Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and Remifentanil Using Bispectral Index as Feedback Variable
Phase: NA
Conditions: Anesthesia
Sponsor: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

Clinical Investigation Plan
Prepared in accordance with UNI EN ISO 14155:2012
Study title
Automatic Control of Total Intravenous Anesthesia:
Closed-loop Delivery of Propofol and Remifentanil
Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2.
Identifier
code
of
the
clinical
investigation
NP-2861
Version number of the clinical
investigation
Version 4
Version date
07/03/2019
NCT number
NCT04432974
Sponsor
Azienda Socio Sanitaria Territoriale degli Spedali
Civili di Brescia
Principal investigator
Dr. Massimiliano Paltenghi
Medical specialist in anesthesia and intensive care
medicine at the 2nd Department of Anesthesia and
Intensive Care, ASST Spedali Civili di Brescia.
Location
Azienda Socio Sanitaria Territoriale degli Spedali
Civili di Brescia, 25123, Brescia, Italy.
Author of the document
Dr. Massimiliano Paltenghi
Document date
17/06/2020
1
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

Index
List of abbreviations................................................................................................................. 3
Summary..................................................................................................................................4
Study rationale and literature review........................................................................................6
Study rationale................................................................................................................... 6
Literature review.................................................................................................................8
Medical device information.....................................................................................................10
Purpose of use for the experimental device..................................................................... 11
Number of experimental medical devices expected to be used.......................................12
Risks and benefits of the medical device...............................................................................13
Expected clinical benefits.................................................................................................13
Predicted clinical risks associated with the device and residual risks..............................13
Risks associated with participation in the clinical investigation........................................14
Interaction with concurrent medical treatments................................................................14
Procedures for risk control or reduction........................................................................... 15
Risks/benefits ratio...........................................................................................................15
Information related to the clinical investigation...................................................................... 15
Clinical study objectives................................................................................................... 15
Clinical study description..................................................................................................15
Measured variables..........................................................................................................16
Participation criteria..........................................................................................................17
Enrollment procedure.......................................................................................................17
Number of patients enrolled............................................................................................. 18
Subject Enrollment Count.................................................................................................18
Study Duration..................................................................................................................19
Concomitant medications and medical treatments...........................................................19
Follow-up..........................................................................................................................19
Statistical analysis............................................................................................................19
Systematic errors prevention methods.............................................................................19
Factors that may compromise the outcome and interpretation of the results...................21
Clinical investigation monitoring plan............................................................................... 21
Ethical considerations............................................................................................................ 22
Data management..................................................................................................................23
Amendments to the clinical evaluation plan...........................................................................23
Deviations from the clinical evaluation plan........................................................................... 23
Device Responsibilities.......................................................................................................... 24
Declaration of Compliance..................................................................................................... 24
Vulnerable Population and Treatments in Emergency Circumstances.................................. 25
Early Termination and Suspension of the Clinical Investigation.............................................26
Data Publication Policy.......................................................................................................... 26
Bibliography........................................................................................................................... 26
2
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

List of abbreviations
ACTIVA = automatic control of total intravenous anesthesia;
ASA = american society of anesthesiologists
BIS = bispectral index scale;
EEG = electroencephalogram;
GUI = graphical user interface;
HR = heart rate;
MBP = mean blood pressure;
MD = medical device;
PC = personal computer;
PID = proportional-integral-derivative;
PONV = postoperative nausea and vomiting;
SQI = signal quality index;
TCI = target controlled infusion;
TIVA = total intravenous anesthesia.
3
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

Summary
Study title
Automatic Control of Total Intravenous Anesthesia:
Closed-loop Delivery of Propofol and Remifentanil
Using Bispectral Index as Feedback Variable.
Acronym
ACTIVA 2
Identifier
code
of
the
clinical
investigation
NP-2861
Version number of the clinical
investigation
Version 4
Data della versione
07/03/2019
NCT number
NCT04432974
Study rationale
This study concerns the clinical evaluation of a
closed
loop
control
system
for
the
automatic
administration
of
anesthetic
drugs
in
total
intravenous anesthesia.
Purpose of the experimentation
Evaluating
the
control
system
reliability, safety,
applicability
and
capability
of
inducing
and
maintaining an optimal anesthetic level.
Primary outcome
Depth of hypnosis adequacy.
Secondary outcome
System dysfunctions, level of satisfaction of the
experimenter, effect of drugs delivery on heart rate,
effect of drugs delivery on mean blood pressure,
postoperative
heart
rate
stability,
postoperative
mean
blood
pressure
stability,
postoperative
sedation,
postoperative
nausea
and
vomiting,
postoperative analgesia.
Inclusion criteria
Adults patients undergoing total intravenous general
anesthesia for elective surgery.
Exclusion criteria
Patients under the age of 18.
Patients incapable of giving consent.
Study design
Pragmatic,
interventional,
nonrandomized,
single-arm, single-center.
Statistical analysis
Descriptive data analysis.
Procedure for the patient
The
patient
will
undergo
an
anesthesiological
treatment
conducted
in
a
closed-loop
manner
according to the study protocol, under constant
4
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

supervision of the investigator. The anesthetic drugs
used are those recommended for total intravenous
general anesthesia: propofol and remifentanil.
Risk/Benefit assessment
The major risk of the study is the malfunction of the
control program, which would require a switch to
manual control (the traditional approach to general
anesthesia). There is constant supervision by the
investigator, and the control software and infusion
pumps have adequate alarm systems in case of
malfunction.
The
ACTIVA
software
has
been
developed and subjected to simulations to ensure
the minimization of risks related to the infusion
system.
The benefits for enrolled patients are related to the
increased stability of anesthesia during induction
and
maintenance
phases.
Constant closed-loop
control of infusions and the level of hypnosis could
lead to a superior quality of the postoperative
recovery. The closed-loop system could also reduce
the hemodynamic impact that general anesthesia
has
on
the
patient,
particularly
by
reducing
hypotension.
Study duration
One year, considering an average enrollment of
three patients per week.
Follow up
Each patient is reassessed at 6 hours and at 24
hours
after
awakening
from
total
intravenous
anesthesia.
5
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

