<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/NCT04432974</url>
  </required_header>
  <id_info>
    <org_study_id>NP-2861</org_study_id>
    <nct_id>NCT04432974</nct_id>
  </id_info>
  <brief_title>Automatic Control of Total Intravenous Anesthesia (ACTIVA)</brief_title>
  <acronym>ACTIVA</acronym>
  <official_title>Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and Remifentanil Using Bispectral Index as Feedback Variable</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Università degli Studi di Brescia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</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 concerns the clinical evaluation of a closed loop control system for the automatic&#xD;
      administration of anesthetic drugs in TIVA (Total Intra Venous Anesthesia).&#xD;
&#xD;
      The purpose of the experimentation is to demonstrate that the control system under study is&#xD;
      reliable, safe, applicable and capable of inducing and maintaining an optimal anesthetic&#xD;
      level.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This clinical study consists of the application of the ACTIVA control software for the&#xD;
      infusion of intravenous drugs during general anesthesia according to the principle of&#xD;
      closed-loop anesthesia.&#xD;
&#xD;
      The objective of the experimentation is to evaluate the reliability, safety and applicability&#xD;
      of the infusion system for anesthetic drugs controlled by the ACTIVA software and to carry&#xD;
      out the clinical evaluation of the automatic control system during the induction and&#xD;
      maintenance of general intravenous anesthesia. The benefits for enrolled patients could be&#xD;
      linked to greater stability of anesthesia in the induction and maintenance phases. Constant&#xD;
      closed-loop control of infusions and the level of hypnosis could also reduce the hemodynamic&#xD;
      impact that general anesthesia has on the patient, by reducing the onset of hypotension&#xD;
      episodes.&#xD;
&#xD;
      Enrolled patients will undergo closed-loop anesthesia under the constant supervision of the&#xD;
      investigator. The anesthetic drugs used are those recommended for general intravenous&#xD;
      anesthesia: propofol and remifentanil.&#xD;
&#xD;
      Identification and description of the medical device:&#xD;
&#xD;
      The medical device object of the clinical investigation consists of the ACTIVA control&#xD;
      software developed to control the infusion of anesthetic drugs during general intravenous&#xD;
      anesthesia. ACTIVA software has been developed to optimize the infusion of anesthetic drugs&#xD;
      according to a closed-loop system that allows the induction and maintenance of a constant and&#xD;
      optimal level of anesthesia on the patient. ACTIVA control software is installed on a&#xD;
      personal computer (PC).&#xD;
&#xD;
      The level of anesthesia is measured according to the Bispectral Index (BIS) which measures&#xD;
      the depth of hypnosis. Through the measurement of the BIS, the administration of anesthetic&#xD;
      drugs is automatically regulated by the ACTIVA software and constantly supervised by the&#xD;
      anesthesiologist through the graphic interface integrated in the software.&#xD;
&#xD;
      The population for which the device is intended is made up of patients to undergo surgery for&#xD;
      which general anesthesia is required, and intravenous anesthesia may be advantageous.&#xD;
&#xD;
      During its operation, the ACTIVA software maintains the desired BIS level, selected by the&#xD;
      anesthesiologist through the graphical user interface, communicating the appropriate infusion&#xD;
      rate of the propofol and remifentanil anesthetic drugs to the syringe pumps. ACTIVA software&#xD;
      communicates with the pumps and the BIS monitoring system with serial connections. These&#xD;
      connections are native to the instrumentation used; therefore, no type of modification or&#xD;
      manipulation has been made on the medical devices used.&#xD;
&#xD;
      Closed-loop anesthesia:&#xD;
&#xD;
      A closed-loop system can be defined as an automatic control system that bases its operation&#xD;
      on the principle of feedback. Its key elements are a system to be controlled, a measuring&#xD;
      device (sensor), a controller and an actuator. The sensor measures the controlled variable&#xD;
      (system output), which is compared with the desired set-point. The difference between the&#xD;
      latter and the output, defined as an error, is used to calculate the value of the control&#xD;
      variable (system input).&#xD;
&#xD;
      In the case of closed-loop anesthesia, the system to be controlled identifies with the&#xD;
      patient, the actuator is represented by the syringe pump, the controlled variable corresponds&#xD;
      to the BIS and the control variable is represented by the rate of infusion of the drugs.&#xD;
&#xD;
      The controller used is a proportional-integral-derivative (PID) it relates the error signal&#xD;
      and the control variable by means of three constants (Kp, Ti and Td) allowing a correct&#xD;
      infusion of the drugs considering the present value of the error ( proportional action), the&#xD;
      past values of the error (integral action) and the advance of the future values of the error&#xD;
      (derivative action). These three constants, if properly calibrated, allow to obtain a&#xD;
      controller with good performance and robustness. For the ACTIVA system the calibration of&#xD;
      these constants was carried out by means of optimization methods performed in simulation.&#xD;
&#xD;
      The anesthesiologist has at his disposal a PC with a graphical user interface through which&#xD;
      he can control the start and end of the drug infusion and on which there are the commands&#xD;
      through which it is possible to interact with the system. The graphical interface also&#xD;
      reports indicators concerning the correct functioning of the control system. In case of&#xD;
      malfunction of the ACTIVA software, the patient monitoring systems are never altered or&#xD;
      damaged and the infusive pumps continue to operate in manual mode. Switching to manual&#xD;
