<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/NCT04500756</url>
  </required_header>
  <id_info>
    <org_study_id>IRB-56500</org_study_id>
    <secondary_id>1R61HL146835-01A1</secondary_id>
    <secondary_id>4R33HL146835-02</secondary_id>
    <nct_id>NCT04500756</nct_id>
  </id_info>
  <brief_title>Limiting AAA With Metformin (LIMIT) Trial</brief_title>
  <acronym>LIMIT</acronym>
  <official_title>LIMItIng AAA With meTformin (LIMIT) Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Stanford University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Kaiser Permanente</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>VA Palo Alto Health Care System</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Stanford University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      In this research, the investigators are looking at the effects of a drug called metformin may&#xD;
      have on the growth of abdominal aortic aneurysm (AAA)s. AAA is an abnormal enlargement of the&#xD;
      aorta, which is the large artery in the abdomen (stomach area). The enlargement of the aorta&#xD;
      carries a risk that it will rupture and cause life-threatening bleeding in the abdomen&#xD;
      (belly). In this study the investigators hope to learn how metformin is associated with the&#xD;
      enlargement or change in size of the AAA in study participants. Smaller studies have&#xD;
      suggested that metformin may reduce the rate at which aortic aneurysms enlarge. This study&#xD;
      will test this question: does metformin prevent AAAs from growing larger?&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 28, 2022</start_date>
  <completion_date type="Anticipated">March 31, 2027</completion_date>
  <primary_completion_date type="Anticipated">March 31, 2027</primary_completion_date>
  <phase>Phase 2</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>
    <intervention_model_description>Prospective, randomized, controlled trial comparing the ability of metformin to prevent AAA disease progression vs. placebo.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>randomized (which means assigned by chance, like flipping a coin) into one of two groups. You will either be assigned to take metformin 500 mg tablet(s) daily or identical tablet(s) that contain no active drug, also taken every day.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>The primary outcome measure will be the change in maximal orthogonal diameter of the infrarenal aorta, as measured by computed tomographic (CT) aortography, in centimeters.</measure>
    <time_frame>Baseline to 2 years</time_frame>
    <description>The change in maximal orthogonal diameter of the infrarenal aorta, as measured by computed tomographic (CT) aortography, over the course of the study in participants taking metformin XR (extended release) vs. placebo. It is calculated as the difference in CTA-determined diameter (in mm) from baseline to the follow-up CT study at the end of study participation, divided by time elapsed between two measurements (e.g., annual rate of change in CT-diameter). The justification for this endpoint is that maximal orthogonal transverse diameter by CTA is the primary standard to measure AAA disease progression, determine need for surgical intervention, and correlate with clinical outcomes.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Profile of Adverse cardiovascular events</measure>
    <time_frame>Baseline to 2 years</time_frame>
    <description>Incidence of adverse cardiovascular events including: unanticipated adverse events (AEs) and serious AEs (SAEs), AEs leading to premature discontinuation from the study intervention and serious treatment-emergent AEs, clinically significant AE events, such as cardiovascular AEs and surgical AAA repairs.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Study drug compliance</measure>
    <time_frame>Baseline to 2 years</time_frame>
    <description>Pill counts will be used to measure study drug compliance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause mortality</measure>
    <time_frame>Baseline to 2 years</time_frame>
    <description>All-cause mortality will be summarized using Kaplan-Meier survival curves for each arm. Participants alive at last follow-up will be censored at last time known alive.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in existing medication regimen as a measure of metformin treatment</measure>
    <time_frame>Baseline to 2 years</time_frame>
    <description>Concurrent medication regimen will be tabulated and listed according to the drug classifications</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serological markers of the liver as a measure of impact of metformin treatment</measure>
    <time_frame>Baseline to 2 years</time_frame>
