<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/NCT03011346</url>
  </required_header>
  <id_info>
    <org_study_id>V 4.0, 13.08.2018</org_study_id>
    <nct_id>NCT03011346</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of the Symetis ACURATE Neo/TF Compared to the Edwards SAPIEN 3 Bioprosthesis.</brief_title>
  <acronym>SCOPE I</acronym>
  <official_title>Safety and Efficacy of the Symetis ACURATE Neo/TF Compared to the Edwards SAPIEN 3 Bioprosthesis for Transcatheter Aortic Valve Implantation by Transfemoral Approach.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Insel Gruppe AG, University Hospital Bern</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Insel Gruppe AG, University Hospital Bern</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Transcatheter aortic valve implantation (TAVI) is an established treatment option for&#xD;
      patients with severe symptomatic aortic stenosis and at increased risk for surgical aortic&#xD;
      valve replacement (SAVR). Many novel devices are currently being developed and established&#xD;
      transcatheter heart valves undergo design reiterations to address limitations and reduce&#xD;
      complication rates associated with the device and implantation procedure. However, device&#xD;
      comparisons by use of randomized trials are scarce in particular for newer generation&#xD;
      transcatheter valves. The aim of this study is to assess non-inferiority of the&#xD;
      self-expandable Symetis ACURATE neo/TF in comparison to the balloon-expandable Edwards SAPIEN&#xD;
      3 transcatheter aortic valve bioprosthesis with regard to early safety and clinical efficacy&#xD;
      at 30 days.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      Transcatheter aortic valve implantation (TAVI) is an established and valuable treatment&#xD;
      option for patients with severe symptomatic aortic stenosis and at increased risk for&#xD;
      surgical aortic valve replacement (SAVR). The use of TAVI is rapidly expanding worldwide and&#xD;
      the indications for TAVI are widening into lower risk populations in view of favorable&#xD;
      outcomes among high and intermediate risk patients. Many novel devices are currently&#xD;
      developed or established devices undergo design reiterations to address limitations, such as&#xD;
      vascular access complications, paravalvular regurgitation, and atrio-ventricular conductance&#xD;
      disturbances. However, device comparisons by use of randomized trials are scarce in&#xD;
      particular for newer generation transcatheter valves.&#xD;
&#xD;
      The Symetis ACURATE neo/TF, a self-expandable transcatheter valve delivered via transfemoral&#xD;
      access, gained Conformité Européenne (CE) marking in September 2014 after showing favorable&#xD;
      procedural and short term results. The SCOPE I trial will compare its performance to the&#xD;
      balloon-expandable Edwards SAPIEN 3, a widely used and well-established transcatheter heart&#xD;
      valve of the second generation, in a randomized fashion.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      The primary objective is the comparison of the Symetis ACURATE neo/TF to the Edwards SAPIEN 3&#xD;
      transcatheter aortic bioprosthesis with regard to early safety and clinical efficacy at 30&#xD;
      days. Secondary objectives involve the comparison between the two devices with regard to&#xD;
      secondary clinical and echocardiographic endpoints at 30 days, 1 year and 3 years.&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      Sample Size: Based on an anticipated incidence proportion of 22% for the primary&#xD;
      non-hierarchical composite endpoint at 30 days in both treatment arms, a non-inferiority&#xD;
      margin of 7.7%, a power of 80%, a one-tailed significance level of α = 0.05, and a low&#xD;
      attrition rate, the total required sample size amounts to 730 patients.&#xD;
&#xD;
      Design: Patients will be allocated to the Symetis ACURATE neo/TF or the Edwards SAPIEN 3&#xD;
      bioprosthesis at a 1:1 ratio by means of a randomly permuted block randomisation stratified&#xD;
      on study center and Society of Thoracic Surgeons' predicted risk of mortality score&#xD;
      (STS-PROM) strata (&lt; 3%, ≥ 3 to &lt; 8%, ≥ 8%).&#xD;
&#xD;
      Analysis: Estimates of the risk-differences between the two treatment arms with regard to the&#xD;
      primary endpoint will be pooled over the predefined STS-PROM strata by means of the&#xD;
      Cochran-Mantel-Haenszel method and Wald-type confidence limits will be calculated using the&#xD;
      Sato variance estimator. The non-inferiority assumption will be tested at a one-sided&#xD;
      significance level with a type I error rate (α) = 0.05. The analysis of the primary composite&#xD;
      endpoint will be conducted according to the intention-to-treat (ITT) and the per protocol&#xD;
      (PP) principle and non-inferiority should be claimed only if met by both.&#xD;
&#xD;
      In case non-inferiority is established, a superiority analysis will be performed using a&#xD;
      two-tailed significance level with a type I error rate of α = 0.05. Further secondary&#xD;
