xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT06028555</url>
    </required_header>
    <id_info>
      <org_study_id>ZEG2022_02</org_study_id>
      <nct_id>NCT06028555</nct_id>
    </id_info>
    <brief_title>International Active Surveillance Study: Native Estrogen Estetrol (E4) Safety Study</brief_title>
    <acronym>INAS-NEES</acronym>
    <official_title>International Active Surveillance Study: Native Estrogen Estetrol (E4) Safety Study</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Center for Epidemiology and Health Research, Germany</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Estetra SRL</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Center for Epidemiology and Health Research, Germany</source>
    <brief_summary>
      <textblock>
        Multinational, comparative, prospective, active surveillance study that follows two cohorts.&#xD;
  &#xD;
        The primary objective of the study is to characterize and compare the risks of&#xD;
        E4/Drospirenone (DRSP) with levonorgestrel-containing combined oral contraceptives (EE/LNG)&#xD;
        in a study population that is representative of the actual users of these preparations. The&#xD;
        main clinical outcome of interest is venous thromboembolism (VTE), specifically deep venous&#xD;
        thrombosis (DVT) and pulmonary embolism (PE). Secondary objectives include measuring the&#xD;
        occurrence of unintended pregnancy, assessing the risk of arterial thromboembolism (ATE),&#xD;
        describing the drug utilization pattern, describing the baseline risk profile for VTE and&#xD;
        ATE, and investigating outcomes associated with foetal exposure to E4/DRSP.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Rationale and background:&#xD;
  &#xD;
        The combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP)&#xD;
        (E4/DRSP) is a novel oral contraceptive containing a fixed dose of E4 (14.2 mg) and DRSP (3&#xD;
        mg). E4 is a natural oestrogen only produced during pregnancy by the foetal liver. When&#xD;
        combined with the progestin DRSP, ovulation is inhibited. The E4/DRSP combination may have&#xD;
        less impact on hepatic and haemostasis parameters in comparison to combinations of ethinyl&#xD;
        estradiol (EE) and levonorgestrel (LNG) or EE and DRSP. Yet, it is unknown whether this&#xD;
        regimen has an impact on the cardiovascular risk associated with the use of hormonal&#xD;
        contraceptives.&#xD;
  &#xD;
        Study design:&#xD;
  &#xD;
        Multinational, comparative, prospective, active surveillance study that follows two cohorts.&#xD;
        The cohorts consist of new users (starters and restarters ) of two different groups of&#xD;
        hormonal contraceptives: E4/DRSP and EE/LNG. The study is taking a non-interventional&#xD;
        approach to provide comprehensive information on these treatments in a routine clinical&#xD;
        practice setting. Study participants will be enrolled via an international network of&#xD;
        COC-prescribing health care professionals (HCPs) and then followed up for one to two years.&#xD;
        All outcomes of interest will be captured by direct contact with the study participants.&#xD;
        Reported outcomes of interest will be validated via attending physicians and relevant source&#xD;
        documents. The classification of outcomes of interest into 'confirmed' and 'not confirmed'&#xD;
        will be verified by blinded independent adjudication.&#xD;
  &#xD;
        Population:&#xD;
  &#xD;
        Approximately 101,000 study participants (50,500 E4/DRSP and 50,500 EE/LNG new users) will be&#xD;
        recruited via a network of COC-prescribing health care professionals in Europe, the USA, and&#xD;
        Brazil. All new users (starters and restarters) prescribed E4/DRSP or EE/LNG who are willing&#xD;
        to participate may be eligible for enrolment in the study.&#xD;
  &#xD;
        Data sources:&#xD;
  &#xD;
        This is a field study that entails exposure to COCs and the occurrence of clinical outcomes&#xD;
        of interest by completing questionnaires at baseline (study entry) and follow-up (at 6-, 12-,&#xD;
        18-, and 24-months post-baseline), in addition to potential confounding factors and potential&#xD;
        effect modifiers. Medical confirmation of the occurrence of a clinical outcome of interest&#xD;
        will be sought from the attending HCP and/or study participant (e.g., diagnostic report,&#xD;
        discharge letter).&#xD;
  &#xD;
        Study size:&#xD;
  &#xD;
        The study is sufficiently powered to show non-inferiority of E4/DRSP compared to EE/LNG&#xD;
        assuming that the VTE risk among E4/DRSP users is not higher than among EE/LNG users. For&#xD;
        this purpose, a total of 101,000 women (50,500 E4/DRSP users and 50,500 EE/LNG users) will be&#xD;
        recruited and followed up taking into account treatment adherence, treatment&#xD;
        stopping/switching, and lost to follow-up (LTFU)/dropout.&#xD;
  &#xD;
        Data analysis:&#xD;
  &#xD;
        The final analyses will include both an &quot;as-treated&quot; (AT) and an &quot;intention-to-treat&quot; (ITT)&#xD;
        analysis. All eligible women will be assigned to the ITT and AT population at baseline. Only&#xD;
        women with follow-up information will be considered for longitudinal analysis. Women who&#xD;
        never started their prescribed baseline medication will be considered in the ITT analysis but&#xD;
        excluded from the AT analysis. Population characteristics, e.g., socio-economic factors,&#xD;
        parameters of reproductive, contraceptive history, and medical history, will be summarized&#xD;
        descriptively and used to estimate the probability of treatment differences. Inverse&#xD;
        probability of treatment weighting combined with time-to-event analysis of VTE will be&#xD;
        carried out based on the extended Cox model to calculate hazard ratios (HR) with 95%&#xD;
        confidence intervals. The null hypothesis to be tested is HR of VTE ≥1.5 (i.e., the VTE HR&#xD;
        for E4/DRSP vs. EE/LNG is higher than or equal to 1.5). The alternative hypothesis is HR of&#xD;
        VTE &lt;1.5.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">June 28, 2023</start_date>
    <completion_date type="Anticipated">October 31, 2028</completion_date>
    <primary_completion_date type="Anticipated">October 31, 2028</primary_completion_date>
    <study_type>Observational</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <observational_model>Cohort</observational_model>
      <time_perspective>Prospective</time_perspective>
    </study_design_info>
    <primary_outcome>
      <measure>Incidence rate of Venous Thromboembolism (VTE)</measure>
      <time_frame>Up to 24 months post baseline</time_frame>
      <description>Occurrence (or absence) of a new (non-recurrent) confirmed Deep Venous Thrombosis (DVT) of the lower extremities (International Classification of Diseases, 10th revision (ICD-10) codes: I80.1 and I80.2) and,&#xD;
  Occurrence (or absence) of a new (non-recurrent) confirmed Pulmonary Embolism (PE) (ICD-10 codes: I26.0 and I26.9)</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Incidence rate of all VTEs, including thromboses of the renal, mesenteric, portal, cerebral and retinal veins</measure>
      <time_frame>Up to 24 months post baseline</time_frame>
      <description>The occurrence (or absence) of a new (non-recurrent) confirmed VTE. A sensitivity analysis will be done for the ICD-10 code I80.3</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence rate of Arterial Thromboembolism (ATE), including acute myocardial infarction (AMI) and cerebrovascular accidents (CVA)</measure>
      <time_frame>Up to 24 months post baseline</time_frame>
      <description>The occurrence (or absence) of new (non-recurrent) confirmed ATE, AMI, and CVA: ICD-10 code I21; CVA: ICD-10 code: I24.9, G45.*, I61.*, I63.1, I63.2, I63.3, I63.4, I63.5, I63.8, I63.9</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incident rate of unintended pregnancy</measure>
      <time_frame>Up to 24 months post baseline</time_frame>
      <description>The occurrence of unintended pregnancy</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incident rate of neonatal malformations associated with foetal exposure to E4/DRSP and EE/LNG in E4/DRSP users and users of EE/LNG</measure>
      <time_frame>Up to 24 months post baseline</time_frame>
      <description>Occurrence of major congenital malformations, according to classification by the European network of population-based registries for the epidemiological surveillance of congenital anomalies (EUROCAT), as reported during follow-up among pregnancies observed&#xD;
  Stillbirth (defined as foetal death with a gestational age ≥20 weeks)&#xD;
  Neonatal death (defined as deaths occurring among live births during the first 28 completed days of life)&#xD;
  Spontaneous/elective abortion (defined as a loss of pregnancy at a gestational age &lt;20 weeks)&#xD;
  Termination of pregnancy for foetal anomaly (TOPFA [where prenatal diagnosis was made of malformation in a live foetus and the pregnancy was then terminated])&#xD;
  Preterm delivery (defined as delivery strictly before 37 completed weeks of gestation)&#xD;
  Low birth weight (defined as a birth weight &lt;2,500g)&#xD;
  Small for gestational age infants</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Compare drug utilization pattern between users of both cohorts</measure>
      <time_frame>Up to 24 months post baseline</time_frame>
      <description>The time-varying exposure to COCs observed from study entry through the follow-up period, with dates and duration of each contraceptive prescription.</description>
    </secondary_outcome>
    <number_of_groups>2</number_of_groups>
    <enrollment type="Anticipated">101000</enrollment>
    <condition>Contraception</condition>
    <condition>Birth Control</condition>
    <arm_group>
      <arm_group_label>Estetrol/drospirenone (E4/DRSP)</arm_group_label>
      <description>Users: Starters and re-starters</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Ethinyl estradiol/levonorgestrel (EE/LNG)</arm_group_label>
      <description>Users: Starters and re-starters</description>
    </arm_group>
    <eligibility>
      <study_pop>
        <textblock>
          Approximately 50,500 E4/ DRSP users and 50,500 EE/LNG new users, including adolescents&#xD;
          (below the age of 18 years eligible based on local legislation) will be recruited via&#xD;
          recruitment centres.&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Non-Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
          New users of E4/DRSP New users of EE/LNG Germany: only recruitment of study participants&#xD;
          who are prescribed the COC within on-label use&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
          -&#xD;
        </textblock>
      </criteria>
      <gender>Female</gender>
      <minimum_age>N/A</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Klaas Heinemann, Dr.</last_name>
      <role>Principal Investigator</role>
      <affiliation>ZEG Berlin GmbH</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Ulrike Amann-Gassner, Dr.</last_name>
      <phone>+49 30 945 101 20</phone>
      <email>u.amann-gassner@zeg-berlin.de</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Silke Zimmermann, Dr.</last_name>
      <phone>+49 30 945 101 20</phone>
      <email>s.zimmermann@zeg-berlin.de</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Berlin Center for Epidemiology and Health Research</name>
        <address>
          <city>Berlin</city>
          <zip>10115</zip>
          <country>Germany</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Ulrike Amann-Gassner, Dr.</last_name>
        <phone>+49 172 3135426</phone>
        <email>u.amann-gassner@zeg-berlin.de</email>
      </contact>
    </location>
    <location_countries>
      <country>Germany</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 4, 2023</study_first_submitted>
    <study_first_submitted_qc>August 31, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 8, 2023</study_first_posted>
    <last_update_submitted>August 31, 2023</last_update_submitted>
    <last_update_submitted_qc>August 31, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 8, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Center for Epidemiology and Health Research, Germany</investigator_affiliation>
      <investigator_full_name>Klaas Heinemann, MD, PhD</investigator_full_name>
      <investigator_title>Managing director</investigator_title>
    </responsible_party>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT06028555
  org study id: ZEG2022_02
  nct id: NCT06028555
  lead sponsor: 
  collaborator: 
  Multinational, comparative, prospective, active surveillance study that follows two cohorts.
  
        The primary objective of the study is to characterize and compare the risks of
        E4/Drospirenone (DRSP) with levonorgestrel-containing combined oral contraceptives (EE/LNG)
        in a study population that is representative of the actual users of these preparations. The
        main clinical outcome of interest is venous thromboembolism (VTE), specifically deep venous
        thrombosis (DVT) and pulmonary embolism (PE). Secondary objectives include measuring the
        occurrence of unintended pregnancy, assessing the risk of arterial thromboembolism (ATE),
        describing the drug utilization pattern, describing the baseline risk profile for VTE and
        ATE, and investigating outcomes associated with foetal exposure to E4/DRSP.
  Rationale and background:
  
        The combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP)
        (E4/DRSP) is a novel oral contraceptive containing a fixed dose of E4 (14.2 mg) and DRSP (3
        mg). E4 is a natural oestrogen only produced during pregnancy by the foetal liver. When
        combined with the progestin DRSP, ovulation is inhibited. The E4/DRSP combination may have
        less impact on hepatic and haemostasis parameters in comparison to combinations of ethinyl
        estradiol (EE) and levonorgestrel (LNG) or EE and DRSP. Yet, it is unknown whether this
        regimen has an impact on the cardiovascular risk associated with the use of hormonal
        contraceptives.
  
        Study design:
  
        Multinational, comparative, prospective, active surveillance study that follows two cohorts.
        The cohorts consist of new users (starters and restarters ) of two different groups of
        hormonal contraceptives: E4/DRSP and EE/LNG. The study is taking a non-interventional
        approach to provide comprehensive information on these treatments in a routine clinical
        practice setting. Study participants will be enrolled via an international network of
        COC-prescribing health care professionals (HCPs) and then followed up for one to two years.
        All outcomes of interest will be captured by direct contact with the study participants.
        Reported outcomes of interest will be validated via attending physicians and relevant source
        documents. The classification of outcomes of interest into 'confirmed' and 'not confirmed'
        will be verified by blinded independent adjudication.
  
        Population:
  
        Approximately 101,000 study participants (50,500 E4/DRSP and 50,500 EE/LNG new users) will be
        recruited via a network of COC-prescribing health care professionals in Europe, the USA, and
        Brazil. All new users (starters and restarters) prescribed E4/DRSP or EE/LNG who are willing
        to participate may be eligible for enrolment in the study.
  
        Data sources:
  
        This is a field study that entails exposure to COCs and the occurrence of clinical outcomes
        of interest by completing questionnaires at baseline (study entry) and follow-up (at 6-, 12-,
        18-, and 24-months post-baseline), in addition to potential confounding factors and potential
        effect modifiers. Medical confirmation of the occurrence of a clinical outcome of interest
        will be sought from the attending HCP and/or study participant (e.g., diagnostic report,
        discharge letter).
  
        Study size:
  
        The study is sufficiently powered to show non-inferiority of E4/DRSP compared to EE/LNG
        assuming that the VTE risk among E4/DRSP users is not higher than among EE/LNG users. For
        this purpose, a total of 101,000 women (50,500 E4/DRSP users and 50,500 EE/LNG users) will be
        recruited and followed up taking into account treatment adherence, treatment
        stopping/switching, and lost to follow-up (LTFU)/dropout.
  
        Data analysis:
  
        The final analyses will include both an "as-treated" (AT) and an "intention-to-treat" (ITT)
        analysis. All eligible women will be assigned to the ITT and AT population at baseline. Only
        women with follow-up information will be considered for longitudinal analysis. Women who
        never started their prescribed baseline medication will be considered in the ITT analysis but
        excluded from the AT analysis. Population characteristics, e.g., socio-economic factors,
        parameters of reproductive, contraceptive history, and medical history, will be summarized
        descriptively and used to estimate the probability of treatment differences. Inverse
        probability of treatment weighting combined with time-to-event analysis of VTE will be
        carried out based on the extended Cox model to calculate hazard ratios (HR) with 95%
        confidence intervals. The null hypothesis to be tested is HR of VTE ≥1.5 (i.e., the VTE HR
        for E4/DRSP vs. EE/LNG is higher than or equal to 1.5). The alternative hypothesis is HR of
        VTE <1.5.
  observational model: Cohort
  time perspective: Prospective
  measure: Incidence rate of Venous Thromboembolism (VTE)
  time frame: Up to 24 months post baseline
  description: Occurrence (or absence) of a new (non-recurrent) confirmed Deep Venous Thrombosis (DVT) of the lower extremities (International Classification of Diseases, 10th revision (ICD-10) codes: I80.1 and I80.2) and,
  Occurrence (or absence) of a new (non-recurrent) confirmed Pulmonary Embolism (PE) (ICD-10 codes: I26.0 and I26.9)
  measure: Incidence rate of all VTEs, including thromboses of the renal, mesenteric, portal, cerebral and retinal veins
  time frame: Up to 24 months post baseline
  description: The occurrence (or absence) of a new (non-recurrent) confirmed VTE. A sensitivity analysis will be done for the ICD-10 code I80.3
  measure: Incidence rate of Arterial Thromboembolism (ATE), including acute myocardial infarction (AMI) and cerebrovascular accidents (CVA)
  time frame: Up to 24 months post baseline
  description: The occurrence (or absence) of new (non-recurrent) confirmed ATE, AMI, and CVA: ICD-10 code I21; CVA: ICD-10 code: I24.9, G45.*, I61.*, I63.1, I63.2, I63.3, I63.4, I63.5, I63.8, I63.9
  measure: Incident rate of unintended pregnancy
  time frame: Up to 24 months post baseline
  description: The occurrence of unintended pregnancy
  measure: Incident rate of neonatal malformations associated with foetal exposure to E4/DRSP and EE/LNG in E4/DRSP users and users of EE/LNG
  time frame: Up to 24 months post baseline
  description: Occurrence of major congenital malformations, according to classification by the European network of population-based registries for the epidemiological surveillance of congenital anomalies (EUROCAT), as reported during follow-up among pregnancies observed
  Stillbirth (defined as foetal death with a gestational age ≥20 weeks)
  Neonatal death (defined as deaths occurring among live births during the first 28 completed days of life)
  Spontaneous/elective abortion (defined as a loss of pregnancy at a gestational age <20 weeks)
  Termination of pregnancy for foetal anomaly (TOPFA [where prenatal diagnosis was made of malformation in a live foetus and the pregnancy was then terminated])
  Preterm delivery (defined as delivery strictly before 37 completed weeks of gestation)
  Low birth weight (defined as a birth weight <2,500g)
  Small for gestational age infants
  measure: Compare drug utilization pattern between users of both cohorts
  time frame: Up to 24 months post baseline
  description: The time-varying exposure to COCs observed from study entry through the follow-up period, with dates and duration of each contraceptive prescription.
  arm group label: Estetrol/drospirenone (E4/DRSP)
  description: Users: Starters and re-starters
  arm group label: Ethinyl estradiol/levonorgestrel (EE/LNG)
  description: Users: Starters and re-starters
  study pop: 
  sampling method: Non-Probability Sample
  criteria: 
  gender: Female
  minimum age: N/A
  maximum age: N/A
  healthy volunteers: Accepts Healthy Volunteers
  last name: Klaas Heinemann, Dr.
  role: Principal Investigator
  affiliation: ZEG Berlin GmbH
  last name: Ulrike Amann-Gassner, Dr.
  phone: +49 30 945 101 20
  email: u.amann-gassner@zeg-berlin.de
  last name: Silke Zimmermann, Dr.
  phone: +49 30 945 101 20
  email: s.zimmermann@zeg-berlin.de
  facility: 
  status: Recruiting
  contact: 
  country: Germany
  responsible party type: Principal Investigator
  investigator affiliation: Center for Epidemiology and Health Research, Germany
  investigator full name: Klaas Heinemann, MD, PhD
  investigator title: Managing director