Study rationale and literature review
Study rationale
In current clinical practice, total intravenous anesthesia (TIVA) can be performed in two
ways: manually or through a computerized system called Target Controlled Infusion (TCI).
In the first case, the anesthesiologist manually manages the administration of anesthetic
drugs, determining the initial doses to be administered during the induction phase and the
infusion rates during the maintenance phase. Manual management of TIVA requires a
thorough knowledge of the pharmacokinetics of the drugs used by the anesthesiologist. It is
not possible to establish fixed initial dosages and infusion rates because they would not
automatically result in a similarly stable concentration of the drug in the brain or plasma.
Instead, it depends on each patient's subjective response to the drug administration, as well
as the duration and speed of the infusion, thus carrying the risk of overdosing or
underdosing. Therefore, for effective manual TIVA, it is necessary to combine knowledge of
pharmacokinetic models that indicate the most appropriate drug doses with a “clinical
calibration” based on the patient's response observed by the anesthesiologist.
Conversely, the TCI methodology involves the use of infusion pumps equipped with
microprocessors programmed with pharmacokinetic models for various drugs. In this mode,
the anesthesiologist interacts with the computerized system by selecting the drug, the
pharmacokinetic model, the desired plasma or brain concentration, and the model covariates
(often represented by the patient's anthropometric measurements). Based on all these data,
the pump can calculate the initial dosage for the induction phase and the infusion rates for
the maintenance phase. The use of TCI reduces the cognitive workload required of the
anesthesiologist because the application of pharmacokinetic models for calculating infusion
rates is performed by the machine and does not have to be done manually by the physician,
as
in
the
case
of
manual management. However, it is important to note that a
pharmacokinetic model is applicable and provides reproducible results only when applied to
patients with characteristics similar to those used to construct the model itself. In most
cases, these models are based on young, healthy, and normal-weight volunteers. Therefore,
caution is required when applying these models to patients who do not possess these
characteristics, and even in cases where they do, there are still inevitable modeling errors
and significant variability in the subjective response to drug administration. It is therefore
evident that actual plasma and brain concentrations are unlikely to be identical to those
predicted by these models and indicated by TCI systems. Thus, even in this mode, the
anesthesiologist will need to make manual adjustments, conducting a 'clinical calibration' of
the model by appropriately adjusting the desired drug concentration values based on the
clinical response observed in the patient.
In light of these considerations, we can assert that TCI represents a so-called “open-loop”
control system because it receives input data and calculates the infusion rates of drugs, but
it does not receive any information regarding the measurement of the clinical effect that
these rates have on the patient. When TCI is employed in clinical practice, the “closure of
the loop” is carried out by the anesthesiologist, who observes the patient's clinical response
and adjusts the TCI's target concentrations accordingly. Therefore, TCI fundamentally
remains a manual control methodology and, although supported by a machine, it does not
eliminate the workload of the anesthesiologist regarding the adjustment of the dosages of
anesthetic drugs.
6
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

The anesthesiologist has a role that includes controlling and regulating various parameters
and vital functions of the patient through the administration of drugs, fluids, and the
adjustment of hypnosis, analgesia, neuromuscular blockade, temperature, metabolic state,
ventilation, and hemodynamics. The complexity of these tasks is further compounded by the
intra- and inter-individual variability of patients and anesthesiologists themselves. These
factors lead to a range of effects: they make human control suboptimal, influence the
outcome of the anesthetic procedure, and significantly limit the ability to establish strict
standards of care.
A step forward in this direction can be provided by so-called “closed-loop” control systems.
These are automatic control systems that operate on the principle of feedback, and their key
elements consist of a measuring device (sensor), a control device (controller), and an
actuating
device
(effector).
The
sensor
measures the controlled variable, which is
representative of the desired behavior of the system (system output). This measurement is
compared with the desired value (set-point), and the difference between these two values
(error) is used by the controller to calculate the value of the control variable (system input).
In the case of TIVA, the system under control is identified as the patient, the effector is
represented by the means through which drugs are administered (for example, infusion
pumps), the manipulated variable is represented by the infusion rate of drugs, the controlled
variable can be a parameter that quantifies the desired effect directly or indirectly, and the
sensor is the respective monitoring system. For example, the controlled variable can be
represented by the depth of hypnosis measured with a brain activity monitoring system
based on the measurement and processing of the patient's electroencephalogram (EEG).
Closed-loop control systems, compared to open-loop control systems, have reduced
sensitivity to external stimuli that can act as disturbances, their performance does not
depend on predetermined pharmacokinetic models, and they can handle interindividual
variability. Furthermore, compared to an anesthesiologist, they can operate at higher
frequencies, more accurately, and without distractions. Their use offers several advantages,
such as increased patient safety, reduced variability in the quality of anesthetic care, and a
decrease in the workload of the anesthesiologist, allowing them to focus on other less
repetitive and less suitable tasks for automation than the control of anesthetic drug
administration. This last point becomes particularly relevant in the event of emergencies
during surgery. Despite these benefits, closed-loop control systems are not yet used in
routine clinical practice. This is primarily due to the lack of a complete, simple, and flexible
control system that can be easily understood and used by anesthesiologists in the operating
room.
This clinical investigation falls within the scope of developing closed-loop control systems for
the automatic administration of anesthetic drugs during total intravenous anesthesia, which
can be effectively used in routine clinical practice. Its focus is on the evaluation of a control
software
called
ACTIVA
and
its
associated
infusion
system.
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.
7
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

Literature review
Closed-loop
control systems for the administration of anesthetic drugs (closed-loop
anesthesia) were first proposed in the 1950s and were followed by intensive research in the
1980s and 1990s. This research initially focused on closed-loop control of end-tidal
concentrations of anesthetic gasses, neuromuscular blockade, and mean arterial pressure.
Further impetus for research in this field came in the 1990s with the introduction of cerebral
monitoring into clinical practice, thanks to its ability to indicate the depth of hypnosis (West
N, 2013) (Dumont GA, 2013).
Several studies have investigated the advantages of closed-loop systems for anesthesia
management compared to manual control or TCI, both in the pediatric and adult populations,
with both limitations and encouraging results, as discussed below.
The first work on closed-loop anesthesia dates back to the late 1980s, conducted on 11
healthy volunteers using EEG (Schwilden H, 1989).
From the mid-1990s, there was a spread of the BIS, and in the early 2000s, BIS was used
with proportional-integral-derivative (PID) control in TCI during the maintenance phase of
intravenous general anesthesia (Absalom AR, 2002) (Absalom AR, 2003). These early
studies only involved the infusion of propofol while remifentanil was left under open-loop
control.
The first multicenter randomized clinical trial on closed-loop anesthesia was conducted in
France by Liu with good results, successfully maintaining the ideal BIS range better than
manual control with equal hemodynamic stability. This study also used propofol as the sole
agent (Liu N, 2006).
In the mid-2000s, the CLADS system by the Indian group led by Puri was developed, and in
2010, the first studies on the McSleepy system by the Canadian group led by Hemmerling
were conducted. Both systems had propofol as the only agent (Puri GD, 2007) (Hemmerling
TM, 2010).
In addition to the adult population, interest in closed-loop anesthesia began to involve
pediatric patients as well. Dumont's group in Canada conducted the first studies, still using
propofol as the only agent and maintaining remifentanil at a constant dose during the
procedure (Dumont GA, 2011) (Van Heusden K, 2012).
In 2011, Liu conducted the first clinical trial using two agents (propofol and remifentanil) in a
closed-loop system, but only during the maintenance phase, while induction used TCI
pumps (Liu N, 2011).
More recent studies have shown encouraging results when closed-loop systems involve both
propofol and remifentanil.
Orliaguet, comparing two groups of pediatric patients undergoing scheduled surgeries
lasting at least one hour, demonstrated that administering Propofol and Remifentanil through
a closed-loop system controlled by BIS values is correlated with a higher percentage of time
in which BIS remains within the predefined range (40-60). This results in a lower percentage
of time when BIS falls below 40 compared to manual control (Orliaguet GA, 2015). Similar
results were obtained by Liu in a multicenter randomized controlled study (Liu Y, 2015).
In a pilot study conducted on patients undergoing aortocoronary bypass surgery, in which a
system for controlling all three components of anesthesia was used, it was possible to
effectively
complete
the
anesthesia
procedure
without
any
intervention
by
the
anesthesiologist in 80% of cases (Zaouter C, 2016). The McSleepy system was also
employed in a randomized controlled trial involving 186 patients undergoing surgeries lasting
at least one hour. The results demonstrate that both hypnosis and analgesia are better
controlled by the automatic system compared to the manual control group. Additionally, the
8
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

