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    Summary
    EudraCT Number:2015-003150-40
    Sponsor's Protocol Code Number:MIT-Es0001-C301
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-01-15
    Trial results View 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 ConcernedSweden - MPA
    A.2EudraCT number2015-003150-40
    A.3Full title of the trial
    A Multicenter, Open-label, Single-Arm Study to Evaluate the Contraceptive Efficacy and Safety of a Combined Oral Contraceptive Containing 15 mg Estetrol and 3 mg Drospirenone
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to investigate the efficacy and safety of a new combination oral contraceptive tablet. All participants will receive the same combination oral contraceptive.
    A.3.2Name or abbreviated title of the trial where available
    E4 FREEDOM
    A.4.1Sponsor's protocol code numberMIT-Es0001-C301
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEstetra SPRL
    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 SPRL
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEstetra SPRL
    B.5.2Functional name of contact pointSophie Ledant
    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+324349 28 22
    B.5.5Fax number+324349 28 21
    B.5.6E-mailClinical.Trials@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.3.2Product code 15 mg estetrol (E4) / 3 mg drospirenone (DRSP)
    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.3.10 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.3.9.2Current sponsor codeDRSP
    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 19.0
    E.1.2Level PT
    E.1.2Classification code 10030970
    E.1.2Term Oral contraception
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    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 contraceptive efficacy of 15 mg E4/3 mg DRSP using the Pearl Index in subjects aged 18 to 35 years inclusive at the time of screening.
    E.2.2Secondary objectives of the trial
    Efficacy:
    1. To evaluate the contraceptive efficacy of 15 mg E4/3 mg DRSP using the method failure Pearl Index and life-table analysis in subjects aged 18 to 35 years inclusive at the time of screening.
    2. To evaluate the contraceptive efficacy of 15 mg E4/3 mg DRSP using the Pearl Index, the method failure Pearl Index and life-table analysis in the overall study population.

    Other:
    3. To evaluate cycle control and bleeding pattern associated with 15 mg E4/3 mg DRSP.
    4. To evaluate general safety of 15 mg E4/3 mg DRSP.
    5. To evaluate the impact of 15 mg E4/4 mg DRSP on physical,
    psychological and social functioning and well being.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Endometrial Safety Sub-study

    167 Subjects

    Objective:
    To evaluate the endometrial safety using histological assessment of endometrial biopsy samples in a subset of subjects aged 18 to 50 years, inclusive at the time of screening.

    Endpoint:
    Change in endometrial histology from baseline to end of treatment in subjects having been treated for at least 10 complete cycles.
    E.3Principal inclusion criteria
    1. Heterosexually active female at risk for pregnancy and requesting contraception.
    2. Negative serum pregnancy test at subject enrollment.
    3. Aged 18 to 50 years (inclusive) at the time of signing the informed consent (IC).
    4. Willing to use the investigational product as the primary method of contraception for 13 consecutive cycles.
    5. Good physical and mental health on the basis of medical, surgical and gynecological history, physical examination, gynecological examination, clinical laboratory, and vital signs.
    6. Body mass index (BMI) below or equal to (≤) 35.0 kg/m2.
    7. Able to fulfill the requirements of the protocol and have indicated a willingness to participate in the study by providing written IC.
    8. Willing and able to complete he diaries and questionnaires.

