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    Summary
    EudraCT Number:2019-003002-27
    Sponsor's Protocol Code Number:MIT-Es001-C303
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2022-05-23
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2019-003002-27
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to investigate the safety, compliance and pharmacokinetics of a combined oral contraceptive in teenage girls who have a menstrual cycle.
    A.4.1Sponsor's protocol code numberMIT-Es001-C303
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/359/2016
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEstetra SRL
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEstetra SRL
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEstetra SRL
    B.5.2Functional name of contact pointSarah Kaddouri
    B.5.3 Address:
    B.5.3.1Street AddressRue Saint Georges 5-7
    B.5.3.2Town/ cityLiège
    B.5.3.3Post code4000
    B.5.3.4CountryBelgium
    B.5.4Telephone number+3243492822
    B.5.5Fax number+3243492821
    B.5.6E-mailskaddouri@mithra.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEstelle
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEstetrol
    D.3.9.1CAS number 15183-37-6
    D.3.9.2Current sponsor codeE4
    D.3.9.3Other descriptive nameEstetrol monohydrate
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDrospirenone
    D.3.9.1CAS number 67392-87-4
    D.3.9.3Other descriptive nameDROSPIRENONE
    D.3.9.4EV Substance CodeSUB06413MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Contraception
    E.1.1.1Medical condition in easily understood language
    Contraception
    E.1.1.2Therapeutic area Body processes [G] - Reproductive physiologi cal processes [G08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10030971
    E.1.2Term Oral contraceptive
    E.1.2System Organ Class 100000004865
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety profile of E4/DRSP 15/3 mg in post-menarchal subjects aged ≥ 15 and ≤ 17 years and 2 months (inclusive) at the time of signing the IC.
    E.2.2Secondary objectives of the trial
    1. To assess the compliance to E4/DRSP 15/3 mg (24 active/4 placebo).
    2. To assess the PK trough levels of E4 and DRSP at steady state.
    3. To assess the cycle control and bleeding pattern associated with E4/DRSP 15/3 mg.
    4. To assess the effect of E4/DRSP 15/3 mg in relieving symptoms of primary dysmenorrhea.
    5. To assess the effect of E4/DRSP 15/3 mg on general health, well-being, physical, social and mental functioning.
    6. To assess the effect of E4/DRSP 15/3 mg on hemostasis parameters.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacokinetics sub-study

    Among subjects enrolled in the study, 30 are planned for enrollment in the PK sub-study.

    The objective of the sub-study is to analyze the pharmacokinetic parameters of E4/DRSP 15/3 mg. Enrollment will be sequential: the first 30 subjects meeting the specific criteria for enrollment in the pharmacokinetic sub-study and willing to participate will be enrolled.
    E.3Principal inclusion criteria
    1. Post-menarchal female subject requesting COC either for contraceptive or for therapeutic use.
    2. Negative serum pregnancy test at screening and negative urine pregnancy test at enrollment.
    3. Aged ≥ 15 and ≤ 17 years and 2 months (inclusive) at the time of signing the IC.
    4. Willing to use the IP 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.

    Additional inclusion criteria for pharmacokinetics sub-study :
    1. BMI below or equal to the percentile 95 (P95) on the local pediatric BMI curves.
    2. Subjects are aware and willing to comply with the following restrictions prior to blood sampling for pharmacokinetic assessment:
    a. The subject should be fasting for 8 hours minimum at the time of blood sampling.
    b. On days when blood sampling for pharmacokinetics is scheduled, the subject should not take the investigational product prior to the blood sampling.
    c. The subject should not smoke during the 30 minutes prior to the blood sampling.
    d. The subject should not perform any physical activity during the 2 hours prior to the blood sampling.
    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 IC.
    E.4Principal exclusion criteria
    1. For subjects 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 IP 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.
    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 (glomerular filtration rate (GFR) < 60 mL/min/1.73m²).
    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.
    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. The Investigator should exercise medical judgment in consideration of the subject’s medical history and/or clinical or laboratory evidence of any of the following:
    a. cystic fibrosis, celiac disease, inflammatory bowel disease, gastritis, ulcers, gastrointestinal or rectal bleeding,
    b. major gastrointestinal tract surgery (this does not include history of appendectomy),
    c. pancreatic injury or pancreatitis,
    d. liver disease or liver injury as indicated by abnormal liver function tests,
    e. impaired renal function if considered as clinically significant,
    f. abnormal urinary constituents (e.g. albumin if considered as clinically significant).
    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 subject is judged by the Investigator to be unsuitable for any reason.
    E.5 End points
    E.5.1Primary end point(s)
    The number, frequency, type, relatedness, and intensity of treatment-emergent adverse events (TEAEs) reported by study subjects.

    In addition to TEAEs reported by the subjects, safety data will be obtained from routine laboratory parameters, vital signs, electrocardiogram, and physical examinations.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After initiation of IP treatment, until Visit 6
    E.5.2Secondary end point(s)
    1. Overall compliance and treatment compliance per cycle.
    2. Pre-dose plasma concentrations of E4 and DRSP measured at Cycles 1, 3, and 6.
    3. Bleeding/spotting patterns based on vaginal bleeding/spotting information recorded daily by the subjects in the e-diary.
    4. Change in the Visual Analogue Scale (VAS) score of dysmenorrhea and, in the number of days with dysmenorrhea and use of rescue medication for dysmenorrheal pain from baseline (pre-treatment cycle) to Cycles 1, 3 and 6.
    5. Change in the Health Questionnaire for Children and Young People KIDSCREEN-27 (KIDSCREEN-27) and Menstrual Distress Questionnaire (MDQ) Form C (Cycle) scores from baseline (Cycle 1 just prior to the first IP intake) to Cycles 1, 3 and 6.
    6. Change in sex hormone binding globulin (SHBG) and Activated protein C resistance endogenous thrombin potential based (APCr [ETP based]) levels from baseline (pre-treatment cycle) to Cycle 6.
    E.5.2.1Timepoint(s) of evaluation of this end point
    After initiation of IP treatment, until Visit 6
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 100
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 100
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients No
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception Yes
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Adolescents aged ≥ 15 and ≤ 17 years and 2 months (inclusive)
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state51
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 100
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Contraceptive counselling
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-08-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-05-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-11-24
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