<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/NCT03760588</url>
  </required_header>
  <id_info>
    <org_study_id>2017-004909-41</org_study_id>
    <nct_id>NCT03760588</nct_id>
  </id_info>
  <brief_title>Prevention of Cardiac Dysfunction During Breast Cancer Therapy</brief_title>
  <acronym>PRADAII</acronym>
  <official_title>PRevention of cArdiac Dysfunction During Adjuvant Breast Cancer Therapy: A Randomized, Placebo-controlled, Multicenter Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Torbjorn Omland</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University Hospital, Akershus</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Oslo University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital of North Norway</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>St. Olavs Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Helse Stavanger HF</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Klinbeforsk</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Norwegian Cancer Society</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Novartis</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital, Akershus</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Breast cancer is the most common cancer among women. The modern post-surgery treatment with&#xD;
      chemotherapy, immunotherapy, radiation and hormone therapy has improved the overall 5-years&#xD;
      survival drastically. However, an unwanted effect of the post-surgery treatment is its&#xD;
      potentially deleterious effect on the heart resulting in cardiac dysfunction. Angiotensin&#xD;
      antagonists are used as part of the heart failure treatment. In smaller studies angiotensin&#xD;
      antagonists have shown to have a cardioprotective effect during breast cancer treatment.&#xD;
      Sacubitril/valsartan is a potent drug that in addition to an angiotensin antagonist contains&#xD;
      a neprilysin inhibitor. Sacubitril/valsartan has proved to be superior to enalapril in&#xD;
      chronic heart failure. In this randomized placebo controlled double blind trial we&#xD;
      hypothesize that sacubitril/valsartan used concomitantly during anthracycline containing&#xD;
      chemotherapy for breast cancer treatment prevents cardiac dysfunction as measured by cardiac&#xD;
      magnetic resonance imaging (CMR). PRADA II is a Norwegian multicenter trial intending to&#xD;
      recruit 214 patients and follow them for 18 months with CMR, cardiac ultrasound, blood&#xD;
      samples, functional capacity tests and health related quality of life questionnaires.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 14, 2019</start_date>
  <completion_date type="Anticipated">September 14, 2025</completion_date>
  <primary_completion_date type="Anticipated">September 14, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Randomized, placebo controlled, double blind design</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in left ventricular ejection fraction by cardiovascular magnetic resonance</measure>
    <time_frame>From randomization to end of blinded therapy (18 months)</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in left ventricular ejection fraction by echocardiography</measure>
    <time_frame>From randomization to end of blinded therapy (18 months)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in left ventricular systolic global longitudinal strain by echocardiography</measure>
    <time_frame>From randomization to end of blinded therapy (18 months)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in left ventricular systolic global longitudinal strain by cardiovascular magnetic resonance (CMR)</measure>
    <time_frame>From randomization to end of blinded therapy (18 months)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in left ventricular end-systolic volume measured by CMR</measure>
    <time_frame>From randomization to end of blinded therapy (18 months)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of a significant reduction in left ventricular systolic function measured by CMR or echocardiography</measure>
    <time_frame>From randomization to end of blinded therapy (18 months)</time_frame>
    <description>An absolute reduction in LVEF ≥ 5% by CMR or a relative percentage reduction of global longitudinal strain (GLS) &gt; 15%</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of cardiotoxicity measured by CMR or echocardiography</measure>
    <time_frame>From randomization to end of blinded therapy (18 months)</time_frame>
    <description>Absolute reduction in LVEF ≥ 10% to a value below 50% as measured either by CMR or Echocardiography, or incidence of clinical heart failure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in circulating cardiac biomarkers</measure>
    <time_frame>From randomization to end of blinded therapy (18 months)</time_frame>
    <description>Cardiac biomarkers defined as cardiac troponins I and T measured by high sensitivity assays (hs-TnI and hs-TnT) and N-terminal proB-type natriuretic peptide (NT-proBNP)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Incidence of adverse events and serious adverse events</measure>
    <time_frame>From randomization to end of blinded therapy (18 months)</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">214</enrollment>
  <condition>Breast Cancer Female</condition>
  <condition>Heart Failure</condition>
  <arm_group>
    <arm_group_label>Sacubitril/valsartan</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Sacubitril/valsartan (target dose 97/103 mg b.i.d.) and matching placebo will be provided orally in a 1:1 parallel fashion stratified by study site and for planned treatment with trastuzumab. Dose titration will be performed as follows: Sacubitril/valsartan 24/26 mg b.i.d. will be administered for 2-4 weeks and provided blood pressure &gt; 100 mmHg, no symptoms of hypotension or other side effects or adverse events (AE), followed by sacubitril/valsartan 49/51 mg b.i.d. for 2-4 weeks. Provided blood pressure &gt; 100 mmHg, no symptoms of hypotension or other side effects or AE a further uptitration to sacubitril/valsartan 97/103 mg b.i.d. will be performed.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Matched to the comparator.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sacubitril/valsartan</intervention_name>
