<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/NCT03302650</url>
  </required_header>
  <id_info>
    <org_study_id>N-68-2017</org_study_id>
    <nct_id>NCT03302650</nct_id>
  </id_info>
  <brief_title>Angiotensin II for Septic Shock Treatment</brief_title>
  <official_title>Angiotensin II for Septic Shock Treatment: Effects On Macro- and Microcirculation A Randomized, Controlled Pilot Trial (ANGSTROM Trial)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cairo University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cairo University</source>
  <oversight_info>
    <has_dmc>Yes</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>
      This study aims to investigate the effect of angiotensin II on microcirculation and&#xD;
      peripheral perfusion in patients with septic shock.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Shock is a syndrome characterized by acute circulatory failure resulting in impaired&#xD;
      peripheral tissue perfusion. Distributive shock is the most common type of shock and is&#xD;
      usually caused by severe sepsis. Distributive shock is characterized by profound&#xD;
      vasodilatation leading to decreased arterial blood pressure and impaired organ perfusion&#xD;
      despite high cardiac output.&#xD;
&#xD;
      The use of vasopressors is an essential management line for distributive sock. Two groups of&#xD;
      vasopressors are usually used for management of shock: catecholamines and vasopressin-like&#xD;
      peptides. There is a continuous need for other vasopressors because:&#xD;
&#xD;
      1- Available vasopressors have narrow therapeutic window. 2- Patients with severe hypotension&#xD;
      refractory to the currently available classes usually die.&#xD;
&#xD;
      A third system is usually engaged in the physiology of shock which is&#xD;
      Renin-Angiotensin-aldosterone system. Angiotensin II is a natural hormone which is a potent&#xD;
      vasopressor; moreover, angiotensin II stimulates the production of both antidiuretic hormone&#xD;
      and adrenocorticotropin hormone.&#xD;
&#xD;
      In a pilot study, angiotensin II was reported as an effective rescue vasopressor in septic&#xD;
      shock patients on multiple vasopressors. Angiotensin II improved mean arterial pressure and&#xD;
      helped in reduction of the doses of catecholamines. In a recent large randomized controlled&#xD;
      trial, angiotensin II improved blood pressure in catecholamine-resistant distributive shock&#xD;
      patients.&#xD;
&#xD;
      Microcirculation is the primary site of oxygen and nutrient exchange. Maintenance of&#xD;
      microcirculatory perfusion is a prerequisite for preservation of organ function. Multiple&#xD;
      organ failure is common in patients with distributive shock despite maintenance of parameters&#xD;
      of global perfusion due to disrupted microcirculatory perfusion. Furthermore, restoration of&#xD;
      microcirculatory perfusion was correlated with improvement in survival. This study aims to&#xD;
      investigate the effect of angiotensin II on peripheral microcirculation in patients with&#xD;
      septic shock.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Suspended</overall_status>
  <why_stopped>
    The drug is not available&#xD;
  </why_stopped>
  <start_date type="Anticipated">April 1, 2019</start_date>
  <completion_date type="Anticipated">August 15, 2019</completion_date>
  <primary_completion_date type="Anticipated">August 1, 2019</primary_completion_date>
  <phase>Phase 3</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Mean flow index</measure>
    <time_frame>6 Hours</time_frame>
    <description>Mean flow index measured by Side stream dark field imaging optical probe (Microscan; MicroVision Medical, Amsterdam, Netherlands). Briefly, after gentle cleansing of the tongue by isotonic-saline-drenched gauze, avoiding pressure artifacts, 5 steady images of at least 20 seconds each will be obtained and stored under a random number. Offline blind analysis of each video will be done using a dedicated software (Automated Vascular Analysis 3.0; Academic Medical Center, University of Amsterdam, The Netherlands).&#xD;
The microvascular flow index (MFI) will be used to quantify microvascular blood flow. In this score, flow is characterized as absent (0), intermittent (1), sluggish (2), or normal (3), for each patient the values from 5 videos will be averaged. Since our investigation will be focused on small vessels, calculations will be separately performed for vessels with a diameter less than 20 ųm.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion of perfused vessels</measure>
    <time_frame>6 Hours</time_frame>
    <description>Proportion of perfused vessels measured by Side stream dark field imaging optical probe (Microscan; MicroVision Medical, Amsterdam, Netherlands). Briefly, after gentle cleansing of the tongue by isotonic-saline-drenched gauze, avoiding pressure artifacts, 5 steady images of at least 20 seconds each will be obtained and stored under a random number. Offline blind analysis of each video will be done using a dedicated software (Automated Vascular Analysis 3.0; Academic Medical Center, University of Amsterdam, The Netherlands)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Perfused vessel density</measure>