      control is always possible if the anesthesiologist considers it appropriate, even without the&#xD;
      presence of system malfunctions.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 2, 2019</start_date>
  <completion_date type="Actual">April 4, 2023</completion_date>
  <primary_completion_date type="Actual">April 4, 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Depth of Hypnosis Adequacy</measure>
    <time_frame>During anesthesia</time_frame>
    <description>The depth of hypnosis adequacy is assessed by means of the Bispectral Index Scale (BIS) in order to evaluate the performance of the system for delivery of propofol and remifentanil</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>System dysfunctions</measure>
    <time_frame>Immediately after surgery, after infusions are over</time_frame>
    <description>Number and Types of Dysfunctions of the ACTIVA Automatic Infusion System</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Level of Satisfaction of the Experimenter</measure>
    <time_frame>Immediately after surgery, after infusions are over</time_frame>
    <description>Level of satisfaction expressed on a scale from 0 to 10 regarding the ease of use of the ACTIVA software and its infusion system, the induction phase of anesthesia and the maintenance phase of anesthesia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of Drugs Delivery on Heart Rate</measure>
    <time_frame>During anesthesia</time_frame>
    <description>The effect of drugs delivery on heart rate is assessed by measuring the heart rate in beats per minute (bpm)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of Drugs Delivery on Mean Blood Pressure</measure>
    <time_frame>During anesthesia</time_frame>
    <description>The effect of drugs delivery on mean blood pressure is assessed by non-invasive measuring of the mean blood pressure in mmHg</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postoperative Heart Rate Stability</measure>
    <time_frame>From end of anesthesia till 24-hours post-surgery</time_frame>
    <description>The postoperative heart rate stability is assessed by measuring the heart rate in beats per minute (bpm)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postoperative Mean Blood Pressure Stability</measure>
    <time_frame>From end of anesthesia till 24-hours post-surgery</time_frame>
    <description>The postoperative mean blood pressure stability is assessed by by non-invasive measuring of the mean blood pressure in mmHg</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postoperative Sedation</measure>
    <time_frame>From end of anesthesia till 24-hours post-surgery</time_frame>
    <description>The postoperative sedation is assessed by means of a Sedation Score scale. It is a 3 point scale from 0 (fully awake) to 3 (fully sedated)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postoperative Nausea and Vomiting (PONV)</measure>
    <time_frame>From end of anesthesia till 24-hours post-surgery</time_frame>
    <description>Postoperative Nausea and Vomiting is assessed by means of the Bellville PONV scale. It is a 3 point scale from 0 (no nausea &amp; vomiting) to 2 (vomiting present)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postoperative Analgesia</measure>
    <time_frame>From end of anesthesia till 24-hours post-surgery</time_frame>
    <description>The postoperative analgesia is assessed using 10-point numeric rating scale (NRS). It is a 10 point scale from 0 (no pain) to 10 (maximum pain).</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">139</enrollment>
  <condition>Anesthesia</condition>
  <arm_group>
    <arm_group_label>ACTIVA</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>ACTIVA closed-loop anesthesia control system</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Automatic closed-loop anesthesia</intervention_name>
    <description>Total intravenous anesthesia performed with the ACTIVA automatic control system</description>
    <arm_group_label>ACTIVA</arm_group_label>
    <other_name>ACTIVA</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult patients undergoing total intravenous general anesthesia for elective surgery&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients under the age of 18&#xD;
&#xD;
          -  Patients incapable of giving consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Massimiliano Paltenghi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</name>
      <address>
        <city>Brescia</city>
        <zip>25123</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Padula F, Ionescu C, Latronico N, Paltenghi M, Visioli A, Vivacqua G. Optimized PID control of depth of hypnosis in anesthesia. Comput Methods Programs Biomed. 2017 Jun;144:21-35. doi: 10.1016/j.cmpb.2017.03.013. Epub 2017 Mar 18.</citation>
    <PMID>28495004</PMID>
  </reference>
  <reference>
    <citation>Merigo L, Beschi M, Padula F, Latronico N, Paltenghi M, Visioli A. Event-Based control of depth of hypnosis in anesthesia. Comput Methods Programs Biomed. 2017 Aug;147:63-83. doi: 10.1016/j.cmpb.2017.06.007. Epub 2017 Jun 23.</citation>
    <PMID>28734531</PMID>
  </reference>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>June 9, 2020</study_first_submitted>
  <study_first_submitted_qc>June 12, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>August 1, 2023</last_update_submitted>
  <last_update_submitted_qc>August 1, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 2, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</investigator_affiliation>
    <investigator_full_name>Massimiliano Paltenghi</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Closed-loop Anesthesia</keyword>
  <keyword>PID Control</keyword>
  <keyword>Medical Control Systems</keyword>
  <keyword>Automated Drug Delivery</keyword>
  <keyword>Propofol</keyword>
  <keyword>Remifentanil</keyword>
  <keyword>Bispectral index</keyword>
  <keyword>BIS</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anesthetics</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/NCT04432974
org study id: NP-2861
nct id: NCT04432974
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This study concerns the clinical evaluation of a closed loop control system for the automatic
      administration of anesthetic drugs in TIVA (Total Intra Venous Anesthesia).

      The purpose of the experimentation is to demonstrate that the control system under study is
      reliable, safe, applicable and capable of inducing and maintaining an optimal anesthetic
      level.
This clinical study consists of the application of the ACTIVA control software for the
      infusion of intravenous drugs during general anesthesia according to the principle of
      closed-loop anesthesia.

      The objective of the experimentation is to evaluate the reliability, safety and applicability
      of the infusion system for anesthetic drugs controlled by the ACTIVA software and to carry
      out the clinical evaluation of the automatic control system during the induction and
      maintenance of general intravenous anesthesia. The benefits for enrolled patients could be
      linked to greater stability of anesthesia in the induction and maintenance phases. Constant
      closed-loop control of infusions and the level of hypnosis could also reduce the hemodynamic
      impact that general anesthesia has on the patient, by reducing the onset of hypotension
      episodes.

      Enrolled patients will undergo closed-loop anesthesia under the constant supervision of the
      investigator. The anesthetic drugs used are those recommended for general intravenous
      anesthesia: propofol and remifentanil.

      Identification and description of the medical device:

      The medical device object of the clinical investigation consists of the ACTIVA control
      software developed to control the infusion of anesthetic drugs during general intravenous
      anesthesia. ACTIVA software has been developed to optimize the infusion of anesthetic drugs
      according to a closed-loop system that allows the induction and maintenance of a constant and
      optimal level of anesthesia on the patient. ACTIVA control software is installed on a
      personal computer (PC).

      The level of anesthesia is measured according to the Bispectral Index (BIS) which measures
      the depth of hypnosis. Through the measurement of the BIS, the administration of anesthetic
      drugs is automatically regulated by the ACTIVA software and constantly supervised by the
      anesthesiologist through the graphic interface integrated in the software.

      The population for which the device is intended is made up of patients to undergo surgery for
      which general anesthesia is required, and intravenous anesthesia may be advantageous.

      During its operation, the ACTIVA software maintains the desired BIS level, selected by the
      anesthesiologist through the graphical user interface, communicating the appropriate infusion
      rate of the propofol and remifentanil anesthetic drugs to the syringe pumps. ACTIVA software
      communicates with the pumps and the BIS monitoring system with serial connections. These
      connections are native to the instrumentation used; therefore, no type of modification or
      manipulation has been made on the medical devices used.

      Closed-loop anesthesia:

      A closed-loop system can be defined as an automatic control system that bases its operation
      on the principle of feedback. Its key elements are a system to be controlled, a measuring
      device (sensor), a controller and an actuator. The sensor measures the controlled variable
      (system output), which is compared with the desired set-point. The difference between the
      latter and the output, defined as an error, is used to calculate the value of the control
      variable (system input).

      In the case of closed-loop anesthesia, the system to be controlled identifies with the
      patient, the actuator is represented by the syringe pump, the controlled variable corresponds
      to the BIS and the control variable is represented by the rate of infusion of the drugs.

      The controller used is a proportional-integral-derivative (PID) it relates the error signal
      and the control variable by means of three constants (Kp, Ti and Td) allowing a correct
      infusion of the drugs considering the present value of the error ( proportional action), the
      past values of the error (integral action) and the advance of the future values of the error
      (derivative action). These three constants, if properly calibrated, allow to obtain a
      controller with good performance and robustness. For the ACTIVA system the calibration of
      these constants was carried out by means of optimization methods performed in simulation.

      The anesthesiologist has at his disposal a PC with a graphical user interface through which
      he can control the start and end of the drug infusion and on which there are the commands
      through which it is possible to interact with the system. The graphical interface also
      reports indicators concerning the correct functioning of the control system. In case of
      malfunction of the ACTIVA software, the patient monitoring systems are never altered or
      damaged and the infusive pumps continue to operate in manual mode. Switching to manual
      control is always possible if the anesthesiologist considers it appropriate, even without the
      presence of system malfunctions.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Depth of Hypnosis Adequacy
time frame: During anesthesia
description: The depth of hypnosis adequacy is assessed by means of the Bispectral Index Scale (BIS) in order to evaluate the performance of the system for delivery of propofol and remifentanil
measure: System dysfunctions
time frame: Immediately after surgery, after infusions are over
description: Number and Types of Dysfunctions of the ACTIVA Automatic Infusion System
measure: Level of Satisfaction of the Experimenter
time frame: Immediately after surgery, after infusions are over
description: Level of satisfaction expressed on a scale from 0 to 10 regarding the ease of use of the ACTIVA software and its infusion system, the induction phase of anesthesia and the maintenance phase of anesthesia
measure: Effect of Drugs Delivery on Heart Rate
time frame: During anesthesia
description: The effect of drugs delivery on heart rate is assessed by measuring the heart rate in beats per minute (bpm)
measure: Effect of Drugs Delivery on Mean Blood Pressure
time frame: During anesthesia
description: The effect of drugs delivery on mean blood pressure is assessed by non-invasive measuring of the mean blood pressure in mmHg
measure: Postoperative Heart Rate Stability
time frame: From end of anesthesia till 24-hours post-surgery
description: The postoperative heart rate stability is assessed by measuring the heart rate in beats per minute (bpm)
measure: Postoperative Mean Blood Pressure Stability
time frame: From end of anesthesia till 24-hours post-surgery
description: The postoperative mean blood pressure stability is assessed by by non-invasive measuring of the mean blood pressure in mmHg
measure: Postoperative Sedation
time frame: From end of anesthesia till 24-hours post-surgery
description: The postoperative sedation is assessed by means of a Sedation Score scale. It is a 3 point scale from 0 (fully awake) to 3 (fully sedated)
measure: Postoperative Nausea and Vomiting (PONV)
time frame: From end of anesthesia till 24-hours post-surgery
description: Postoperative Nausea and Vomiting is assessed by means of the Bellville PONV scale. It is a 3 point scale from 0 (no nausea & vomiting) to 2 (vomiting present)
measure: Postoperative Analgesia
time frame: From end of anesthesia till 24-hours post-surgery
description: The postoperative analgesia is assessed using 10-point numeric rating scale (NRS). It is a 10 point scale from 0 (no pain) to 10 (maximum pain).
arm group label: ACTIVA
arm group type: Experimental
description: ACTIVA closed-loop anesthesia control system
intervention type: Device
intervention name: Automatic closed-loop anesthesia
description: Total intravenous anesthesia performed with the ACTIVA automatic control system
arm group label: ACTIVA
other name: ACTIVA
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Massimiliano Paltenghi, MD
role: Principal Investigator
affiliation: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
facility: 
country: Italy
citation: Padula F, Ionescu C, Latronico N, Paltenghi M, Visioli A, Vivacqua G. Optimized PID control of depth of hypnosis in anesthesia. Comput Methods Programs Biomed. 2017 Jun;144:21-35. doi: 10.1016/j.cmpb.2017.03.013. Epub 2017 Mar 18.
PMID: 28495004
citation: Merigo L, Beschi M, Padula F, Latronico N, Paltenghi M, Visioli A. Event-Based control of depth of hypnosis in anesthesia. Comput Methods Programs Biomed. 2017 Aug;147:63-83. doi: 10.1016/j.cmpb.2017.06.007. Epub 2017 Jun 23.
PMID: 28734531
responsible party type: Principal Investigator
investigator affiliation: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
investigator full name: Massimiliano Paltenghi
investigator title: Principal Investigator
mesh term: Anesthetics
sharing ipd: No