duration of episodes with poor or inadequate hypnosis control was significantly shorter in the
first group (Hemmerling TM, 2013).
Even when using entropy as a method of brain monitoring, closed-loop systems have shown
the ability to maintain the controlled variable within the desired range longer compared to
TCI (Liu N, 2012).
A closed-loop system for administering Propofol and Remifentanil based on BIS values also
yielded good results in obese patients. These patients are considered at high anesthetic risk
and have different pharmacokinetic and pharmacodynamic profiles compared to the general
population, which are not taken into account by common TCI algorithms (Liu N, 2015).
Ramos-Luengo and Asensio-Merino demonstrated that using a closed-loop system for
Propofol
administration
based
on BIS values reduces discharge times for patients
undergoing vascular surgery (safenectomy) (Ramos-Luengo A, 2017).
In 2017, the first meta-analysis of randomized clinical trials on closed-loop anesthesia versus
manual administration or TCI was published. The study, published in Anesthesia &
Analgesia, concluded that during induction, the closed-loop system reduces the need for
propofol, better maintains the desired depth of anesthesia during the maintenance phase,
and reduces wake-up times (Pasin L, 2017).
On the other hand, these tools can pose some risks. In particular, if the system controller is
designed inaccurately, exerting either too tight or overly weak control, it can lead to instability
in the system. Furthermore, the performance of such systems can be affected not only by
system response delays but also by their potential variability over time.
To overcome these limitations, it is important for the feedback controller to be carefully
designed to strike a balance between optimal performance and system robustness. One of
the most commonly used controllers with these characteristics is the PID controller (Astrom
KJ, 2006) (Ang KH, 2005).
The PID controller, by relating error and control signals with three constants, allows for the
correct infusion of drugs based on the difference between the depth of hypnosis and the set
point (proportional function). It also takes into account past values (integral function) and
anticipates future differences (derivative function) (West N, 2013) (Dumont GA, 2013)
(Nascu I, 2015).
According to the principles outlined in the editorial written by Kuck and Johnson (Kuck K,
2017), the use of closed-loop systems in anesthesia is governed by three key principles:
1.
Patient Safety and Benefit. The use of these systems should not harm patients and
should provide clear benefits to them. Even if the system encounters operational
issues during its use, it should not negatively impact the patient's well-being. The
primary focus should always be on ensuring the safety and well-being of the patient.
2.
Transparency. The system must reliably, predictably, and achieve the predefined
targets in a comprehensible manner. Anesthesiologists should be able to anticipate
the system's future behavior based on its operating principles. It is important that the
limits related to the controlled variable are well-defined, and it should be clear
whether the system is maintaining the variable within these limits.
3.
Reduction
of
Cognitive
Workload.
Closed-loop
systems
should
allow
anesthesiologists to concentrate on tasks that require their expertise and are less
amenable to automation compared to drug infusion. To make this possible, the
system should not demand excessive and prolonged attention from the medical
practitioner and should operate correctly. It is essential to prioritize patient well-being
9
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

and the efficiency of the surgical team. However, it's important to note that these
systems are not intended to completely replace the anesthesiologist's role; the
anesthesiologist must always maintain adequate vigilance (Mandel JE, 2012).
In summary, these principles aim to ensure that closed-loop systems enhance patient safety
and the efficiency of anesthesia delivery while allowing anesthesiologists to focus on critical
aspects of patient care and decision-making. Closed-loop systems are seen as tools that aid
medical professionals rather than as substitutes for their expertise and oversight.
Medical device information
The medical device under investigation is composed of the ACTIVA software, developed to
automatically control the infusion of drugs during total intravenous general anesthesia. The
ACTIVA software has been designed to optimize the infusion of anesthetic drugs using a
closed-loop system, ensuring the maintenance of a constant and optimal level of anesthesia
for the patient. The device under investigation is a software application installed on a
personal computer (PC) running the Windows operating system and developed using
Matlab. The software consists of an executable file named ACTIVA.exe, located on the
desktop of the dedicated PC for the clinical investigation. The primary investigator can start
the software by double-clicking the ACTIVA.exe file after powering on the PC. The file is
write-protected and locked against deletion to prevent accidental modifications. The PC with
the ACTIVA software installed has a label on its external surface indicating “For clinical
investigations only.” The considered version of the ACTIVA software is version 1.0 from
2017. The depth of anesthesia is measured using the Bispectral Index Scale (BIS) from
Aspect Medical Systems, Norwood, USA, which provides an index capable of quantifying the
depth of anesthesia. The administration of anesthetic drugs is automatically regulated by the
ACTIVA
software
based
on
BIS
readings
and
is
constantly
supervised
by
the
anesthesiologist through the graphical user interface (GUI) integrated into the software. The
control algorithm is implemented as a part of a full control software, which has been
developed with Matlab (MathWorks Inc., Natick, Massachusetts, USA) and runs on a
Hewlett-Packard 15-da1000nl (HP Inc., Palo Alto, California, USA) personal computer. The
control software executes the control algorithm, provides a user-friendly graphical user
interface (GUI) and manages the communication with a Dräger Infinity Delta (Drägerwerk,
Lübeck, DE) patient monitor, which is used to obtain the BIS and other parameters of
interest, and two Alaris GH syringe pumps (Becton, Dickinson and Company, Franklin
Lakes, New Jersey, USA), which are used as actuators to administer propofol (20 mg/ml)
and remifentanil (50 μg/ml). The data are acquired from the patient monitor with a sampling
period of 1 second. New values of propofol and remifentanil infusion rates are sent to the
pumps every 5 seconds. The connections between the personal computer and the medical
devices are made by means of three USB-RS232 converter cables. The full control system
is shown in Figure 1. A screenshot of the control software’s GUI is shown in Figure 2.
The infusion system also includes commonly used medical equipment in the clinical setting
for intravenous anesthesia administration, specifically:
●
Sterile single-use 60 ml syringes without needles with a Luer Lock connection,
latex-free.
10
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

