<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/NCT04434170</url>
  </required_header>
  <id_info>
    <org_study_id>Entresto CPET</org_study_id>
    <nct_id>NCT04434170</nct_id>
  </id_info>
  <brief_title>Effects of Sacubitril/Valsartan on Exercise Capacity, Natriuretic Peptides and Ventricular Remodeling in Heart Failure</brief_title>
  <official_title>Valutazione Della capacità d'Esercizio, Della funzionalità Respiratoria e Del Rimodellamento Ventricolare Sinistro in Pazienti Affetti da Scompenso Cardiaco a Frazione d'Eiezione Ridotta Trattati Con Sacubitril/Valsartan</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centro Cardiologico Monzino</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Centro Cardiologico Monzino</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</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>
      Background: Sacubitril/valsartan, a novel therapy in the treatment of heart failure with&#xD;
      reduced ejection fraction (HFrEF), has recently proved efficacy in improving exercise&#xD;
      tolerance and cardiac performance. Cardiopulmonary exercise test (CPET) provides functional&#xD;
      prognostic parameters for patient with HFrEF (i.e. peakVO2 and ventilation/CO2 production&#xD;
      [VE/VCO2] slope) and it is a well-recognized, valuable, accurate tool for risk&#xD;
      stratification.&#xD;
&#xD;
      Aim of the study and methods: The aim of the study is to prospectively enroll a cohort of 100&#xD;
      HFrEF outpatients eligible for sacubitril/valsartan and perform serial CPET, laboratory and&#xD;
      echocardiographic assessments before and during the gradual titration of the treatment, in&#xD;
      order to evaluate its effects on cardiopulmonary function and left ventricular remodeling.&#xD;
      The procedures will be repeated along the follow-up at 1, 2 and 3 months after the enrollment&#xD;
      (titration period) and at 6 months after the reach of the maximum tolerated dose.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Given the recent introduction of the drug into the clinical routine, the evaluation of the&#xD;
      experience &quot;on the field&quot; is important to refine the clinical management of patients treated&#xD;
      with sacubitril / valsartan. Furthermore, at the moment sacubitril / valsartan has proven&#xD;
      effective in some small preliminary studies in improving the ejection fraction and some&#xD;
      echocardiographic parameters of ventricular remodeling on top of the concomitant optimal&#xD;
      medical therapy, although further data are needed in this regard.&#xD;
&#xD;
      In particular, the potential benefits on exercise capacity, respiratory function parameters&#xD;
      and left ventricular remodeling in heart failure patients treated with sacubitril / valsartan&#xD;
      has not been studied extensively at the moment. In this regard, the cardiopulmonary exercise&#xD;
      test (CPET) allows to obtain prognostic functional parameters in patients with chronic heart&#xD;
      failure such as peak V02 (peak V02) and the ventilation / production of C02 slope (VE / VC02&#xD;
      slope). CPET is a valid, recognized and accurate tool for risk stratification in heart&#xD;
      failure patients.&#xD;
&#xD;
      Furthermore, few data are available on lung diffusion (DLCO) and on specific markers of the&#xD;
      alveolar-capillary membrane, such as type B surfactant proteins (SPB) in patients treated&#xD;
      with sacubtril / valsartan. Our team has already shown how these biomarkers and DLCO are&#xD;
      influenced by drug treatments such as Levosimendan and Ace inhibitors.&#xD;
&#xD;
      The aim of the study is to evaluate the exercise capacity, spirometry, echocardiographic&#xD;
      parameters of left ventricular sistolic and diastolic function, Nt-proBNP dosage and quality&#xD;
      of life and the related dose-effect correlation in a multicenter cohort of 100 patients with&#xD;
      stable heart failure (class functional NYHA II e lII) and reduced left ventricular ejection&#xD;
      fraction in patients eligible for sacubitril / valsartan treatment.&#xD;
&#xD;
      A subgroup of patients will be also analyzed for data relating to the effect of sacubitril /&#xD;
      valsartan on DLCO and blood levels of Surfactant Bindig protein (SPB).&#xD;
&#xD;
      Sacubitril / Valsartan will be prescribed according to guidelines, initially at the lowest&#xD;
      dosage of 24/26 mg b.i.d. to verify its tolerability with the prospect of gradually&#xD;
      increasing the dosage during subsequent follow-up visits. The re-evaluation of the treatment&#xD;
      and the titration of the sacubitril / valsartan dose will take place every 4 weeks until the&#xD;
      maximum tolerated dose is reached. The dose under study will be the maximum tolerated by the&#xD;
      patient (however not higher than 97 mg / 103mg bd).&#xD;
&#xD;
      Cardiological examination with ECG, spirometry, CPET, the Kansas City Cardiomyopathy&#xD;
      Questionnaire, blood count, creatinine, nitrogen, sodium, potassium, chlorine and NTproBNP&#xD;
      will be performed at each visit (from Baseline to 6 months). The colordoppler echocardiogram&#xD;
      will instead be performed only at the baseline and after 6 months.&#xD;
&#xD;
      A subset of patients will also be subjected to analysis of the blood levels of SPB and DLCO&#xD;
      at baseline and 6 months after reaching the maximum tolerated dose.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">October 15, 2018</start_date>
  <completion_date type="Anticipated">September 15, 2021</completion_date>
  <primary_completion_date type="Actual">November 30, 2020</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>VO2 evaluation after treatment</measure>
    <time_frame>1 month after start of treatment with sacubitril/valsartan</time_frame>
    <description>changes in peak VO2 at cardiopulmonary exercise test</description>
  </primary_outcome>
  <primary_outcome>
    <measure>VO2 evaluation after treatment</measure>
    <time_frame>2 months after start of treatment with sacubitril/valsartan</time_frame>
    <description>changes in peak VO2 at cardiopulmonary exercise test</description>
  </primary_outcome>
  <primary_outcome>
    <measure>VO2 evaluation after treatment</measure>
    <time_frame>3 months after start of treatment with sacubitril/valsartan</time_frame>
    <description>changes in peak VO2 at cardiopulmonary exercise test</description>
  </primary_outcome>
  <primary_outcome>
    <measure>VO2 evaluation after treatment</measure>
    <time_frame>9 months after start of treatment with sacubitril/valsartan</time_frame>
    <description>changes in peak VO2 at cardiopulmonary exercise test</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>lung function evaluation after treatment</measure>
    <time_frame>1 month after start of treatment with sacubitril/valsartan</time_frame>
    <description>changes in FVC, FEV1, PEF and FEV1%, by spirometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>lung function evaluation after treatment</measure>
    <time_frame>2 months after start of treatment with sacubitril/valsartan</time_frame>
    <description>changes in FVC, FEV1, PEF and FEV1%, by spirometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>lung function evaluation after treatment</measure>
    <time_frame>3 months after start of treatment with sacubitril/valsartan</time_frame>
    <description>changes in FVC, FEV1, PEF and FEV1%, by spirometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>lung function evaluation after treatment</measure>
    <time_frame>9 months after start of treatment with sacubitril/valsartan</time_frame>
    <description>changes in FVC, FEV1, PEF and FEV1%, by spirometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DLCO</measure>
    <time_frame>1 month after start of treatment with sacubitril/valsartan</time_frame>
    <description>DLCO evaluation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DLCO</measure>
    <time_frame>9 months after start of treatment with sacubitril/valsartan</time_frame>
    <description>DLCO evaluation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Surfactant B-type protein after treatment</measure>
    <time_frame>1 month after start of treatment with sacubitril/valsartan</time_frame>
    <description>SPB quantification</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Surfactant B-type protein after treatment</measure>
    <time_frame>9 months after start of treatment with sacubitril/valsartan</time_frame>
    <description>SPB quantification</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>left ventricular remodeling</measure>
    <time_frame>1 month after start of treatment with sacubitril/valsartan</time_frame>
    <description>ejection fraction</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>left ventricular remodeling</measure>
    <time_frame>2 months after start of treatment with sacubitril/valsartan</time_frame>
    <description>ejection fraction</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>left ventricular remodeling</measure>
    <time_frame>9 months after start of treatment with sacubitril/valsartan</time_frame>
    <description>ejection fraction</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>left ventricular remodeling</measure>
    <time_frame>1 month after start of treatment with sacubitril/valsartan</time_frame>
    <description>End-diastolic and end-systolic left ventricular volumes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>left ventricular remodeling</measure>
    <time_frame>2 months after start of treatment with sacubitril/valsartan</time_frame>
    <description>End-diastolic and end-systolic left ventricular volumes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>left ventricular remodeling</measure>
    <time_frame>9 months after start of treatment with sacubitril/valsartan</time_frame>
    <description>End-diastolic and end-systolic left ventricular volumes</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Heart Failure</condition>
  <arm_group>
    <arm_group_label>Heart failure</arm_group_label>
    <description>outpatients with heart failure with reduced ejection fraction in treatment with sacubitril/valsartan according to guidelines</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sacubitril-Valsartan</intervention_name>
    <description>outpatients who start treatment with sacubitril/valsartan according to guidelines will andergo cardiopulmonary exercise testing evaluation</description>
    <arm_group_label>Heart failure</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        HFrEF outpatients eligible for sacubitril/valsartan according to guidelines and perform&#xD;
        serial CPET, laboratory and echocardiographic assessments before and during the gradual&#xD;
        titration of the treatment&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  New York Heart Association Class (NYHA) II-III&#xD;
&#xD;
          -  stable clinical conditions&#xD;
&#xD;
          -  reduced ejection fraction (&lt; 35%)&#xD;
&#xD;
          -  capability to perform a cardiopulmonary exercise test (CPET)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  moderate-severe chronic obstructive pulmonary disease&#xD;
&#xD;
          -  chronic oxygen therapy&#xD;
&#xD;
          -  contraindication to CPET&#xD;
&#xD;
          -  planned procedures (i.e. cardiac surgery, revascularization procedures, CRT&#xD;
             implantation) that could per se impact on CPET, echocardiography and laboratory values&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Piergiuseppe Agostoni, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Centro Cardiologico Monzino</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Centro Cardiologico Monzino</name>
      <address>
        <city>Milan</city>
        <zip>20138</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>June 4, 2020</study_first_submitted>
  <study_first_submitted_qc>June 12, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>February 3, 2021</last_update_submitted>
  <last_update_submitted_qc>February 3, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 4, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Centro Cardiologico Monzino</investigator_affiliation>
    <investigator_full_name>Piergiuseppe Agostoni</investigator_full_name>
    <investigator_title>Prof</investigator_title>
  </responsible_party>
  <keyword>sacubitril/valsartan</keyword>
  <keyword>exercise</keyword>
  <keyword>cardiopulmonary exercise test</keyword>
  <keyword>left ventricular remodeling</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
    <mesh_term>Ventricular Remodeling</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>Undecided</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/NCT04434170
org study id: Entresto CPET
nct id: NCT04434170
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Background: Sacubitril/valsartan, a novel therapy in the treatment of heart failure with
      reduced ejection fraction (HFrEF), has recently proved efficacy in improving exercise
      tolerance and cardiac performance. Cardiopulmonary exercise test (CPET) provides functional
      prognostic parameters for patient with HFrEF (i.e. peakVO2 and ventilation/CO2 production
      [VE/VCO2] slope) and it is a well-recognized, valuable, accurate tool for risk
      stratification.

      Aim of the study and methods: The aim of the study is to prospectively enroll a cohort of 100
      HFrEF outpatients eligible for sacubitril/valsartan and perform serial CPET, laboratory and
      echocardiographic assessments before and during the gradual titration of the treatment, in
      order to evaluate its effects on cardiopulmonary function and left ventricular remodeling.
      The procedures will be repeated along the follow-up at 1, 2 and 3 months after the enrollment
      (titration period) and at 6 months after the reach of the maximum tolerated dose.
Given the recent introduction of the drug into the clinical routine, the evaluation of the
      experience "on the field" is important to refine the clinical management of patients treated
      with sacubitril / valsartan. Furthermore, at the moment sacubitril / valsartan has proven
      effective in some small preliminary studies in improving the ejection fraction and some
      echocardiographic parameters of ventricular remodeling on top of the concomitant optimal
      medical therapy, although further data are needed in this regard.

      In particular, the potential benefits on exercise capacity, respiratory function parameters
      and left ventricular remodeling in heart failure patients treated with sacubitril / valsartan
      has not been studied extensively at the moment. In this regard, the cardiopulmonary exercise
      test (CPET) allows to obtain prognostic functional parameters in patients with chronic heart
      failure such as peak V02 (peak V02) and the ventilation / production of C02 slope (VE / VC02
      slope). CPET is a valid, recognized and accurate tool for risk stratification in heart
      failure patients.

      Furthermore, few data are available on lung diffusion (DLCO) and on specific markers of the
      alveolar-capillary membrane, such as type B surfactant proteins (SPB) in patients treated
      with sacubtril / valsartan. Our team has already shown how these biomarkers and DLCO are
      influenced by drug treatments such as Levosimendan and Ace inhibitors.

      The aim of the study is to evaluate the exercise capacity, spirometry, echocardiographic
      parameters of left ventricular sistolic and diastolic function, Nt-proBNP dosage and quality
      of life and the related dose-effect correlation in a multicenter cohort of 100 patients with
      stable heart failure (class functional NYHA II e lII) and reduced left ventricular ejection
      fraction in patients eligible for sacubitril / valsartan treatment.

      A subgroup of patients will be also analyzed for data relating to the effect of sacubitril /
      valsartan on DLCO and blood levels of Surfactant Bindig protein (SPB).

