Clinical trial NCT04792385: Safety, Compliance and Pharmacokinetics of Estetrol Monohydrate/Drospirenone 15/3 mg in Post-menarchal Female Adolescents
Official title: A Multicenter, Open-label, Single-Arm Study to Evaluate the Safety, Compliance and Pharmacokinetics Associated With the Use of a Combined Oral Contraceptive Containing 15 mg Estetrol Monohydrate and 3 mg Drospirenone in Post-menarchal Female Adolescents for 6 Cycles
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Safety
Keywords: Estetrol
Drospirenone
Combined oral contraceptive
Oral contraception
Cycle control
Pharmacokinetics
Lead sponsor: Estetra
Sponsor class: INDUSTRY
First posted: 2021-03-11
Enrollment: 145
Sex: FEMALE
Minimum age (years): 12
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: To evaluate the safety, compliance, and pharmacokinetics profile of estetrol monohydrate (E4) 15 mg combined with drospirenone (DRSP) 3 mg in post-menarchal participants between the age of 12 and 17 years + 2 months.

Detailed description: This is a Phase 3, open-label, non-controlled study in healthy post-menarchal female participants who will be enrolled to receive once daily E4/DRSP 15/3 mg for six (6) 28-day cycles in a 24/4-day regimen (i.e. 24 days of active tablets followed by 4 days of placebo tablets \[4-day hormone-free interval\]). The study will include 6 visits:

At screening visit (Visit 1), informed consent will be signed by the participants and their parent(s) or legal representative(s) and the screening procedures will be performed. The site will also complete an Eligibility confirmation phone call to the participant after Visit 1. During the enrollment visit (Visit 2, between Days 12 and 19 of the pre-treatment cycle), eligibility criteria will be reviewed and the participant participation will be confirmed. Participants will be trained in the use of an electronic diary and will receive the study drug. A follow-up call will be performed after Visit 2, within 7 days following the first investigational product intake. Afterwards, the participants will attend 3 on-treatment visits at the clinical site \[between Days 14 and 21 of the Cycle 1(Visit 3), Cycle 3 (Visit 4), and Cycle 6 (Visit 5)\] and one visit after end of Cycle 6 (Visit 6).

For participants who consent to participate in a pharmacokinetics sub-study, blood samples for this sub-study will be taken at Visit 3 and Visit 5.

Adverse events will be followed throughout the study.

Eligibility criteria: Inclusion Criteria:

1. Post-menarchal female participant requesting combined oral contraceptive (COC) either for contraceptive or for therapeutic use.
2. Negative serum pregnancy test at screening and negative urine pregnancy test at enrollment.
3. Aged 12 to 17 years and 2 months (inclusive) \[Estonia-specific: 15 to 17 years and 2 months (inclusive)\] at the time of signing the informed consent.
4. Willing to use the investigational product for 6 consecutive cycles.
5. Good physical and mental health on the basis of medical, surgical and gynecological history, physical examination, clinical laboratory, and vital signs.
6. Body mass index (BMI) below or equal to the percentile 97 (P97) on the local pediatric BMI curves.
7. Able to fulfill the requirements of the protocol, undergo all study procedures including e-diary and questionnaires completion.
8. Having indicated the willingness to participate in the study by providing written assent.
9. Having parent(s) or legal representative(s) willing and able to provide written informed consent.

Exclusion Criteria:

1. For participants who are not using hormonal contraception at screening, a menstrual cycle length shorter than 21 days or longer than 45 days.
2. Currently using an injectable or a dermally implantable hormonal method of contraception.
3. Known hypersensitivity to any of the investigational product ingredients.
4. Currently pregnant or breastfeeding or with the intention to become pregnant during the course of the study.
5. Less than 6 weeks since last delivery/2nd trimester abortion and before spontaneous menstruation has occurred following a delivery or 2nd trimester abortion.
6. Any condition representing a contraindication / precaution to the use of COCs, including but not limited to:

