<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/NCT02989740</url>
  </required_header>
  <id_info>
    <org_study_id>9241</org_study_id>
    <nct_id>NCT02989740</nct_id>
  </id_info>
  <brief_title>Optical Coherence Tomography Morphologic and Fractional Flow Reserve Assessment in Diabetes Mellitus Patients</brief_title>
  <acronym>COMBINE</acronym>
  <official_title>Combined Optical Coherence Tomography Morphologic and Fractional Flow Reserve Hemodynamic Assessment of Non-Culprit Lesions to Better Predict Adverse Event Outcomes in Diabetes Mellitus Patients. COMBINE (OCT-FFR) Prospective Register</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Diagram B.V.</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Isala</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>St. Jude Medical Nederland B.V.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Diagram B.V.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Title:&#xD;
&#xD;
      Combined Optical Coherence Tomography Morphologic and Fractional Flow Reserve Hemodynamic&#xD;
      Assessment of Non-Culprit Lesions to Better Predict Adverse Event Outcomes in Diabetes&#xD;
      Mellitus Patients COMBINE (OCT-FFR) Prospective Register&#xD;
&#xD;
      To study the natural evolution of patients with at least one intermediate angiographic but&#xD;
      non-hemodynamic significant stenotic lesion, in two subgroups of patients, with TCFA vs. no&#xD;
      TCFA as detected by OCT imaging and to compare these two groups of patients with each other&#xD;
      as well as to a subset of patients with FFR-positive and PCI-treated intermediate lesions on&#xD;
      future MACE.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hypothesis Diabetes Mellitus (DM) patients with angiographically intermediate coronary&#xD;
      lesions remain at risk for future MACE events, including those patients with fractional flow&#xD;
      reserve (FFR) negative lesions. Use of FFR measurements combined with Optimal Coherence&#xD;
      Tomography (OCT) detection of thin-cap fibroatheroma (TCFA) in will help predict future MACE&#xD;
      rates.&#xD;
&#xD;
      Objective To study the natural evolution of patients with at least one intermediate&#xD;
      angiographic but non-hemodynamic significant stenotic lesion, in two subgroups of patients,&#xD;
      with TCFA vs. no TCFA as detected by OCT imaging and to compare these two groups of patients&#xD;
      with each other as well as to a subset of patients with FFR-positive and PCI-treated&#xD;
      intermediate lesions on future MACE.&#xD;
&#xD;
      Design Prospective, open label natural history registry. DM patients bearing target lesions&#xD;
      {Any de novo lesion with an angiographic visual estimation of ≥ 40%- ≤ 80% Diameter Stenosis&#xD;
      (DS) that is located in a non-grafted coronary segment. In patients with an MI at&#xD;
      presentation the target lesion should be different from the culprit lesion} and have&#xD;
      undergone FFR and OCT imaging as for clinical routine will be prospectively enrolled and&#xD;
      followed. Patients with negative FFR (&gt; 0.80) will be divided in two categories depending on&#xD;
      corelab OCT imaging findings: No-TCFA (cap thickness &gt;65µ) (Group A) or TCFA (cap thickness ≤&#xD;
      65µ) (group B). All patients that had a positive FFR and therefore have been treated with PCI&#xD;
      as per standard care in all target lesions will also be followed (group C), however if after&#xD;
      the PCI there is at least one remaining target lesion where FFR was negative these patients&#xD;
      should be followed in group A or B depending on the OCT findings. Clinical endpoints at 1.5&#xD;
      year will be recorded.&#xD;
&#xD;
      The investigators strongly recommend that all major epicardial coronary vessels of stentable&#xD;
      size that show any form of atherosclerosis to be interrogated with FFR and OCT.&#xD;
&#xD;
      The investigators strongly recommend to not perform cap thickness measurements in the&#xD;
      cathlab. The plaque cap thickness as measured in the corelab will not be disclosed to&#xD;
      operators and patients.&#xD;
&#xD;
      Population Patients aged ≥18 years Diabetes mellitus (DM) patients with any presentation.&#xD;
      Coronary angiography, FFR and OCT imaging in at least one coronary de novo stenosis in a&#xD;
      native vessel with a visually estimated diameter of stenosis (DS) of ≥ 40%-≤ 80% (target&#xD;
      lesion).&#xD;
&#xD;
      Angiographic criteria target lesion:&#xD;
&#xD;
      (i) ≥ 40%-≤ 80% diameter stenosis (DS) (ii) de novo lesion located in native non-grafted&#xD;
      vessel (iii) target lesion reference diameter of ≥ 2.0 mm (iv) TIMI 3 flow&#xD;
&#xD;
      Primary Endpoint The per patient incidence of the target lesion(s) related composite MACE&#xD;
      defined as Cardiac Death, MI, clinically-driven target lesion revascularisation or&#xD;
      hospitalization due to unstable or progressive angina at 18 months in the FFR-negative&#xD;
      No-TCFA (Group A) and FFR-negative TCFA (Group B).&#xD;
&#xD;
      Statistics This is an observational study (prospective natural history register) where no&#xD;
      randomization takes place, therefore a power calculation is strictly not necessary.&#xD;
&#xD;
      However, in order to observe meaningful differences between groups (as described in the&#xD;
      design) and deduct founded conclusions, the minimal number of patients required was&#xD;
      calculated as follows. The target lesion related primary endpoint at 18 months in the A and B&#xD;
      group respectively are assumed to be 5 % and 20% respectively. Taking into account an&#xD;
      expected loss in FU of 7%, a total of 500 patients enrolled in the study will provide 80%&#xD;
      power to reject the null hypothesis with 5% type I error (alpha). The enrolment in group C&#xD;
      will stop after the first 166 patients have been enrolled in this group. The rest of the rest&#xD;
      of 334 patients will be distributed in groups A and B depending on the OCT corelab findings.&#xD;
      Nul hypothesis: the MACE rate in group B is not different from group A.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 26, 2015</start_date>
  <completion_date type="Actual">February 28, 2021</completion_date>
  <primary_completion_date type="Actual">June 30, 2020</primary_completion_date>
  <study_type>Observational [Patient Registry]</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>
  <target_duration>18 Months</target_duration>
  <primary_outcome>
    <measure>The per patient incidence of the target lesion(s) related composite MACE</measure>
    <time_frame>18 months after procedure</time_frame>
    <description>The per patient incidence of the target lesion(s) related composite MACE defined as Cardiac Death, MI, clinically-driven target lesion revascularisation or hospitalization due to unstable or progressive angina at 18 months in the FFR-negative No-TCFA (Group A) and FFR-negative TCFA (Group B).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The per patient incidence of the target lesion(s) related composite MACE:</measure>
    <time_frame>18 months after procedure</time_frame>
    <description>Cardicac death, MI, clinically- driven revascularization or hospitalization due to unstable or progressive angina between FFR-negative TCFA (Group B) and the group of patients with PCI-treated FFR-positive lesions (Group C).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The per patient incidence composite MACE</measure>
    <time_frame>18 months after procedure</time_frame>
    <description>The per patient incidence composite MACE: Cardiac death, MI, any clinically driven-revascularization or hospitalization due to unstable or progressive angina between FFR-negative TCFA (Group B) and the group of patients with PCI treated FFR positive lesions (Group C).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of MACE (Cardiac death, MI, any clinically driven-revascularization or hospitalization due to unstable or progressive angina)</measure>
    <time_frame>18 months after procedure</time_frame>
    <description>deriving from non PCI treated lesions between TCFA hosting patients anywhere in the major coronary of stentable size vs. patients with no TCFA (this analysis will be run in the total pool of patients after treatment of all FFR positive lesions and does not take in account the angiographic severity of the lesions ie. the location of the TCFA can be elsewhere than the target lesion )</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">550</enrollment>
  <condition>Diabetes Mellitus</condition>
  <condition>Coronary Artery Disease</condition>
  <condition>Coronary Atheroscleroses</condition>
  <arm_group>
    <arm_group_label>Group A</arm_group_label>
    <description>Patients with negative FFR (&gt; 0.80) in the target lesion &amp; decided on OCT (Optical Coherence Tomography) imaging findings with NO thin-cap fibroatheroma</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group B</arm_group_label>
    <description>Patients with negative FFR (&gt; 0.80) in the target lesion &amp; decided on OCT (Optical Coherence Tomography) imaging findings presence of ≥ thin-cap fibroatheroma</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group C</arm_group_label>
    <description>Patients hosting FFR-positive target lesions that have been treated with PCI as per standard care and have further no TCFA lesions.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Optical Coherence Tomography</intervention_name>
    <description>Patients aged ≥ 18 years bearing target lesions that fulfil the inclusion criteria and have undergone FFR and OCT imaging as per clinical practice will be enrolled in the study.</description>
    <arm_group_label>Group A</arm_group_label>
    <arm_group_label>Group B</arm_group_label>
    <arm_group_label>Group C</arm_group_label>
    <other_name>OCT</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        The COMBINE (OCT-FFR) Trial is an investigator driven study: a prospective natural history&#xD;
        registry. Patients aged ≥ 18 years bearing target lesions (see definition section) that&#xD;
        fulfil the inclusion criteria and have undergone FFR and OCT imaging as per clinical&#xD;
        practice will be enrolled in the study.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥ 18 years&#xD;
&#xD;
          2. History of DM with any indication for angiography (Stable Angina (SA) or any type of&#xD;
             Acute Coronary Syndrome (ACS) including ST-Elevation MI).&#xD;
&#xD;
          3. Coronary angiography, including FFR and OCT imaging of at least one coronary de novo&#xD;
             stenosis in a native not-grafted vessel with a visually estimated diameter stenosis&#xD;
             (DS) of ≥ 40 - ≤ 80% (target lesion) . Target lesion should be other than the culprit&#xD;
             lesion(s) in patients presenting with MI (STEMI or non-STEMI).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. TIMI flow &lt; 3 in the target lesion(s)&#xD;
&#xD;
          2. Target lesion reference diameter (on visual estimation) &lt; 2.0 mm&#xD;
&#xD;
          3. Known left ventricular ejection fraction &lt;30%&#xD;
&#xD;
          4. Known malignancy&#xD;
&#xD;
          5. Life expectancy &lt; 2 years&#xD;
&#xD;
          6. Unwilling or unable to provide inform consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>E Kedhi, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Erasmus Academical Hospital Brussels</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Isala</name>
      <address>
        <city>Zwolle</city>
        <state>Overijssel</state>
        <zip>8025 AB</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <link>
    <url>http://cardiab.biomedcentral.com/articles/10.1186/s12933-016-0464-8</url>
    <description>Cardiovascular Diabetology</description>
  </link>
  <reference>
    <citation>Kennedy MW, Fabris E, Ijsselmuiden AJ, Nef H, Reith S, Escaned J, Alfonso F, van Royen N, Wojakowski W, Witkowski A, Indolfi C, Ottervanger JP, Suryapranata H, Kedhi E. Combined optical coherence tomography morphologic and fractional flow reserve hemodynamic assessment of non- culprit lesions to better predict adverse event outcomes in diabetes mellitus patients: COMBINE (OCT-FFR) prospective study. Rationale and design. Cardiovasc Diabetol. 2016 Oct 10;15(1):144. doi: 10.1186/s12933-016-0464-8.</citation>
    <PMID>27724869</PMID>
  </reference>
  <results_reference>
    <citation>Kedhi E, Berta B, Roleder T, Hermanides RS, Fabris E, IJsselmuiden AJJ, Kauer F, Alfonso F, von Birgelen C, Escaned J, Camaro C, Kennedy MW, Pereira B, Magro M, Nef H, Reith S, Al Nooryani A, Rivero F, Malinowski K, De Luca G, Garcia Garcia H, Granada JF, Wojakowski W. Thin-cap fibroatheroma predicts clinical events in diabetic patients with normal fractional flow reserve: the COMBINE OCT-FFR trial. Eur Heart J. 2021 Dec 1;42(45):4671-4679. doi: 10.1093/eurheartj/ehab433.</citation>
    <PMID>34345911</PMID>
  </results_reference>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>December 8, 2016</study_first_submitted>
  <study_first_submitted_qc>December 8, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 12, 2016</study_first_posted>
  <last_update_submitted>August 30, 2021</last_update_submitted>
  <last_update_submitted_qc>August 30, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 5, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Diabetes Mellitus</keyword>
  <keyword>Thincap fibroatheroma</keyword>
  <keyword>Optical Coherence Tomography</keyword>
  <keyword>Fractional Flow Reserve</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Coronary Artery Disease</mesh_term>
    <mesh_term>Myocardial Ischemia</mesh_term>
    <mesh_term>Atherosclerosis</mesh_term>
    <mesh_term>Diabetes Mellitus</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/NCT02989740
org study id: 9241
nct id: NCT02989740
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
Title:

      Combined Optical Coherence Tomography Morphologic and Fractional Flow Reserve Hemodynamic
      Assessment of Non-Culprit Lesions to Better Predict Adverse Event Outcomes in Diabetes
      Mellitus Patients COMBINE (OCT-FFR) Prospective Register

      To study the natural evolution of patients with at least one intermediate angiographic but
      non-hemodynamic significant stenotic lesion, in two subgroups of patients, with TCFA vs. no
      TCFA as detected by OCT imaging and to compare these two groups of patients with each other
      as well as to a subset of patients with FFR-positive and PCI-treated intermediate lesions on
      future MACE.
Hypothesis Diabetes Mellitus (DM) patients with angiographically intermediate coronary
      lesions remain at risk for future MACE events, including those patients with fractional flow
      reserve (FFR) negative lesions. Use of FFR measurements combined with Optimal Coherence
      Tomography (OCT) detection of thin-cap fibroatheroma (TCFA) in will help predict future MACE
      rates.

      Objective To study the natural evolution of patients with at least one intermediate
      angiographic but non-hemodynamic significant stenotic lesion, in two subgroups of patients,
      with TCFA vs. no TCFA as detected by OCT imaging and to compare these two groups of patients
      with each other as well as to a subset of patients with FFR-positive and PCI-treated
      intermediate lesions on future MACE.

      Design Prospective, open label natural history registry. DM patients bearing target lesions
      {Any de novo lesion with an angiographic visual estimation of ≥ 40%- ≤ 80% Diameter Stenosis
      (DS) that is located in a non-grafted coronary segment. In patients with an MI at
      presentation the target lesion should be different from the culprit lesion} and have
      undergone FFR and OCT imaging as for clinical routine will be prospectively enrolled and
      followed. Patients with negative FFR (> 0.80) will be divided in two categories depending on
      corelab OCT imaging findings: No-TCFA (cap thickness >65µ) (Group A) or TCFA (cap thickness ≤
      65µ) (group B). All patients that had a positive FFR and therefore have been treated with PCI
      as per standard care in all target lesions will also be followed (group C), however if after
      the PCI there is at least one remaining target lesion where FFR was negative these patients
      should be followed in group A or B depending on the OCT findings. Clinical endpoints at 1.5
      year will be recorded.

      The investigators strongly recommend that all major epicardial coronary vessels of stentable
      size that show any form of atherosclerosis to be interrogated with FFR and OCT.

      The investigators strongly recommend to not perform cap thickness measurements in the
      cathlab. The plaque cap thickness as measured in the corelab will not be disclosed to
      operators and patients.

      Population Patients aged ≥18 years Diabetes mellitus (DM) patients with any presentation.
      Coronary angiography, FFR and OCT imaging in at least one coronary de novo stenosis in a
      native vessel with a visually estimated diameter of stenosis (DS) of ≥ 40%-≤ 80% (target
      lesion).

      Angiographic criteria target lesion:

      (i) ≥ 40%-≤ 80% diameter stenosis (DS) (ii) de novo lesion located in native non-grafted
      vessel (iii) target lesion reference diameter of ≥ 2.0 mm (iv) TIMI 3 flow

      Primary Endpoint The per patient incidence of the target lesion(s) related composite MACE
      defined as Cardiac Death, MI, clinically-driven target lesion revascularisation or
      hospitalization due to unstable or progressive angina at 18 months in the FFR-negative
      No-TCFA (Group A) and FFR-negative TCFA (Group B).

      Statistics This is an observational study (prospective natural history register) where no
      randomization takes place, therefore a power calculation is strictly not necessary.