    <description>Target dose 97/103 mg b.i.d .</description>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_label>Sacubitril/valsartan</arm_group_label>
    <other_name>Entresto®</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Women with histological evidence of invasive early breast cancer scheduled for&#xD;
             adjuvant therapy with anti-cancer regimens that include anthracyclines&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group performance status 0-1&#xD;
&#xD;
          -  Sinus rhythm&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Age &lt;18 years&#xD;
&#xD;
          -  Renal failure, i.e. serum creatinine greater than 133 mol/L (1.5mg/dL) or estimated&#xD;
             glomerular filtration rate (eGFR) &lt; 45 mL/min/1.73m2&#xD;
&#xD;
          -  Hyperkalemia, i.e. serum potassium greater than 5.0 mmol/L&#xD;
&#xD;
          -  Systolic blood pressure &lt; 100 mgHg&#xD;
&#xD;
          -  Uncontrolled hypertension&#xD;
&#xD;
          -  Acute myocardial infarction within the last three months&#xD;
&#xD;
          -  Contraindication to ACEI or ARB or sacubitril/valsartan, including previous&#xD;
             hypersensitivity reaction, angioedema and renal artery stenosis&#xD;
&#xD;
          -  ACEI, ARB, aldosterone antagonist or sacubitril/valsartan use within 4 weeks of study&#xD;
             start&#xD;
&#xD;
          -  Clear indication for ACEI, ARB, aldosterone antagonist or sacubitril/valsartan&#xD;
             therapy, including symptomatic heart failure&#xD;
&#xD;
          -  History of hemodynamically significant valvular disease&#xD;
&#xD;
          -  Active liver disease, i.e. alanine aminotransferase or aspartate aminotransferase&#xD;
             greater than 1.5 times the upper limit of normal&#xD;
&#xD;
          -  Participation in another pharmaceutical clinical trial of an investigational medicinal&#xD;
             product (IMP) less than 4 weeks prior to inclusion or use of other investigational&#xD;
             drugs within 5 halflives of enrollment, whichever is longer&#xD;
&#xD;
          -  Conditions that would affect the participants to comply with the study protocol as&#xD;
             psychiatric or mental disorders, alcohol abuse or other substance abuse, suspected&#xD;
             poor drug compliance, language barriers or other factors&#xD;
&#xD;
          -  Contraindication or inability to undergo CMR examination&#xD;
&#xD;
          -  Fertile women with inadequate birth control, pregnancy, and/or breastfeeding. Adequate&#xD;
             contraception includes oral, injected or implanted hormonal methods of contraception,&#xD;
             placement of an intrauterine device or system, vasectomized partner or sexual&#xD;
             abstinence. Fertile women are defined as following menarche and until becoming&#xD;
             postmenopausal unless permanently sterile. A postmenopausal state is defined as no&#xD;
             menses for 12 months without an alternative medical cause&#xD;
&#xD;
          -  Life expectancy &lt; 12 months&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Torbjørn Omland, MD,PhD,MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospital, Akershus</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Akershus University Hospital</name>
      <address>
        <city>Lørenskog</city>
        <zip>1478</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stavanger University Hospital</name>
      <address>
        <city>Stavanger</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of North Norway</name>
      <address>
        <city>Tromsø</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St Olavs Hospital</name>
      <address>
        <city>Trondheim</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Norway</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>November 12, 2018</study_first_submitted>
  <study_first_submitted_qc>November 29, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 30, 2018</study_first_posted>
  <last_update_submitted>March 16, 2023</last_update_submitted>
  <last_update_submitted_qc>March 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 17, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital, Akershus</investigator_affiliation>
    <investigator_full_name>Torbjorn Omland</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>LCZ696</keyword>
  <keyword>CMR</keyword>
  <keyword>Echocardiography</keyword>
  <keyword>Cardio-oncology</keyword>
  <keyword>Circulating biomarkers</keyword>
  <keyword>Breast Cancer</keyword>
  <keyword>Anthracyclines</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Valsartan</mesh_term>
    <mesh_term>Sacubitril and valsartan sodium hydrate drug combination</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


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/NCT03760588
org study id: 2017-004909-41
nct id: NCT03760588
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Breast cancer is the most common cancer among women. The modern post-surgery treatment with
      chemotherapy, immunotherapy, radiation and hormone therapy has improved the overall 5-years
      survival drastically. However, an unwanted effect of the post-surgery treatment is its
      potentially deleterious effect on the heart resulting in cardiac dysfunction. Angiotensin
      antagonists are used as part of the heart failure treatment. In smaller studies angiotensin
      antagonists have shown to have a cardioprotective effect during breast cancer treatment.