      analyses will evaluate between group differences in relation to demographic, clinical,&#xD;
      procedural, functional and imaging characteristics. Pre-specified subgroup analyses will be&#xD;
      conducted by use of appropriate interaction tests contrasting categories of sex, STS-PROM&#xD;
      score (&lt; 3%, ≥ 3 to &lt; 8%, ≥ 8%), left ventricular ejection fraction (&lt; 50% vs. ≥ 50%), and&#xD;
      native aortic valve eccentricity index (≤ 0.25 vs. &gt; 0.25).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 8, 2017</start_date>
  <completion_date type="Actual">February 16, 2022</completion_date>
  <primary_completion_date type="Actual">May 2, 2019</primary_completion_date>
  <phase>N/A</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Modified* combined early safety and clinical efficacy as defined by the Valve Academic Research Consortium-2 (VARC-2)</measure>
    <time_frame>30 days</time_frame>
    <description>(* &quot;NYHA class III or IV&quot; is omitted due to lack of objectiveness in its ascertainment)&#xD;
All-cause mortality&#xD;
All stroke (disabling and non-disabling)&#xD;
Life-threatening or disabling bleeding&#xD;
Acute kidney injury (stage 2 or 3, including renal replacement therapy)&#xD;
Coronary artery obstruction requiring intervention&#xD;
Major vascular complication&#xD;
Valve related dysfunction requiring repeat procedure (balloon aortic valvuloplasty, TAVI or SAVR in a separate intervention)&#xD;
Rehospitalization for valve-related symptoms or worsening congestive heart failure&#xD;
Valve-related dysfunction: prosthetic aortic valve stenosis (mean gradient ≥ 20 mmHg, effective orifice area ≤ 0.9-1.1cm2 and/or Doppler velocity index &lt; 0.35) AND/OR ≥ moderate prosthetic valve regurgitation)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Device success</measure>
    <time_frame>30 days</time_frame>
    <description>Combined endpoint composed of:&#xD;
Absence of procedural mortality AND&#xD;
Correct positioning of a single prosthetic heart valve into the proper anatomical location AND&#xD;
Intended performance of the prosthetic heart valve (no prosthesis-patient mismatch and mean aortic valve gradient &lt; 20 mmHg or peak velocity &lt; 3 m/s, AND no moderate or severe prosthetic valve regurgitation)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Early safety</measure>
    <time_frame>30 days</time_frame>
    <description>Combined endpoint composed of:&#xD;
All-cause mortality&#xD;
All stroke (disabling and non-disabling)&#xD;
Life-threatening or disabling bleeding&#xD;
Acute kidney injury - stage 2 or 3 (including renal replacement therapy)&#xD;
Coronary artery obstruction requiring intervention&#xD;
Major vascular complication&#xD;
Valve-related dysfunction requiring repeat procedure (balloon aortic valvuloplasty, TAVI, or SAVR)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical efficacy</measure>
    <time_frame>30 days</time_frame>
    <description>Combined endpoint composed of:&#xD;
All-cause mortality&#xD;
All stroke (disabling and non-disabling)&#xD;
Requiring hospitalizations for valve-related symptoms or worsening congestive heart failure&#xD;
NYHA class III or IV&#xD;
Valve-related dysfunction (mean aortic valve gradient ≥ 20 mmHg, effective orifice area (EOA) ≤ 0.9-1.1 cm2 and/or Doppler velocity index (DVI) &lt; 0. 35 m/s, AND/OR moderate or severe prosthetic valve regurgitation)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time-related valve safety</measure>
    <time_frame>30 days, 1 year</time_frame>
    <description>Combined endpoint composed of:&#xD;
Structural valve deterioration (Valve-related dysfunction (mean aortic valve gradient ≥ 20 mmHg, EOA ≤ 0.9-1.1 cm2 (depending on body surface area (BSA)) and/or DVI &lt; 0.35 m/s AND/OR moderate or severe prosthetic valve regurgitation)) OR Requiring repeat procedure (TAVI or SAVR)&#xD;
Prosthetic valve endocarditis&#xD;
Prosthetic valve thrombosis&#xD;
Thrombo-embolic events (e.g. stroke)&#xD;
VARC bleeding, unless clearly unrelated to valve therapy (e.g. trauma)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause mortality</measure>
    <time_frame>30 days, 1 year, 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All stroke (disabling and non-disabling)</measure>
    <time_frame>30 days, 1 year, 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Life-threatening or disabling bleeding</measure>
    <time_frame>30 days, 1 year, 3 years</time_frame>
    <description>Fatal bleeding (Bleeding Academic Research Consortium (BARC) type 5)OR&#xD;
Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or pericardial necessitating pericardiocentesis, or intramuscular with compartment syndrome (BARC type 3b and 3c) OR&#xD;
Bleeding causing hypovolaemic shock or severe hypotension requiring vasopressors or surgery (BARC type 3b) OR&#xD;
Overt source of bleeding with drop in haemoglobin ≥5 g/dL or whole blood or packed red blood cells (RBCs) transfusion ≥4 units (BARC type 3b)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acute kidney injury (stage 2 or 3, including renal replacement therapy)</measure>
    <time_frame>30 days, 1 year, 3 years</time_frame>
    <description>Stage 2: Increase in serum creatinine to 200-299% (2.0-2.99 × increase compared with baseline) OR Urine output &lt;0.5 mL/kg/h for &gt;12 but &lt;24 h&#xD;
