Clinical trial NCT03091595: E4/DRSP Ovarian Function Inhibition Study
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prevention of Pregnancy
Lead sponsor: Estetra
Sponsor class: INDUSTRY
First posted: 2017-03-27
Enrollment: 82
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Proportion of subjects with ovarian inhibition at treatment Cycle 1
timeFrame: 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).
measure: Proportion of subjects with ovarian inhibition at treatment Cycle 3
timeFrame: 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 outcomes:
measure: Serum level of luteinizing hormone (LH)
timeFrame: 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)
measure: Serum level of follicle stimulating hormone (FSH)
timeFrame: 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)
measure: Serum level of estradiol (E2)
timeFrame: 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)
measure: Serum level of progesterone (P)
timeFrame: 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)
measure: Maximum endometrial thickness
timeFrame: 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)
measure: Mean diameter of the largest follicle
timeFrame: Day 3 to Day 24 of Post-Treatment Cycle
measure: Number of participants who experience at least one Treatment-Emergent Adverse Event (TEAE)
timeFrame: Day 1 to Follow-Up Visit (+ 30 days)
measure: Number of participants who experience pregnancy during treatment
timeFrame: Cycle 1 Day 1 to Follow-Up Visit (+ 30 days) (each treatment cycle = 28 days)
measure: Number of participants who experience a clinically significant change in physical examination results
timeFrame: Day 1 to End of Follow-Up Visit (+ 30 Days)
measure: Number of participants who experience a clinically significant change in gynecological examination results
timeFrame: Day 1 to End of Follow-Up Visit (+ 30 Days)
measure: Number of participants who experience a clinically significant change in clinical laboratory results
timeFrame: Day 1 to End of Follow-Up Visit (+ 30 Days)
measure: Number of participants who experience a clinically significant change in electrocardiogram (ECG) results
timeFrame: Day 1 to End of Cycle 3 (Day 28) (each treatment cycle = 28 days)
measure: Number of participants who experience a clinically significant change in echocardiogram results
timeFrame: Day 1 to End of Cycle 3 (Day 28) (each treatment cycle = 28 days)
measure: Change from Baseline in diastolic blood pressure
timeFrame: 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)
measure: Change from Baseline in systolic blood pressure
timeFrame: 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)
measure: Change from Baseline in pulse rate
timeFrame: 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)
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: Dinox BV
Study officials:
affiliation: Dinox BV
name: Christine Klipping
role: PRINCIPAL_INVESTIGATOR
References: