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    EudraCT Number:2013-003046-17
    Sponsor's Protocol Code Number:BAY88-8223/16506
    National Competent Authority:Norway - NOMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-10-08
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedNorway - NOMA
    A.2EudraCT number2013-003046-17
    A.3Full title of the trial
    A re-treatment safety study of radium-223 dichloride in subjects with
    castration-resistant prostate cancer with bone metastases who received an initial course of six doses of radium-223 dichloride 50 kBq/kg every four weeks
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study investigating the safety of radium-223 dichloride, given as a 50kBq/kg dose every four weeks to patients with castration-resistant prostate cancer that has spread to bone, who have already been treated with a course of six doses of radium-223 dichloride 50kBq/kg every four weeks.
    A.4.1Sponsor's protocol code numberBAY88-8223/16506
    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 HealthCare AG
    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 HealthCare AG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer HealthCare AG
    B.5.2Functional name of contact pointBayer Clinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street AddressCTP Team/Ref:"EU CTR"/ Bayer Pharma AG
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    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 nameRadium-223 Dichloride
    D.3.2Product code BAY88-8223
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRadium-223 dichloride
    D.3.9.1CAS number 444811-40-9
    D.3.9.2Current sponsor codeBAY 88-8223
    D.3.9.3Other descriptive nameRADIUM-223 CHLORIDE
    D.3.9.4EV Substance CodeSUB73831
    D.3.10 Strength
    D.3.10.1Concentration unit kBq/ml kilobecquerel(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Castration Resistant Prostate cancer patients with bone metastases
    E.1.1.1Medical condition in easily understood language
    Patients with prostate cancer which has spread to the bone
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level LLT
    E.1.2Classification code 10036916
    E.1.2Term Prostate cancer stage D
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the safety of re-treatment with up to 6 doses of radium-223 dichloride 50 kBq/kg given every 4 weeks in subjects with castration-resistant prostate cancer (CRPC) with bone metastases who received an initial course of 6 doses of radium-223 dichloride 50 kBq/kg.
    E.2.2Secondary objectives of the trial
    • Radiological progression free survival
    • Time to radiological bone progression
    • Total alkaline phosphatase (ALP) response rate
    • Time to total ALP progression
    • Percentage change in total ALP
    • Prostate specific antigen (PSA) response rate
    • Time to PSA progression
    • Overall survival
    • Pain response rate
    • Time to pain progression
    • Time to first skeletal related event (SRE)
    • SRE-free survival
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Histologically or cytologically confirmed adenocarcinoma of the prostate at any given point in time during disease history

    - CRPC (castration-resistant prostate cancer) with clinical or radiologically confirmed bone progression

    - Treatment with 6 injections of radium-223 dichloride 50 kBq/kg and no evidence of progression to bone (according to Prostate Cancer Clinical Trials Working Group 2 [PCWG2] criteria) during the first course of treatment

    - Re-treatment with radium-223 dichloride is indicated based on one or
    more of the following:
    o Radiological progression (according to PCWG2 criteria) in bone after the initial course of radium-223 dichloride treatment or
    o Clinical progression defined as:
    - Confirmed rising PSA (2 subsequent values showing PSA increase, at least 1 week apart) after the initial course of radium-223 dichloride treatment or
    - Substantial worsening of pain after the initial course of radium-223 dichloride treatment (increase of ≥ 2 in the worst pain score of the Brief Pain Inventory Short Form [BPI-SF], where baseline is the value measured at the end of treatment visit of the initial course of radium-223
    dichloride treatment) (Scher HI, et al. J Clin Oncol. 2008;26:1148-59)

    - Signed written informed consent prior to participating in any study related procedures. Willing and able to comply with the protocol, including follow-up visits and examinations
    E.4Principal exclusion criteria
    - History of a radium-223 dichloride-related serious adverse event (SAE) or CTCAE Grade 3 or 4 adverse event (AE) during or after the initial course of radium-223 dichloride treatment that led to the discontinuation of treatment

    - Less than 30 days from the last dose administered in the initial course of radium-223 dichloride treatment

