First In Human Clinical Investigation of the FIRE1* System in Heart Failure Patients_ Pilot Study of the FIRE1TM System in Heart Failure Patients

3. CLINICAL INVESTIGATION BACKGROUND
Heart failure (HF) is a growing global healthcare issue with an estimated
worldwide prevalence of 26 million patients. Despite recent advances in cardiac
intervention, device therapy and pharmacology the resultant economic burden
remains significant. Indeed HF accounts for 1-3% of all hospital admissions
with an average length of stay between 5-10 days and an estimated 1-2% of
healthcare expenditure in the USA and Europe (Ambrosy et al., 2014). The
majority (60%) of these costs are driven by hospitalisation for acute
decompensation (Heidenreich et al., 2013). Additionally, readmission rates
following an acute decompensation are high with 24% of patients readmitted
within 30 days, and 46% readmitted within 60 days of discharge. With the
majority (90%) of HF admissions occurring in those with known chronic heart
failure (CHF), there remains an essential role for the development of novel
therapies and interventions to detect prognostic physiological changes early in
the course of decompensation to facilitate and optimize medical intervention in
a bid to reduce HF associated hospitalisation, morbidity and mortality.
(Ambrosy et al., 2014). With the ageing of the worldwide population, as well as
increased survival from ischaemic heart disease, HF rates will continue to
increase, along with the resultant global economic burden.

The majority of HF patients present with symptoms attributable to volume
overload such as dyspnea (89%), rales (68%) and peripheral oedema (66%)
(Koniari, Parissis, Paraskevaidis, and Anastasiou- Nana, 2012). Timely and
accurate assessment and management of volume overload is therefore a critical
component of HF management. Early detection of volume overload allows prompt
intervention with pharmacological agents, aiming to restore euvolaemia with
out-patient treatment, without progressing to hospital admission. Conversely,
detection of volume depletion/dehydration is an important factor in preventing
symptomatic hypotension and renal dysfunction due to over-diuresis.
Traditionally, volume status is determined by clinical examination including:
assessment of the height of the jugular venous pressure above the sternal
angle, auscultation of the lung fields for signs of pulmonary oedema,
assessment of peripheral oedema, and monitoring of patients* weight. Clinical
measurement of volume status, however, can be difficult and has been shown to
correlate poorly with clinical status. The absence of physical and radiological
signs of congestion does not necessarily correlate with normal pulmonary
capillary wedge pressure (Chakko, Woska, and Martinez, 1991) nor confidently
exclude volume overload. It is well documented that volume/pressure changes
precede development of clinical symptoms and therefore detection of these
changes before symptoms arise provides a potential target for optimising the
care of patients with HF.

Haemodynamic monitoring using an indwelling pulmonary artery pressure (PAP)
monitor as an index of volume has been shown to significantly reduce
hospitalisations in patients with NYHA III HF (Abraham et al., 2011). Evidence
from the CHAMPION trial demonstrated that when using an
implantable PAP monitoring system (CardioMEMS), lowering remotely monitored PAP
would result in reduced HFH risk. CHAMPION clearly evidenced the benefit of
accurate haemodynamic monitoring in HF patients, over and above clinical
assessment and standard of care HF management. A more recent trial was
conducted to assess the utility of CardioMEMS in a broader HF population, the
GUIDEHF trial. The GUIDE-HF trial enrolled 1000 HF patients with NYHA class
II-IV to CardioMEMS-guided management vs standard of care (no CardioMEMS).
Results show that there was no difference between cohorts in the primary
endpoints of the study, which assessed cumulative HF events and mortality at 12
months. However, a pre-COVID analysis indicated the primary endpoint was
significantly reduced in favour of CardioMEMS (Lindenfeld et al., 2021).

In many instances volume overload precedes pressure overload, with a relatively
large change in volume resulting in little corresponding change in pressure,
until a critical point is reached at which pressure increases (Moreno, Kotz,
Gold, Reddy, and Tech, 1970). Recent work in HF patients has indicated that
pressure based assessment of congestion in ambulatory HF patients does not
accurately represent intravascular volume providing evidence of pressure-volume
discordance (Yaranov et al., 2022). Therefore, detection of elevated PAP may
signify impending decompensation later than increased volume. The inferior vena
cava (IVC), continuously changes its diameter and collapsibility along the
pressure-volume curve (Moreno et al., 1970). Proof of concept experiments in an
animal model have shown that IVC changes were significantly more sensitive than
cardiac filling pressures following manipulation of intravascular volume,
vascular tone and cardiac dysfunction (Ivey et al., 2021). Changes in IVC
diameter can therefore reflect changes in volume that occur prior to increasing
pressure. We hypothesize monitoring the IVC diameter would allow earlier
detection of congestion resulting in more rapid medical intervention to prevent
an impending decompensation and subsequent hospitalisation.