●
Single-use
sterile
PVC
extension
lines
(1mm)
with
a
length
of
200
cm,
male-to-female, with a ring.
●
Single-use, sterile, latex-free infusion kits.
●
Single-use, latex-free BIS Quatro sensors.
Purpose of use for the experimental device
The target population for the device consists of surgical patients undergoing elective
procedures
requiring
general
anesthesia,
and
for
whom
intravenous
anesthesia
is
advantageous.
The
ACTIVA
software
is
programmed
to operate exclusively during
intravenous anesthesia when propofol is administered as a hypnotic agent and remifentanil
as an analgesic. The experimenters must be specialists in anesthesia and intensive care
with adequate knowledge of the operation of the ACTIVA software and its GUI. In particular,
familiarity with the user manual is required. The primary experimenter is responsible for
training the experimenters in the use of the ACTIVA software before its clinical application
and for providing guidance during the clinical investigation until the experimenters achieve
complete autonomy in using the ACTIVA software.
Figure 1: Schematic representation of the infusion system for anesthetic drugs based on the ACTIVA software.
11
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

Figure 2: Graphical User Interface (GUI) of the ACTIVA software.
Number of experimental medical devices expected to be used
It is expected to use a single experimental medical device.
Risks and benefits of the medical device
The sponsor is responsible for evaluating the safety of the medical device under
investigation
in
the
clinical
trial,
reviewing
recorded
adverse
events,
conducting
investigations
into
unforeseen
serious
adverse
events, and notifying the regulatory
authorities as per applicable regulations. The sponsor is also responsible for training
investigators prior to the commencement of the study, including reporting of serious adverse
events. The sponsor will oversee the procedures for adverse events related to the clinical
investigation and may assist investigators in the medical review of reported adverse events.
The principal investigator is responsible for ensuring the safety and health of enrolled
subjects and must report adverse events to the manufacturer, the relevant ethics committee,
and the investigational site. The investigator must provide all necessary information for the
completion of the adverse event form at the investigational site. The principal investigator is
responsible for reporting a serious adverse event to the Ethics Committee and the relevant
regulatory authority according to local regulations. The investigator must assist the sponsor
and the manufacturer in the clinical review of the adverse event, providing all available
documentation. The sponsor and the principal investigator are obligated to inform other
investigators, regulatory authorities, and the ethics committee of the serious adverse event
in accordance with local regulations.
Expected clinical benefits
The medical device ACTIVA, the subject of the clinical investigation, has been developed to
be reliable, safe for the patient, and clinically effective. Specifically, the device is designed to
be user-friendly through its user-friendly (GUI).
12
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

In a clinical setting, the medical device should be effective in maintaining the enrolled subject
within the desired hypnosis range (BIS between 40 and 60), minimizing periods during which
the enrolled subject exhibits anesthesia levels that are either too shallow or too deep.
Predicted clinical risks associated with the device and residual risks
The clinical risk associated with the use of the ACTIVA software should not exceed the
clinical risk associated with manual control (standard of care). In cases where the results
obtained during simulations are not replicated in a clinical setting, it is possible that the
software may fail to ensure adequate levels of anesthesia. The principal investigator will
decide to interrupt the system and switch to manual mode (current standard of care).
The clinical investigation of the ACTIVA software is the first of its kind for the system, where
anticipated adverse events related to the device and risk analysis are the primary focus of
this
clinical
study. During the software development, the primary objective was to
eliminate/minimize these risks.
To minimize device-related risks, the ACTIVA software cannot be initiated if the connected
devices are not functioning correctly (refer to the user manual). The proper functioning of the
control software and its components is indicated on the graphical user interface with a green
light, allowing the principal investigator to promptly assess the system's correct operation.
Although
the
device
has
undergone
extensive
testing
and
simulations
during
its
development, it is possible for it to stop functioning during use. Therefore, the ACTIVA
software
must
be
under
constant supervision by the investigator, who can detect
malfunctions or anomalies through the graphical user interface and take prompt action.
In particular, simulation tests have been conducted to verify that the ACTIVA control system
can be interrupted and switched to manual mode (standard of care) in less than 20 seconds.
This time period is shorter or overlapping with the time it takes for an anesthesiologist to
manage a normal infusion pump that needs to be turned off and restarted and much shorter
than the time required to replace a malfunctioning infusion pump.
In the event of a malfunction during drug infusion, the ACTIVA software is capable of
promptly alerting the investigator by emitting appropriate auditory and visual signals (red
light) on the graphical interface and auditory signals directly from the infusion pumps.
Additionally, the investigator can easily and quickly switch to manual control mode for the
pumps (see user manual). Examples of malfunctions may include:
●
Software freeze/crash.
●
Data transmission malfunctions.
●
Infusion pump malfunctions.
The ACTIVA software always generates a report file, even in the case of malfunctions,
containing all the data from patient monitoring, infusion pumps, and the software itself, along
with notes entered by the principal investigator. Through data analysis, it is possible to
identify the source of the technical issue.
In the event of ACTIVA software malfunction, the patient monitoring systems, particularly the
Bispectral Index (BIS), are never altered or damaged (the data flow is only outbound to the
computer where the ACTIVA software is installed), while the infusion pumps continue to
operate in manual mode (standard/classic mode controlled by the anesthesiologist).
Switching to manual control is always possible at the discretion of the principal investigator,
even in the absence of system malfunctions.
13
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

Risks associated with participation in the clinical investigation
The investigator monitors the system to prevent any consequences for the enrolled subject
in the clinical investigation in case the reliability and safety of the system are compromised.
From a clinical perspective, it is possible for the software to provide stable and adequate
anesthesia. The investigator may choose to switch to manual control if this is not the case.
The drugs Propofol and Remifentanil have received marketing authorization and are
standard of care for intravenous general anesthesia. The ACTIVA software does not
increase the known risks associated with the infusion of these drugs.
The pumps and the monitor are not altered in their original functions by the software;
therefore, the risks associated with these devices are not increased.
Interaction with concurrent medical treatments
The ACTIVA control system does not interfere in any way with the surgical procedure, and
therefore, there are no surgical risks attributable to the control system.
During intravenous general anesthesia, medications that interact with the anesthetic drugs
Propofol and Remifentanil may be administered for clinical reasons. This also occurs during
the operation of the ACTIVA software. There are no additional risks compared to normal
clinical practice regarding these interactions.
Procedures for risk control or reduction
For patient safety, approval must be obtained from the competent ethics committee for the
investigational site, as well as authorization from the investigational site.
Investigators will be trained by the principal investigator and the manufacturer to ensure a
clear understanding of the protocol, user manual, and all relevant study processes.
Each investigator will be registered on a list of investigators, which will be signed, expressing
their commitment to conducting the study according to the protocol, recording the required
data, and maintaining continuous supervision over the device.
A dedicated advisory board has been established to continuously assess subject safety and
the suitability of the ACTIVA software to continue the clinical investigation. The group's
responsibility also includes suggesting to the sponsor whether to continue or terminate the
clinical investigation.
Risks are minimized by adhering to the protocol, using the device according to the user
manual, following the hospital procedures of the sponsor's site, adhering to subject selection
criteria, and maintaining constant supervision of the subject and ACTIVA software through
the graphical user interface.
Risks/benefits ratio
The ACTIVA software should prove to be safe, reliable, and feasible. Furthermore,
considering that the sample size of the study is calculated based on the clinical evaluation of
the infusion system, it is possible that it will demonstrate the ability to maintain an optimal
level of anesthesia compared to what is described in the literature for other similar systems
and better than the standard of care.
14
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

Information related to the clinical investigation
Clinical study objectives
The primary objective of the clinical investigation is to investigate the clinical performances
obtainable by the control system under study in terms of depth of hypnosis adequacy.
The secondary objective is to evaluate the reliability, safety and applicability of the control
system under study and to carry out the clinical evaluation of the automatic control system
during the induction, maintenance and recovery of general intravenous anesthesia.
Clinical study description
The clinical study ACTIVA 2 is a pragmatic, interventional, nonrandomized, single-arm,
single-center.
The
investigation
is
for
research
purposes
(for
publication
in
scientific
journals),
non-commercial, and for clinical development of the ACTIVA control software.
The primary outcome measure is the depth of hypnosis adequacy. It is assessed by means
of the percentage of the anesthesia maintenance duration in which the BIS is kept inside the
recommended range from 40 to 60. The percentage of the anesthesia maintenance duration
in which the BIS is kept below 40 is also specified. Maintenance duration is the period of
time that goes from the end of anesthesia induction to the point at which the automatic
control is turned off at the conclusion of surgery. The end of anesthesia induction is defined
as the time instant when the BIS drops below 40 for the first time and remains there for the
subsequent 30 seconds.
The secondary outcomes measures are:
●
Number and types of dysfunctions of the ACTIVA automatic infusion system.
●
Level of satisfaction of the experimenter. It is 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.
●
Effect of drugs delivery on heart rate. It is assessed by means of the percentage of
the anesthesia maintenance duration in which the heart rate (HR) is kept inside the
range from 50 to 100 beats per minute. The percentage of the anesthesia
maintenance duration in which the HR is kept below 50 is also specified.
●
Effect of drugs delivery on mean blood pressure. It is assessed by means of the
percentage of the anesthesia maintenance duration in which the non-invasively
measured mean blood pressure (MBP) is kept inside the range from 65 to 110
mmHg. The percentage of the anesthesia maintenance duration in which the MBP is
kept below 65 is also specified.
●
Postoperative heart rate stability. It is assessed by measuring the HR in bpm.
●
Postoperative Mean Blood Pressure Stability. It is assessed by non-invasive
measuring of the mean blood pressure in mmHg.
15
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

●
Postoperative sedation. It is assessed by means of a Sedation Score scale. It is a 3
point scale from 0 (fully awake) to 3 (fully sedated).
●
Postoperative nausea and vomiting (PONV). It is assessed by means of the Bellville
PONV scale. It is a 3 point scale from 0 (no nausea and vomiting) to 3 (vomiting
present).
●
Postoperative analgesia. It is assessed using a 10-point numeric rating scale (NRS).
It is a 10 point scale from 0 (no pain) to 10 (maximum pain).
Measured variables
For each patient enrolled in the study, the following variables will be collected:
●
Age.
●
Gender.
●
Weight
●
Height
●
Type of surgical procedure
●
Anesthesiological
risk
assessment
according
to
the
American
Society
of
Anesthesiologists (ASA) physical status classification system.
●
PONV risk assessment according to the Apfel simplified risk score.
These data are collected by the principal investigator at patient arrival in the operating room,
before surgery and they are noted on the patient’s anesthesiology clinical record form.
The following variables are automatically collected by the ACTIVA software, they are
recorded in real-time every second and stored on a “.csv” file:
●
HR.
●
Peripheral oxygen saturation.
●
MBP.
●
BIS.
●
BIS signal quality index (SQI).
●
Burst suppression ratio1 .
●
Infusion rates of propofol and remifentanil.
The following data are collected by the principal investigator after surgery and noted on the
patient’s anesthesiology clinical record form.
●
System dysfunctions.
●
Level of satisfaction of the experimenter.
●
HR.
●
MBP.
●
Postoperative sedation.
1 Burst suppression is defined as a period on the EEG trace characterized by attenuated or suppressed signal
(<10 mV) alternating with brief periods of cortical activity, precisely termed 'bursts.' More than 50% of this
period is dominated by attenuated/suppressed activity. This effect may sometimes be intentionally induced, for
example, during neuroanesthesia, as a protective measure against cerebral ischemia, as it coincides with a
reduction in cerebral metabolism. However, it is important to consider that it is also associated with a higher
incidence of postoperative delirium.
16
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

●
PONV.
●
Postoperative analgesia.
Participation criteria
The population considered in the clinical study consists of adult patients scheduled for
elective surgery for whom total intravenous general anesthesia is indicated, using the
hypnotic drug propofol and the analgesic drug remifentanil, and who have provided
appropriate informed consent. Patients under the age of 18 and patients incapable of
understanding and consenting are excluded from the study.
The selection of patients is made regardless of age (provided they are over 18), gender,
weight, height, as well as anesthetic risk and the type of surgical procedure. This reduces
systematic errors associated with specific patient selection for enrollment in the study.
Enrollment procedure
The enrolled patients underwent an anesthesiological treatment conducted in a closed-loop
system
following
the
clinical
protocol
and
under
the
constant
supervision
of
the
experimenter.
The
experimentation
took
place
in
a
single
operating
room
at
the
experimenter's center where plastic surgery procedures are performed. This allowed for
maintaining a consistent surgical and environmental setting.
Patients are informed of the possibility to participate in the study during the preoperative
anesthesia visit, which typically occurs two weeks before the surgical procedure. If the
patient chooses to participate in the study, informed consent is obtained before the start of
the medical procedure subject to the experimentation.
The patient enrolled in the study arrives in the operating room on the day of the procedure
and undergoes the standard preoperative preparation, which is administered to all patients
undergoing intravenous general anesthesia, regardless of their enrollment in the study. In
particular:
●
Venous access is established.
●
Instrumental monitoring includes blood pressure, electrocardiogram, peripheral
oxygen saturation, and BIS (Bispectral Index).
●
Infusion pumps are connected to the venous access.
The ACTIVA control software is then initiated by the lead experimenter, who enters the
necessary anthropometric data into the GUI, initializes the system, and starts the automatic
control. During the surgical phase, the experimenter supervises the system and ensures its
proper functioning. If necessary, annotations are added to the system according to the
protocol. Once the surgical procedure is completed, the experimenter stops the drug
infusions through the GUI but continues recording the BIS and other patient monitoring
parameters. The patient awakens spontaneously. After awakening, the ACTIVA software is
turned off by the experimenter.
The patient is then transferred to the recovery room where they undergo standard
post-operative procedures. The study concludes 24 hours after the patient awakens from
anesthesia with a postoperative anesthesia visit.
17
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