    - Visceral metastases 1 cm or greater in largest diameter and / or requiring local or systemic therapeutic intervention, as assessed by abdominal and pelvic magnetic resonance imaging (MRI) / computed tomography (CT) scan and / or chest X-ray within 30 days of the start of treatment

    - Lymphadenopathy with lymph nodes exceeding 6 cm in short-axis diameter and / or requiring local or systemic therapeutic intervention. Enlarged lymph nodes of any size if the lymphadenopathy is thought to be a contributor to concurrent hydronephrosis

    - Current central nervous system (CNS) metastases

    - Chronic conditions associated with non-malignant abnormal bone growth (e.g., confirmed Paget’s disease of bone)

    - Treatment with chemotherapy after the initial course of radium-223 dichloride treatment

    - Prior hemibody external radiotherapy

    - Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186, or rhenium-188

    - Any other serious illness or medical conditions
    -- Crohn’s disease or ulcerative colitis
    -- History of documented bone marrow dysplasia
    -- Unmanageable fecal incontinence

    - Imminent or established spinal cord compression based on clinical findings and / or MRI that has not yet been treated

    - Other malignancy treated within the last 3 years (except non-melanoma skin cancer or low-grade superficial bladder cancer)
    E.5 End points
    E.5.1Primary end point(s)
    1) Number of participants with either treatment-related AEs (adverse events) or SAEs (serious adverse events)

    2) Number of participants with Radium-223 dichloride-related SAEs in the active follow-up period

    3) Change in complete blood count

    4) Number of participants who discontinue Radium-223 dichloride treatment due to treatment emergent AEs or death
    E.5.1.1Timepoint(s) of evaluation of this end point
    1) Up to 7 months - Treatment 2 (Day 1, 8, 15, 22), Day 1 of Treatment 2,3,4,5,6

    2) Up to 2 years after last treatment - q4 weeks for 12 weeks then q12 weeks until 2 years post-last dose and end of follow-up

    3) Up to 2.5 years - screen, visit 2-10 then q4 weeks for 12 weeks then q12 weeks until 2 years post-last dose and end of follow-up

    4) Up to 7 months
    E.5.2Secondary end point(s)
    1) Radiological progression free survival

    2) Time to radiological bone progression

    3) Pain response rate (defined as the number of subjects with pain response, divided by the total number of subjects evaluable for pain response)

    4) Time to pain progression (defined as the time in days from the start of treatment until occurrence of the first pain progression event)

    5) Overall survival

    6) Time to first skeletal related event (SRE)

    7) SRE-free survival
    E.5.2.1Timepoint(s) of evaluation of this end point
    1)Visit 8, 30 days post-last-dose,q4 weeks for 12 weeks then q12 weeks until 2 years post-last dose & end of follow-up
    2)Visit 8, 30 days post-last-dose,q4 weeks for 12 weeks then q12 weeks until 2 years post-last dose & end of follow-up
    3)Visit 2, 6, 7, 8, 9, 10 and 30 days post-last-dose
    4)Visit 2, 6, 7, 8, 9, 10 and 30 days post-last-dose
    5)Visit 1-10,30 days post-last-dose, q4 weeks for 12 weeks then q12 weeks until 2 years post-last dose and end of follow-up,q6 mo until 7 yrs post-late-dose
    6)Visit 1-10,30 days post-last-dose,q4 weeks for 12 weeks then q12 weeks until 2 years post-last dose & end of follow-up
    7)Visit 1-10,30 days post-last-dose,q4 weeks for 12 weeks then q12 weeks until 2 years post-last dose & end of follow-up
    Refer to protocol section 7.6 for further details
    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. 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 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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
    United States
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months5
    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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 32
    F.4.2.2In the whole clinical trial 40
    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 last dose of study drug subjects enter the active follow-up phase (clinic visits); monitored every 4 weeks for the first 12 weeks, then every 12 weeks for up to 2 years. Thereafter, subjects enter the extended active follow-up phase (telephone follow-up); follow-up every 6 months for up to 7 years after the last dose of study drug. Other therapies are allowed during the follow-up period. Subjects receiving other anticancer therapy will enter the telephone follow-up group.
    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 Decision2013-10-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-10-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-04-12
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