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    Summary
    EudraCT Number:2020-003093-48
    Sponsor's Protocol Code Number:21140
    National Competent Authority:Latvia - SAM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-12-01
    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 ConcernedLatvia - SAM
    A.2EudraCT number2020-003093-48
    A.3Full title of the trial
    A randomized, double-blind, placebo-controlled Phase 3 study of darolutamide in addition to androgen deprivation therapy (ADT) versus placebo plus ADT in
    men with metastatic hormone-sensitive prostate cancer (mHSPC).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A trial to learn how well darolutamide plus androgen deprivation therapy (ADT) works in comparison to placebo plus ADT in men with prostate cancer that has spread to other parts of their body
    A.3.2Name or abbreviated title of the trial where available
    ARANOTE
    A.4.1Sponsor's protocol code number21140
    A.5.4Other Identifiers
    Name:BAY Number:1841788
    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 SponsorBayer Consumer Care AG
    B.1.3.4CountrySwitzerland
    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 supportBayer Consumer Care AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer AG
    B.5.2Functional name of contact pointBayer Clinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street AddressMüllerstraße 178
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13353
    B.5.3.4CountryGermany
    B.5.4Telephone number004930300139005
    B.5.6E-mailclinical-trials-contact@bayer.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 Yes
    D.2.1.1.1Trade name NUBEQA
    D.2.1.1.2Name of the Marketing Authorisation holderBayer AG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameDarolutamide 300mg film-coated tablet
    D.3.2Product code BAY 1841788
    D.3.4Pharmaceutical form Film-coated 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 INNDAROLUTAMIDE
    D.3.9.1CAS number 1297538-32-9
    D.3.9.2Current sponsor codeDarolutamide
    D.3.9.3Other descriptive nameBAY 1841788
    D.3.9.4EV Substance CodeSUB185326
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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 placeboFilm-coated tablet
    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
    Metastatic hormone-sensitive prostate cancer (mHSPC)
    E.1.1.1Medical condition in easily understood language
    Metastatic prostate cancer responsive to hormone therapy which works by either stopping the body from making testosterone, or by stopping testosterone from reaching the cancer cells.
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10036909
    E.1.2Term Prostate cancer metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 if darolutamide in addition to ADT is superior to placebo plus ADT by improving rPFS in participants with mHSPC.
    E.2.2Secondary objectives of the trial
    - To evaluate efficacy of darolutamide in addition to ADT compared to placebo plus ADT by improving OS, time to progress to CRPC, time to initiation of subsequent anti-cancer therapy, time to PSA progression, and undetectable PSA rates
    - To estimate the participant’s quality of life benefit of darolutamide in addition to ADT compared to placebo plus ADT by improving symptomatic time
    to pain progression
    - To assess the safety of darolutamide in addition to ADT compared to placebo plus ADT in participants with mHSPC
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Whole genome sequencing (WGS) will be offered to all participants. The WGS analysis will only be carried out in samples from those participants who have provided respective optional informed consent. Participants who do not wish to have their sample(s) analysed for WGS may still participate in the study.
    E.3Principal inclusion criteria
    1. Written informed consent obtained.
    Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in
    this protocol.
    2. Males ≥18 years of age.
    3. Histologically or cytologically confirmed adenocarcinoma of prostate.
    4. Documented metastatic disease by conventional imaging method either by a positive 99mTc-phosphonate bone scan, or soft tissue or visceral metastases, either by contrastenhanced abdominal/pelvic/chest CT or MRI scan assessed by central review.
    Note: participants with a baseline "superscan" (bone scan showing a diffuse, intense, skeletal uptake of the tracer with absent renal and background activity) are considered ineligible.
    Note: Metastatic disease is defined as either malignant lesions in bone scan or measurable lymph nodes above the aortic bifurcation or soft tissue/visceral lesions according to RECIST version 1.1. Lymph nodes are measurable if the short axis diameter is ≥15 mm,
    soft tissue/visceral lesions are measurable if the long axis diameter is ≥10 mm.
    Regional lymph node metastases only (N1, below the aortic bifurcation) will not be considered as metastases eligible for the study. Only participants with non-regional lymph node metastases (M1a) and/or bone metastases (M1b) and/or other sites of metastases with or without bone disease (M1c), assessed according to National Comprehensive Cancer Network (NCCN) classification, will be eligible.
    5. Started ADT (LHRH agonist/antagonist or orchiectomy) with or without first generation anti–androgen, but not earlier than 12 weeks before randomization. For participants receiving LHRH agonists, treatment in combination with a first generation anti–androgen for at least 14 days prior to randomization is recommended.
    6. First generation anti–androgen must be discontinued at least 1 day before study treatment start.
    7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1 or 2.
    8. Blood counts at Screening: hemoglobin ≥9.0 g/dL, absolute neutrophil count ≥1.5x109/L,
    platelet count ≥100x109/L (participant must not have received any growth factor within 4 weeks or a blood transfusion within 7 days of the hematology laboratory sample obtained at Screening).
    9. Screening values of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤1.5 x ULN, total bilirubin ≤1.5 x ULN, creatinine ≤2.0 x ULN (for Canada: Screening values of serum alanine aminotransferase (ALT) and aspartate inotransferase (AST) =1.5 x ULN, total bilirubin =1.5 x ULN).