   1. dyslipoproteinaemia,
   2. diabetes mellitus with vascular involvement (nephropathy, retinopathy, neuropathy, other),
   3. arterial hypertension (controlled and uncontrolled)
   4. personal or first-degree family history of deep vein thrombosis or pulmonary embolism,
   5. current or planned prolonged immobilization,
   6. known inherited or acquired hypercoagulopathies or thrombogenic mutations (e.g. Factor V Leiden mutation),
   7. current treatment with anticoagulants,
   8. presence or history of arterial thromboembolism,
   9. complicated valvular heart disease,
   10. systemic lupus erythematosus,
   11. presence or history of migraine with aura,
   12. symptomatic gallbladder disease,
   13. porphyria.
7. Within the past 6 months, undiagnosed (unexplained) abnormal vaginal bleeding, or any abnormal bleeding that could possibly recur during the study.
8. Presence or history of recurrent pelvic inflammatory disease.
9. Any clinically relevant lower genital tract infection (including gonorrhea and chlamydia infections) until successfully treated, in the opinion of the Investigator.
10. Presence or history of hepatic disease as long as liver function values have not returned to normal.
11. Renal impairment
12. Hyperkalemia or presence of conditions that predispose to hyperkalemia such as renal impairment, hepatic impairment, adrenal insufficiency and daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration (e.g. angiotensin-converting-enzyme (ACE) inhibitors, angiotensin-II receptor antagonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonist and non-steroidal anti-inflammatory drugs).
13. History of organ transplantation within 5 years before screening or chronic disease potentially necessitating organ transplantation during the anticipated course of the study.
14. Presence or history of sex hormone-related malignancy.
15. History of non-hormone-related malignancy within 5 years before screening.
16. Current regular use or regular use within 1 month prior to Visit 2 of drugs potentially triggering interactions with COCs including but not limited to:

    1. Cytochrome P450 3A4 (CYP 3A4) inducers: barbiturates, primidone, bosentan, felbamate, griseofulvin, oxcarbazepine, topiramate, carbamazepine, phenytoin, rifampicin, St John's wort (Hypericum perforatum L).
    2. CYP 3A4 inhibitors: azole antifungals excluding topical fluconazole, phenylbutazone, modafinil, cimetidine, verapamil, macrolides excluding azithromycin, diltiazem and grapefruit juice.
    3. Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors.
17. History of alcohol or drug abuse (including laxatives) within 12 months prior to screening.
18. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs.
19. Uncontrolled thyroid disorders.
20. Participation in another investigational drug clinical study within 1 month (30 days) or have received an investigational drug within the last month (30 days) prior to screening.
21. Sponsor, Contract Research Organization (CRO) or Investigator's site personnel directly affiliated with this study.
22. The participant is judged by the Investigator to be unsuitable for any reason.
23. \[Estonia-specific: Subjects who are at a gynecologist visit for the first time in their life may not sign the informed consent during this first visit.\]