Stage 3: Increase in serum creatinine to ≥300% (&gt;3 × increase compared with baseline) OR serum creatinine of ≥4.0 mg/dL (≥354 mmol/L) with an acute increase of at least 0.5 mg/dL (44 mmol/L) OR Urine output &lt;0.3 ml/kg/h for ≥24 h OR Anuria for ≥12 h Notes: The increase in creatinine must occur within 48 h. Patients receiving renal replacement therapy are considered to meet Stage 3 criteria irrespective of other criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Coronary artery obstruction requiring intervention</measure>
    <time_frame>30 days, 1 year, 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Major vascular complication</measure>
    <time_frame>30 days, 1 year, 3 years</time_frame>
    <description>Aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, or new apical aneurysm/pseudo-aneurysm OR&#xD;
Access-related vascular injury (dissection, stenosis, perforation, rupture, arterio-venous fistula, pseudoaneurysm, haematoma, irreversible nerve injury, compartment syndrome, percutaneous closure device failure) leading to death, life-threatening or major bleeding, visceral ischaemia, or neurological impairment OR&#xD;
Distal embolization (non-cerebral) from a vascular source requiring surgery or resulting in amputation or irreversible end-organ damage OR&#xD;
Use of unplanned endovascular or surgical intervention associated with death, major bleeding, visceral ischaemia or neurological impairment OR&#xD;
Any new ipsilateral lower extremity ischaemia documented by patient symptoms, physical exam, and/or decreased or absent blood flow on lower extremity angiogram OR&#xD;
Surgery for access site-related nerve injury OR&#xD;
Permanent access site-related nerve injury</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Valve related dysfunction requiring repeat procedure (balloon aortic valvuloplasty, TAVI or SAVR in a separate intervention)</measure>
    <time_frame>30 days, 1 year, 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rehospitalization for valve-related symptoms or worsening congestive heart failure</measure>
    <time_frame>30 days, 1 year, 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Valve-related dysfunction: prosthetic aortic valve stenosis AND/OR ≥ moderate prosthetic valve regurgitation</measure>
    <time_frame>30 days, 1 year, 3 years</time_frame>
    <description>Prosthetic aortic valve stenosis: mean gradient ≥ 20 mmHg, EOA ≤ 0.9-1.1cm2 and/or DVI &lt; 0.35)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Conversion to open heart surgery</measure>
    <time_frame>procedural</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Annular rupture</measure>
    <time_frame>procedural</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New pacemaker implantation</measure>
    <time_frame>30 days, 1 year, 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Valve thrombosis</measure>
    <time_frame>30 days, 1 year, 3 years</time_frame>
    <description>Any thrombus attached to or near an implanted valve that occludes part of the blood flow path, interferes with valve function, or is sufficiently large to warrant treatment. Note that valve-associated thrombus identified at autopsy in a patient whose cause of death was not valve-related should not be reported as valve thrombosis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean trans-prosthetic aortic gradient</measure>
    <time_frame>30 days, 1 year, 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Aortic regurgitation</measure>
    <time_frame>30 days, 1 year, 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 score</measure>
    <time_frame>30 days, 1 year, 3 years</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">739</enrollment>
  <condition>Aortic Valve Stenosis</condition>
  <arm_group>
    <arm_group_label>Symetis ACURATE neo/TF transfemoral TAVI system</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Symetis ACURATE neo/TF transfemoral TAVI system: self-expandable transcatheter aortic bioprosthesis, support frame made of nitinol, supra-annular processed trileaflet porcine pericardial valve and an outer skirt to mitigate paravalvular regurgitation (manufactured by Symetis SA, Ecublens, Switzerland)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Edwards Sapien 3 Transcatheter Heart Valve</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Edwards SAPIEN 3 Transcatheter Heart Valve system: balloon-expandable transcatheter aortic bioprosthesis, support frame made of cobalt-chromium, three leaflets constructed of processed bovine pericardial tissue and an outer polyethylene terephthalate (PET) sealing cuff to mitigate paravalvular regurgitation (manufactured by Edwards Lifesciences, Inc., Irvine, California, USA)</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Symetis ACURATE neo/TF transfemoral TAVI system</intervention_name>
    <description>Transcatheter aortic valve implantation of a Symetis ACURATE neo/TF bioprosthesis by transfemoral access, pre-dilatation mandatory.</description>
    <arm_group_label>Symetis ACURATE neo/TF transfemoral TAVI system</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Edwards Sapien 3 Transcatheter Heart Valve</intervention_name>