    10. Sexually active male participants must agree to use condoms as an effective barrier method and refrain from sperm donation, and/or their female partners of reproductive potential to use a method of effective birth control, during the treatment with study drug and for 4 weeks after the last does of the study treatment with study drug.
    11. For Canada: At Screening; estimated glomerular filtration rate (eGFR) eGFR = 30 mL/min/1.73m2 (calculated by the CKD-EPI formula.
    E.4Principal exclusion criteria
    1. Pathological finding consistent with small cell, ductal or neuroendocrine carcinoma of the prostate.
    2. Known brain/ leptomeningeal metastases Note: Brain CT/MRI scan should be performed only in case of symptoms.
    3. Prior treatment with:
    - LHRH agonist/antagonists started >12 weeks before randomization starts except neoadjuvant and /or adjuvant therapy for a duration ≤ 24 months and completed ≥ 12 months prior to randomization
    - Second–generation androgen receptor (AR) inhibitors such as enzalutamide, darolutamide, apalutamide or other investigational AR inhibitors
    - Cytochrome P 17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as anti-cancer treatment for prostate cancer
    - Chemotherapy including docetaxel or immunotherapy for prostate cancer
    - Use of systemic corticosteroid with dose greater than the equivalent 10 mg of prednisone/day within 28 days prior to randomization
    - radiopharmaceuticals
    - Any other anti-cancer treatment for prostate cancer, excluding local therapies and ADT
    4. Treatment with radiotherapy (external beam radiation therapy [EBRT], brachytherapy) within 2 weeks before randomization.
    5. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs.
    6. Contraindication to iodinated CT and gadolinium chelate MRI intravenous contrast agent(s).
    7. Any prior malignancy (other than adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in complete remission) within 5 years prior to randomization.
    8. An active viral hepatitis (defined as Hepatitis B surface antigen [HBsAg] reactive or detectable [qualitative] hepatitis B virus [HBV] DNA or defined as hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected), known human immunodeficiency virus (HIV) infection with detectable viral load, or chronic liver disease with a need of treatment.
    Note: No testing for Hepatitis B and/or Hepatitis C is required unless mandated by local authority. No HIV testing is required unless mandated by local authority.
    9. Had any of the following within 6 months before randomization: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, congestive heart failure (New York Heart Association Class III or IV).
    10. Uncontrolled hypertension as indicated by a resting systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg despite medical management.
    11. A gastrointestinal (GI) disorder or procedure which is expected to interfere significantly with absorption of study drug.
    12. Previous (within 28 days before the start of study drug or 5 half–lives of the investigational treatment of the previous study, whichever is longer) or concomitant participation in another clinical study with investigational medicinal product(s).
    13. Any other serious or unstable illness, or medical, social, or psychological condition, that could jeopardize the safety of the
    participant and/or his/her compliance with study procedures or may interfere with the participant's participation in the study or evaluation of the study results.
    14. Inability to swallow oral medications.
    E.5 End points
    E.5.1Primary end point(s)
    Radiological progression-free survival
    E.5.1.1Timepoint(s) of evaluation of this end point
    From the date of randomization to the date of first documentation of radiological progressive disease or death due to any cause, whichever occurs first, assessed 36 months after first patient randomized.
    E.5.2Secondary end point(s)
    1) Overall survival (OS)
    2) Time to castration–resistant prostate cancer (CRPC)
    3) Time to initiation of subsequent anti-cancer therapy
    4) Time to PSA progression
    5) Percentage of participants with detectable PSA values (≥0.2 ng/mL) at baseline which become undetectable (<0.2 ng/mL)
    6) Time to pain progression
    7) Number of participants with treatment emergent adverse events
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Time from the date of randomization to the date of death from any cause at 3 years
    2) From the date of randomization to the date of first castration resistant event (radiological progression, PSA progression or symptomatic skeletal events, whichever occurs first), assessed at 3 years.
    3) From the date of randomization to initiation of first subsequent anti-cancer therapy for prostate cancer, assessed at 3 years.
    4) From the date of randomization to the date of first PSA progression , assessed at 3 years.
    5) Baseline and during study treatment.
    6) From the date of randomization to pain progression, assessed at 3 years.
    7) After the first dose of study drug until 30 days (+7 days) after the last treatment with darolutamide/placebo assessed at 3 years.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Whole genome sequencing
    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 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 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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 EEA22
    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
    Australia
    Brazil
    Canada
    Chile
    China
    India
    New Zealand
    Peru
    South Africa
    Taiwan
    United States
    Latvia
    Lithuania
    Spain
    Russian Federation
    Ukraine
    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
    LSLV
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    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: 221
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 444
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    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 state82
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 115
    F.4.2.2In the whole clinical trial 665
    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)
    Following the unblinding, those participants who are on study treatment (darolutamide or placebo) will be offered the opportunity to receive darolutamide through open-label period in this study, at the discretion of the investigator. Those participants who do not choose to continue with open-label darolutamide treatment, will have an end-of study treatment visit at the time of unblinding.
    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 Decision2021-01-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-02-03
    P. End of Trial
    P.End of Trial StatusOngoing
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