<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/NCT03800862</url>
  </required_header>
  <id_info>
    <org_study_id>HEVA2018_RJ0002</org_study_id>
    <nct_id>NCT03800862</nct_id>
  </id_info>
  <brief_title>The Evaluation of the Roles of New Cardiac Imaging in Patients With Chest Pain</brief_title>
  <official_title>The Role of Computed Tomography-Derived Fractional Flow Reserve (CT-FFR) and Myocardial Computed Tomographic Perfusion (CTP) in Patients Presenting With Chest Discomfort</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lancaster General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Lancaster General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_unapproved_device>Yes</is_unapproved_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a prospective, observational study designed to evaluate the role of dynamic computed&#xD;
      tomographic perfusion (CTP) and Computed Tomography-Derived Fractional Flow Reserve (CT-FFR)&#xD;
      in patients presenting with chest discomfort.Patients with lesions greater than 50% and who&#xD;
      meet all other inclusion/exclusion criteria will qualify to be a subject in the CTP study&#xD;
      /CT-FFR 49. Those who agree to participate will be scheduled to have the CT-FFR and CTP&#xD;
      performed within sixty days of the initial Coronary CTA procedure. A CTA will be performed at&#xD;
      rest for FFR. The patient will then take approximately a 30 min break. Regadenoson will then&#xD;
      be administered and the dynamic CT procedure will be done for perfusion. If patients are&#xD;
      deemed to be appropriate for invasive angiography by the referring physician, coronary&#xD;
      lesions between 40% and 80% will get a fractional flow measurement performed if indicated on&#xD;
      a clinical basis. Stenosis in vessels less than 1.5 mm will be excluded from the study. The&#xD;
      CT-FFR and CTP will be performed in these patients within 60 days of index coronary&#xD;
      angiography.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Coronary artery computed tomographic angiography (CCTA) is a widely used, highly accurate&#xD;
      technique for the detection of coronary artery disease (CAD), with sensitivity and negative&#xD;
      predictive values of over 90% 1-4. Patients with normal CCTA findings have an excellent&#xD;
      prognosis and do not require further testing for CAD 5. However, like invasive coronary&#xD;
      angiography (CATH), CCTA is an anatomic test and, cannot reliably predict the impairment of&#xD;
      flow (functional significance) of Coronary stenoses.&#xD;
&#xD;
      For this reason, in approximately 15-25% of patients, additional functional testing may be&#xD;
      required after CCTA, usually in the form of stress testing 6-8. Stress testing is commonly&#xD;
      done by exercise or pharmacologic stress with electrocardiographic monitoring and often,&#xD;
      imaging of myocardial perfusion by nuclear scintigraphy (MPI) or detection of abnormal&#xD;
      contraction by echocardiography. Furthermore, in patients with previously known CAD, CCTA&#xD;
      alone is not an adequate test, because in most cases there are multiple lesions that are&#xD;
      possible sources of ischemia. Over the last two decades the number of abnormal stress studies&#xD;
      have decreased substantially from 40.9% in 1991 to 8.7% in 20099. This underscores the need&#xD;
      for an accurate mechanism to identify which patients best benefit from invasive angiography.&#xD;
&#xD;
      Myocardial Computed Tomographic Perfusion (CTP) and Computed Tomography-Derived Fractional&#xD;
      Flow Reserve (CT-FFR) have emerged as promising ways to identify ischemia when there is&#xD;
      coronary disease identified by CCTA. The two tests provide different and perhaps&#xD;
      complimentary information. Fractional Flow Reserve (FFR) measures the difference in flow&#xD;
      created by a coronary stenosis before and after the administration of a vasodilator agent by&#xD;
      measuring the drop in pressure across the stenosis. Coronary Flow Reserve (CFR) measures flow&#xD;
      at maximum vasodilation versus flow at rest in a given arterial tree.&#xD;
&#xD;
      This is a prospective, observational study designed to evaluate the role of dynamic computed&#xD;
      tomographic perfusion (CTP) and Computed Tomography-Derived Fractional Flow Reserve (CT-FFR)&#xD;
      in patients presenting with chest discomfort.Patients with lesions greater than 50% will&#xD;
      qualify to be a subject in the CTP study /CT-FFR 49. Those who agree to participate will be&#xD;
      scheduled to have the CT-FFR and CTP performed within sixty days of the initial Coronary CTA&#xD;
      procedure. A CTA will be performed at rest for FFR. The patient will then take approximately&#xD;
      a 30 min break. Regadenoson will then be administered and the dynamic CT procedure will be&#xD;
      done for perfusion. If patients are deemed to be appropriate for invasive angiography by the&#xD;
      referring physician, coronary lesions between 40% and 80% will get a fractional flow&#xD;
      measurement performed if indicated on a clinical basis. Stenosis in vessels less than 1.5 mm&#xD;
      will be excluded from the study. The CT-FFR and CTP will be performed in these patients&#xD;
      within 60 days of index coronary angiography.&#xD;
&#xD;
      The CT scanner to be used for this study is an Aquilion ONE ViSION edition 320-detector row&#xD;
      scanner with 0.5-mm nominal width detector elements (Toshiba Medical Systems, Otawara,&#xD;
      Japan). The scanner has a minimum rotation time of 275 ms. The CT acquisition software&#xD;
      includes a novel dose reduction technology (Adaptive Iterative Dose Reduction 3D (AIDR 3D)&#xD;
      Toshiba Medical Systems, Otawara, Japan).&#xD;
&#xD;
      Prior to imaging procedures&#xD;
&#xD;
      Patients will have two 18-20 gauge intravenous lines placed, one preferably in an anticubital&#xD;
      vein for contrast administration.&#xD;
&#xD;
      Coronary CTA for FFR&#xD;
&#xD;
      All patients receive sublingual nitroglycerine prior to scanning to ensure coronary&#xD;
      vasodilatation, while additional oral and/or intravenous beta-blockers will be administered&#xD;
      to achieve a pre-scan heart rate of &lt;75 beats per minute (bpm).&#xD;
&#xD;
      For CT-FFR, a standard protocol for coronary CTA will be applied, according to the&#xD;
      established protocol at Lancaster General Hospital. Prior to the scan, an automated bolus&#xD;
      tracking algorithm (SUREStart) will be used to time the image acquisition to occur during the&#xD;
      arterial phase at or near peak contrast. Scan parameters will be as follows: single heart&#xD;
      beat half-scan volume acquisition mode with detector collimation 320 x 0.5 mm or less as&#xD;
      necessary to cover heart (typically 120 mm); tube voltage 100-120 kV; gantry rotation time&#xD;
      270 ms. To adjust for patient size, tube potential (kV) and tube current (mA) are determined&#xD;
      with use of automatic exposure control (SUREExposure3D, and SUREkV, Toshiba Medical Systems).&#xD;
      These features reduce variances in image quality by adjusting the acquisition parameters for&#xD;
      body habitus.&#xD;
&#xD;
      Prospective electrocardiogram (ECG) triggering will be used to obtain 70-99% of the R-R&#xD;
      interval. Radiation dose relevant indices (CT dose index (CTDI vol), dose length product&#xD;
      (DLP), and patient size) will be obtained for each examination. Size Specific Dose Estimates&#xD;
      (SSD) and Effective Dose (ED) will be calculated by using conversion factors according to&#xD;
      standard methodology.&#xD;
&#xD;
      Four phases of the R-R Interval (RR) will be reconstructed covering the range from 70% - 99%&#xD;
      (typically 70%, 80%, 90%, and 99%). Reconstruction parameters will be as follows: Medium&#xD;
      Calibrated Field of View (CFOV), Filter Convolution (FC) 03 reconstruction kernel, 0.5 mm&#xD;
      acquisition thickness with 0.25mm interval, AIDR 3D iterative reconstruction. Adaptive motion&#xD;
      correction and FIRST will be used if available.&#xD;
&#xD;
      Dynamic CTP procedure&#xD;
&#xD;
      The CTP procedure involves infusion of a stress agent and a contrast bolus prior to image&#xD;
      acquisition. See Figure 2 for a representation of the CTP procedure, and Table 1 for CTP&#xD;
      parameters.&#xD;
&#xD;
      No stress agent is FDA-approved specifically for use in CT perfusion. The investigator's&#xD;
      choice of stress agent for this study is regadenoson (Lexiscan), a vasodilator widely used in&#xD;
      standard-of-care nuclear stress testing. It has been used previously in CT perfusion (12).&#xD;
      Regadenoson was chosen for its ease of use and its favorable safety/tolerability profile in&#xD;
      patients (37). Its mechanism of action is vasodilation of the coronary vasculature and&#xD;
      augmentation of coronary blood flow. Arteries with hemodynamically significant stenosis are&#xD;