Number of patients enrolled
The sample size was determined based on the primary outcome measure concerning the
depth of hypnosis adequacy provided by the ACTIVA control software. Specifically, it was
calculated with the aim to assess the proportion of patients for whom the percentage of the
anesthesia maintenance duration in which the BIS is kept inside the recommended range
from 40 to 60 is greater than 43%. This latter value is the average percentage that was
observed in a previous data acquisition campaign concerning manually controlled TIVA,
which was performed in the same clinical setting considered for the present clinical trial
(Study acronym: ACTIVA 1, Id code: NP-1843).
The proportion was estimated to be 90% of patients with a 95% confidence interval and a
margin of error of 10%. The resulting sample size is 139 patients. This number of enrolled
subjects also ensures that the ACTIVA control software is adequately tested for safety,
reliability, feasibility, and applicability. Secondary outcome measures were not considered in
the sample size calculation.
Subject Enrollment Count
All subjects enrolled in the clinical investigation (including patients withdrawn from the study
before its initiation who have provided informed consent and patients lost to follow-up) must
be counted and documented. If a subject withdraws from the study, the reasons should be
documented and recorded. These patients will not be included in the sample size calculation
for the study or in the primary or secondary objectives.
Patients who are withdrawn from the study before the initiation of the ACTIVA software due
to device safety, reliability, or feasibility issues are considered enrolled in the study and will
be followed throughout the study's duration.
Patients who discontinue the study during the operation of the ACTIVA software are
considered fully enrolled, and all available data will be analyzed.
Study Duration
The expected duration of the study is 1 year, assuming a weekly enrollment of 3 patients.
For each enrolled subject, their participation in the study concludes at the 24-hour
post-awakening follow-up after intravenous general anesthesia.
Concomitant medications and medical treatments
The ACTIVA control system is used during intravenous general anesthesia for elective
surgical procedures. During the operation of the ACTIVA software, the surgical procedure is
ongoing. However, the ACTIVA control system does not interfere with the surgical procedure
in any way.
For clinical needs, medications that interact with propofol and remifentanil may be
administered. However, with the ACTIVA control system, there are no additional risks
compared to the normal clinical practice of TIVA regarding these interactions. However,
these medications could alter the interpretation of the outcome measures used to evaluate
the secondary objective of the study. For this reason, the experimenter records the use of
such medications in the notes section of the GUI so that this event is documented in the
report file and can be considered during the analysis of the results.
Follow-up
Each enrolled patient was reassessed 6 hours and 24 hours after awakening from
anesthesia during the postoperative anesthesia visits.
18
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

Statistical analysis
The statistical analysis consists in the descriptive statistics of the collected data.
Synthetic statistical data are calculated for all study variables.
For quantitative data mean and standard deviation, or median and interquartile range are
calculated
according
to
data
distribution.
Data
normality
is
checked by using the
Shapiro-Wilk test.
Categorical variables are synthesized by using patient count and percentage of patients
belonging to each category.
Systematic errors prevention methods
Interaction between the ACTIVA software and the experimenter.
The user interface has been developed to make it easy for the experimenter to initiate the
infusion system. Specifically, once the necessary connections between the monitor, PC, and
infusion pumps have been set up, the experimenter can start the ACTIVA software and
quickly check for any issues with the system. The software only starts when the
experimenter has entered all the required data for startup, and the connections between the
devices are correct and functioning. If the experimenter has not entered all the required data
or if the devices are not functioning correctly or have not been turned on, the ACTIVA
software cannot begin the infusion phase. This ensures both adequate safety and prevents
incorrect or incomplete operation.
Selection bias during patient recruitment.
The clinical trial recruits patients to undergo intravenous general anesthesia for elective
surgery. The experimentation takes place in a single operating room of the experimenter's
center where plastic surgery procedures are performed, ensuring a constant surgical and
environmental setting. Patient selection, excluding those under 18 years of age, is done
regardless of age, gender, weight, height, anesthesiologic risk, or type of surgical procedure.
This reduces systematic errors associated with specific patient selection.
Selection bias at the time of analysis.
The clinical trial requires that closed-loop anesthesia be practiced from the initiation of the
ACTIVA software until the end of the surgical procedure. However, it may happen that:
●
The primary experimenter decides to interrupt the software; in this case, it must be
recorded in the report file.
●
The software or its components (monitors, infusion pumps) may cease to function
correctly; in this case, the system is halted and switches to manual mode or requires
the experimenter's intervention. The experimenter must record the event in the report
file. If the above occurs, it is the responsibility of the experimenter to assess the
possibility of including in the data analysis what has been collected up to the moment
of system interruption.
Measurement bias during data collection.
It is possible that during the operation of the ACTIVA software, there is a failure to read the
BIS or a disturbance causing artifacts. The absence of a BIS signal or its distortion is not
uncommon during normal clinical practice and is indirectly reported by the SQI and on the
patient monitor. Such problems are usually caused by poor adherence of the BIS Quatro
sensor to the skin. The experimenter can resolve the issue without consequences for the
19
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