    <time_frame>6 Hours</time_frame>
    <description>Perfused vessel density measured by Side stream dark field imaging optical probe (Microscan; MicroVision Medical, Amsterdam, Netherlands). Briefly, after gentle cleansing of the tongue by isotonic-saline-drenched gauze, avoiding pressure artifacts, 5 steady images of at least 20 seconds each will be obtained and stored under a random number. Offline blind analysis of each video will be done using a dedicated software (Automated Vascular Analysis 3.0; Academic Medical Center, University of Amsterdam, The Netherlands)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>systolic blood pressure</measure>
    <time_frame>6 hours</time_frame>
    <description>systolic blood pressure measured in mmHg</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diastolic blood pressure</measure>
    <time_frame>6 hours</time_frame>
    <description>diastolic blood pressure measured in mmHg</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Heart rate</measure>
    <time_frame>6 hours</time_frame>
    <description>heart rate in beats per minute</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum lactate</measure>
    <time_frame>6 hours</time_frame>
    <description>Serum lactate measured in milligrams per deciliter</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urine output</measure>
    <time_frame>6 hours</time_frame>
    <description>quantity of urine in milliliters</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum Creatinine</measure>
    <time_frame>24 hours</time_frame>
    <description>serum creatinine measured in milligrams per deciliter</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum Sodium</measure>
    <time_frame>24 hours</time_frame>
    <description>Serum sodium measured in milligrams per deciliter</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum potassium</measure>
    <time_frame>24 hours</time_frame>
    <description>Serum potassium measured in milligrams per deciliter</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiac output</measure>
    <time_frame>6 hours</time_frame>
    <description>quantity of blood pumper by the heart measured by electrical cardiometry in liters per minute</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>systemic vascular resistance</measure>
    <time_frame>6 hours</time_frame>
    <description>systemic vascular resistance measured by electrical cardiometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Norepinephrine requirements</measure>
    <time_frame>6 hours</time_frame>
    <description>total requirement of norepinephrine needed to maintain mean arterial blood pressure above 65 mmHg</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>perfusion index</measure>
    <time_frame>6 hours</time_frame>
    <description>proportion of pulsatile to non-pulsatile portions in peripheral circulation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>total fluid intake</measure>
    <time_frame>24 hours</time_frame>
    <description>amount of fluids received by the patient in milliliters</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Septic Shock</condition>
  <arm_group>
    <arm_group_label>Angiotensin group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive Angiotensin II at a starting dose of 20 ng/Kg/min. During the first 30 minutes after randomization, the angiotensin II infusion will be titrated to achieve a mean arterial pressure of 65-75 mmHg while the norepinephrine infusion will be withdrawn and stopped. Following a stabilization of 60 minutes, the angiotensin II infusion is titrated to achieve a mean arterial pressure of 85-95 mmHg. Following a 30 minutes wash-in period and a 60 minutes stabilization period, a third set of measurements will be taken. Then, the angiotensin II infusion will be withdrawn in small steps and replaced by a norepinephrine infusion which will then be titrated to achieve a mean arterial pressure of 65-75 mmHg. Then, the final set of measurements will be taken.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Normal saline group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients will receive normal saline infusion in addition to norepinephrine infusion. The same mean arterial pressure levels (65-75 mmHg &gt; 85-95 mmHg &gt; 65-75 mmHg) will be achieved by titration of the norepinephrine infusion. Identical wash-in and stabilization periods will be kept as in the study group. Measurements will be taken at the same time points as in the study group. The maximum dose of norepinephrine applied will be 0.7 mcg/kg/min.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Angiotensin II</intervention_name>
    <description>Patients will receive angiotensin-II at a starting dose of 20 ng/Kg/min.</description>
    <arm_group_label>Angiotensin group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Normal saline</intervention_name>
    <description>Patients will receive normal saline.</description>
    <arm_group_label>Normal saline group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Norepinephrine</intervention_name>
    <description>patients will receive norepinephrine infusion adjusted according to blood pressure</description>
