to End of Follow-Up Visit (+ 30 Days) | 
| Number of participants who experience a clinically significant change in clinical laboratory results |  | Day 1 to End of Follow-Up Visit (+ 30 Days) | 
| Number of participants who experience a clinically significant change in electrocardiogram (ECG) results |  | Day 1 to End of Cycle 3 (Day 28) (each treatment cycle = 28 days) | 
| Number of participants who experience a clinically significant change in echocardiogram results |  | Day 1 to End of Cycle 3 (Day 28) (each treatment cycle = 28 days) | 
| Change from Baseline in diastolic blood pressure |  | From Baseline (study day 1), through 3 treatment cycles and up to Cycle Day 36 (±1) of the Post-Treatment Cycle (study day 120 (±1)) (each treatment cycle = 28 days) | 
| Change from Baseline in systolic blood pressure |  | From Baseline (study day 1), through 3 treatment cycles and up to Cycle Day 36 (±1) of the Post-Treatment Cycle (study day 120 (±1)) (each treatment cycle = 28 days) | 
| Change from Baseline in pulse rate |  | From Baseline (study day 1), through 3 treatment cycles and up to Cycle Day 36 (±1) of the Post-Treatment Cycle (study day 120 (±1)) (each treatment cycle = 28 days) |