    <description>Transcatheter aortic valve implantation of an Edwards Sapien 3 bioprosthesis by transfemoral access.</description>
    <arm_group_label>Edwards Sapien 3 Transcatheter Heart Valve</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient with severe aortic stenosis defined by an aortic valve area (AVA) &lt; 1cm2 or&#xD;
             AVA indexed to body surface area (BSA) of &lt; 0.6 cm2/m2, including low-flow severe&#xD;
             aortic stenosis defined by stroke volume index (SVI) &lt; 35ml/m2, as assessed by&#xD;
             integration of echocardiographic and invasive measurements&#xD;
&#xD;
          -  Subject is symptomatic (heart failure symptoms with New York Heart Association (NYHA)&#xD;
             Functional Class &gt; I, angina or syncope)&#xD;
&#xD;
          -  Patient is considered at increased risk for mortality if undergoing conventional&#xD;
             surgical aortic valve replacement or judged as not operable as determined either&#xD;
&#xD;
               -  by a Logistic EuroSCORE &gt; 20 % OR&#xD;
&#xD;
               -  by a STS-PROM score &gt; 10% OR&#xD;
&#xD;
               -  by the heart team consisting of at least one cardiologist and cardiac surgeon&#xD;
                  based on the integration of individual clinical and anatomical factors not&#xD;
                  captured by risk-scores, the patient's age, frailty and life-expectancy&#xD;
&#xD;
          -  The heart team agrees on eligibility of the patient for participation and that TAVI by&#xD;
             transfemoral access constitutes the most appropriate treatment modality, from which&#xD;
             the patient will likely benefit most&#xD;
&#xD;
          -  Aortic annulus dimensions suitable for both valve types (area range: 338-573 mm2 AND&#xD;
             perimeter range: 66-85 mm) based on ECG-gated multislice computed tomographic&#xD;
             measurements. Findings of transesophageal echocardiography (TEE) and conventional&#xD;
             aortography should be integrated in the anatomic assessment if available&#xD;
&#xD;
          -  Arterial aorto-iliac-femoral axis suitable for transfemoral access with a minimum&#xD;
             access vessel diameter ≥ 6 mm as assessed by multislice computed tomographic&#xD;
             angiography and/or conventional angiography&#xD;
&#xD;
          -  Written informed consent of the patient or her/his legal representative&#xD;
&#xD;
          -  Patient understands the purpose, the potential risks as well as benefits of the trial&#xD;
             and is willing to participate in all parts of the follow-up&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Non-valvular aortic stenosis&#xD;
&#xD;
          -  Congenital aortic stenosis or unicuspid or bicuspid aortic valve&#xD;
&#xD;
          -  Non-calcific acquired aortic stenosis&#xD;
&#xD;
          -  Anatomy not appropriate for transfemoral transcatheter aortic valve implantation due&#xD;
             to size of the aortic annulus or degree or eccentricity of calcification of the native&#xD;
             aortic valve or tortuosity of the aorta or ilio-femoral arteries&#xD;
&#xD;
          -  Emergency procedure including patients in cardiogenic shock (low cardiac output,&#xD;
             vasopressor dependence, mechanical hemodynamic support)&#xD;
&#xD;
          -  Severely reduced left ventricular (LV) function (ejection fraction &lt; 20%)&#xD;
&#xD;
          -  Pre-existing prosthetic heart valve in aortic position&#xD;
&#xD;
          -  Presence of mitral valve prosthesis&#xD;
&#xD;
          -  Concomitant planned procedure except for percutaneous coronary intervention (PCI)&#xD;
&#xD;
          -  Planned non-cardiac surgery within 30 days&#xD;
&#xD;
          -  Stroke within 30 days of the procedure.&#xD;
&#xD;
          -  Myocardial infarction within 30 days of the procedure (except type 2)&#xD;
&#xD;
          -  Evidence of intra-cardiac mass, thrombus or vegetation&#xD;
&#xD;
          -  Severe coagulation conditions&#xD;
&#xD;
          -  Inability to tolerate anticoagulation/anti-platelet therapy&#xD;
&#xD;
          -  Active bacterial endocarditis or other active infections&#xD;
&#xD;
          -  Hypertrophic cardiomyopathy with or without obstruction&#xD;
&#xD;
          -  Contraindication to contrast media or allergy to nitinol&#xD;
&#xD;
          -  Participation in another trial, which would lead to deviations in the preparation or&#xD;
             performance of the intervention or the post-implantation management from this protocol&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>75 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Thomas Pigrim, Prof. MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Bern University Hospital, Dep. of Cardiology, 3010 Bern, Switzerland</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Herz- und Gefäss-Klinik GmbH Bad Neustadt</name>
      <address>
        <city>Bad Neustadt An Der Saale</city>
        <state>Bad Neustadt</state>
        <zip>97616</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinkum Augsburg</name>
      <address>
        <city>Augsburg</city>
        <zip>86156</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Zentralklinik Bad Berka</name>
