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    Summary
    EudraCT Number:2020-004828-42
    Sponsor's Protocol Code Number:ATOS-016R
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-10-26
    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 ConcernedSweden - MPA
    A.2EudraCT number2020-004828-42
    A.3Full title of the trial
    A Phase 2, Randomized, Double-blinded, Placebo - controlled, Dose Response Study of Oral (Z)-endoxifen in Premenopausal Women with Measurable Breast Density
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2, Randomized, Double-blinded, Placebo - controlled, Dose Response Study of Oral (Z)-endoxifen in Premenopausal Women with Measurable Breast Density
    A.4.1Sponsor's protocol code numberATOS-016R
    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 SponsorAtossa Therapeutics Inc.
    B.1.3.4CountryUnited States
    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 supportAtossa Therapeutics Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAtossa Therapeutics Inc.
    B.5.2Functional name of contact pointHeather Fraser, VP Clinical
    B.5.3 Address:
    B.5.3.1Street Address107 Spring Street
    B.5.3.2Town/ citySeattle
    B.5.3.3Post codeWA 98104
    B.5.3.4CountryUnited States
    B.5.6E-mailheather.fraser@atossainc.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 name(Z)-endoxifen
    D.3.4Pharmaceutical form Capsule
    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 INN(Z)-Endoxifen
    D.3.9.1CAS number 112093-28-4
    D.3.9.3Other descriptive name4_[(Z)-1-[4-[2-(methylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol
    D.3.9.4EV Substance CodeSUB193570
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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.IMP: 2
    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 name(Z)-endoxifen
    D.3.4Pharmaceutical form Capsule
    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 INN(Z)-Endoxifen
    D.3.9.1CAS number 112093-28-4
    D.3.9.3Other descriptive name4_[(Z)-1-[4-[2-(methylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol
    D.3.9.4EV Substance CodeSUB193570
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 placeboCapsule
    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
    The mammographic density reduction in healthy women
    E.1.1.1Medical condition in easily understood language
    Mammographic breast tissue density reduction
    E.1.1.2Therapeutic area Body processes [G] - Physiological processes [G07]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the dose-response relationship of daily oral (Z) endoxifen by measurement of mammographic breast density area (cm2) reduction.
    E.2.2Secondary objectives of the trial
    The secondary objective of this study is to assess the safety and tolerability of daily oral (Z)-endoxifen.

    The exploratory objectives of this study are:
    -To determine if daily oral (Z)-endoxifen for a maximum of six months results in at least a one category reduction in the BI-RADS® scale
    -To determine the durability of (Z)-endoxifen on breast density response at 24 months post standard of care screening mammogram (difference between end of treatment and 24-month breast density)
    -To evaluate the levels of endoxifen over time and correlate endoxifen values to density change
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects
    2.Attending the national mammography screening program. The screening mammogram should have been performed within 3 month of study inclusion.
    3.Mammographic density assessed as BI-RADS® score B, C or D.
    4.40-55 years old premenopausal women (defined as having at least one menstruation during the prior 12 months; women whose status is questionable in the mind of the PI will have an FSH test to confirm (FSH<26 U/L).
    5.Women of childbearing potential using a highly effective method of birth control throughout the study period and willing to comply with monthly pregnancy testing.
    E.4Principal exclusion criteria
    1.Any previous diagnosis of breast cancer, including carcinoma in situ, or any other cancer. Non-melanoma skin cancer and in situ cancer of the cervix are not exclusion criteria.
    2.A history of breast surgery, e.g., reduction or enlargement, which might affect mammographic density measurements.
    3.Mammographic BI-RADS® malignancy code ≥3 at baseline.
    4.Previous treatment with an anti-oestrogen, including experimental drug studies (e.g., Karma CREME, Karisma-1 or Karisma-2).
    5.A history of thromboembolic disease such as embolus, deep vein thrombosis, stroke, TIA (transient ischemic attack) or myocardial infarction.
    6.Moderate hypertension at baseline defined as systolic pressure higher than 160 mm Hg or diastolic higher than 100 mm Hg.
    7.BMI > 30.
    8.Known APC (activated protein C) resistance, an inherited coagulation disorder.
    9.Prescribed and regular use of anticoagulants (defined as substances included in group B01A in the ATC-system).
    10.Allergy to endoxifen or any of its components.
    11.Agents that have the potential to decrease endoxifen levels through increased metabolic clearance:
    a.Certain anti-epileptic therapies (carbamazepine, fenytoin, fenobarbital, lamotrigine)
    b.Certain antibiotics (rifamycins)
    c.St John’s wort (in Swedish: johannesört)
    d.Certain HIV medications (efavirenz, ritonavir)
    12. Current, or within prior 6 months, use of hormone replacement therapy to treat menopausal symptoms
    13. Women who have an increased risk of venous thrombosis due to immobilization, e.g., using wheelchair.
    14.Uncontrolled diabetes (defined as HbA1c >50 mmol/mol).
    15.Cataract.
    16.Pregnant or plan to become pregnant in the next year.
    17.Lactating.
    18.Not able to understand the study information and/or informed consent.
    19.Participation in another investigational clinical trial in the last 6 months.
    20.Any reason for which the investigator considers the patient is not suitable for the study.
    E.5 End points
    E.5.1Primary end point(s)
    Change of mammographic density area (cm2) assessed by iCAD® software after 6 months of daily
    (Z) endoxifen treatment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months
    E.5.2Secondary end point(s)
    Change from baseline of safety and tolerability of daily oral (Z)-endoxifen by subject responses to the BCPT Eight Symptom Scale (BESS) questionnaire and AE collection.
    Clinical assessment, laboratory tests, and participant responses to questionnaires.
    Change from baseline on the BI-RADS® scale assessed by iCAD® software after 3 and 6 months of daily (Z)-endoxifen treatment.
    Exploratory endpoints:
    Reduction of at least one category on the BI-RADS® scale assessed by both iCAD® and Stratus software after a maximum of 6 months of daily (Z)-endoxifen treatment.
    Durability of breast density response at 24 months post standard of care screening mammogram (difference between end of treatment and 24-month breast density).
    E.5.2.1Timepoint(s) of evaluation of this end point
    3, 6 months
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    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 Yes
    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 years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    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: 240
    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 Yes
    F.3.2Patients No
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state240
    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)
    None.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Södersjukhuset AB, Breast and Mammographic unit
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-06-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-08-30
    P. End of Trial
    P.End of Trial StatusOngoing
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