      not as capable of augmenting flow, resulting in relative under-perfusion in the downstream&#xD;
      territory.&#xD;
&#xD;
      The invesitgators will use the standard intravenous dose of Lexiscan recommended for use in&#xD;
      nuclear stress testing in this population, which is 5 ml (0.4 mg). Lexiscan, which comes in a&#xD;
      prefilled 5 ml syringe containing 0.4 mg of regadenoson, is administered as a rapid&#xD;
      (approximately 10-15 seconds) injection into a peripheral vein followed immediately by a 5 ml&#xD;
      saline flush. Addendum 1 gives detailed study procedures for myocardial CT perfusion,&#xD;
      including the use of Lexiscan, and Addendum 2 gives the Lancaster General Hospital Lexiscan&#xD;
      Administration Guidelines.&#xD;
&#xD;
      A 12 lead ECG will be performed at baseline. After this, rhythm monitor leads for CT will be&#xD;
      placed. Patient will be positioned supine on the on the CT gantry with continuous ECG&#xD;
      monitoring after the baseline ECG is performed as above. If heart rate is greater than 65&#xD;
      beats/minute and blood pressure is greater than 100/60 mm of mercury metoprolol will be&#xD;
      administered as per established Lancaster General Health (LGH) protocol for Coronary CTA.&#xD;
      Regadenoson will be injected at 0.4 mg / ml followed by 5 ml saline Flush. One minute after&#xD;
      regadenoson administration the scanner will be instructed to acquire the heart rate and&#xD;
      adjust the gantry rotation time. If patients is stable and has a steady heart rate, 50 cc of&#xD;
      contrast will be administered no later than 1.5 minutes after the administration of&#xD;
      regadenoson followed by 30 cc - 50 cc of normal saline. The rate of injection for both&#xD;
      contrast and saline is 6m/s. A prospectively gated scan will be performed at 70% - 80% of the&#xD;
      R - R cycle for every heart beat for a total of 25 seconds. Myocardial Blood flow will be&#xD;
      calculated for 17 segments (Table I) . A 12 lead ECG will be obtained immediately after&#xD;
      acquisition of images and each subsequent minute for 5 minutes. In the event of ECG changes,&#xD;
      the ECG will be repeated every 60 to 90 seconds until it returns to baseline.&#xD;
&#xD;
      For patients who experience stress induced adverse reactions during CTP, aminophylline will&#xD;
      be administered IV by a co-investigator physician at a dose of 50-250 mg, using the lowest&#xD;
      effective dose. Intravenous Aminophylline is a non-selective phosphodiesterase inhibitor that&#xD;
      is FDA approved for the treatment of symptoms and reversible airway obstruction due to asthma&#xD;
      and other chronic lung diseases. In addition, it is widely accepted as the primary reversal&#xD;
      agent of adenosine, dipyridamole, and regadenoson when patients experience pharmacologic&#xD;
      vasodilator stress induced adverse reactions during nuclear cardiac stress testing. The dose&#xD;
      used for reactions during stress testing, and which the investigator will use for reactions&#xD;
      during CTP, is lower than the FDA approved dose of 5.7 mg/kg dose used in patients with acute&#xD;
      symptoms of lung disease.&#xD;
&#xD;
      The CTP examination will be graded using the standard 17-segment myocardial model recommended&#xD;
      by the American College of Cardiology Foundation / American Heart Association for nuclear&#xD;
      myocardial perfusion and stress echocardiography, in comparison to the myocardial appearance&#xD;
      from the baseline coronary CTA. Areas of myocardial hypo-enhancement (decreased CT signal)&#xD;
      under hyperemic conditions (coronary vasodilation during the regadenoson infusion) indicate&#xD;
      possible ischemia.&#xD;
&#xD;
      Clinical follow-up&#xD;
&#xD;
      If clinically indicated by the initial CCTA and the study CTP, the invasive angiography will&#xD;
      be performed at the discretion of the evaluating cardiologist based on a clinical evaluation.&#xD;
      Lesions between 40% and 80% will have an FFR. Patients' coronary angiography and FFR will be&#xD;
      as per the protocol in Penn Medicine Lancaster General Health.&#xD;
&#xD;
      Long Term Follow-up&#xD;
&#xD;
      Patients medical charts will be reviewed for long term cardiac related outcomes (MACE events,&#xD;
      etc) 1 year after the study procedure. This will not require direct participation from the&#xD;
      patient.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    PI departure from institution + Enrollment Challenges&#xD;
  </why_stopped>
  <start_date type="Actual">March 27, 2019</start_date>
  <completion_date type="Actual">October 27, 2022</completion_date>
  <primary_completion_date type="Actual">October 27, 2022</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>Performance of dynamic CTP and CT-FFR for each vessel assessed in patients presenting with chest pain.</measure>
    <time_frame>Day of imaging (processing of CT-FFR images and reading of CTP images expected to be performed within 48 hours of imaging)</time_frame>
    <description>Performance of CT-FFR compared to CTP for each vessel assessed, as per the below common suite of measures: sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, discrimination</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cardiac Long Term Outcomes</measure>
    <time_frame>MACE: One year from imaging; Performance compared to invasive FFR: Day of imaging for CT-FFR and CTP, invasive FFR performed within 60 days of imaging; Agreement in imaging subsets: Day of imaging</time_frame>
    <description>One-year incidence of MACE events for subjects that undergo CTP and CT-FFR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compare measures of CTP and CT-FFR with Coronary Angiography and invasive FFR (in cases where clinically indicated)</measure>
    <time_frame>MACE: One year from imaging; Performance compared to invasive FFR: Day of imaging for CT-FFR and CTP, invasive FFR performed within 60 days of imaging; Agreement in imaging subsets: Day of imaging</time_frame>
    <description>Sensitivity, specificity, PPV, NPV, accuracy, and discrimination of CTP and CT-FFR compared to invasive FFR. Invasive FFR results may be obtained during Coronary Angiography in cases where clinically indicated. If FFR is not performed by invasive angiography a reference standard of &gt;50% stenosis by invasive coronary angiography will be taken when conventional stress testing has demonstrated ischemia in the distribution supplied by the vessel with stenosis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Outcome agreement CTP and CT-FFR (when CT-FFR values are &lt;.80 and &gt;0.80</measure>
    <time_frame>MACE: One year from imaging; Performance compared to invasive FFR: Day of imaging for CT-FFR and CTP, invasive FFR performed within 60 days of imaging; Agreement in imaging subsets: Day of imaging</time_frame>
    <description>Agreement between CTP and CT-FFR when CT-FFR values are &lt; .80 and &gt;0.80.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">14</enrollment>
  <condition>Cardiology</condition>
  <condition>Radiology</condition>
  <condition>Stenoses</condition>
  <arm_group>
    <arm_group_label>CTP and CT-FFR</arm_group_label>
    <description>This will be a prospective, observational study designed to include a convenience sample of all qualifying patients undergoing myocardial CTP and CT-FFR.&#xD;
The study will enroll patients who have chest discomfort and will require further evaluation for the presence of coronary artery disease. Patients in the study will include those who have had a clinically indicated CCTA for suspicion of coronary artery disease and are determined to have a coronary stenosis ≥50% and ≤99%. However, patients with Left main disease greater than 50% and occluded vessels Coronary Artery Disease Reporting and Data System (CAD RADS 5) will be excluded from the study. CCTA is a clinically indicated and standard of care procedure at Lancaster General Hospital.&#xD;
.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>CT-FFR and CTP</intervention_name>
    <description>Those who agree to participate will be scheduled to have the CT-FFR and CTP performed within sixty days of the initial Coronary CTA procedure. A CTA will be performed at rest for FFR. The patient will then take approximately a 30 min break. Regadenoson will then be administered and the dynamic CT procedure will be done for perfusion.</description>
    <arm_group_label>CTP and CT-FFR</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        The study will enroll patients who have chest discomfort and will require further&#xD;
        evaluation for the presence of coronary artery disease. Patients in the study will include&#xD;
        those who have had a clinically indicated CCTA for suspicion of coronary artery disease and&#xD;
        are determined to have a coronary stenosis ≥50% and ≤99%. However, patients with Left main&#xD;
        disease greater than 50% and occluded vessels (CAD RADS 5) will be excluded from the study.&#xD;