infusion system. During the software development phase, these events have been
anticipated, and appropriate filters and event checks have been incorporated, allowing for
short-term toleration of BIS signal deficiencies (both qualitative - disturbances, and
quantitative - signal absences). If the problem persists beyond 30 seconds or the
experimenter deems it necessary, the system switches to manual mode. It should be
emphasized that the BIS Monitor is an approved and certified instrument and undergoes
regular maintenance by the clinical engineering service of the experimenter's center.
It is possible that during the operation of the ACTIVA software, there may be an issue with
the infusion of one or both drugs due to malfunction or lack of control of the pumps (either
one or both). The pumps are periodically checked and tested by the clinical engineering
service of the experimenter's center, minimizing risks. In case of lack of control by the
ACTIVA software, the pump emits an audible signal, and the user interface highlights the
lack of connection on the corresponding pump with a red light. This allows the primary
experimenter to rectify the problem or decide to halt the infusion system. During simulations,
no issues with the infusion pumps were identified, and the infusion rates corresponded to
what was commanded by the ACTIVA software and indicated on the GUI. This was made
possible by developing a control system that respects the maximum infusion rates that the
pump is capable of, in accordance with its mechanical components.
Instrument-phenomenon interaction.
The system relies on feedback control in which infusion rates are regulated by software after
receiving BIS data to maintain the desired level of hypnosis. It is likely that the control
system is better able to maintain the desired BIS level compared to manual control with or
without TCI. If the primary experimenter observes an inability to maintain the BIS within the
desired range despite apparent correct software operation, they may choose to suspend the
software and switch to manual mode. This should be noted in the designated notes section
and recorded in the report file.
Improper working conditions
The current version of the ACTIVA software is designed for exclusive use in the operating
room with the equipment specified in the user manual. ACTIVA software should only be used
with the propofol and remifentanil drugs for intravenous general anesthesia. The ACTIVA
software must always be supervised by the primary experimenter and should not be used as
a substitute for an anesthesiologist in any way.
Factors that may compromise the outcome and interpretation of the results
It is possible that the use of other sedative drugs in addition to propofol and remifentanil may
affect the secondary objectives of the study, both in a negative and positive sense. The
experimenter enters the use of such drugs in the notes of the ACTIVA software GUI, and this
event remains recorded in the report file and will be considered during the analysis of the
results.
It is possible that the experimenter may forget to enter events, drugs, or assessments
relevant to the primary and secondary objectives in the notes of the ACTIVA software GUI.
To minimize this risk, experimenters are trained according to the user manual and the
current clinical protocol.
It is possible that the ACTIVA software, despite the pre-clinical development process and
numerous simulations, does not meet reliability and safety criteria. In such a case, the study
20
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

will be interrupted, and the manufacturer will assess for a prompt solution. Only after
producing a reliable version of the ACTIVA software can the clinical investigation resume.
It is possible that the monitor or one or both of the pumps may experience malfunctions
during the clinical investigation. These malfunctions are not attributed to the ACTIVA
software but will be recorded in the report file and evaluated during the results analysis.
Repairing or replacing the faulty device resolves the issue.
It is possible that the primary experimenter may decide to discontinue the control system to
switch to manual control or another anesthesiological technique, noting the choice, which will
be recorded in the report file. Switching to manual control or another anesthesiological
technique is possible at any time if the experimenter deems it appropriate, even in the
absence of system malfunctions.
Clinical investigation monitoring plan
The clinical investigation monitoring plan is the responsibility of the principal investigator and
the advisory board specifically established for this clinical investigation. Monitoring of the
clinical investigation ensures constant adherence to the clinical protocol by investigators and
the application of all recommendations in this protocol.
The principal investigator and the advisory board verify that data is collected and stored
adequately
and
reported
correctly
without alterations, in compliance with timelines,
adequacy, accuracy, and truthfulness.
The task of the advisory board is to ensure that the investigation has sufficient and adequate
investigators and resources to be conducted safely and effectively.
Monitoring of the clinical investigation occurs on a monthly basis for the following:
●
Adequate preparation of investigators.
●
Regular enrollment (informed consent and informational sheets).
●
Evaluation of the ACTIVA software (with reference to primary outcome measure).
●
Regular data collection and storage.
●
Regular follow-up of enrolled subjects.
●
Analysis of emerging issues as directed by the investigator.
●
Analysis of safety-related notes regarding the ACTIVA software.
The principal investigator is required to maintain the report files generated by the ACTIVA
software in their integrity and make them available to the competent Ethics Committee, the
manufacturer, and the investigational site.
Ethical considerations
Clinical experimentation was preceded by a careful phase of risk and benefit assessment
resulting from the use of the control software under investigation. The main risk of the study
21
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

is constituted by the malfunction of the control software. This leads to a transition to manual
control (current clinical standard) of general anesthesia without causing any clinical
problems for the patient. Furthermore, the control software, infusion pumps, and monitor
have adequate alarm systems in case of malfunction. The drugs propofol and remifentanil
have received marketing authorization and are drugs used in the current clinical standard for
intravenous general anesthesia. The ACTIVA control software does not increase the known
risks associated with the infusion of these drugs. The infusion pumps and the monitor are
not altered in their original functions by the control software. Therefore, the risks associated
with the use of these devices are not increased by their connection to the control software.
Thus, the clinical risk associated with the use of ACTIVA software is not considered higher
than the clinical risk associated with manual control of intravenous general anesthesia. Risks
are further reduced by adhering to the clinical protocol, using the device according to the
user manual, following the hospital procedures of the sponsoring center, adhering to subject
selection criteria, and maintaining constant supervision of the infusion system controlled by
the ACTIVA software. In this regard, the investigators have been trained by the principal
investigator and the manufacturer to ensure that the protocol, user manual, and all relevant
study processes were well understood.
The expected benefits for patients are related to the increased stability of anesthesia during
induction and maintenance phases achievable through constant closed-loop control of
infusions, minimizing periods in which the patient presents anesthesia levels that are too
shallow or too deep.
The experimentation has been approved by the competent ethics committee and has
obtained the authorization of the co-investigator.
The patient is informed of the possibility to participate in the study during the preoperative
anesthesiology visit, which usually takes place two weeks before the surgical procedure. On
this occasion, the patient receives adequate information through an informative sheet and a
discussion with the investigator. The informative sheet will then be retained by the patient.
This document briefly describes the purpose of the study and its conduct, indicating the
novelty of the clinical investigation compared to common clinical practice. If the patient
intends to participate in the study, informed consent is signed before the start of the medical
procedure subject to the experimentation.
Data management
The data management activities have been carried out in such a way as to ensure that data
processing is complete, consistent, and logical, and that all data described in the clinical
investigation are included in the study. The file recorded by the ACTIVA control software
allows for the analysis of the control system's performance regarding malfunctions and/or
critical issues identified by the experimenter, recorded in the form of notes. Furthermore, it
contains recordings of time series data for drug infusion rates, BIS (Bispectral Index), and
other standard monitoring data for general anesthesia. The report file allows for offline
analysis of the control system's performance. The report file is generated automatically by
the ACTIVA control software. Post-operative data, on the other hand, are manually recorded
by the experimenter on the designated data collection sheet. Experimenters have filled out
the data collection sheet and entered notes on the GUI during the operation of the ACTIVA
software as prescribed. During the conduct of the clinical study, the data resulting from the
study are stored by the lead experimenter in their original form on the PC dedicated to the
22
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