    For the endometrial safety sub-study:
    9. Subset of subjects from the main study willing to participate in the endometrial safety sub-study by giving their consent for the endometrial safety sub-study.
    10. Endometrial biopsy taken at screening that reveals no abnormal results, i.e. presence of hyperplasia (simple or complex, with or without atypia) or presence of carcinoma.
    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 35 days
    2. Clinically relevant abnormal laboratory result at screening in the opinion of the investigator with an understanding of the central
    laboratory normal range
    3. Known hypersensitivity to any of the investigational product
    ingredients
    4. Currently pregnant or wth the intention to become pregnant during the course of the study
    5. Currently breastfeeding or before two spontaneous menstruations have occurred after cessation of breastfeeding prior to start of trial medication
    6. Less than 6 weeks since last delivery/2nd trimester of abortion and before spontaneous menstruation has occurred following a delivery or 2nd trimester of abortion
    7. Smoking if >= 35 years old at screening
    8. Dyslipoproteinemia requiring active treatment with antilipidemic agent
    9. Diabetes mellitus with vascular involvement or diabetes mellitus of more than 20 years duration
    10. Any arterial hypertension (controlled and uncontrolled) defined by blood pressure values
    11. Personal history of deep vein thrombosis or pulmonary embolism
    12. Current prolonged immobilization or major surgery with prolonged immobilization planned in the next 12 months
    13. Known inherited or acquired hypercoagulopathies or thrombogenic mutations
    14. Current treatment with anticoagulants
    15. Presence or history of arterial thromboembolism
    16. Complicated valvular heart disease
    17. History of pregnancy related cardiomyopathy or moderately or severely impaired cardiac function
    18. Systemic lupus erythematosus
    19. Presence or history of migraine with aura at any age or migraine without aura if >35 years old
    20. Within the past 6 months, has had undiagnosed (unexplained) abnormal vaginal bleeding or any abnormal bleeding that is expected to recur during the trial
    21. In case of Chlamydial or Gonococcal infection at screening, when no treatment initiated at subject enrollment
    22. Abnormal Pap test (written documentation of prior test at screening exam) based on provided criteria
    23. Presence of an undiagnosed breast mass
    24. Current symptomatic gallbladder disease
    25. History of COC related cholestasis
    26. Presence or history of severe hepatic disease as long as liver
    function values have not returned to normal
    27. Presence or history of pancreatitis if associated with hypertriglyceridemia
    28. Porphyria
    29. Presence or history of hepatocellular adenoma or malignant liver tumors
    30. Renal impairment
    31. Hyperkaliemia or presence of conditions that predispose to
    hyperkaliemia such as renal impairment, hepatic impairment, adrenal insufficiency and women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum
    potassium concentration
    32. History of organ transplantation within 5 years before screening or chronic disease potentially necessitating organ transplantation during the anticipated course of the study
    33. Presence or history of hormone-related malignancy
    34. History of non-hormone-related malignancy within 5 years before screening. Subjects with a non-melanoma skin cancer are allowed in the study
    35. Current regular use or regular use within 1 month prior to subject enrollment of drugs potentially triggering interactions with COCs
    36. Use of an injectable hormonal method of contraception within 10 months prior to screening of an injection with a 3-month duration, within 6 months prior to screening of an injection with a 2-month duration, within 3 months prior to screening of an injection with a 1-month duration
    37. History of alcohol or drug abuse (including laxatives) within 12 months prior to screening
    38. Any prior procedure, disease or condition that could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the investigational product
    39. Uncontrolled thyroid disorders
    40. Participation in another investigational drug clinical study within 1 month or have received an investigational drug within the last 3 months prior to study entry. Subjects who participated in an oral contraceptive study, using FDA/EU approved active ingredients, may be enrolled 2 months after completing the preceding study
    41. Sponsor, the Contract Research Organization (CRO) or Investigator's site personnel directly affiliated with this study
    42. Is judged by the Investigator to be unsuitable for any reason

    For the endometrial safety sub-study:
    43. Use of hormone-releasing intra-uterine system immediately prior to the study treatment
    44. Acute genital infection as diagnosed at the discretion of the
    Investigator
    E.5 End points
    E.5.1Primary end point(s)
    The number of on-treatment pregnancies as assessed by the Pearl Index in subjects aged 18 to 35 years, inclusive at the time of screening.
    E.5.1.1Timepoint(s) of evaluation of this end point
    From day 1 of treatment until 2 days after the last intake of investigational product (whether active or inactive tablet)
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints:
    1. The number of on-treatment pregnancies as assessed by the method failure Pearl Index and the cumulative pregnancy rate in subjects aged 18 to 35 years, inclusive at time of screening
    2. The number of on-treatment pregnancies as assessed by the Pearl Index, the method failure Pearl Index and the cumulative pregnancy rate in the overall study population.

    Other secondary endpoints:
    3. Cycle control and bleeding pattern evaluated based on vaginal
    bleeding information as recorded daily by the subjects in the diaries.
    4. Safety data in the overall study population obtained from routine laboratory parameters, vital signs and physical, gynecological and breast examinations and by number, frequency, type and intensity of adverse events (AEs) and serious adverse events (SAEs).
    5. Change from baseline to end of treatment in the different items of well-established questionnaires.
    E.5.2.1Timepoint(s) of evaluation of this end point
    From day 1 of treatment until 2 days after the last intake of investigational product (whether active or inactive tablet)
    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 Yes
    E.6.6Pharmacokinetic No
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA61
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Czech Republic
    Finland
    Germany
    Hungary
    Norway
    Poland
    Russian Federation
    Sweden
    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 months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months7
    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 No
    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) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1550
    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 Yes
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state204
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1350
    F.4.2.2In the whole clinical trial 1550
    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)
    No further treatment/supervision for patients who successfully finish.

    Women who discontinue to pursue pregnancy will be followed. They will be contacted every 6-8 weeks for a max. of 1 year. The date of the 1st spontaneous menstruation will be recorded. When pregnancy is reported or a new contraceptive method started, the date will be recorded and contact will stop.

    Patients who have an on-treatment pregnancy identified during the course of the study will be monitored to completion.
    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 Decision2016-03-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-02-10
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-04-26
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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