        CCTA is a clinically indicated and standard of care procedure at Lancaster General&#xD;
        Hospital. See Figure 2 for CT Perfusion Workflows at Lancaster General Hospital.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age 45 - 85 years.&#xD;
&#xD;
          2. Clinically indicated coronary CTA with one or more lesions greater than 50% in the&#xD;
             epicardial vessels.&#xD;
&#xD;
          3. Referring physician agreement to approach the patient for consent.&#xD;
&#xD;
          4. Informed consent from the patient or authorized representative.&#xD;
&#xD;
          5. Scheduled CTA for CT-FFR and CTP within 60 days of the clinically indicated CCTA and&#xD;
             prior to any indicated coronary angiography.&#xD;
&#xD;
             -&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. CCTA complication. After an observation period of at least 20 minutes after the index&#xD;
             CCTA, any evidence of MACE, allergy, or any other untoward clinical event that reduces&#xD;
             CTP safety or suitability (as defined by attending physician) will exclude a patient&#xD;
             from eligibility.&#xD;
&#xD;
          2. Medical record of acute ischemia as evidenced on ECG or positive cardiac biomarkers in&#xD;
             the interim between index CCTA and CTA for CT-FFR and CTP. Electrocardiographic&#xD;
             evidence of acute ischemia includes acute STEMI (ST elevation equal to or greater than&#xD;
             1mm in two or more leads), ST segment depression and/or T wave inversion (not known to&#xD;
             be old and thought to be evidence of ongoing ischemia). Positive cardiac biomarkers&#xD;
             include elevated troponin, myoglobin).&#xD;
&#xD;
          3. History of asthma or chronic obstructive pulmonary disease requiring bronchodilators&#xD;
             or steroid therapy within the past 3 months.&#xD;
&#xD;
          4. Inability to tolerate beta blockers.&#xD;
&#xD;
          5. Atrio-ventricular block (Type II-III), prolonged QT interval or sick sinus syndrome.&#xD;
&#xD;
          6. Renal insufficiency (creatinine ≥1.6 and/or, Glomerular Filtration Rate (GFR) &lt; 60&#xD;
             ml/m) or renal failure requiring dialysis&#xD;
&#xD;
          7. Atrial fibrillation or other markedly irregular rhythm.&#xD;
&#xD;
          8. Psychological unsuitability or extreme claustrophobia.&#xD;
&#xD;
          9. BMI &gt; 35.&#xD;
&#xD;
         10. Pregnancy or unknown pregnancy status.&#xD;
&#xD;
         11. Clinical instability as deemed by the attending physician; including but not limited&#xD;
             to: cardiogenic shock, hypotension (systolic blood pressure &lt; 90 mmHg), refractory&#xD;
             hypertension (systolic blood pressure &gt; 180 mmHg), sustained ventricular or atrial&#xD;
             arrhythmia requiring intravenous medications.&#xD;
&#xD;
         12. Use of Viagra or Cialis in the past 24 hours.&#xD;
&#xD;
         13. Known history of allergy or adverse reactions to x-ray dye, regadenoson or&#xD;
             aminophylline.&#xD;
&#xD;
         14. Use of caffeine within the previous 12 hours (inactivates regadenoson).&#xD;
&#xD;
         15. History of severe aortic stenosis.&#xD;
&#xD;
         16. Left main disease greater than 50% and occluded vessels (CAD RADS 5) identified by&#xD;
             index Coronary CTA&#xD;
&#xD;
         17. Left Ventricular Ejection Fraction (LVEF) of less than 30%.&#xD;
&#xD;
         18. Significant radiation exposure in the past 18 months (&gt;5 rems OR 2 nuclear or CT&#xD;
             studies)&#xD;
&#xD;
         19. Contraindication to CT-FFR: History of myocardial infarction (MI), chronic total&#xD;
             occlusions (CTO), stent insertion or PCI, coronary artery bypass grafting (CABG), or&#xD;
             arrhythmias; presence of anomalous coronary arteries, anomalous origins of the&#xD;
             coronary arteries, or a single coronary artery.&#xD;
&#xD;
             -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>45 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ron M Jacob, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Penn Medicine/Lancaster General Health</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Penn Medicine / Lancaster General Hospital</name>
      <address>
        <city>Lancaster</city>
        <state>Pennsylvania</state>
        <zip>17602</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Budoff MJ, Dowe D, Jollis JG, Gitter M, Sutherland J, Halamert E, Scherer M, Bellinger R, Martin A, Benton R, Delago A, Min JK. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol. 2008 Nov 18;52(21):1724-32. doi: 10.1016/j.jacc.2008.07.031.</citation>
    <PMID>19007693</PMID>
  </reference>
  <reference>
    <citation>Hamon M, Biondi-Zoccai GG, Malagutti P, Agostoni P, Morello R, Valgimigli M, Hamon M. Diagnostic performance of multislice spiral computed tomography of coronary arteries as compared with conventional invasive coronary angiography: a meta-analysis. J Am Coll Cardiol. 2006 Nov 7;48(9):1896-910. doi: 10.1016/j.jacc.2006.08.028. Epub 2006 Sep 26.</citation>
    <PMID>17084268</PMID>
  </reference>
  <reference>
    <citation>Meijboom WB, Meijs MF, Schuijf JD, Cramer MJ, Mollet NR, van Mieghem CA, Nieman K, van Werkhoven JM, Pundziute G, Weustink AC, de Vos AM, Pugliese F, Rensing B, Jukema JW, Bax JJ, Prokop M, Doevendans PA, Hunink MG, Krestin GP, de Feyter PJ. Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study. J Am Coll Cardiol. 2008 Dec 16;52(25):2135-44. doi: 10.1016/j.jacc.2008.08.058.</citation>
    <PMID>19095130</PMID>
  </reference>
  <reference>
    <citation>Miller JM, Rochitte CE, Dewey M, Arbab-Zadeh A, Niinuma H, Gottlieb I, Paul N, Clouse ME, Shapiro EP, Hoe J, Lardo AC, Bush DE, de Roos A, Cox C, Brinker J, Lima JA. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med. 2008 Nov 27;359(22):2324-36. doi: 10.1056/NEJMoa0806576.</citation>
    <PMID>19038879</PMID>
  </reference>
  <reference>
    <citation>Abdulla J, Asferg C, Kofoed KF. Prognostic value of absence or presence of coronary artery disease determined by 64-slice computed tomography coronary angiography a systematic review and meta-analysis. Int J Cardiovasc Imaging. 2011 Mar;27(3):413-20. doi: 10.1007/s10554-010-9652-x. Epub 2010 Jun 12.</citation>
    <PMID>20549366</PMID>
  </reference>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>December 17, 2018</study_first_submitted>
  <study_first_submitted_qc>January 10, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 11, 2019</study_first_posted>
  <last_update_submitted>December 22, 2022</last_update_submitted>
  <last_update_submitted_qc>December 22, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 27, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Stenoses</keyword>
  <keyword>Chest pain</keyword>
  <keyword>Myocardial Infarction</keyword>
  <keyword>Heart Attack</keyword>
  <keyword>Radiology</keyword>
  <keyword>Cardiac Imaging</keyword>
  <keyword>Coronary artery disease</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Constriction, Pathologic</mesh_term>
    <mesh_term>Chest Pain</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/NCT03800862
org study id: HEVA2018_RJ0002
nct id: NCT03800862
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
is unapproved device: Yes
This is a prospective, observational study designed to evaluate the role of dynamic computed
      tomographic perfusion (CTP) and Computed Tomography-Derived Fractional Flow Reserve (CT-FFR)
      in patients presenting with chest discomfort.Patients with lesions greater than 50% and who
      meet all other inclusion/exclusion criteria will qualify to be a subject in the CTP study
      /CT-FFR 49. Those who agree to participate will be scheduled to have the CT-FFR and CTP
      performed within sixty days of the initial Coronary CTA procedure. A CTA will be performed at
      rest for FFR. The patient will then take approximately a 30 min break. Regadenoson will then
      be administered and the dynamic CT procedure will be done for perfusion. If patients are
      deemed to be appropriate for invasive angiography by the referring physician, coronary
      lesions between 40% and 80% will get a fractional flow measurement performed if indicated on
      a clinical basis. Stenosis in vessels less than 1.5 mm will be excluded from the study. The
      CT-FFR and CTP will be performed in these patients within 60 days of index coronary
      angiography.
Coronary artery computed tomographic angiography (CCTA) is a widely used, highly accurate
      technique for the detection of coronary artery disease (CAD), with sensitivity and negative
      predictive values of over 90% 1-4. Patients with normal CCTA findings have an excellent
      prognosis and do not require further testing for CAD 5. However, like invasive coronary
      angiography (CATH), CCTA is an anatomic test and, cannot reliably predict the impairment of
      flow (functional significance) of Coronary stenoses.

      For this reason, in approximately 15-25% of patients, additional functional testing may be
      required after CCTA, usually in the form of stress testing 6-8. Stress testing is commonly
      done by exercise or pharmacologic stress with electrocardiographic monitoring and often,
      imaging of myocardial perfusion by nuclear scintigraphy (MPI) or detection of abnormal
      contraction by echocardiography. Furthermore, in patients with previously known CAD, CCTA
      alone is not an adequate test, because in most cases there are multiple lesions that are
      possible sources of ischemia. Over the last two decades the number of abnormal stress studies
      have decreased substantially from 40.9% in 1991 to 8.7% in 20099. This underscores the need
      for an accurate mechanism to identify which patients best benefit from invasive angiography.

      Myocardial Computed Tomographic Perfusion (CTP) and Computed Tomography-Derived Fractional
      Flow Reserve (CT-FFR) have emerged as promising ways to identify ischemia when there is
      coronary disease identified by CCTA. The two tests provide different and perhaps
      complimentary information. Fractional Flow Reserve (FFR) measures the difference in flow
      created by a coronary stenosis before and after the administration of a vasodilator agent by
      measuring the drop in pressure across the stenosis. Coronary Flow Reserve (CFR) measures flow
      at maximum vasodilation versus flow at rest in a given arterial tree.

      This is a prospective, observational study designed to evaluate the role of dynamic computed
      tomographic perfusion (CTP) and Computed Tomography-Derived Fractional Flow Reserve (CT-FFR)
      in patients presenting with chest discomfort.Patients with lesions greater than 50% will
      qualify to be a subject in the CTP study /CT-FFR 49. Those who agree to participate will be
      scheduled to have the CT-FFR and CTP performed within sixty days of the initial Coronary CTA
      procedure. A CTA will be performed at rest for FFR. The patient will then take approximately
      a 30 min break. Regadenoson will then be administered and the dynamic CT procedure will be
      done for perfusion. If patients are deemed to be appropriate for invasive angiography by the
      referring physician, coronary lesions between 40% and 80% will get a fractional flow
      measurement performed if indicated on a clinical basis. Stenosis in vessels less than 1.5 mm
      will be excluded from the study. The CT-FFR and CTP will be performed in these patients
      within 60 days of index coronary angiography.

      The CT scanner to be used for this study is an Aquilion ONE ViSION edition 320-detector row
      scanner with 0.5-mm nominal width detector elements (Toshiba Medical Systems, Otawara,
      Japan). The scanner has a minimum rotation time of 275 ms. The CT acquisition software
      includes a novel dose reduction technology (Adaptive Iterative Dose Reduction 3D (AIDR 3D)
      Toshiba Medical Systems, Otawara, Japan).