Primary outcomes:
measure: Number of participants with treatment-emergent adverse events
timeFrame: From Cycle 1 to end of study (between Days 16 and 23 of Cycle 7) (each cycle is 28 days)
measure: Number of participants with treatment-emergent adverse events related to the investigational product
timeFrame: From Cycle 1 to end of study (between Days 16 and 23 of Cycle 7) (each cycle is 28 days)
measure: Number of participants with abnormal physical examination results
timeFrame: At Baseline and at the end of treatment (Cycle 6) (each cycle is 28 days)
measure: Number of participants with abnormal vital sign results
timeFrame: From Baseline to end of treatment (Cycle 6) (each cycle is 28 days)
measure: Number of participants with abnormal electrocardiogram (ECG) results
timeFrame: At Baseline and at the end of treatment (Cycle 6) (each cycle is 28 days)
measure: Number of participants with abnormal clinical laboratory assessment results
timeFrame: At Baseline and at the end of treatment (Cycle 6) (each cycle is 28 days)
Secondary outcomes:
measure: Percentage of compliance by cycle [Estonia-specific: and overall compliance]
timeFrame: At Cycles 1, 2, 3, 4, 5 ,6 (each cycle is 28 days)
measure: Mean plasma estetrol (E4) concentration
timeFrame: At Cycle 1 and at the end of treatment (Cycle 6) (each cycle is 28 days)
measure: Mean plasma drospirenone (DRSP) concentration
timeFrame: At Cycle 1 and at the end of treatment (Cycle 6) (each cycle is 28 days)
measure: Number of participants with unscheduled bleeding and/or spotting episodes
timeFrame: At Cycles 1,2, 3, 4, 5, 6 (each cycle is 28 days)
measure: Number of participants with absence of bleeding/spotting episodes
timeFrame: At Cycles 1,2, 3, 4, 5, 6 (each cycle is 28 days)
measure: Mean number of unscheduled bleeding and spotting days per cycle
timeFrame: At Cycles 1,2, 3, 4, 5, 6 (each cycle is 28 days)
measure: Mean number of scheduled bleeding and spotting days per cycle
timeFrame: At Cycles 1,2, 3, 4, 5, 6 (each cycle is 28 days)
measure: Change in the Score of the Menstrual Distress Questionnaire (MDQ) from baseline to Cycles 1, 3 and 6
timeFrame: At Baseline and at Cycles 1, 3 and 6 (each cycle is 28 days)
measure: Change in the Visual Analogue Scale (VAS) score of dysmenorrhea from baseline to Cycles 1, 3 and 6
timeFrame: At Baseline, Cycles 1, 3, and at the end of treatment (Cycle 6) (each cycle is 28 days)
measure: Change in the number of days with dysmenorrhea from baseline to Cycles 1, 3 and 6
timeFrame: At Baseline, Cycles 1, 3, and at the end of treatment (Cycle 6) (each cycle is 28 days)
measure: Number of participants who will use rescue medication for dysmenorrheal pain from baseline to Cycles 1, 3 and 6
timeFrame: At Baseline, Cycles 1, 3, and at the end of treatment (Cycle 6) (each cycle is 28 days)
measure: Change in Health Questionnaire for children and Young People (KIDSCREEN-27 questionnaire) from baseline to Cycles 1, 3 and 6
timeFrame: At Baseline, Cycles 1, 3, and at the end of treatment (Cycle 6) (each cycle is 28 days)
measure: Change in sex-hormone binding globulin (SHBG) level from baseline to Cycle 6
timeFrame: At Baseline and at the end of treatment (Cycle 6) (each cycle is 28 days)
measure: Change in Activated protein C resistance endogenous thrombin potential based (APCr [ETP based]) level from baseline to Cycle 6
timeFrame: At Baseline and at the end of treatment (Cycle 6) (each cycle is 28 days)
Other outcomes:
Locations:
city: Parnu
country: Estonia
facility: KVL Medical Office/KVL Arstikabinet
city: Tallinn
country: Estonia
facility: East-Tallinn Central Hospital
city: Tallinn
country: Estonia
facility: Sexual Health Clinic, Tallinn
city: Tartu
country: Estonia
facility: Sexual Health Clinic, Tartu
city: Helsinki
country: Finland
facility: VL-Medi Oy
city: Kuopio
country: Finland
facility: Lääkärikeskus Mehiläinen
city: Oulu
country: Finland
facility: Lääkärikeskus Gyneko
city: Batumi
country: Georgia
facility: Estetra Study Site
city: Tbilisi
country: Georgia
facility: Estetra Study Site
city: Tbilisi
country: Georgia
facility: Estetra Study Site
city: Tbilisi
country: Georgia
facility: Estetra Study Site
city: Daugavpils
country: Latvia
facility: A. Krumpane practice
city: Riga
country: Latvia
facility: Childrens Clinical University Hospital
city: Bialystok
country: Poland
facility: Estetra Study Site
city: Katowice
country: Poland
facility: Estetra Study Site
city: Lublin
country: Poland
facility: Estetra Study Site
city: Ostrowiec Świętokrzyski
country: Poland
facility: Estetra Study Site
city: Poznań
country: Poland
facility: Estetra Study Site
city: Raszyn
country: Poland
facility: Estetra Study Site
city: Wroclaw
country: Poland
facility: Estetra Study Site
city: Stockholm
country: Sweden
facility: Akardo Medsite at Sturebadet Health Care
city: Stockholm
country: Sweden
facility: Karolinska University, Department of Gynecology and Reproductive Medicine
city: Stockholm
country: Sweden
facility: Karolinska University, WHO Center
Study officials:
affiliation: Estetra
name: Estetra
role: STUDY_DIRECTOR
References: