<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/NCT03021525</url>
  </required_header>
  <id_info>
    <org_study_id>301116</org_study_id>
    <nct_id>NCT03021525</nct_id>
  </id_info>
  <brief_title>Individualized Perioperative Hemodynamic Goal-directed Therapy in Major Abdominal Surgery (iPEGASUS-trial)</brief_title>
  <acronym>iPEGASUS</acronym>
  <official_title>Individualized Perioperative Hemodynamic Goal-directed Therapy in Major Abdominal Surgery (iPEGASUS-trial) - A Multi-center, Prospective, Randomized Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Universitätsklinikum Hamburg-Eppendorf</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Giessen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Rostock</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Universitätsklinikum Hamburg-Eppendorf</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>
      To evaluate the impact of perioperative, algorithm driven, hemodynamic therapy based on&#xD;
      individualized fluid and cardiac output optimization on postoperative moderate and severe&#xD;
      complications in patients undergoing major abdominal surgery including visceral, urological,&#xD;
      and gynecological operations.&#xD;
&#xD;
      In the proposed study, hemodynamic therapy is tailored individually to each patient, based on&#xD;
      individual preload optimization by the functional parameter &quot;pulse pressure variation (PPV)&quot;&#xD;
      and based on an individually titrated goal of cardiac index. The proposed study therefore&#xD;
      further develops the concept of hemodynamic goal-directed therapy to individually set goals&#xD;
      and is designed to assess its impact on morbidity and mortality.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Postoperative mortality in patients undergoing surgery is on average still 4% in Europe as&#xD;
      evaluated recently in a cohort study across 28 European countries and is considered to be&#xD;
      even higher in high risk surgery. But besides this significant risk of death, in particular&#xD;
      moderate and severe postoperative complications, affecting up to 40% of patients after major&#xD;
      surgery, frequently lead to severe reductions of quality of life and cause high healthcare&#xD;
      costs in western nations. Perioperative hemodynamic goal-directed optimization is believed to&#xD;
      be an integral part to reduce in particular postoperative morbidity significantly and&#xD;
      possibly also mortality. Algorithm driven optimization of macrocirculation aiming on best&#xD;
      possible oxygen and substrate delivery to end organs and tissues is thought to be the&#xD;
      theoretical mechanism of this therapy. A recent large multi-center trial based on such a&#xD;
      pragmatic, non-individualized protocol failed to reduce composite morbidity underlining this&#xD;
      weak point of this approach. The reason for failing statistically significant improvement of&#xD;
      clinical outcome first of all has to be seen in not taking into account individual&#xD;
      hemodynamic needs of each single patient. Every patient was hemodynamically treated according&#xD;
      to a &quot;one size fits all of maximizing stroke volume&quot; approach. In contrast, a first&#xD;
      mono-center trial gave evidence that individualized early goal-directed therapy based on an&#xD;
      individually optimized volumetric cardiac preload parameter (global end-diastolic volume)&#xD;
      reduces complications and ICU length of stay after cardiac surgery. Further, and even more&#xD;
      important, a first multi-center pilot study using a goal-directed algorithm aiming to&#xD;
      optimize blood flow oriented on individual cardiac capacities (individualized optimal cardiac&#xD;
      index) in major abdominal surgery demonstrated feasibility and a reduction in postoperative&#xD;
      complications. This finding needs to be confirmed in a multi-center study that is adequately&#xD;
      powered to detect changes in specific complications and in mortality before clinical practice&#xD;
      can be changed accordingly. Therefore, the hypothesis of this proposed prospective two arm&#xD;
      randomized study is that algorithm driven individualized hemodynamic goal-directed therapy&#xD;
      reduces moderate and severe postoperative complications being a massive burden on quality of&#xD;
      life and health care costs. The proposed study develops the concept of hemodynamic&#xD;
      goal-directed therapy to individually set goals and is designed to assess its impact on&#xD;
      morbidity and mortality.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 23, 2017</start_date>
  <completion_date type="Anticipated">September 27, 2023</completion_date>
  <primary_completion_date type="Actual">February 27, 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>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Composite of morbidity and mortality on day 28</measure>
    <time_frame>28 days</time_frame>
    <description>Considering the high relevance for the individual patient and the society, postoperative outcome is most appropriately reflected by a combination of morbidity and mortality. Therefore, the primary endpoint is a composite comprising rate of patients with one or more moderate or severe postoperative complications or death within 28 days post surgery. Moderate and severe postoperative complications are defined on the basis of a consensus statement of an ESA (European Society of Anesthesiology)- ESICM (European Society of Intensive Care Medicine) joint task force on perioperative outcome measures.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Morbidity</measure>
    <time_frame>Day 1,3,5,7 and 180</time_frame>
    <description>At these days both, number of complications and number of patients having at least one moderate or severe complication, will be assessed in total and for every complication. The additional secondary endpoints including days alive and free of mechanical ventilation at 7 days and 28 days, days alive and free of vasopressor therapy at 7 days and 28 days, days alive and free of renal replacement therapy at 7 days and 28 days, length of ICU and hospital stay further characterize perioperative morbidity and its socioeconomic impacts.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life after 6 months</measure>
    <time_frame>Time point of enrolment and on day180</time_frame>
    <description>For assessment of quality of life an interview (personal or by telephone) based on the EQ-5D-5L (EuroQol Research Foundation) questionnaire is performed at the time point of enrolment and 6 months after surgery.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>Day 180</time_frame>
    <description>Mortality is assessed 6 months after surgery.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">380</enrollment>
  <condition>Hemodynamic Instability</condition>
  <condition>Cardiac Output, High</condition>
  <condition>Peroperative Complication</condition>
  <arm_group>
    <arm_group_label>Individualized Goal Directed Therapy (iGDT)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive fluids and catecholamines following a protocol of individualized parameters achieved by extended hemodynamic monitoring.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients in the control group will be treated according to established basic treatment goals.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Individualized Goal Directed Therapy</intervention_name>
    <description>The trial intervention period will commence from the induction of anesthesia until 8 hours after surgery, or until discharging from the postoperative intensive or intermediate care unit. All patients in the intervention group receive basic vital sign monitoring. For inotropic support dobutamine, and as vasopressor norepinephrine are drugs of choice. Hemodynamic management is performed according to standard treatment until an arterial line is placed. The signal of the arterial line is then processed either by calibrated or non-calibrated pulse contour analysis for pulse pressure variation (PPV) and cardiac index (CI) measurement. Fluid challenge will be performed by infusion of 500 ml in &lt;15 minute. Choice of fluid in case of indicated fluid loading is determined on basis of the recent guideline for intravasal volume therapy. Patients receive fluids and vasoactive agents following a protocol of individualized parameters regularly achieved by extended hemodynamic monitoring.</description>
    <arm_group_label>Individualized Goal Directed Therapy (iGDT)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Control Group</intervention_name>
    <description>Patients in the control group will be treated according to established basic treatment goals (heart rate &lt;100 bpm, mean arterial pressure &gt;65 mmHg, SpO2&gt;94%, and core temperature &gt;36° C). Basic anesthesiological monitoring by five-lead-electrocardiogram, pulse oximetry, non-invasive blood pressure monitoring and capnography is performed in every patient of the control group. Placement of an arterial and central venous line, as well as fluid and catecholamines administration, are at the discretion of the treating clinician.</description>
    <arm_group_label>Control</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  To provide high generalizability and representativeness the high number of patients&#xD;
             with laparotomy and major surgical trauma is included into this study. - Therefore,&#xD;
             open visceral, urological, and gynecological surgery is covered by this study.&#xD;
&#xD;
          -  Expected duration of surgery must be ≥ 120 minutes and requirement of volume therapy&#xD;
             needs to be expected ≥ 2 liters.&#xD;
&#xD;
          -  Risk for any postoperative complications needs to be ≥10% assessed by the ACS&#xD;
             (American College of Surgery)- NSQUIP (National Surgical Quality Improvement Program)&#xD;
             risk calculator.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients &lt;18 years,&#xD;
&#xD;
          -  laparoscopic approach,&#xD;
&#xD;
          -  patients not having sinus rhythm,&#xD;
&#xD;
          -  patients having highly impaired left ventricular function (ejection fraction &lt;30%) or&#xD;
             severe aortic valve stenosis (aortic valve area &lt;1 cm2, mean gradient &gt;40 mmHg),&#xD;