      Prior to imaging procedures

      Patients will have two 18-20 gauge intravenous lines placed, one preferably in an anticubital
      vein for contrast administration.

      Coronary CTA for FFR

      All patients receive sublingual nitroglycerine prior to scanning to ensure coronary
      vasodilatation, while additional oral and/or intravenous beta-blockers will be administered
      to achieve a pre-scan heart rate of <75 beats per minute (bpm).

      For CT-FFR, a standard protocol for coronary CTA will be applied, according to the
      established protocol at Lancaster General Hospital. Prior to the scan, an automated bolus
      tracking algorithm (SUREStart) will be used to time the image acquisition to occur during the
      arterial phase at or near peak contrast. Scan parameters will be as follows: single heart
      beat half-scan volume acquisition mode with detector collimation 320 x 0.5 mm or less as
      necessary to cover heart (typically 120 mm); tube voltage 100-120 kV; gantry rotation time
      270 ms. To adjust for patient size, tube potential (kV) and tube current (mA) are determined
      with use of automatic exposure control (SUREExposure3D, and SUREkV, Toshiba Medical Systems).
      These features reduce variances in image quality by adjusting the acquisition parameters for
      body habitus.

      Prospective electrocardiogram (ECG) triggering will be used to obtain 70-99% of the R-R
      interval. Radiation dose relevant indices (CT dose index (CTDI vol), dose length product
      (DLP), and patient size) will be obtained for each examination. Size Specific Dose Estimates
      (SSD) and Effective Dose (ED) will be calculated by using conversion factors according to
      standard methodology.