Absolute IVC diameter and degree of collapsibility with inspiration
(collapsibility index, CI) has been established as a sensitive and specific
tool to estimate right arterial pressure (RAP) (Rudski et al., 2010). IVC
dilation has been shown to be associated with an increased risk of early
readmission and short-term mortality in patients hospitalized for acute
decompensated HF (ADHF) (Jobs et al., 2017), while in patients with CHF,
increasing IVC diameter has been demonstrated to correlate with adverse
outcomes (Pellicori et al., 2013). It is therefore proposed that the use of an
indwelling device which can monitor IVC geometry (size and collapsibility) may
allow earlier detection of impending volume overload, allowing therapeutic
interventions to take place more promptly thereby reducing HFH rates.

The FIRE1* System utilises a Sensor permanently implanted into the IVC that
conforms to and changes with the geometry of the vessel. The Sensor does not
contain a battery and is wirelessly energised by an external Belt and Hardware
Unit. FIRE1* System Data are transmitted to the FIRE1* Web App for the primary
purpose of displaying the data to the Investigator.

There are two generations of the FIRE1 System (Gen 1 and Gen 2), both of which
are made up of the same type of components (i.e., the implantable FIRE1* Sensor
and Delivery System, the FIRE1* External System, and FIRE1* Web App) and with
the same mode of operation. Learnings from the use of the first-generation
System (*Gen 1*) with 4 patients have led to design enhancements to the
implantable FIRE1* Sensor, the FIRE1* External System and the FIRE1* Web App,
which are used to obtain data from the Sensor. No changes have been made to the
delivery system used in the implantation procedure, or to the implantation
procedure itself. Beyond the first 4 patients, additional patients will be
enrolled and implanted with the FIRE1* Gen 2 Sensor. All enrolled patients will
receive the FIRE1* Gen 2 External System. Differences in Sensor versions will
be accounted for during data analysis, as data generated from Cohort A (i.e., 4
patients with the Gen 1 Sensor) will be analysed separately from data generated
from Cohort B (i.e., patients with the Gen 2 Sensor).

This CIP provides information that is relevant to both the FIRE1* Gen 1 and Gen
2 Systems. Where information specifically relates to only Gen 1 or Gen 2
(System, Sensor, External System or Web App), the relevant generation will be
specified.

Further information from the background literature review relating to the
design of the

The objectives of this clinical investigation are:
1. To demonstrate that the FIRE1* Sensor can be safely deployed into the
inferior vena cava (IVC)
2. To demonstrate that the FIRE1* Sensor can provide a signal to the FIRE1*
External System
3. To investigate the individual daily variability in FIRE1* System Data,
including IVC area and IVC collapsibility, and their relationship to
conventional clinical heart failure (HF) parameters
4. To investigate the changes in FIRE1* System Data that occur in the period
before, during and after a HF decompensation

This is a prospective, single arm, multi-centre clinical investigation
involving the implantation and monitoring of the FIRE1* System in approximately
50
HF patients recruited from up to 20 sites. HF patients at increased risk of HF
events as evidenced by an acute HF admission/treatment in the prior 12 months
or raised BNP or NT-proBNP levels, who provide informed consent, and
successfully pass screening and baseline testing will be implanted with the
novel FIRE1 Sensor.

The FIRE1* System utilises a Sensor permanently implanted into the IVC that
conforms to and continuously adapts to the vessel geometry.

When excited by an external radio frequency source, the FIRE1* Sensor is
designed to track changes of the IVC geometry. In this investigation, device
safety will be evaluated using radiological imaging modalities and
physiological assessments detailed in the schedule of events. Daily data will
be obtained from the patient using the FIRE1* System.

There are two generations of the FIRE1 System (Gen 1 and Gen 2), both of which
are made up of the same type of components (i.e., the implantable FIRE1* Sensor
and Delivery System, the FIRE1* External System, and FIRE1* Web App) and with
the same mode of operation. Learnings from the use of the first-generation
System (*Gen 1*) in 4 patients have led to design
enhancements to the implantable FIRE1* Sensor, the FIRE1* External System and
the FIRE1* Web App, which are used to obtain data from the Sensor. No changes
have been made to the delivery system used during the implantation procedure,
or to the implantation procedure itself.

Beyond the first 4 patients, additional patients will be enrolled and implanted
with the FIRE1* Gen 2 Sensor. All enrolled patients will receive the FIRE1* Gen
2 External System. Differences in Sensor versions will be accounted for during
data analysis, as data generated from Cohort A (i.e., 4 patients with the Gen 1
Sensor) will be analysed separately from data generated from Cohort B (i.e.,
patients with the Gen 2 Sensor). This Clinical Investigation Plan (CIP)
provides information that is relevant to both the FIRE1* Gen 1 and Gen 2
Systems. Where information specifically relates to only Gen 1 or Gen 2 (System,
Sensor, External System or Web App), the relevant generation will be specified.

The patient specific FIRE1* System Data could potentially be used as one input
into the investigators clinical decision making for individual participants
enrolled in the study. An illustrative treatment guidance, in line with current
internationally accepted HF management guidelines, is provided and may be used,
in conjunction with other available clinical data, by investigators following
their analysis of the FIRE1* System Data.

The primary endpoints will be assessed at Month 3 and patients will continue to
be followed with clinical visits until Month 24, followed by annual follow ups
till month 60.

At a limited number of clinical investigation centres, additional data may be
obtained from volume challenges (assessing the ability of the FIRE1* Sensor to
detect changes in the IVC and provide a signal that reflects the acute volume
change) and dedicated physiological data collection sessions (simultaneously
record vital signs and FIRE1* System data while monitoring patient safety).
These assessments will be performed after Month 3, and the data will be used to
inform the feasibility of measuring respiration rate (RR) and heart rate (HR)
using the FIRE1* Sensor.

The clinical investigation will be executed in 2 phases, i.e., phase 1 (n=14)
and phase 2. Phase 1 is designed to assess the initial safety and technical
feasibility of the FIRE1 system and the ability of the system to provide a
signal. Phase 2 is an expansion of the clinical investigation to increase the
number of subjects and thus increase the learnings associated with assessment
of safety, technical feasibility, and data acquisition from the FIRE1 System.
The Sponsor will obtain all necessary approvals prior to initiating this
clinical investigation.

NA

JUSTIFICATION OF CLINICAL INVESTIGATION DESIGN

Given the review of published literature referenced above, we propose that when
used in the target HF population, the FIRE1* System should detect changes in
volume status that precede clinical symptoms or deterioration allowing prompt
intervention with medical therapy and a more rapid return to euvolaemia,
thereby reducing the frequency of HFH.

The design of this clinical investigation is based on the evaluation of
pre-clinical data and aligns with the results of the risk assessment relating
to the FIRE1* System. The clinical evaluation process for the FIRE1* System
incorporates both pre-clinical testing and risk assessment activities. An
assessment of the current state-of-the-art in HF management and the expected
clinical performance, effectiveness and safety of the FIRE1* System were
completed. The clinical development stages starting with exploratory, pilot
clinical investigations and moving to confirmatory pivotal clinical
investigations for the FIRE1* System have been defined from this assessment and
are outlined in FIRE1* System Clinical Evaluation Plan (CEP).

In line with the clinical development stages identified in the CEP, the
intended purpose of this FIH clinical investigation is (1) to demonstrate that
the FIRE1* Sensor can be safely deployed into the IVC, (2) to demonstrate that
the FIRE1* Sensor can provide a signal to the FIRE1* External System, (3) to
investigate the individual daily variability in FIRE1* System Data, including
IVC area and IVC collapsibility, and their relationship to conventional
clinical HF parameters, (4) to investigate the changes in FIRE1* System Data
that occur in the period before, during and after a HF
decompensation. As this is a proof-of-concept clinical investigation, in order
to meet these outcomes, the device will be implanted in patients with a HF
decompensation resulting in a HFH, HF treatment in a hospital day-care setting
or urgent outpatient HF visit in the last 6 months and who meet all the
inclusion criteria and none of the exclusion criteria. The patients will be
assessed over the period of 3 months for the primary endpoints. Assessment of
the primary endpoints at 3 months was chosen as, based on pre-clinical data, it
is believed that the Sensor will have become well endothelialized within the
vessel, and as such, the safety of the implant can be adequately assessed.

