<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/NCT03837704</url>
  </required_header>
  <id_info>
    <org_study_id>P1-AAA-02-JP</org_study_id>
    <nct_id>NCT03837704</nct_id>
  </id_info>
  <brief_title>Comparison of Abdominal Aortic Aneurysm Growth in Adult Smoking Patients Who Either Switch to IQOS, Continue Smoking, or Quit Smoking.</brief_title>
  <official_title>A Controlled, Open-label, 3-arm Parallel Group, Multi-center Study to Evaluate the Abdominal Aortic Aneurysm (AAA) Growth Rate in Adult Smoking Patients Randomized to Either Cigarette Smoking or IQOS Use and to Compare With the AAA Growth Rate in Patients Who Had Stopped Smoking</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Philip Morris Products S.A.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Philip Morris Products S.A.</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>
      The purpose of this study is to evaluate the reduction of the Abdominal Aortic Aneurysm (AAA)&#xD;
      annual growth rate in patients who switch from smoking cigarettes to using IQOS as compared&#xD;
      to patients who continue to smoke cigarettes. The study also aims to provide context to the&#xD;
      scale of reduction in the growth rate, by comparing the AAA annual growth rates for&#xD;
      continuing to smoke and switching to IQOS with the AAA annual growth rate in smokers who had&#xD;
      stopped smoking. The study will further evaluate the effects of switching to IQOS on&#xD;
      co-morbidities observed in AAA patients that are related to smoking as well as to assess the&#xD;
      effects on relevant clinical risk endpoints linked to smoking related diseases.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a controlled, open-label, 3-arm parallel group, multi-center study in patients&#xD;
      diagnosed with Abdominal Aortic Aneurysm (AAA) to evaluate the AAA annual growth rate in&#xD;
      adult smokers randomized to either continue smoking combustible cigarettes (CC) or to switch&#xD;
      to IQOS and in adults who had stopped smoking, as a non-randomized control arm.&#xD;
&#xD;
      This is a descriptive study, designed to gain an understanding of how changes in smoking&#xD;
      behaviors impact AAA growth rate and disease progression. Therefore, there are no formal&#xD;
      statistical hypotheses to be tested.&#xD;
&#xD;
      Smoking patients with AAA who did not quit smoking after their AAA diagnosis, and who are not&#xD;
      intending to quit within the next 6 months will be screened for enrollment and randomization&#xD;
      in the CC and IQOS arms if all other eligibility criteria are met.&#xD;
&#xD;
      Smoking patients with AAA who had completely stopped smoking and using of any other tobacco&#xD;
      or nicotine-containing products within 2 months of their AAA diagnosis, and are still&#xD;
      abstinent at the time of the Screening Visit and of the Baseline Visit will be screened to be&#xD;
      enrolled in the smoking cessation (SC) arm without randomization.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 3, 2018</start_date>
  <completion_date type="Actual">August 28, 2023</completion_date>
  <primary_completion_date type="Actual">April 8, 2023</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>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>AAA annual growth rate over time</measure>
    <time_frame>At 6-month intervals from baseline to 5 years</time_frame>
    <description>AAA annual growth rate will be measured in AAA patients who switch from smoking cigarettes to using IQOS, and AAA patients who continue to smoke CC, as compared to AAA patients who had stopped smoking. Maximum minor-axis AAA diameter in mm will be measured. Annual growth rate will be calculated by annualizing the slope of the linear regression over the available diameter measurements.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Period of time from diagnosis of the AAA until open surgical AAA treatment or AAA endovascular repair or AAA rupture</measure>
    <time_frame>From diagnosis of AAA to 5 years</time_frame>
    <description>The time from diagnosis of the AAA until open surgical AAA treatment or AAA endovascular repair or AAA rupture will be measured in AAA patients who switch from smoking CC to using IQOS, as compared to AAA patients who continue smoking CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of open surgical AAA treatment or AAA endovascular repair and AAA rupture</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>The incidence of open surgical AAA treatment or AAA endovascular repair and AAA rupture will be measured in AAA patients who switch from smoking CC to using IQOS, as compared to AAA patients who continue to smoke CC and AAA patients who had stopped smoking. Incidence rate will be calculated annually.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of AAA growth above 5 mm within 6 months</measure>
    <time_frame>At 6-month intervals from baseline to 5 years</time_frame>
    <description>Incidence of AAA growth above 5 mm within 6 months will be measured in AAA patients who switch from smoking CC to using IQOS, as compared to AAA patients who continue smoking CC and AAA patients who had stopped smoking. Incidence rate will be calculated annually by counting the number of patients with an increase in maximum minor-axis AAA diameter of more than 5 mm within 6 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AAA patients with an overall maximum minor-axis AAA diameter of &gt;55mm in male patients and &gt;50mm in female patients</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>The number of AAA patients with an overall maximum minor-axis AAA diameter &gt;55mm in male AAA patients and &gt;50mm in female AAA patients will be counted in AAA patients who switch from smoking CC to using IQOS, as compared to AAA patients who continue smoking CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of ischemic heart disease (IHD) in AAA patients</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>Number of AAA patients with a diagnosis of IHD, IHD progression (by number of new myocardial infarction, stroke or death) or IHD related event annually.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of chronic obstructive pulmonary disease (COPD) in AAA patients</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>Number of AAA patients with a diagnosis of COPD, COPD progression (by disease stage) or a COPD related event annually.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of hypertension in AAA patients</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>Number of AAA patients with a diagnosis of hypertension, progression of their hypertension (by disease stage), or a hypertension related event annually.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of peripheral arterial disease (PAD) in AAA patients</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>Number of AAA patients with a diagnosis of PAD, PAD progression (by disease stage) or PAD related event annually.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence rate of other smoking-related diseases, and their related events, in AAA patients</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>Number of AAA patients with adverse events related to the diagnosis of other co-morbidities, events related to the other co-morbidities.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urinary nicotine equivalents (NEQ)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>To measure nicotine exposure over time in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC, and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systolic blood pressure</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint (systolic blood pressure) will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diastolic blood pressure</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint (diastolic blood pressure) will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body weight</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint (body weight) will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Waist circumference</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint (waist circumference) will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>High sensitive C-reactive protein (hs-CRP)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Low density lipoprotein (LDL)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>High density lipoprotein (HDL)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total Cholesterol (TC)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Triglyceride (TG)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fasting blood glucose</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hemoglobin A1c (HbA1c)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>White blood cell (WBC) and platelet counts</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>D-dimer</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fibrinogen</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total Antioxidant Capacity (TAC)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>11-dehydro-thromboxane B2 (11-DTX-B2)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>8-Epi Prostaglandin F2 Alpha (8-epi-PGF2α)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metalloproteinase 2 (MMP- 2)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, patients who continue to smoke CC and patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metalloproteinase 9 (MMP-9)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, patients who continue to smoke CC and patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Soluble inter-cellular adhesion molecule-1 (sICAM-1)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apolipoprotein A1 (Apo A1)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apolipoprotein B (Apo B)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Homocysteine (Hcy)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This biomarker of exposure to a tobacco smoke constituent will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total N-nitrosonornicotine (Total NNN)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This biomarker of exposure to a tobacco smoke constituent will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>2-cyanoethylmercapturic acid (CEMA)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>This biomarker of exposure to a tobacco smoke constituent will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ankle-brachial index (ABI)</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>The ABI will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC, and AAA patients who had stopped smoking.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Transcriptomic profile assessment in blood samples</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>To evaluate differential changes in gene expressions, transcriptomics analyses will be performed on collected blood samples. Isolated RNAs will be applied to a gene chip that contains 54,000 transcripts. The gene chip will then be scanned using Affymetrix. The outcome measurements that will be reported are relative changes and relative fold changes in gene expressions in AAA patients who continue smoking cigarettes and those switching to IQOS.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proteomic profile assessment in plasma derived from blood samples</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>To evaluate changes in selected protein concentrations, targeted proteomics analyses will be performed on plasma derived from collected blood samples. Proteins will be isolated from plasma and targeted proteomics analyses will be performed using liquid chromatography mass spectrometry (LC MS/MS) and antibody-based Luminex. The outcome measurements that will be reported are the concentrations of the selected proteins measured in AAA patients who continue smoking cigarettes and those switching to IQOS.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lipidomic profile assessment in plasma derived from blood samples</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>To evaluate changes in selected ceramide concentrations, targeted lipidomics analyses will be performed on plasma derived from collected blood samples. Ceramides will be isolated from plasma and targeted lipidomics analyses will be performed using liquid chromatography mass spectrometry (LC MS/MS). The outcome measurements that will be reported are the concentrations of the selected ceramides measured in AAA patients who continue smoking cigarettes and those switching to IQOS.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lipidomic profile assessment in urine</measure>
    <time_frame>From baseline to 5 years</time_frame>
    <description>To evaluate changes in selected eicosanoid concentrations, targeted lipidomics analyses will be performed in urine. Eicosanoids will be isolated from urine and targeted lipidomics analyses will be performed using liquid chromatography mass spectrometry (LC MS/MS). The outcome measurements that will be reported are the concentrations of selected eicosanoids measured in AAA patients who continue smoking cigarettes and those switching to IQOS.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">48</enrollment>
  <condition>Smoking</condition>
  <condition>Abdominal Aortic Aneurysm</condition>
  <condition>IQOS Use</condition>
  <arm_group>
    <arm_group_label>IQOS Arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients diagnosed with AAA, switching from cigarette smoking to IQOS use</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CC Arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients diagnosed with AAA, continuing to smoke cigarettes</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Smoking Cessation Arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients diagnosed with AAA, who have completely stopped smoking and are not using any other tobacco or nicotine-containing product(s)</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>IQOS</intervention_name>
    <description>AAA patients will switch from cigarette smoking to ad libitum IQOS use, with no flavor variant restrictions.</description>
    <arm_group_label>IQOS Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Cigarette</intervention_name>
    <description>AAA patients will continue to smoke their cigarettes ad libitum, with no brand restrictions.</description>
    <arm_group_label>CC Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Smoking Cessation</intervention_name>
    <description>AAA patients who have completely quit smoking will continue to remain abstinent from smoking cigarettes or using any tobacco or nicotine-containing product(s)</description>
    <arm_group_label>Smoking Cessation Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        General Inclusion Criteria:&#xD;
&#xD;
          -  Patient diagnosed with AAA (infrarenal, fusiform type) with a current aortic maximum&#xD;
             minor-axis diameter of 30 to ≤ 49 mm (in male patient) and 30 to ≤ 44 mm (in female&#xD;
             patient).&#xD;
&#xD;
          -  Patient has smoked on average at least 10 commercially available CC per day (no brand&#xD;
             restrictions) for at least 5 years prior to AAA diagnosis, based on self-reporting&#xD;
&#xD;
          -  Patient is ready to comply with the study protocol (e.g., to use their assigned&#xD;
             product/regimen during the course of the study)&#xD;
&#xD;
        Inclusion criteria specific to patients screened for enrollment and randomization to the CC&#xD;
        or IQOS arm:&#xD;
&#xD;
          -  Patient has smoked on average at least 10 commercially available CC per day (no brand&#xD;
             restriction) for the last 12 months, based on self-reporting. Intermittent attempts to&#xD;
             quit smoking not exceeding 2 months or short-term interruption of smoking up to 10&#xD;
             days within the last 12 months will be allowed. Smoking status will be verified based&#xD;
             on a urinary cotinine test (i.e., cotinine ≥ 200 ng/mL).&#xD;
&#xD;
          -  Not intending to quit smoking within the next 6 months.&#xD;
&#xD;
        Inclusion Criteria specific to patients screened for enrollment into the SC arm:&#xD;
&#xD;
          -  Patient had completely quit smoking and stopped the use of any other tobacco or&#xD;
             nicotine-containing products within 2 months after AAA diagnosis, and is still&#xD;
             abstinent at Screening and at Baseline. Smoking status will be verified based on a&#xD;
             urinary cotinine test (i.e., cotinine &lt; 100 ng/mL).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patient is legally incompetent, physically or mentally incapable of giving consent.&#xD;
&#xD;
          -  Patient is a current or former employee of the tobacco industry or their first-degree&#xD;
             relatives (parent and child); patient is an employee of the investigational site or&#xD;
             any other parties involved in the study or their first-degree relatives (parent and&#xD;
             child).&#xD;
&#xD;
          -  Patient has been previously screened or enrolled in this study or was enrolled in any&#xD;
             clinical study within 3 months prior to the Screening Visit.&#xD;
&#xD;
          -  Female patient who is pregnant or breast-feeding.&#xD;
&#xD;
          -  Patient is ineligible as judged by the Investigator to participate in the study for&#xD;
             any reason.&#xD;
&#xD;
          -  Patient with acute severe cardiovascular events or respiratory diseases, within the&#xD;
             last 3 months; with currently active cancer or history of cancer within the last 5&#xD;
             years; with dissecting aneurysm(s) of the aorta; with infrarenal pseudo-AAA (false&#xD;
             AAA); with a diagnosis of COPD Stage 3 and 4 in the medical history; with a recent&#xD;
             (within 1 year) or current history of alcohol or other substance abuse based on&#xD;
             self-reporting.&#xD;
&#xD;
          -  Patient with a diagnosis of concomitant genetic diseases such as but not limited to&#xD;
             Marfan syndrome, Loeys-Dietz syndrome, Vascular Ehlers-Danlos syndrome, Turner&#xD;
             syndrome, Polycystic kidney disease, Noonan syndrome, Alagile syndrome, Arterial&#xD;
             tortuosity syndrome and Cutis laxa.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Christelle Haziza, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Philip Morris Products SA</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Atsugi City Hospital</name>
      <address>
        <city>Atsugi</city>
        <state>Kanagawa Prefecture</state>
        <zip>243-8588</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Japan</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>January 21, 2019</study_first_submitted>
  <study_first_submitted_qc>February 7, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 12, 2019</study_first_posted>
  <last_update_submitted>September 6, 2023</last_update_submitted>
  <last_update_submitted_qc>September 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aneurysm</mesh_term>
    <mesh_term>Aortic Aneurysm</mesh_term>
    <mesh_term>Aortic Aneurysm, Abdominal</mesh_term>
  </condition_browse>
  <!-- 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/NCT03837704
org study id: P1-AAA-02-JP
nct id: NCT03837704
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to evaluate the reduction of the Abdominal Aortic Aneurysm (AAA)
      annual growth rate in patients who switch from smoking cigarettes to using IQOS as compared
      to patients who continue to smoke cigarettes. The study also aims to provide context to the
      scale of reduction in the growth rate, by comparing the AAA annual growth rates for
      continuing to smoke and switching to IQOS with the AAA annual growth rate in smokers who had
      stopped smoking. The study will further evaluate the effects of switching to IQOS on
      co-morbidities observed in AAA patients that are related to smoking as well as to assess the
      effects on relevant clinical risk endpoints linked to smoking related diseases.
This is a controlled, open-label, 3-arm parallel group, multi-center study in patients
      diagnosed with Abdominal Aortic Aneurysm (AAA) to evaluate the AAA annual growth rate in
      adult smokers randomized to either continue smoking combustible cigarettes (CC) or to switch
      to IQOS and in adults who had stopped smoking, as a non-randomized control arm.

      This is a descriptive study, designed to gain an understanding of how changes in smoking
      behaviors impact AAA growth rate and disease progression. Therefore, there are no formal
      statistical hypotheses to be tested.

      Smoking patients with AAA who did not quit smoking after their AAA diagnosis, and who are not
      intending to quit within the next 6 months will be screened for enrollment and randomization
      in the CC and IQOS arms if all other eligibility criteria are met.

      Smoking patients with AAA who had completely stopped smoking and using of any other tobacco
      or nicotine-containing products within 2 months of their AAA diagnosis, and are still
      abstinent at the time of the Screening Visit and of the Baseline Visit will be screened to be
      enrolled in the smoking cessation (SC) arm without randomization.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: AAA annual growth rate over time
time frame: At 6-month intervals from baseline to 5 years
description: AAA annual growth rate will be measured in AAA patients who switch from smoking cigarettes to using IQOS, and AAA patients who continue to smoke CC, as compared to AAA patients who had stopped smoking. Maximum minor-axis AAA diameter in mm will be measured. Annual growth rate will be calculated by annualizing the slope of the linear regression over the available diameter measurements.
measure: Period of time from diagnosis of the AAA until open surgical AAA treatment or AAA endovascular repair or AAA rupture
time frame: From diagnosis of AAA to 5 years
description: The time from diagnosis of the AAA until open surgical AAA treatment or AAA endovascular repair or AAA rupture will be measured in AAA patients who switch from smoking CC to using IQOS, as compared to AAA patients who continue smoking CC and AAA patients who had stopped smoking.
measure: Incidence of open surgical AAA treatment or AAA endovascular repair and AAA rupture
time frame: From baseline to 5 years
description: The incidence of open surgical AAA treatment or AAA endovascular repair and AAA rupture will be measured in AAA patients who switch from smoking CC to using IQOS, as compared to AAA patients who continue to smoke CC and AAA patients who had stopped smoking. Incidence rate will be calculated annually.
measure: Incidence of AAA growth above 5 mm within 6 months
time frame: At 6-month intervals from baseline to 5 years
description: Incidence of AAA growth above 5 mm within 6 months will be measured in AAA patients who switch from smoking CC to using IQOS, as compared to AAA patients who continue smoking CC and AAA patients who had stopped smoking. Incidence rate will be calculated annually by counting the number of patients with an increase in maximum minor-axis AAA diameter of more than 5 mm within 6 months.
measure: AAA patients with an overall maximum minor-axis AAA diameter of >55mm in male patients and >50mm in female patients
time frame: From baseline to 5 years
description: The number of AAA patients with an overall maximum minor-axis AAA diameter >55mm in male AAA patients and >50mm in female AAA patients will be counted in AAA patients who switch from smoking CC to using IQOS, as compared to AAA patients who continue smoking CC and AAA patients who had stopped smoking.
measure: Incidence of ischemic heart disease (IHD) in AAA patients
time frame: From baseline to 5 years
description: Number of AAA patients with a diagnosis of IHD, IHD progression (by number of new myocardial infarction, stroke or death) or IHD related event annually.
measure: Incidence of chronic obstructive pulmonary disease (COPD) in AAA patients
time frame: From baseline to 5 years
description: Number of AAA patients with a diagnosis of COPD, COPD progression (by disease stage) or a COPD related event annually.
measure: Incidence of hypertension in AAA patients
time frame: From baseline to 5 years
description: Number of AAA patients with a diagnosis of hypertension, progression of their hypertension (by disease stage), or a hypertension related event annually.
measure: Incidence of peripheral arterial disease (PAD) in AAA patients
time frame: From baseline to 5 years
description: Number of AAA patients with a diagnosis of PAD, PAD progression (by disease stage) or PAD related event annually.
measure: Incidence rate of other smoking-related diseases, and their related events, in AAA patients
time frame: From baseline to 5 years
description: Number of AAA patients with adverse events related to the diagnosis of other co-morbidities, events related to the other co-morbidities.
measure: Urinary nicotine equivalents (NEQ)
time frame: From baseline to 5 years
description: To measure nicotine exposure over time in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC, and AAA patients who had stopped smoking.
measure: Systolic blood pressure
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint (systolic blood pressure) will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Diastolic blood pressure
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint (diastolic blood pressure) will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Body weight
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint (body weight) will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Waist circumference
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint (waist circumference) will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: High sensitive C-reactive protein (hs-CRP)
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Low density lipoprotein (LDL)
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: High density lipoprotein (HDL)
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Total Cholesterol (TC)
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Triglyceride (TG)
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Fasting blood glucose
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Hemoglobin A1c (HbA1c)
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: White blood cell (WBC) and platelet counts
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: D-dimer
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Fibrinogen
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Total Antioxidant Capacity (TAC)
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: 11-dehydro-thromboxane B2 (11-DTX-B2)
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: 8-Epi Prostaglandin F2 Alpha (8-epi-PGF2α)
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Metalloproteinase 2 (MMP- 2)
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, patients who continue to smoke CC and patients who had stopped smoking.
measure: Metalloproteinase 9 (MMP-9)
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, patients who continue to smoke CC and patients who had stopped smoking.