      Four phases of the R-R Interval (RR) will be reconstructed covering the range from 70% - 99%
      (typically 70%, 80%, 90%, and 99%). Reconstruction parameters will be as follows: Medium
      Calibrated Field of View (CFOV), Filter Convolution (FC) 03 reconstruction kernel, 0.5 mm
      acquisition thickness with 0.25mm interval, AIDR 3D iterative reconstruction. Adaptive motion
      correction and FIRST will be used if available.

      Dynamic CTP procedure

      The CTP procedure involves infusion of a stress agent and a contrast bolus prior to image
      acquisition. See Figure 2 for a representation of the CTP procedure, and Table 1 for CTP
      parameters.

      No stress agent is FDA-approved specifically for use in CT perfusion. The investigator's
      choice of stress agent for this study is regadenoson (Lexiscan), a vasodilator widely used in
      standard-of-care nuclear stress testing. It has been used previously in CT perfusion (12).
      Regadenoson was chosen for its ease of use and its favorable safety/tolerability profile in
      patients (37). Its mechanism of action is vasodilation of the coronary vasculature and
      augmentation of coronary blood flow. Arteries with hemodynamically significant stenosis are
      not as capable of augmenting flow, resulting in relative under-perfusion in the downstream
      territory.

      The invesitgators will use the standard intravenous dose of Lexiscan recommended for use in
      nuclear stress testing in this population, which is 5 ml (0.4 mg). Lexiscan, which comes in a
      prefilled 5 ml syringe containing 0.4 mg of regadenoson, is administered as a rapid
      (approximately 10-15 seconds) injection into a peripheral vein followed immediately by a 5 ml
      saline flush. Addendum 1 gives detailed study procedures for myocardial CT perfusion,
      including the use of Lexiscan, and Addendum 2 gives the Lancaster General Hospital Lexiscan
      Administration Guidelines.

      A 12 lead ECG will be performed at baseline. After this, rhythm monitor leads for CT will be
      placed. Patient will be positioned supine on the on the CT gantry with continuous ECG
      monitoring after the baseline ECG is performed as above. If heart rate is greater than 65
      beats/minute and blood pressure is greater than 100/60 mm of mercury metoprolol will be
      administered as per established Lancaster General Health (LGH) protocol for Coronary CTA.
      Regadenoson will be injected at 0.4 mg / ml followed by 5 ml saline Flush. One minute after
      regadenoson administration the scanner will be instructed to acquire the heart rate and
      adjust the gantry rotation time. If patients is stable and has a steady heart rate, 50 cc of
      contrast will be administered no later than 1.5 minutes after the administration of
      regadenoson followed by 30 cc - 50 cc of normal saline. The rate of injection for both
      contrast and saline is 6m/s. A prospectively gated scan will be performed at 70% - 80% of the
      R - R cycle for every heart beat for a total of 25 seconds. Myocardial Blood flow will be
      calculated for 17 segments (Table I) . A 12 lead ECG will be obtained immediately after
      acquisition of images and each subsequent minute for 5 minutes. In the event of ECG changes,
      the ECG will be repeated every 60 to 90 seconds until it returns to baseline.

      For patients who experience stress induced adverse reactions during CTP, aminophylline will
      be administered IV by a co-investigator physician at a dose of 50-250 mg, using the lowest
      effective dose. Intravenous Aminophylline is a non-selective phosphodiesterase inhibitor that
      is FDA approved for the treatment of symptoms and reversible airway obstruction due to asthma
      and other chronic lung diseases. In addition, it is widely accepted as the primary reversal
      agent of adenosine, dipyridamole, and regadenoson when patients experience pharmacologic
      vasodilator stress induced adverse reactions during nuclear cardiac stress testing. The dose
      used for reactions during stress testing, and which the investigator will use for reactions
      during CTP, is lower than the FDA approved dose of 5.7 mg/kg dose used in patients with acute
      symptoms of lung disease.

      The CTP examination will be graded using the standard 17-segment myocardial model recommended
      by the American College of Cardiology Foundation / American Heart Association for nuclear
      myocardial perfusion and stress echocardiography, in comparison to the myocardial appearance
      from the baseline coronary CTA. Areas of myocardial hypo-enhancement (decreased CT signal)
      under hyperemic conditions (coronary vasodilation during the regadenoson infusion) indicate
      possible ischemia.

      Clinical follow-up

      If clinically indicated by the initial CCTA and the study CTP, the invasive angiography will
      be performed at the discretion of the evaluating cardiologist based on a clinical evaluation.
      Lesions between 40% and 80% will have an FFR. Patients' coronary angiography and FFR will be
      as per the protocol in Penn Medicine Lancaster General Health.