      <address>
        <city>Bad Berka</city>
        <zip>99437</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Herz- und Gefässzentrum Bad Beversen</name>
      <address>
        <city>Bad Bevensen</city>
        <zip>29549</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kerckhoff-Klinik</name>
      <address>
        <city>Bad Nauheim</city>
        <zip>61231</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St.-Johannes-Hospital</name>
      <address>
        <city>Dortmund</city>
        <zip>44137</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Herzzentrum Dresden</name>
      <address>
        <city>Dresden</city>
        <zip>01307</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitäres Herzzentrum Hamburg GmbH</name>
      <address>
        <city>Hamburg</city>
        <zip>20251</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Städtisches Klinikum Karlsruhe</name>
      <address>
        <city>Karlsruhe</city>
        <zip>76133</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ViDia Kliniken</name>
      <address>
        <city>Karlsruhe</city>
        <zip>76135</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinik für Herzchirurgie Karlsruhe</name>
      <address>
        <city>Karlsruhe</city>
        <zip>76185</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Herzzentrum Uniklinik Köln</name>
      <address>
        <city>Köln</city>
        <zip>50931</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Herzzentrum Leipzig</name>
      <address>
        <city>Leipzig</city>
        <zip>04289</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Deutsches Herzzentrum München</name>
      <address>
        <city>München</city>
        <zip>80636</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinik und Poliklinik für Herz-, Thorax- und herznahe Gefäßchirurgie</name>
      <address>
        <city>Regensburg</city>
        <zip>93053</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Medical Center Utrecht</name>
      <address>
        <city>Utrecht</city>
        <zip>3584 CX</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bern University Hospital</name>
      <address>
        <city>Bern</city>
        <zip>3010</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Luzerner Kantonsspital</name>
      <address>
        <city>Luzern</city>
        <zip>6000</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsspital Zürich</name>
      <address>
        <city>Zürich</city>
        <zip>8091</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St Thomas' Hospital</name>
      <address>
        <city>London</city>
        <zip>SE1 7EH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
    <country>Netherlands</country>
    <country>Switzerland</country>
    <country>United Kingdom</country>
  </location_countries>
  <results_reference>
    <citation>Lanz J, Kim WK, Walther T, Burgdorf C, Mollmann H, Linke A, Redwood S, Thilo C, Hilker M, Joner M, Thiele H, Conzelmann L, Conradi L, Kerber S, Schymik G, Prendergast B, Husser O, Stortecky S, Heg D, Juni P, Windecker S, Pilgrim T; SCOPE I investigators. Safety and efficacy of a self-expanding versus a balloon-expandable bioprosthesis for transcatheter aortic valve replacement in patients with symptomatic severe aortic stenosis: a randomised non-inferiority trial. Lancet. 2019 Nov 2;394(10209):1619-1628. doi: 10.1016/S0140-6736(19)32220-2. Epub 2019 Sep 27.</citation>
    <PMID>31570258</PMID>
  </results_reference>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>January 2, 2017</study_first_submitted>
  <study_first_submitted_qc>January 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 5, 2017</study_first_posted>
  <last_update_submitted>March 9, 2022</last_update_submitted>
  <last_update_submitted_qc>March 9, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 10, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Aortic valve stenosis</keyword>
  <keyword>Transcatheter aortic valve implantation</keyword>
  <keyword>Transcatheter aortic valve replacement</keyword>
  <keyword>Randomized controlled trial</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aortic Valve Stenosis</mesh_term>
  </condition_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/NCT03011346
org study id: V 4.0, 13.08.2018
nct id: NCT03011346
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Transcatheter aortic valve implantation (TAVI) is an established treatment option for
      patients with severe symptomatic aortic stenosis and at increased risk for surgical aortic
      valve replacement (SAVR). Many novel devices are currently being developed and established
      transcatheter heart valves undergo design reiterations to address limitations and reduce
      complication rates associated with the device and implantation procedure. However, device
      comparisons by use of randomized trials are scarce in particular for newer generation
      transcatheter valves. The aim of this study is to assess non-inferiority of the
      self-expandable Symetis ACURATE neo/TF in comparison to the balloon-expandable Edwards SAPIEN
      3 transcatheter aortic valve bioprosthesis with regard to early safety and clinical efficacy
      at 30 days.