    <arm_group_label>Angiotensin group</arm_group_label>
    <arm_group_label>Normal saline group</arm_group_label>
    <other_name>Noradrenaline</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Septic shock patients.&#xD;
&#xD;
          -  Aged above 18 years.&#xD;
&#xD;
          -  With cardiac index &gt; 2.4 L/min/BSA 1.73 m2.&#xD;
&#xD;
          -  On high dose vasopressors (defined as norepinephrine infusion above 0.1 mcg/Kg/min)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Acute coronary syndrome.&#xD;
&#xD;
          -  Impaired cardiac contractility&#xD;
&#xD;
          -  Bronchospasm.&#xD;
&#xD;
          -  Major burns&#xD;
&#xD;
          -  Liver failure.&#xD;
&#xD;
          -  Active bleeding.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ahmed Mukhtar, Professor</last_name>
    <role>Study Director</role>
    <affiliation>Head of research committee section in anesthesia department</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Martin W Dünser, Professor</last_name>
    <role>Study Director</role>
    <affiliation>Department of critical care, University of London college hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cairo University</name>
      <address>
        <city>Cairo</city>
        <country>Egypt</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Egypt</country>
  </location_countries>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>October 1, 2017</study_first_submitted>
  <study_first_submitted_qc>October 1, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 5, 2017</study_first_posted>
  <last_update_submitted>January 14, 2019</last_update_submitted>
  <last_update_submitted_qc>January 14, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 16, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cairo University</investigator_affiliation>
    <investigator_full_name>Ahmed Hasanin</investigator_full_name>
    <investigator_title>Assistant professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Shock, Septic</mesh_term>
    <mesh_term>Shock</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Norepinephrine</mesh_term>
    <mesh_term>Angiotensin II</mesh_term>
    <mesh_term>Giapreza</mesh_term>
    <mesh_term>Angiotensinogen</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03302650
org study id: N-68-2017
nct id: NCT03302650
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This study aims to investigate the effect of angiotensin II on microcirculation and
      peripheral perfusion in patients with septic shock.
Shock is a syndrome characterized by acute circulatory failure resulting in impaired
      peripheral tissue perfusion. Distributive shock is the most common type of shock and is
      usually caused by severe sepsis. Distributive shock is characterized by profound
      vasodilatation leading to decreased arterial blood pressure and impaired organ perfusion
      despite high cardiac output.

      The use of vasopressors is an essential management line for distributive sock. Two groups of
      vasopressors are usually used for management of shock: catecholamines and vasopressin-like
      peptides. There is a continuous need for other vasopressors because:

      1- Available vasopressors have narrow therapeutic window. 2- Patients with severe hypotension
      refractory to the currently available classes usually die.

      A third system is usually engaged in the physiology of shock which is
      Renin-Angiotensin-aldosterone system. Angiotensin II is a natural hormone which is a potent
      vasopressor; moreover, angiotensin II stimulates the production of both antidiuretic hormone
      and adrenocorticotropin hormone.

      In a pilot study, angiotensin II was reported as an effective rescue vasopressor in septic
      shock patients on multiple vasopressors. Angiotensin II improved mean arterial pressure and
      helped in reduction of the doses of catecholamines. In a recent large randomized controlled
      trial, angiotensin II improved blood pressure in catecholamine-resistant distributive shock
      patients.

      Microcirculation is the primary site of oxygen and nutrient exchange. Maintenance of
      microcirculatory perfusion is a prerequisite for preservation of organ function. Multiple
      organ failure is common in patients with distributive shock despite maintenance of parameters
      of global perfusion due to disrupted microcirculatory perfusion. Furthermore, restoration of
      microcirculatory perfusion was correlated with improvement in survival. This study aims to
      investigate the effect of angiotensin II on peripheral microcirculation in patients with
      septic shock.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Mean flow index
time frame: 6 Hours
description: Mean flow index measured by Side stream dark field imaging optical probe (Microscan; MicroVision Medical, Amsterdam, Netherlands). Briefly, after gentle cleansing of the tongue by isotonic-saline-drenched gauze, avoiding pressure artifacts, 5 steady images of at least 20 seconds each will be obtained and stored under a random number. Offline blind analysis of each video will be done using a dedicated software (Automated Vascular Analysis 3.0; Academic Medical Center, University of Amsterdam, The Netherlands).
The microvascular flow index (MFI) will be used to quantify microvascular blood flow. In this score, flow is characterized as absent (0), intermittent (1), sluggish (2), or normal (3), for each patient the values from 5 videos will be averaged. Since our investigation will be focused on small vessels, calculations will be separately performed for vessels with a diameter less than 20 ųm.
measure: Proportion of perfused vessels
time frame: 6 Hours
description: Proportion of perfused vessels measured by Side stream dark field imaging optical probe (Microscan; MicroVision Medical, Amsterdam, Netherlands). Briefly, after gentle cleansing of the tongue by isotonic-saline-drenched gauze, avoiding pressure artifacts, 5 steady images of at least 20 seconds each will be obtained and stored under a random number. Offline blind analysis of each video will be done using a dedicated software (Automated Vascular Analysis 3.0; Academic Medical Center, University of Amsterdam, The Netherlands)
measure: Perfused vessel density
time frame: 6 Hours
description: Perfused vessel density measured by Side stream dark field imaging optical probe (Microscan; MicroVision Medical, Amsterdam, Netherlands). Briefly, after gentle cleansing of the tongue by isotonic-saline-drenched gauze, avoiding pressure artifacts, 5 steady images of at least 20 seconds each will be obtained and stored under a random number. Offline blind analysis of each video will be done using a dedicated software (Automated Vascular Analysis 3.0; Academic Medical Center, University of Amsterdam, The Netherlands)
measure: systolic blood pressure
time frame: 6 hours
description: systolic blood pressure measured in mmHg
measure: Diastolic blood pressure
time frame: 6 hours
description: diastolic blood pressure measured in mmHg
measure: Heart rate
time frame: 6 hours
description: heart rate in beats per minute
measure: Serum lactate
time frame: 6 hours
description: Serum lactate measured in milligrams per deciliter
measure: Urine output
time frame: 6 hours
description: quantity of urine in milliliters
measure: Serum Creatinine
time frame: 24 hours
description: serum creatinine measured in milligrams per deciliter
measure: Serum Sodium
time frame: 24 hours
description: Serum sodium measured in milligrams per deciliter
measure: Serum potassium
time frame: 24 hours
description: Serum potassium measured in milligrams per deciliter
measure: Cardiac output
time frame: 6 hours
description: quantity of blood pumper by the heart measured by electrical cardiometry in liters per minute
measure: systemic vascular resistance
time frame: 6 hours
description: systemic vascular resistance measured by electrical cardiometry
measure: Norepinephrine requirements
time frame: 6 hours
description: total requirement of norepinephrine needed to maintain mean arterial blood pressure above 65 mmHg
measure: perfusion index
time frame: 6 hours
description: proportion of pulsatile to non-pulsatile portions in peripheral circulation
measure: total fluid intake
time frame: 24 hours
description: amount of fluids received by the patient in milliliters
arm group label: Angiotensin group
arm group type: Experimental
description: Patients will receive Angiotensin II at a starting dose of 20 ng/Kg/min. During the first 30 minutes after randomization, the angiotensin II infusion will be titrated to achieve a mean arterial pressure of 65-75 mmHg while the norepinephrine infusion will be withdrawn and stopped. Following a stabilization of 60 minutes, the angiotensin II infusion is titrated to achieve a mean arterial pressure of 85-95 mmHg. Following a 30 minutes wash-in period and a 60 minutes stabilization period, a third set of measurements will be taken. Then, the angiotensin II infusion will be withdrawn in small steps and replaced by a norepinephrine infusion which will then be titrated to achieve a mean arterial pressure of 65-75 mmHg. Then, the final set of measurements will be taken.
arm group label: Normal saline group
arm group type: Placebo Comparator
description: Patients will receive normal saline infusion in addition to norepinephrine infusion. The same mean arterial pressure levels (65-75 mmHg > 85-95 mmHg > 65-75 mmHg) will be achieved by titration of the norepinephrine infusion. Identical wash-in and stabilization periods will be kept as in the study group. Measurements will be taken at the same time points as in the study group. The maximum dose of norepinephrine applied will be 0.7 mcg/kg/min.
intervention type: Drug
intervention name: Angiotensin II
description: Patients will receive angiotensin-II at a starting dose of 20 ng/Kg/min.
arm group label: Angiotensin group
intervention type: Drug
intervention name: Normal saline
description: Patients will receive normal saline.
arm group label: Normal saline group
intervention type: Drug
intervention name: Norepinephrine
description: patients will receive norepinephrine infusion adjusted according to blood pressure
arm group label: Angiotensin group
arm group label: Normal saline group
other name: Noradrenaline
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Ahmed Mukhtar, Professor
role: Study Director
affiliation: Head of research committee section in anesthesia department
last name: Martin W Dünser, Professor
role: Study Director
affiliation: Department of critical care, University of London college hospital
facility: 
country: Egypt
responsible party type: Principal Investigator
investigator affiliation: Cairo University
investigator full name: Ahmed Hasanin
investigator title: Assistant professor
mesh term: Shock, Septic
mesh term: Shock
mesh term: Norepinephrine
mesh term: Angiotensin II
mesh term: Giapreza
mesh term: Angiotensinogen
sharing ipd: Undecided