      Long Term Follow-up

      Patients medical charts will be reviewed for long term cardiac related outcomes (MACE events,
      etc) 1 year after the study procedure. This will not require direct participation from the
      patient.
observational model: Cohort
time perspective: Prospective
measure: Performance of dynamic CTP and CT-FFR for each vessel assessed in patients presenting with chest pain.
time frame: Day of imaging (processing of CT-FFR images and reading of CTP images expected to be performed within 48 hours of imaging)
description: Performance of CT-FFR compared to CTP for each vessel assessed, as per the below common suite of measures: sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, discrimination
measure: Cardiac Long Term Outcomes
time frame: MACE: One year from imaging; Performance compared to invasive FFR: Day of imaging for CT-FFR and CTP, invasive FFR performed within 60 days of imaging; Agreement in imaging subsets: Day of imaging
description: One-year incidence of MACE events for subjects that undergo CTP and CT-FFR.
measure: Compare measures of CTP and CT-FFR with Coronary Angiography and invasive FFR (in cases where clinically indicated)
time frame: MACE: One year from imaging; Performance compared to invasive FFR: Day of imaging for CT-FFR and CTP, invasive FFR performed within 60 days of imaging; Agreement in imaging subsets: Day of imaging
description: Sensitivity, specificity, PPV, NPV, accuracy, and discrimination of CTP and CT-FFR compared to invasive FFR. Invasive FFR results may be obtained during Coronary Angiography in cases where clinically indicated. If FFR is not performed by invasive angiography a reference standard of >50% stenosis by invasive coronary angiography will be taken when conventional stress testing has demonstrated ischemia in the distribution supplied by the vessel with stenosis.
measure: Outcome agreement CTP and CT-FFR (when CT-FFR values are <.80 and >0.80
time frame: MACE: One year from imaging; Performance compared to invasive FFR: Day of imaging for CT-FFR and CTP, invasive FFR performed within 60 days of imaging; Agreement in imaging subsets: Day of imaging
description: Agreement between CTP and CT-FFR when CT-FFR values are < .80 and >0.80.
arm group label: CTP and CT-FFR
description: This will be a prospective, observational study designed to include a convenience sample of all qualifying patients undergoing myocardial CTP and CT-FFR.
The study will enroll patients who have chest discomfort and will require further evaluation for the presence of coronary artery disease. Patients in the study will include those who have had a clinically indicated CCTA for suspicion of coronary artery disease and are determined to have a coronary stenosis ≥50% and ≤99%. However, patients with Left main disease greater than 50% and occluded vessels Coronary Artery Disease Reporting and Data System (CAD RADS 5) will be excluded from the study. CCTA is a clinically indicated and standard of care procedure at Lancaster General Hospital.
.
intervention type: Device
intervention name: CT-FFR and CTP
description: Those who agree to participate will be scheduled to have the CT-FFR and CTP performed within sixty days of the initial Coronary CTA procedure. A CTA will be performed at rest for FFR. The patient will then take approximately a 30 min break. Regadenoson will then be administered and the dynamic CT procedure will be done for perfusion.
arm group label: CTP and CT-FFR
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 45 Years
maximum age: 85 Years
healthy volunteers: No
last name: Ron M Jacob, MD
role: Principal Investigator
affiliation: Penn Medicine/Lancaster General Health
facility: 
country: United States
citation: Budoff MJ, Dowe D, Jollis JG, Gitter M, Sutherland J, Halamert E, Scherer M, Bellinger R, Martin A, Benton R, Delago A, Min JK. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol. 2008 Nov 18;52(21):1724-32. doi: 10.1016/j.jacc.2008.07.031.
PMID: 19007693
citation: Hamon M, Biondi-Zoccai GG, Malagutti P, Agostoni P, Morello R, Valgimigli M, Hamon M. Diagnostic performance of multislice spiral computed tomography of coronary arteries as compared with conventional invasive coronary angiography: a meta-analysis. J Am Coll Cardiol. 2006 Nov 7;48(9):1896-910. doi: 10.1016/j.jacc.2006.08.028. Epub 2006 Sep 26.
PMID: 17084268
citation: Meijboom WB, Meijs MF, Schuijf JD, Cramer MJ, Mollet NR, van Mieghem CA, Nieman K, van Werkhoven JM, Pundziute G, Weustink AC, de Vos AM, Pugliese F, Rensing B, Jukema JW, Bax JJ, Prokop M, Doevendans PA, Hunink MG, Krestin GP, de Feyter PJ. Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study. J Am Coll Cardiol. 2008 Dec 16;52(25):2135-44. doi: 10.1016/j.jacc.2008.08.058.
PMID: 19095130
citation: Miller JM, Rochitte CE, Dewey M, Arbab-Zadeh A, Niinuma H, Gottlieb I, Paul N, Clouse ME, Shapiro EP, Hoe J, Lardo AC, Bush DE, de Roos A, Cox C, Brinker J, Lima JA. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med. 2008 Nov 27;359(22):2324-36. doi: 10.1056/NEJMoa0806576.
PMID: 19038879
citation: Abdulla J, Asferg C, Kofoed KF. Prognostic value of absence or presence of coronary artery disease determined by 64-slice computed tomography coronary angiography a systematic review and meta-analysis. Int J Cardiovasc Imaging. 2011 Mar;27(3):413-20. doi: 10.1007/s10554-010-9652-x. Epub 2010 Jun 12.
PMID: 20549366
responsible party type: Sponsor
mesh term: Constriction, Pathologic
mesh term: Chest Pain
sharing ipd: No