      Sacubitril / Valsartan will be prescribed according to guidelines, initially at the lowest
      dosage of 24/26 mg b.i.d. to verify its tolerability with the prospect of gradually
      increasing the dosage during subsequent follow-up visits. The re-evaluation of the treatment
      and the titration of the sacubitril / valsartan dose will take place every 4 weeks until the
      maximum tolerated dose is reached. The dose under study will be the maximum tolerated by the
      patient (however not higher than 97 mg / 103mg bd).

      Cardiological examination with ECG, spirometry, CPET, the Kansas City Cardiomyopathy
      Questionnaire, blood count, creatinine, nitrogen, sodium, potassium, chlorine and NTproBNP
      will be performed at each visit (from Baseline to 6 months). The colordoppler echocardiogram
      will instead be performed only at the baseline and after 6 months.

      A subset of patients will also be subjected to analysis of the blood levels of SPB and DLCO
      at baseline and 6 months after reaching the maximum tolerated dose.
observational model: Cohort
time perspective: Prospective
measure: VO2 evaluation after treatment
time frame: 1 month after start of treatment with sacubitril/valsartan
description: changes in peak VO2 at cardiopulmonary exercise test
measure: VO2 evaluation after treatment
time frame: 2 months after start of treatment with sacubitril/valsartan
description: changes in peak VO2 at cardiopulmonary exercise test
measure: VO2 evaluation after treatment
time frame: 3 months after start of treatment with sacubitril/valsartan
description: changes in peak VO2 at cardiopulmonary exercise test
measure: VO2 evaluation after treatment
time frame: 9 months after start of treatment with sacubitril/valsartan
description: changes in peak VO2 at cardiopulmonary exercise test
measure: lung function evaluation after treatment
time frame: 1 month after start of treatment with sacubitril/valsartan
description: changes in FVC, FEV1, PEF and FEV1%, by spirometry
measure: lung function evaluation after treatment
time frame: 2 months after start of treatment with sacubitril/valsartan
description: changes in FVC, FEV1, PEF and FEV1%, by spirometry
measure: lung function evaluation after treatment
time frame: 3 months after start of treatment with sacubitril/valsartan
description: changes in FVC, FEV1, PEF and FEV1%, by spirometry
measure: lung function evaluation after treatment
time frame: 9 months after start of treatment with sacubitril/valsartan
description: changes in FVC, FEV1, PEF and FEV1%, by spirometry
measure: DLCO
time frame: 1 month after start of treatment with sacubitril/valsartan
description: DLCO evaluation
measure: DLCO
time frame: 9 months after start of treatment with sacubitril/valsartan
description: DLCO evaluation
measure: Surfactant B-type protein after treatment
time frame: 1 month after start of treatment with sacubitril/valsartan
description: SPB quantification
measure: Surfactant B-type protein after treatment
time frame: 9 months after start of treatment with sacubitril/valsartan
description: SPB quantification
measure: left ventricular remodeling
time frame: 1 month after start of treatment with sacubitril/valsartan
description: ejection fraction
measure: left ventricular remodeling
time frame: 2 months after start of treatment with sacubitril/valsartan
description: ejection fraction
measure: left ventricular remodeling
time frame: 9 months after start of treatment with sacubitril/valsartan
description: ejection fraction
measure: left ventricular remodeling
time frame: 1 month after start of treatment with sacubitril/valsartan
description: End-diastolic and end-systolic left ventricular volumes
measure: left ventricular remodeling
time frame: 2 months after start of treatment with sacubitril/valsartan
description: End-diastolic and end-systolic left ventricular volumes
measure: left ventricular remodeling
time frame: 9 months after start of treatment with sacubitril/valsartan
description: End-diastolic and end-systolic left ventricular volumes
arm group label: Heart failure
description: outpatients with heart failure with reduced ejection fraction in treatment with sacubitril/valsartan according to guidelines
intervention type: Drug
intervention name: Sacubitril-Valsartan
description: outpatients who start treatment with sacubitril/valsartan according to guidelines will andergo cardiopulmonary exercise testing evaluation
arm group label: Heart failure
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Piergiuseppe Agostoni, MD
role: Principal Investigator
affiliation: Centro Cardiologico Monzino
facility: 
country: Italy
responsible party type: Principal Investigator
investigator affiliation: Centro Cardiologico Monzino
investigator full name: Piergiuseppe Agostoni
investigator title: Prof
mesh term: Heart Failure
mesh term: Ventricular Remodeling
mesh term: Valsartan
mesh term: Sacubitril and valsartan sodium hydrate drug combination
sharing ipd: Undecided