Background:

      Transcatheter aortic valve implantation (TAVI) is an established and valuable treatment
      option for patients with severe symptomatic aortic stenosis and at increased risk for
      surgical aortic valve replacement (SAVR). The use of TAVI is rapidly expanding worldwide and
      the indications for TAVI are widening into lower risk populations in view of favorable
      outcomes among high and intermediate risk patients. Many novel devices are currently
      developed or established devices undergo design reiterations to address limitations, such as
      vascular access complications, paravalvular regurgitation, and atrio-ventricular conductance
      disturbances. However, device comparisons by use of randomized trials are scarce in
      particular for newer generation transcatheter valves.

      The Symetis ACURATE neo/TF, a self-expandable transcatheter valve delivered via transfemoral
      access, gained Conformité Européenne (CE) marking in September 2014 after showing favorable
      procedural and short term results. The SCOPE I trial will compare its performance to the
      balloon-expandable Edwards SAPIEN 3, a widely used and well-established transcatheter heart
      valve of the second generation, in a randomized fashion.

      Objectives:

      The primary objective is the comparison of the Symetis ACURATE neo/TF to the Edwards SAPIEN 3
      transcatheter aortic bioprosthesis with regard to early safety and clinical efficacy at 30
      days. Secondary objectives involve the comparison between the two devices with regard to
      secondary clinical and echocardiographic endpoints at 30 days, 1 year and 3 years.

      Methods:

      Sample Size: Based on an anticipated incidence proportion of 22% for the primary
      non-hierarchical composite endpoint at 30 days in both treatment arms, a non-inferiority
      margin of 7.7%, a power of 80%, a one-tailed significance level of α = 0.05, and a low
      attrition rate, the total required sample size amounts to 730 patients.

      Design: Patients will be allocated to the Symetis ACURATE neo/TF or the Edwards SAPIEN 3
      bioprosthesis at a 1:1 ratio by means of a randomly permuted block randomisation stratified
      on study center and Society of Thoracic Surgeons' predicted risk of mortality score
      (STS-PROM) strata (< 3%, ≥ 3 to < 8%, ≥ 8%).

      Analysis: Estimates of the risk-differences between the two treatment arms with regard to the
      primary endpoint will be pooled over the predefined STS-PROM strata by means of the
      Cochran-Mantel-Haenszel method and Wald-type confidence limits will be calculated using the
      Sato variance estimator. The non-inferiority assumption will be tested at a one-sided
      significance level with a type I error rate (α) = 0.05. The analysis of the primary composite
      endpoint will be conducted according to the intention-to-treat (ITT) and the per protocol
      (PP) principle and non-inferiority should be claimed only if met by both.