      Sacubitril/valsartan is a potent drug that in addition to an angiotensin antagonist contains
      a neprilysin inhibitor. Sacubitril/valsartan has proved to be superior to enalapril in
      chronic heart failure. In this randomized placebo controlled double blind trial we
      hypothesize that sacubitril/valsartan used concomitantly during anthracycline containing
      chemotherapy for breast cancer treatment prevents cardiac dysfunction as measured by cardiac
      magnetic resonance imaging (CMR). PRADA II is a Norwegian multicenter trial intending to
      recruit 214 patients and follow them for 18 months with CMR, cardiac ultrasound, blood
      samples, functional capacity tests and health related quality of life questionnaires.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomized, placebo controlled, double blind design
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in left ventricular ejection fraction by cardiovascular magnetic resonance
time frame: From randomization to end of blinded therapy (18 months)
measure: Change in left ventricular ejection fraction by echocardiography
time frame: From randomization to end of blinded therapy (18 months)
measure: Change in left ventricular systolic global longitudinal strain by echocardiography
time frame: From randomization to end of blinded therapy (18 months)
measure: Change in left ventricular systolic global longitudinal strain by cardiovascular magnetic resonance (CMR)
time frame: From randomization to end of blinded therapy (18 months)
measure: Change in left ventricular end-systolic volume measured by CMR
time frame: From randomization to end of blinded therapy (18 months)
measure: Incidence of a significant reduction in left ventricular systolic function measured by CMR or echocardiography
time frame: From randomization to end of blinded therapy (18 months)
description: An absolute reduction in LVEF ≥ 5% by CMR or a relative percentage reduction of global longitudinal strain (GLS) > 15%
measure: Incidence of cardiotoxicity measured by CMR or echocardiography
time frame: From randomization to end of blinded therapy (18 months)
description: Absolute reduction in LVEF ≥ 10% to a value below 50% as measured either by CMR or Echocardiography, or incidence of clinical heart failure
measure: Change in circulating cardiac biomarkers
time frame: From randomization to end of blinded therapy (18 months)
description: Cardiac biomarkers defined as cardiac troponins I and T measured by high sensitivity assays (hs-TnI and hs-TnT) and N-terminal proB-type natriuretic peptide (NT-proBNP)
measure: Incidence of adverse events and serious adverse events
time frame: From randomization to end of blinded therapy (18 months)
arm group label: Sacubitril/valsartan
arm group type: Experimental
description: Sacubitril/valsartan (target dose 97/103 mg b.i.d.) and matching placebo will be provided orally in a 1:1 parallel fashion stratified by study site and for planned treatment with trastuzumab. Dose titration will be performed as follows: Sacubitril/valsartan 24/26 mg b.i.d. will be administered for 2-4 weeks and provided blood pressure > 100 mmHg, no symptoms of hypotension or other side effects or adverse events (AE), followed by sacubitril/valsartan 49/51 mg b.i.d. for 2-4 weeks. Provided blood pressure > 100 mmHg, no symptoms of hypotension or other side effects or AE a further uptitration to sacubitril/valsartan 97/103 mg b.i.d. will be performed.
arm group label: Placebo
arm group type: Placebo Comparator
description: Matched to the comparator.
intervention type: Drug
intervention name: Sacubitril/valsartan
description: Target dose 97/103 mg b.i.d .
arm group label: Placebo
arm group label: Sacubitril/valsartan
other name: Entresto®
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Torbjørn Omland, MD,PhD,MPH
role: Principal Investigator
affiliation: University Hospital, Akershus
facility: 
facility: 
facility: 
facility: 
country: Norway
responsible party type: Sponsor-Investigator
investigator affiliation: University Hospital, Akershus
investigator full name: Torbjorn Omland
investigator title: Professor
mesh term: Breast Neoplasms
mesh term: Valsartan
mesh term: Sacubitril and valsartan sodium hydrate drug combination
sharing ipd: No