A volume challenge of up to 500 ml of saline infusion (dependent on patient
weight), may be performed after Month 3 in the initial phase of the clinical
investigation to assess the ability of the FIRE1* Sensor to detect changes in
volume and provide a signal that reflects this acute change. This volume
challenge is limited to the patients enrolled in Phase 1 of the clinical
investigation (n=14). The volume challenge will be coupled with invasive Right
Heart Catheterization, (RHC) and non-invasive monitoring to provide
haemodynamic assessment of the patients. This will ensure safety and provide
comparative data for exploratory analyses of FIRE1* Sensor Data. Non-invasive
monitoring may include, but is not limited to, electrocardiogram (ECG), blood
pressure (BP), non-invasive oxygen saturation, noninvasive haemoglobin
monitoring and respiration rate (RR). Intravascular ultrasound (IVUS) will also
be used to record changes in internal vessel geometry during the challenge and
compared to the FIRE1* Sensor signal. The volume challenge will only be
performed if, in the opinion of the Investigator, the patient is stable and
capable of tolerating the saline infusion without undue risk.

The data recorded by the FIRE1* System will be presented via the FIRE1* Web App
which will allow investigators to explore FIRE1* System Data such as IVC area
and CI measurements (Monitor Period). The Investigator will also be able to
compare FIRE1* System Data with conventional clinical HF parameters recorded
during the clinical investigation, particularly those recorded before, during
and after a HF decompensation when treatment and/or hospitalisation have
occurred.

The Investigator will be required to review the FIRE1* System Data on a regular
basis. No clinical decisions or changes to patient care will be made based on
this data alone. The information may prompt the Investigator to contact a
patient to assess their HF status over the telephone or via an inclinic visit.
The Investigator will be asked to document their decision-making process with
respect to any additional assessments carried out and/or treatment changes made
for these patients in accordance with institutional and standard guidelines for
HF management. In line with current
internationally accepted HF management guidelines (McDonagh et al., 2021;
Maddox et al., 2021; Yancy et al., 2017), an illustrative treatment guidance is
provided (see appendix 6), which may be used by investigators following their
analysis of the FIRE1* System data and in conjunction with other available
clinical data. If judged necessary by the clinical investigator, alterations in
HF treatment may require an in-person clinic visit and will be recorded as an
unscheduled visit. Relevant blood sampling, e.g., electrolytes and renal
function, will be performed as deemed clinically indicated by the clinical
Investigator.

To maximise the observed variations in IVC area and fluid volume status during
the clinical investigation with the minimum number of patients, standard
clinical manoeuvres, such as standing from a seated position, may be performed
during FIRE1* System recordings at clinical follow-up visits. The movements
from these clinical perturbations will potentially trigger fluid shifts and
allow changes in FIRE1* System Data to be explored. Patients will be asked to
perform additional simple manoeuvres at home while obtaining FIRE1* readings
(for example, a breath hold, sitting upright and moving to a standing
position). The observed variations in FIRE1* System Data will be used to
determine a patient*s individual normal IVC range, as measured by the FIRE1*
Sensor. These insights will be valuable in learning more about how the
information provided by the FIRE1* System may be operationalised to support the
safe management of HF patients.

Dedicated physiological data collection sessions will be undertaken after 3
months to simultaneously record vital signs and FIRE1* System Data. Patient
safety will be closely monitored throughout these data collection sessions. The
data will be used to further inform the feasibility of using the FIRE1*System
to measure additional signals such as RR and Heart Rate (HR) and to support
algorithm development as part of ongoing system development.

As outlined in the CEP, confirming the preliminary safety of the FIRE1* System
and successfully obtaining a signal from the Sensor in vivo are key objectives
of this FIH clinical investigation. The exploratory assessments and learnings
will be used as inputs into the further development of the
FIRE1* System, including updated algorithms and refined treatment guidance to
further aid management of HF patients in the future. This clinical
investigation design ensures that the results generated from the investigation
will be clinically relevant and scientifically valid, will adequately
address the clinical objectives of the investigation and will further inform
the benefit-risk analysis of the FIRE1* System.

This is an early-stage, exploratory pilot clinical investigation aimed at
evaluating the limitations and potential benefits of the FIRE1* System. In
accordance with ISO14155: 2020 Annex I, there is no mandatory pre-specification
of a statistical hypothesis required for a pre-market exploratory clinical
investigation. However, the information gained from this clinical investigation
will be used to plan further steps of device development and crucial to this
end is the attainment of sufficient HF ev