      In case non-inferiority is established, a superiority analysis will be performed using a
      two-tailed significance level with a type I error rate of α = 0.05. Further secondary
      analyses will evaluate between group differences in relation to demographic, clinical,
      procedural, functional and imaging characteristics. Pre-specified subgroup analyses will be
      conducted by use of appropriate interaction tests contrasting categories of sex, STS-PROM
      score (< 3%, ≥ 3 to < 8%, ≥ 8%), left ventricular ejection fraction (< 50% vs. ≥ 50%), and
      native aortic valve eccentricity index (≤ 0.25 vs. > 0.25).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Modified* combined early safety and clinical efficacy as defined by the Valve Academic Research Consortium-2 (VARC-2)
time frame: 30 days
description: (* "NYHA class III or IV" is omitted due to lack of objectiveness in its ascertainment)
All-cause mortality
All stroke (disabling and non-disabling)
Life-threatening or disabling bleeding
Acute kidney injury (stage 2 or 3, including renal replacement therapy)
Coronary artery obstruction requiring intervention
Major vascular complication
Valve related dysfunction requiring repeat procedure (balloon aortic valvuloplasty, TAVI or SAVR in a separate intervention)
Rehospitalization for valve-related symptoms or worsening congestive heart failure
Valve-related dysfunction: prosthetic aortic valve stenosis (mean gradient ≥ 20 mmHg, effective orifice area ≤ 0.9-1.1cm2 and/or Doppler velocity index < 0.35) AND/OR ≥ moderate prosthetic valve regurgitation)
measure: Device success
time frame: 30 days
description: Combined endpoint composed of:
Absence of procedural mortality AND
Correct positioning of a single prosthetic heart valve into the proper anatomical location AND
Intended performance of the prosthetic heart valve (no prosthesis-patient mismatch and mean aortic valve gradient < 20 mmHg or peak velocity < 3 m/s, AND no moderate or severe prosthetic valve regurgitation)
measure: Early safety
time frame: 30 days
description: Combined endpoint composed of:
All-cause mortality
All stroke (disabling and non-disabling)
Life-threatening or disabling bleeding
Acute kidney injury - stage 2 or 3 (including renal replacement therapy)
Coronary artery obstruction requiring intervention
Major vascular complication
Valve-related dysfunction requiring repeat procedure (balloon aortic valvuloplasty, TAVI, or SAVR)
measure: Clinical efficacy
time frame: 30 days
description: Combined endpoint composed of:
All-cause mortality
All stroke (disabling and non-disabling)
Requiring hospitalizations for valve-related symptoms or worsening congestive heart failure
NYHA class III or IV
Valve-related dysfunction (mean aortic valve gradient ≥ 20 mmHg, effective orifice area (EOA) ≤ 0.9-1.1 cm2 and/or Doppler velocity index (DVI) < 0. 35 m/s, AND/OR moderate or severe prosthetic valve regurgitation)
measure: Time-related valve safety
time frame: 30 days, 1 year
description: Combined endpoint composed of:
Structural valve deterioration (Valve-related dysfunction (mean aortic valve gradient ≥ 20 mmHg, EOA ≤ 0.9-1.1 cm2 (depending on body surface area (BSA)) and/or DVI < 0.35 m/s AND/OR moderate or severe prosthetic valve regurgitation)) OR Requiring repeat procedure (TAVI or SAVR)
Prosthetic valve endocarditis
Prosthetic valve thrombosis
Thrombo-embolic events (e.g. stroke)
VARC bleeding, unless clearly unrelated to valve therapy (e.g. trauma)
measure: All-cause mortality
time frame: 30 days, 1 year, 3 years
measure: All stroke (disabling and non-disabling)
time frame: 30 days, 1 year, 3 years
measure: Life-threatening or disabling bleeding
time frame: 30 days, 1 year, 3 years
description: Fatal bleeding (Bleeding Academic Research Consortium (BARC) type 5)OR
Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or pericardial necessitating pericardiocentesis, or intramuscular with compartment syndrome (BARC type 3b and 3c) OR
Bleeding causing hypovolaemic shock or severe hypotension requiring vasopressors or surgery (BARC type 3b) OR
Overt source of bleeding with drop in haemoglobin ≥5 g/dL or whole blood or packed red blood cells (RBCs) transfusion ≥4 units (BARC type 3b)
measure: Acute kidney injury (stage 2 or 3, including renal replacement therapy)
time frame: 30 days, 1 year, 3 years
description: Stage 2: Increase in serum creatinine to 200-299% (2.0-2.99 × increase compared with baseline) OR Urine output <0.5 mL/kg/h for >12 but <24 h
Stage 3: Increase in serum creatinine to ≥300% (>3 × increase compared with baseline) OR serum creatinine of ≥4.0 mg/dL (≥354 mmol/L) with an acute increase of at least 0.5 mg/dL (44 mmol/L) OR Urine output <0.3 ml/kg/h for ≥24 h OR Anuria for ≥12 h Notes: The increase in creatinine must occur within 48 h. Patients receiving renal replacement therapy are considered to meet Stage 3 criteria irrespective of other criteria.