    <description>Albumin and total protein, total bilirubin, ALT, and AST will be assessed for these serological markers.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serological markers of the kidney as a measure of impact of metformin treatment</measure>
    <time_frame>Baseline to 2 years</time_frame>
    <description>Urea nitrogen (BUN) and creatinine will be assessed for these serological markers.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serological markers of the hematopoietic function as a measure of impact of metformin treatment</measure>
    <time_frame>Baseline to 2 years</time_frame>
    <description>Complete Blood Count (CBC) will be assessed for this serological marker.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in Living with Abdominal Aortic Aneurysm (AAA) Survey</measure>
    <time_frame>Baseline to 2 years</time_frame>
    <description>62 question instrument for evaluating AAA specific Quality of Life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in Short Form (SF-36) health survey</measure>
    <time_frame>Baseline to 2 years</time_frame>
    <description>36 question instrument for evaluating Health-Related Quality of Life</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">480</enrollment>
  <condition>Abdominal Aortic Aneurysm</condition>
  <arm_group>
    <arm_group_label>Metformin group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will either be assigned to take metformin 500 mg tablet(s) daily or identical tablet(s) that contain no active drug, also taken every day. Over the first four weeks of the study, you will increase your dosage every week by one pill, so at the end of the first month you will be taking up to four pills per day. If you develop any symptoms or side effects from pill ingestion during this process, your dose will be decreased to the last number of pills you were able to take without developing side effects.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo Group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will either be assigned to take metformin 500 mg tablet(s) daily or identical tablet(s) that contain no active drug, also taken every day. Over the first four weeks of the study, you will increase your dosage every week by one pill, so at the end of the first month you will be taking up to four pills per day. If you develop any symptoms or side effects from pill ingestion during this process, your dose will be decreased to the last number of pills you were able to take without developing side effects.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <description>Smaller studies have suggested that metformin may reduce the rate at which aortic aneurysms enlarge. This study will test this question: does metformin prevent AAAs from growing larger?</description>
    <arm_group_label>Metformin group</arm_group_label>
    <other_name>AAA</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>One group will be randomized to receive the study drug Metformin and the other group will receive a placebo</description>
    <arm_group_label>Placebo Group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Provision of signed and dated informed consent;&#xD;
&#xD;
          2. Stated willingness to comply with all study procedures and availability for the&#xD;
             duration of the study&#xD;
&#xD;
          3. Male or female, aged 55 to 95 years inclusive;&#xD;
&#xD;
          4. 4. Have a maximal orthogonal infrarenal aortic diameter between 35 and &lt; 50 mm for&#xD;
             males and between 30 and &lt; 45 mm for females as measured by CTA;&#xD;
&#xD;
          5. Eligible participants must have an estimated glomerular filtration rate (eGFR) of ≥ 30&#xD;
             ml/min/1.73 m2 at the initiation of trial participation, and must remain ≥ 30&#xD;
             ml/min/1.73 m2 throughout the term of the study to continue participation;&#xD;
&#xD;
          6. HgbA1c must be ≤ 6.5% at initiation to receive study medication;&#xD;
&#xD;
          7. Ability to take oral medication and be willing to adhere to the medication regimen&#xD;
             throughout the course of the trial;&#xD;
&#xD;
          8. Must be willing and able to undergo two computed tomographic aortograms (CTA, with&#xD;
             timed intravenous iodinated contrast injections) at initiation and termination of&#xD;
             study participation;&#xD;
&#xD;
          9. For females of reproductive potential: use of highly effective contraception for at&#xD;
             least 1 month prior to screening, with an agreement to use such a method of&#xD;
             contraception during study participation and for an additional 4 weeks after the end&#xD;
             of study drug administration.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Diagnosis of, or taking medications for, diabetes mellitus, as defined as HgbA1c &gt;&#xD;
             6.5% at baseline evaluation;&#xD;
&#xD;
          2. Known hypersensitivity to metformin hydrochloride. Individuals with known prior&#xD;
             anaphylactic reaction to iodinated contrast will have the option of CT scan without&#xD;
             contrast or will not be eligible to participate. Individuals with a prior allergic&#xD;
             reaction not including anaphylaxis will be managed with the standard CT protocol for&#xD;
             premedication for allergy to contrast - 3 doses of prednisone (50 mg p.o. per)&#xD;
             beginning 13 hours prior to the procedure as well as 50 mg of Benadryl p.o.&#xD;
             Premedication start times are as follows:&#xD;
&#xD;
        13 hours before contrast, 50 mg PO prednisone 7 hours before contrast, 50 mg PO prednisone&#xD;
&#xD;
        1 hour before contrast, 50 mg PO prednisone + 50 mg PO diphenhydramine These individuals&#xD;
        will also be given the option of CT scan without contrast if unwilling to follow the&#xD;
        premedication as indicated above;&#xD;
&#xD;
        3. Presence of metabolic acidosis, defined as total CO2 below the lower limit of normal on&#xD;
        chemistry panel obtained during determination of study eligibility;&#xD;
&#xD;
        4. Expected survival less than two years;&#xD;
&#xD;
        5. Prior surgical AAA repair, or anticipated repair within two years;&#xD;
&#xD;
        6. Known thoracic aortic aneurysm disease, as defined as a prior dissection or thoracic&#xD;
        aortic diameter &gt; 5 cm);&#xD;
&#xD;
        7. The presence of known syndromic aortic conditions, including but not limited to Ehlers&#xD;
        Danlos or Marfan Syndromes, or the at-risk allele in the ACTA2 gene mutation or similar&#xD;
        conditions;&#xD;
&#xD;
        8. Severe liver disease, jaundice, or active hepatitis;&#xD;
&#xD;
        9. Severe anemia, defined as a Hgb &lt; 10g/dl;&#xD;
&#xD;
        10. Concurrent participation in other investigational drug trials;&#xD;
&#xD;
        11. For female participants of childbearing potential: pregnancy, intent to become&#xD;
        pregnant, lactation, or unwilling or unable to use an effective method of contraception;&#xD;
&#xD;
        12. Alcoholism or chronic excessive alcohol intake;&#xD;
&#xD;
        13. Common iliac artery aneurysms &gt; 3.0 cm;&#xD;
&#xD;
        14. Uncontrolled hypertension defined as Systolic BP≥200, or considered to have&#xD;
        hypertensive emergency or urgency.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>55 Years</minimum_age>
    <maximum_age>95 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ronald Dalman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Stanford University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Shea Smith</last_name>
    <phone>650-724-6211</phone>
    <email>sgluhm@stanford.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Ronald Dalman, MD</last_name>
    <phone>650-725-5227</phone>
    <email>rld@stanford.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Stanford Hospital and Clinics</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lori McDonnell</last_name>
      <phone>650-498-5521</phone>
      <email>lorimcd2@stanford.edu</email>
    </contact>
    <contact_backup>
      <last_name>Ronald Dalman, MD</last_name>
      <phone>650-725-5227</phone>
      <email>rld@stanford.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>June 6, 2020</study_first_submitted>
  <study_first_submitted_qc>August 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 5, 2020</study_first_posted>
  <last_update_submitted>May 4, 2023</last_update_submitted>
  <last_update_submitted_qc>May 4, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Stanford University</investigator_affiliation>
    <investigator_full_name>Ronald L. Dalman, MD</investigator_full_name>
    <investigator_title>Division Chief of Stanford Vascular Surgery</investigator_title>
  </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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
  </intervention_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/NCT04500756
org study id: IRB-56500
secondary id: 1R61HL146835-01A1
secondary id: 4R33HL146835-02
nct id: NCT04500756
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
In this research, the investigators are looking at the effects of a drug called metformin may
      have on the growth of abdominal aortic aneurysm (AAA)s. AAA is an abnormal enlargement of the
      aorta, which is the large artery in the abdomen (stomach area). The enlargement of the aorta
      carries a risk that it will rupture and cause life-threatening bleeding in the abdomen
      (belly). In this study the investigators hope to learn how metformin is associated with the
      enlargement or change in size of the AAA in study participants. Smaller studies have
      suggested that metformin may reduce the rate at which aortic aneurysms enlarge. This study
      will test this question: does metformin prevent AAAs from growing larger?
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Prospective, randomized, controlled trial comparing the ability of metformin to prevent AAA disease progression vs. placebo.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: randomized (which means assigned by chance, like flipping a coin) into one of two groups. You will either be assigned to take metformin 500 mg tablet(s) daily or identical tablet(s) that contain no active drug, also taken every day.
measure: The primary outcome measure will be the change in maximal orthogonal diameter of the infrarenal aorta, as measured by computed tomographic (CT) aortography, in centimeters.
time frame: Baseline to 2 years
description: The change in maximal orthogonal diameter of the infrarenal aorta, as measured by computed tomographic (CT) aortography, over the course of the study in participants taking metformin XR (extended release) vs. placebo. It is calculated as the difference in CTA-determined diameter (in mm) from baseline to the follow-up CT study at the end of study participation, divided by time elapsed between two measurements (e.g., annual rate of change in CT-diameter). The justification for this endpoint is that maximal orthogonal transverse diameter by CTA is the primary standard to measure AAA disease progression, determine need for surgical intervention, and correlate with clinical outcomes.
measure: Profile of Adverse cardiovascular events
time frame: Baseline to 2 years
description: Incidence of adverse cardiovascular events including: unanticipated adverse events (AEs) and serious AEs (SAEs), AEs leading to premature discontinuation from the study intervention and serious treatment-emergent AEs, clinically significant AE events, such as cardiovascular AEs and surgical AAA repairs.
measure: Study drug compliance
time frame: Baseline to 2 years
description: Pill counts will be used to measure study drug compliance.
measure: All-cause mortality
time frame: Baseline to 2 years
description: All-cause mortality will be summarized using Kaplan-Meier survival curves for each arm. Participants alive at last follow-up will be censored at last time known alive.
measure: Change in existing medication regimen as a measure of metformin treatment
time frame: Baseline to 2 years
description: Concurrent medication regimen will be tabulated and listed according to the drug classifications
measure: Change in serological markers of the liver as a measure of impact of metformin treatment
time frame: Baseline to 2 years
description: Albumin and total protein, total bilirubin, ALT, and AST will be assessed for these serological markers.
measure: Change in serological markers of the kidney as a measure of impact of metformin treatment
time frame: Baseline to 2 years
description: Urea nitrogen (BUN) and creatinine will be assessed for these serological markers.
measure: Change in serological markers of the hematopoietic function as a measure of impact of metformin treatment
time frame: Baseline to 2 years
description: Complete Blood Count (CBC) will be assessed for this serological marker.
measure: Change from baseline in Living with Abdominal Aortic Aneurysm (AAA) Survey
time frame: Baseline to 2 years
description: 62 question instrument for evaluating AAA specific Quality of Life
measure: Change from baseline in Short Form (SF-36) health survey
time frame: Baseline to 2 years
description: 36 question instrument for evaluating Health-Related Quality of Life
arm group label: Metformin group
arm group type: Active Comparator
description: Participants will either be assigned to take metformin 500 mg tablet(s) daily or identical tablet(s) that contain no active drug, also taken every day. Over the first four weeks of the study, you will increase your dosage every week by one pill, so at the end of the first month you will be taking up to four pills per day. If you develop any symptoms or side effects from pill ingestion during this process, your dose will be decreased to the last number of pills you were able to take without developing side effects.
arm group label: Placebo Group
arm group type: Placebo Comparator
description: Participants will either be assigned to take metformin 500 mg tablet(s) daily or identical tablet(s) that contain no active drug, also taken every day. Over the first four weeks of the study, you will increase your dosage every week by one pill, so at the end of the first month you will be taking up to four pills per day. If you develop any symptoms or side effects from pill ingestion during this process, your dose will be decreased to the last number of pills you were able to take without developing side effects.
intervention type: Drug
intervention name: Metformin
description: Smaller studies have suggested that metformin may reduce the rate at which aortic aneurysms enlarge. This study will test this question: does metformin prevent AAAs from growing larger?
arm group label: Metformin group
other name: AAA
intervention type: Other
intervention name: Placebo
description: One group will be randomized to receive the study drug Metformin and the other group will receive a placebo
arm group label: Placebo Group
criteria: 
gender: All
minimum age: 55 Years
maximum age: 95 Years
healthy volunteers: No
last name: Ronald Dalman, MD
role: Principal Investigator
affiliation: Stanford University
last name: Shea Smith
phone: 650-724-6211
email: sgluhm@stanford.edu
last name: Ronald Dalman, MD
phone: 650-725-5227
email: rld@stanford.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Stanford University
investigator full name: Ronald L. Dalman, MD
investigator title: Division Chief of Stanford Vascular Surgery
mesh term: Aneurysm
mesh term: Aortic Aneurysm
mesh term: Aortic Aneurysm, Abdominal
mesh term: Metformin
sharing ipd: No