      However, in order to observe meaningful differences between groups (as described in the
      design) and deduct founded conclusions, the minimal number of patients required was
      calculated as follows. The target lesion related primary endpoint at 18 months in the A and B
      group respectively are assumed to be 5 % and 20% respectively. Taking into account an
      expected loss in FU of 7%, a total of 500 patients enrolled in the study will provide 80%
      power to reject the null hypothesis with 5% type I error (alpha). The enrolment in group C
      will stop after the first 166 patients have been enrolled in this group. The rest of the rest
      of 334 patients will be distributed in groups A and B depending on the OCT corelab findings.
      Nul hypothesis: the MACE rate in group B is not different from group A.
observational model: Cohort
time perspective: Prospective
measure: The per patient incidence of the target lesion(s) related composite MACE
time frame: 18 months after procedure
description: The per patient incidence of the target lesion(s) related composite MACE defined as Cardiac Death, MI, clinically-driven target lesion revascularisation or hospitalization due to unstable or progressive angina at 18 months in the FFR-negative No-TCFA (Group A) and FFR-negative TCFA (Group B).
measure: The per patient incidence of the target lesion(s) related composite MACE:
time frame: 18 months after procedure
description: Cardicac death, MI, clinically- driven revascularization or hospitalization due to unstable or progressive angina between FFR-negative TCFA (Group B) and the group of patients with PCI-treated FFR-positive lesions (Group C).
measure: The per patient incidence composite MACE
time frame: 18 months after procedure
description: The per patient incidence composite MACE: Cardiac death, MI, any clinically driven-revascularization or hospitalization due to unstable or progressive angina between FFR-negative TCFA (Group B) and the group of patients with PCI treated FFR positive lesions (Group C).
measure: The incidence of MACE (Cardiac death, MI, any clinically driven-revascularization or hospitalization due to unstable or progressive angina)
time frame: 18 months after procedure
description: deriving from non PCI treated lesions between TCFA hosting patients anywhere in the major coronary of stentable size vs. patients with no TCFA (this analysis will be run in the total pool of patients after treatment of all FFR positive lesions and does not take in account the angiographic severity of the lesions ie. the location of the TCFA can be elsewhere than the target lesion )
arm group label: Group A
description: Patients with negative FFR (> 0.80) in the target lesion & decided on OCT (Optical Coherence Tomography) imaging findings with NO thin-cap fibroatheroma
arm group label: Group B
description: Patients with negative FFR (> 0.80) in the target lesion & decided on OCT (Optical Coherence Tomography) imaging findings presence of ≥ thin-cap fibroatheroma
arm group label: Group C
description: Patients hosting FFR-positive target lesions that have been treated with PCI as per standard care and have further no TCFA lesions.
intervention type: Procedure
intervention name: Optical Coherence Tomography
description: Patients aged ≥ 18 years bearing target lesions that fulfil the inclusion criteria and have undergone FFR and OCT imaging as per clinical practice will be enrolled in the study.
arm group label: Group A
arm group label: Group B
arm group label: Group C
other name: OCT
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: E Kedhi, MD PhD
role: Principal Investigator
affiliation: Erasmus Academical Hospital Brussels
facility: 
country: Netherlands
url: http://cardiab.biomedcentral.com/articles/10.1186/s12933-016-0464-8
description: Cardiovascular Diabetology
citation: Kennedy MW, Fabris E, Ijsselmuiden AJ, Nef H, Reith S, Escaned J, Alfonso F, van Royen N, Wojakowski W, Witkowski A, Indolfi C, Ottervanger JP, Suryapranata H, Kedhi E. Combined optical coherence tomography morphologic and fractional flow reserve hemodynamic assessment of non- culprit lesions to better predict adverse event outcomes in diabetes mellitus patients: COMBINE (OCT-FFR) prospective study. Rationale and design. Cardiovasc Diabetol. 2016 Oct 10;15(1):144. doi: 10.1186/s12933-016-0464-8.
PMID: 27724869
citation: Kedhi E, Berta B, Roleder T, Hermanides RS, Fabris E, IJsselmuiden AJJ, Kauer F, Alfonso F, von Birgelen C, Escaned J, Camaro C, Kennedy MW, Pereira B, Magro M, Nef H, Reith S, Al Nooryani A, Rivero F, Malinowski K, De Luca G, Garcia Garcia H, Granada JF, Wojakowski W. Thin-cap fibroatheroma predicts clinical events in diabetic patients with normal fractional flow reserve: the COMBINE OCT-FFR trial. Eur Heart J. 2021 Dec 1;42(45):4671-4679. doi: 10.1093/eurheartj/ehab433.
PMID: 34345911
responsible party type: Sponsor
mesh term: Coronary Artery Disease
mesh term: Myocardial Ischemia
mesh term: Atherosclerosis
mesh term: Diabetes Mellitus
sharing ipd: No