&#xD;
          -  pregnant women,&#xD;
&#xD;
          -  emergency surgeries (surgery required within 24 hours),&#xD;
&#xD;
          -  primarily vascular surgery,&#xD;
&#xD;
          -  patients suffering from septic shock,&#xD;
&#xD;
          -  patients having phaeochromocytoma,&#xD;
&#xD;
          -  patients suffering from non-cardiac chest pain,&#xD;
&#xD;
          -  refusal of consent,&#xD;
&#xD;
          -  patients receiving palliative treatment only (likely to die within 6 months) and&#xD;
             patients suffering from acute myocardial ischemia (within 30 days before&#xD;
             randomization) are excluded from the study.&#xD;
&#xD;
          -  Further, in case that clinicians intended to use cardiac output monitoring for&#xD;
             clinical reasons patients should also not be included in the study.&#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_contact>
    <last_name>Daniel A Reuter, MD</last_name>
    <phone>+49 40 7410 52415</phone>
    <email>dreuter@uke.de</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Sebastian A Haas, MD</last_name>
    <phone>+49 40 7410 52415</phone>
    <email>shaas@uke.de</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Justus-Liebig-University Giessen</name>
      <address>
        <city>Giessen</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>University Medical Center Hamburg-Eppendorf</name>
      <address>
        <city>Hamburg</city>
        <zip>20246</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Christian Zoellner, Prof.</last_name>
      <phone>+49 40 7410 52415</phone>
      <email>c.zoellner@uke.de</email>
    </contact>
    <contact_backup>
      <last_name>Daniel A Reuter, Prof.</last_name>
      <phone>+49 40 7410 52415</phone>
      <email>dreuter@uke.de</email>
    </contact_backup>
    <investigator>
      <last_name>Sandra Funcke, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Bernd Saugel, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Daniel A Reuter, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Sebastian A Haas, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Medicine Rostock</name>
      <address>
        <city>Rostock</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Università degli Studi di Ferrara</name>
      <address>
        <city>Ferrara</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
  </location>
  <location>
    <facility>
      <name>Università degli Studi di Genova</name>
      <address>
        <city>Genoa</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
  </location>
  <location>
    <facility>
      <name>Hospital Santa Creu i Sant Pau</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
  </location>
  <location>
    <facility>
      <name>Hospital Universitari i Politécnic La Fe</name>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
  </location>
  <location_countries>
    <country>Germany</country>
    <country>Italy</country>
    <country>Spain</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>January 12, 2017</study_first_submitted>
  <study_first_submitted_qc>January 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 16, 2017</study_first_posted>
  <last_update_submitted>July 17, 2023</last_update_submitted>
  <last_update_submitted_qc>July 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Goal-directed therapy</keyword>
  <keyword>postoperative morbidity</keyword>
  <keyword>haemodynamic optimisation</keyword>
  <keyword>individualised medicine</keyword>
  <keyword>Pulse pressure variation</keyword>
  <keyword>Cardiac output</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cardiac Output, High</mesh_term>
    <mesh_term>Intraoperative Complications</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>To enter a patient into the iPEGASUS trial, research staff at site will log on to a secure web-based randomization system via a link to the respective website and complete the patient's details without individual participant data (name, date of birth etc.) to obtain a unique patient number and allocation to a treatment group. The local main investigator (LMI) will then be informed about patient's enrollment. For correct patient's data follow up only the LMI will set up a list with the possibility to retrace the patient's history. Personalized data will be handled by the LMI according to GCP (good clinical practice) requirements and will be stored separately from the obtained study data. Thereby, data in the eCRF (electronic case report form) itself will not be re-traceable anymore and visible only for the Principal Coordinators (PCs) for data analysis. Data management of the eCRF will be performed by a company specialized in full service study data management.</ipd_description>
  </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/NCT03021525
org study id: 301116
nct id: NCT03021525
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
To evaluate the impact of perioperative, algorithm driven, hemodynamic therapy based on
      individualized fluid and cardiac output optimization on postoperative moderate and severe
      complications in patients undergoing major abdominal surgery including visceral, urological,
      and gynecological operations.

      In the proposed study, hemodynamic therapy is tailored individually to each patient, based on
      individual preload optimization by the functional parameter "pulse pressure variation (PPV)"
      and based on an individually titrated goal of cardiac index. The proposed study therefore
      further develops the concept of hemodynamic goal-directed therapy to individually set goals
      and is designed to assess its impact on morbidity and mortality.
Postoperative mortality in patients undergoing surgery is on average still 4% in Europe as
      evaluated recently in a cohort study across 28 European countries and is considered to be
      even higher in high risk surgery. But besides this significant risk of death, in particular
      moderate and severe postoperative complications, affecting up to 40% of patients after major
      surgery, frequently lead to severe reductions of quality of life and cause high healthcare
      costs in western nations. Perioperative hemodynamic goal-directed optimization is believed to
      be an integral part to reduce in particular postoperative morbidity significantly and
      possibly also mortality. Algorithm driven optimization of macrocirculation aiming on best
      possible oxygen and substrate delivery to end organs and tissues is thought to be the
      theoretical mechanism of this therapy. A recent large multi-center trial based on such a
      pragmatic, non-individualized protocol failed to reduce composite morbidity underlining this
      weak point of this approach. The reason for failing statistically significant improvement of
      clinical outcome first of all has to be seen in not taking into account individual
      hemodynamic needs of each single patient. Every patient was hemodynamically treated according
      to a "one size fits all of maximizing stroke volume" approach. In contrast, a first
      mono-center trial gave evidence that individualized early goal-directed therapy based on an
      individually optimized volumetric cardiac preload parameter (global end-diastolic volume)
      reduces complications and ICU length of stay after cardiac surgery. Further, and even more
      important, a first multi-center pilot study using a goal-directed algorithm aiming to
      optimize blood flow oriented on individual cardiac capacities (individualized optimal cardiac
      index) in major abdominal surgery demonstrated feasibility and a reduction in postoperative
      complications. This finding needs to be confirmed in a multi-center study that is adequately
      powered to detect changes in specific complications and in mortality before clinical practice
      can be changed accordingly. Therefore, the hypothesis of this proposed prospective two arm
      randomized study is that algorithm driven individualized hemodynamic goal-directed therapy
      reduces moderate and severe postoperative complications being a massive burden on quality of
      life and health care costs. The proposed study develops the concept of hemodynamic
      goal-directed therapy to individually set goals and is designed to assess its impact on
      morbidity and mortality.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: Composite of morbidity and mortality on day 28
time frame: 28 days
description: Considering the high relevance for the individual patient and the society, postoperative outcome is most appropriately reflected by a combination of morbidity and mortality. Therefore, the primary endpoint is a composite comprising rate of patients with one or more moderate or severe postoperative complications or death within 28 days post surgery. Moderate and severe postoperative complications are defined on the basis of a consensus statement of an ESA (European Society of Anesthesiology)- ESICM (European Society of Intensive Care Medicine) joint task force on perioperative outcome measures.
measure: Morbidity
time frame: Day 1,3,5,7 and 180
description: At these days both, number of complications and number of patients having at least one moderate or severe complication, will be assessed in total and for every complication. The additional secondary endpoints including days alive and free of mechanical ventilation at 7 days and 28 days, days alive and free of vasopressor therapy at 7 days and 28 days, days alive and free of renal replacement therapy at 7 days and 28 days, length of ICU and hospital stay further characterize perioperative morbidity and its socioeconomic impacts.
measure: Quality of life after 6 months
time frame: Time point of enrolment and on day180
description: For assessment of quality of life an interview (personal or by telephone) based on the EQ-5D-5L (EuroQol Research Foundation) questionnaire is performed at the time point of enrolment and 6 months after surgery.
measure: Mortality
time frame: Day 180
description: Mortality is assessed 6 months after surgery.
arm group label: Individualized Goal Directed Therapy (iGDT)
arm group type: Experimental
description: Patients receive fluids and catecholamines following a protocol of individualized parameters achieved by extended hemodynamic monitoring.
arm group label: Control
arm group type: Active Comparator
description: Patients in the control group will be treated according to established basic treatment goals.
intervention type: Procedure
intervention name: Individualized Goal Directed Therapy
description: The trial intervention period will commence from the induction of anesthesia until 8 hours after surgery, or until discharging from the postoperative intensive or intermediate care unit. All patients in the intervention group receive basic vital sign monitoring. For inotropic support dobutamine, and as vasopressor norepinephrine are drugs of choice. Hemodynamic management is performed according to standard treatment until an arterial line is placed. The signal of the arterial line is then processed either by calibrated or non-calibrated pulse contour analysis for pulse pressure variation (PPV) and cardiac index (CI) measurement. Fluid challenge will be performed by infusion of 500 ml in <15 minute. Choice of fluid in case of indicated fluid loading is determined on basis of the recent guideline for intravasal volume therapy. Patients receive fluids and vasoactive agents following a protocol of individualized parameters regularly achieved by extended hemodynamic monitoring.
arm group label: Individualized Goal Directed Therapy (iGDT)
intervention type: Procedure
intervention name: Control Group
description: Patients in the control group will be treated according to established basic treatment goals (heart rate <100 bpm, mean arterial pressure >65 mmHg, SpO2>94%, and core temperature >36° C). Basic anesthesiological monitoring by five-lead-electrocardiogram, pulse oximetry, non-invasive blood pressure monitoring and capnography is performed in every patient of the control group. Placement of an arterial and central venous line, as well as fluid and catecholamines administration, are at the discretion of the treating clinician.
arm group label: Control
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Daniel A Reuter, MD
phone: +49 40 7410 52415
email: dreuter@uke.de
last name: Sebastian A Haas, MD
phone: +49 40 7410 52415
email: shaas@uke.de
facility: 
status: Recruiting
facility: 
status: Not yet recruiting
contact: 
contact backup: 
investigator: 
investigator: 
investigator: 
investigator: 
facility: 
status: Recruiting
facility: 
status: Not yet recruiting
facility: 
status: Not yet recruiting
facility: 
status: Not yet recruiting
facility: 
status: Not yet recruiting
country: Germany
country: Italy
country: Spain
responsible party type: Sponsor
mesh term: Cardiac Output, High
mesh term: Intraoperative Complications
sharing ipd: No
ipd description: To enter a patient into the iPEGASUS trial, research staff at site will log on to a secure web-based randomization system via a link to the respective website and complete the patient's details without individual participant data (name, date of birth etc.) to obtain a unique patient number and allocation to a treatment group. The local main investigator (LMI) will then be informed about patient's enrollment. For correct patient's data follow up only the LMI will set up a list with the possibility to retrace the patient's history. Personalized data will be handled by the LMI according to GCP (good clinical practice) requirements and will be stored separately from the obtained study data. Thereby, data in the eCRF (electronic case report form) itself will not be re-traceable anymore and visible only for the Principal Coordinators (PCs) for data analysis. Data management of the eCRF will be performed by a company specialized in full service study data management.