measure: Coronary artery obstruction requiring intervention
time frame: 30 days, 1 year, 3 years
measure: Major vascular complication
time frame: 30 days, 1 year, 3 years
description: Aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, or new apical aneurysm/pseudo-aneurysm OR
Access-related vascular injury (dissection, stenosis, perforation, rupture, arterio-venous fistula, pseudoaneurysm, haematoma, irreversible nerve injury, compartment syndrome, percutaneous closure device failure) leading to death, life-threatening or major bleeding, visceral ischaemia, or neurological impairment OR
Distal embolization (non-cerebral) from a vascular source requiring surgery or resulting in amputation or irreversible end-organ damage OR
Use of unplanned endovascular or surgical intervention associated with death, major bleeding, visceral ischaemia or neurological impairment OR
Any new ipsilateral lower extremity ischaemia documented by patient symptoms, physical exam, and/or decreased or absent blood flow on lower extremity angiogram OR
Surgery for access site-related nerve injury OR
Permanent access site-related nerve injury
measure: Valve related dysfunction requiring repeat procedure (balloon aortic valvuloplasty, TAVI or SAVR in a separate intervention)
time frame: 30 days, 1 year, 3 years
measure: Rehospitalization for valve-related symptoms or worsening congestive heart failure
time frame: 30 days, 1 year, 3 years
measure: Valve-related dysfunction: prosthetic aortic valve stenosis AND/OR ≥ moderate prosthetic valve regurgitation
time frame: 30 days, 1 year, 3 years
description: Prosthetic aortic valve stenosis: mean gradient ≥ 20 mmHg, EOA ≤ 0.9-1.1cm2 and/or DVI < 0.35)
measure: Conversion to open heart surgery
time frame: procedural
measure: Annular rupture
time frame: procedural
measure: New pacemaker implantation
time frame: 30 days, 1 year, 3 years
measure: Valve thrombosis
time frame: 30 days, 1 year, 3 years
description: Any thrombus attached to or near an implanted valve that occludes part of the blood flow path, interferes with valve function, or is sufficiently large to warrant treatment. Note that valve-associated thrombus identified at autopsy in a patient whose cause of death was not valve-related should not be reported as valve thrombosis.
measure: Mean trans-prosthetic aortic gradient
time frame: 30 days, 1 year, 3 years
measure: Aortic regurgitation
time frame: 30 days, 1 year, 3 years
measure: Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 score
time frame: 30 days, 1 year, 3 years
arm group label: Symetis ACURATE neo/TF transfemoral TAVI system
arm group type: Active Comparator
description: Symetis ACURATE neo/TF transfemoral TAVI system: self-expandable transcatheter aortic bioprosthesis, support frame made of nitinol, supra-annular processed trileaflet porcine pericardial valve and an outer skirt to mitigate paravalvular regurgitation (manufactured by Symetis SA, Ecublens, Switzerland)
arm group label: Edwards Sapien 3 Transcatheter Heart Valve
arm group type: Active Comparator
description: Edwards SAPIEN 3 Transcatheter Heart Valve system: balloon-expandable transcatheter aortic bioprosthesis, support frame made of cobalt-chromium, three leaflets constructed of processed bovine pericardial tissue and an outer polyethylene terephthalate (PET) sealing cuff to mitigate paravalvular regurgitation (manufactured by Edwards Lifesciences, Inc., Irvine, California, USA)
intervention type: Device
intervention name: Symetis ACURATE neo/TF transfemoral TAVI system
description: Transcatheter aortic valve implantation of a Symetis ACURATE neo/TF bioprosthesis by transfemoral access, pre-dilatation mandatory.
arm group label: Symetis ACURATE neo/TF transfemoral TAVI system
intervention type: Device
intervention name: Edwards Sapien 3 Transcatheter Heart Valve
description: Transcatheter aortic valve implantation of an Edwards Sapien 3 bioprosthesis by transfemoral access.
arm group label: Edwards Sapien 3 Transcatheter Heart Valve
criteria: 
gender: All
minimum age: 75 Years
maximum age: N/A
healthy volunteers: No
last name: Thomas Pigrim, Prof. MD
role: Principal Investigator
affiliation: Bern University Hospital, Dep. of Cardiology, 3010 Bern, Switzerland
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country: Germany
country: Netherlands
country: Switzerland
country: United Kingdom
citation: Lanz J, Kim WK, Walther T, Burgdorf C, Mollmann H, Linke A, Redwood S, Thilo C, Hilker M, Joner M, Thiele H, Conzelmann L, Conradi L, Kerber S, Schymik G, Prendergast B, Husser O, Stortecky S, Heg D, Juni P, Windecker S, Pilgrim T; SCOPE I investigators. Safety and efficacy of a self-expanding versus a balloon-expandable bioprosthesis for transcatheter aortic valve replacement in patients with symptomatic severe aortic stenosis: a randomised non-inferiority trial. Lancet. 2019 Nov 2;394(10209):1619-1628. doi: 10.1016/S0140-6736(19)32220-2. Epub 2019 Sep 27.
PMID: 31570258
responsible party type: Sponsor
mesh term: Aortic Valve Stenosis
sharing ipd: No