ACTIVA software and backed up on the experimenter center's PC. At the end of the study,
all data have been migrated and are stored on a dedicated PC at the experimenter center.
Access to the data is restricted to authorized individuals.
Amendments to the clinical evaluation plan
Any amendment to the protocol will be submitted to the competent authorities for
authorization or appropriate notification, depending on the nature of the change. Additionally,
all administrative updates that do not require submission to the competent authorities or the
ethics committee will still be documented. An administrative update is defined as a change
that has no impact on patient safety, health, or the scientific validity of the study.
Deviations from the clinical evaluation plan
Except in cases of necessity, the principal investigator is not authorized to deviate from the
clinical protocol. Deviations from the clinical evaluation plan that are decided upon by the
investigator to protect the rights, safety, and health of the patient will be documented and
communicated to the manufacturer and the sponsor as soon as possible.
The sponsor will define the level of deviations as major or minor and will present them to the
relevant Ethics Committee for evaluation accordingly. Major deviations are defined as
changes in the conduct of the clinical investigation compared to the current protocol that
could compromise the subject's rights, safety, health, completeness, accuracy, or scientific
integrity of the data.
Deviations should be reported to the principal investigator and recorded in the patient's
chart. Cases where a regularly enrolled patient does not complete the study due to ACTIVA
software issues or at the investigator's discretion are not considered deviations; the patient
will not be considered for secondary outcome measures but will be evaluated for the primary
outcome measure.
Device Responsibilities
Access to the investigational device will be restricted to the investigators, and the device
must be used exclusively in accordance with this protocol.
The sponsor must keep track of the device's location, which may be returned to the
manufacturer for inspections or updates following the assessments described in this clinical
investigation plan. The device will then be returned to the sponsor/principal investigator for
the continuation of the study once the necessary inspections or updates by the manufacturer
have been completed.
In the event that device inspection by the manufacturer is deemed necessary at the request
of the Principal Investigator or the advisory board, documents should be prepared, including:
1.
Date of submission to the manufacturer.
2.
Number of the last subject enrolled in the study.
3.
Date of receipt from the manufacturer.
23
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

4.
Report from the manufacturer regarding the device inspection and any modifications
or updates to the ACTIVA software.
Once the device has been received, the trial may continue with communication to the
relevant authorities.
Declaration of Compliance
The clinical investigation involving the ACTIVA software will be conducted under conditions
similar to the normal conditions of device use, and the procedures used for conducting the
clinical investigation are appropriate for the device under examination.
During the planning of the clinical investigation, all relevant characteristics, including those
related to device safety, performance, and potential effects on the patient, have been
examined, and these characteristics will be monitored throughout the duration of the
investigation.
The clinical investigation will be conducted according to an appropriate clinical protocol that
takes into account the current state of scientific and technical knowledge and is designed to
confirm or refute the manufacturer's claims regarding the device. This investigation includes
a sufficient number of observations to ensure the scientific validity of the conclusions.
The clinical investigation, with regard to the responsibility of the manufacturer/authorized
representative, will be conducted in accordance with the provisions of Annexes VIII and X of
Legislative Decree February 24, 1997, no. 46 and subsequent amendments, and Annexes 6
and 7 of Legislative Decree December 14, 1992, no. 507 and subsequent amendments, in
compliance with the Declaration of Helsinki, as well as applicable sections of the ICH/GCP
guidelines, UNI EN ISO 14155-2012, and subsequent updates or other internationally
recognized equivalent standards. This will occur only after approval by the competent Ethics
Committee of the experimental protocol, informed consent text, and documentation required
by the aforementioned standards.
The medical device complies with the essential requirements as defined by current
regulations, except for aspects that are the subject of the investigation. Necessary
precautions have been taken to protect the health and safety of the patient.
Risk assessment has been performed in accordance with UNI EN ISO 14971:2012 and
subsequent amendments, and all necessary measures have been taken to minimize these
risks.
All serious adverse events will be fully recorded and immediately reported to the 6th Office of
the DGDMF of the Ministry of Health and to all other competent authorities of the member
states involved in the clinical investigation, in accordance with point 2.3.5 of Annex 7 of
Legislative Decree December 14, 1992, no. 507 and subsequent amendments, and point
2.3.5 of Annex X of Legislative Decree February 24, 1997, no. 46 and subsequent
amendments.
All financial burdens related to the clinical investigation are borne by the manufacturer and
do not fall on the National Health Service or the patients.
The Clinical Trial Office of the Ministry of Health and the competent ethics committees will
receive the final report prepared by the investigator at the end of the clinical investigation,
including a critical evaluation of all data obtained during the study. This clinical investigation
plan is prepared in accordance with UNI EN ISO 14155:2012 and subsequent updates.
24
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

Documents for obtaining informed consent have been prepared and have undergone
evaluation by the competent Ethics Committee.
The manufacturer undertakes to make available to the Ministry of Health the dossier for the
investigator and complete documentation related to risk analysis.
The manufacturer commits to provide the Ministry with all relevant information regarding the
ACTIVA software, including the design, manufacturing methods, and descriptions and
explanations necessary for understanding the aforementioned designs and schematics and
the
product's
operation; the results of design calculations, controls, technical tests
performed, and similar assessments conducted.
Vulnerable
Population
and
Treatments
in
Emergency
Circumstances
Not applicable.
Early Termination and Suspension of the Clinical Investigation
The clinical investigation may terminate prematurely in the event that:
1.
Patient enrollment occurs at a faster rate than anticipated.
2.
The ACTIVA software is found to be unreliable or unfeasible in a clinical setting with
no possibility of correction.
3.
Risks emerge that necessitate the immediate termination of the clinical investigation
with no possibility of mitigating or eliminating these risks.
The clinical investigation may be suspended in the event that:
1.
The ACTIVA software exhibits reliability, safety, or feasibility issues that warrant
reevaluation by the manufacturer but are considered solvable.
2.
Whenever the investigator deems it necessary to suspend the study, deferring the
decision on resumption to the Principal Investigator. The Principal Investigator will
analyze the reasons and determine a possible solution, possibly after consultation
with the manufacturer and the advisory board."
Data Publication Policy
The results of the clinical investigation will be submitted for publication in scientific journals
after the study is completed, and the data have been analyzed according to the statistical
plan.
Publication may be sought in journals specializing in anesthesia and intensive care,
anesthesia and analgesia, or national and international surgical journals.
Additionally, publication may be sought in other scientific journals deemed suitable by the
manufacturer, even if the manufacturer has not previously published in those journals.
25
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

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26
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.

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27
Clinical Investigation Plan
Automatic Control of Total Intravenous Anesthesia: Closed-loop Delivery of Propofol and
Remifentanil Using Bispectral Index as Feedback Variable.
Acronym: ACTIVA 2. Id code: NP-2861. NCT number: NCT04432974.