measure: Soluble inter-cellular adhesion molecule-1 (sICAM-1)
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Apolipoprotein A1 (Apo A1)
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Apolipoprotein B (Apo B)
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Homocysteine (Hcy)
time frame: From baseline to 5 years
description: This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL)
time frame: From baseline to 5 years
description: This biomarker of exposure to a tobacco smoke constituent will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Total N-nitrosonornicotine (Total NNN)
time frame: From baseline to 5 years
description: This biomarker of exposure to a tobacco smoke constituent will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: 2-cyanoethylmercapturic acid (CEMA)
time frame: From baseline to 5 years
description: This biomarker of exposure to a tobacco smoke constituent will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking.
measure: Ankle-brachial index (ABI)
time frame: From baseline to 5 years
description: The ABI will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC, and AAA patients who had stopped smoking.
measure: Transcriptomic profile assessment in blood samples
time frame: From baseline to 5 years
description: To evaluate differential changes in gene expressions, transcriptomics analyses will be performed on collected blood samples. Isolated RNAs will be applied to a gene chip that contains 54,000 transcripts. The gene chip will then be scanned using Affymetrix. The outcome measurements that will be reported are relative changes and relative fold changes in gene expressions in AAA patients who continue smoking cigarettes and those switching to IQOS.
measure: Proteomic profile assessment in plasma derived from blood samples
time frame: From baseline to 5 years
description: To evaluate changes in selected protein concentrations, targeted proteomics analyses will be performed on plasma derived from collected blood samples. Proteins will be isolated from plasma and targeted proteomics analyses will be performed using liquid chromatography mass spectrometry (LC MS/MS) and antibody-based Luminex. The outcome measurements that will be reported are the concentrations of the selected proteins measured in AAA patients who continue smoking cigarettes and those switching to IQOS.
measure: Lipidomic profile assessment in plasma derived from blood samples
time frame: From baseline to 5 years
description: To evaluate changes in selected ceramide concentrations, targeted lipidomics analyses will be performed on plasma derived from collected blood samples. Ceramides will be isolated from plasma and targeted lipidomics analyses will be performed using liquid chromatography mass spectrometry (LC MS/MS). The outcome measurements that will be reported are the concentrations of the selected ceramides measured in AAA patients who continue smoking cigarettes and those switching to IQOS.
measure: Lipidomic profile assessment in urine
time frame: From baseline to 5 years
description: To evaluate changes in selected eicosanoid concentrations, targeted lipidomics analyses will be performed in urine. Eicosanoids will be isolated from urine and targeted lipidomics analyses will be performed using liquid chromatography mass spectrometry (LC MS/MS). The outcome measurements that will be reported are the concentrations of selected eicosanoids measured in AAA patients who continue smoking cigarettes and those switching to IQOS.
arm group label: IQOS Arm
arm group type: Active Comparator
description: Patients diagnosed with AAA, switching from cigarette smoking to IQOS use
arm group label: CC Arm
arm group type: Active Comparator
description: Patients diagnosed with AAA, continuing to smoke cigarettes
arm group label: Smoking Cessation Arm
arm group type: Active Comparator
description: Patients diagnosed with AAA, who have completely stopped smoking and are not using any other tobacco or nicotine-containing product(s)
intervention type: Other
intervention name: IQOS
description: AAA patients will switch from cigarette smoking to ad libitum IQOS use, with no flavor variant restrictions.
arm group label: IQOS Arm
intervention type: Other
intervention name: Cigarette
description: AAA patients will continue to smoke their cigarettes ad libitum, with no brand restrictions.
arm group label: CC Arm
intervention type: Other
intervention name: Smoking Cessation
description: AAA patients who have completely quit smoking will continue to remain abstinent from smoking cigarettes or using any tobacco or nicotine-containing product(s)
arm group label: Smoking Cessation Arm
criteria: 
gender: All
minimum age: 50 Years
maximum age: N/A
healthy volunteers: No
last name: Christelle Haziza, PhD
role: Study Chair
affiliation: Philip Morris Products SA
facility: 
country: Japan
responsible party type: Sponsor
mesh term: Aneurysm
mesh term: Aortic Aneurysm
mesh term: Aortic Aneurysm, Abdominal