A follow-up study to investigate the functionality of a glucose sensor device in the human eye.

NovioSense is developing a new minimally-invasive glucose monitoring device.
This device will be positioned in the eye (inferior conjunctival fornix) and
will monitor the glucose levels in tear fluid. In a functional device, the
information will be transmitted to a cell phone receiver that will translate
the tear glucose into equivalent blood glucose levels. In this way, diabetict
subjects can better control their blood glucose levels and keep it within
acceptable bounds as much as possible. This pilot study will evaluate ability
of the sensor to measure glucose in the tear fluid of a human eye, thus the
functional wired prototype of the device will be used. It*s configuration is
identical in dimension, materials and shape to the final functional device with
the exception that the electronics portion is connected to an industry standard
measurement system to avoid any effects of the electronics on sensor
performance. The device underwent a positive animal test where 5 sheep in total
were examined. The maximum exposure time of the dummy device in the eye was 5
hours and no irritation or damage to the eye was observed (see IMDD for summary
of animal experiments). The tolerability of the device has been also assessed
in a pilot study performed on 4 healthy volunteers, carried out in Sf. Spiridon
Hospital, Iasi, Romania on 7th of August 2015 (see summary of the report NS
01-2015). Dummy devices were placed into the inferior conjunctival fornix of
the human eye and the subjects were examined for 5 hours by an ophthalmologist.
No signs of reddening of the conjunctiva or conjunctival fornix were observed
and the devices worn by the subjects, did not induce any discomfort or pain.
The rational for the relatively short duration of the device placement in the
eye was to maintain the evaluation time comparable to the input from previous
animal tests.
On 24h November 2017, the study protocol NSGS201702 received approval from
Medisch Ethische Toetsingscommissie Zuidwest Holland with given identification
number NL61532.098.17. Six clinical subjects successfully completed the pilot
clinical trial conducted between 22nd of December 2017 and 13th of April 2018.
The tear glucose sensor was able to measure stable and repeatable signals for
up to 5 hours with high tolerance. The analysed data gave evidence for the
correlation between glucose in tears and blood and interstitial fluid. However,
the population of enrolled subjects (six subjects) was not enough to provide a
more comprehensive analysis of the capability of the sensor and to assess the
lag time between blood and tear glucose. On completion of this pilot study
without major adverse events, such as significant irritation or damage to the
eye and good tolerability, a new study will investigate the accuracy of the
device by continual measurement of glucose concentrations in a tear fluid of
human eye involving a larger group of subjects. Therefore a folllow-up study is
initiated where additional 24 clinical subjects will be recruited.
In this study, the evaluation time will also be limited to 6 hours. The
rational with a short time scale trials and not to include a longer duration
pilot is to collect additional feedback about tolerability and measurement
ability before continuing with longer- term experiments. These longer-term
studies do require a different logistic, for example, to have an
ophthalmologist stand-by during the night-time periods. So, before proceeding
to this set-up the initial feedback will be collected in this follow-up case
and analysed.

The objective of this pilot study is to investigate the efficiency of a glucose
monitor device placed in a tear fluid of human eye to measure glucose for up to
6 hours and its correlation to blood glucose values. Additionally, more
information will be collected to confirm the tolerance of the device in a human
eye.

This is a non-randomized, single-center sponsor initiated follow-up study by
enrolling volunteers with diagnosed diabetes type 1, insulin dependent, that
signed an informed consent form.
This study is initiated to investigate the efficiency of a prototype glucose
sensor device able to measure glucose levels in a tear fluid of human eye. 24
volunteers, a mix of gender will be recruited, all following the in- and
exclusion criteria. It is expected to dedicate a day for each subject,
separately. Before the follow-up study will take place, the subject is expected
to report to the site fasted but on their normal basal insulin where the basic
eye examination supported with pictures will take place by ophthalmologist. The
commercial available CGM device (Abbott FreeStyle Libre device) must be
attached into subject upper arm at least one day prior the trial and used as an
additional reference through all pilot study. Blood samples to measure glucose
values during the experiment time points will be taken with Point-Of-Care
system and serve as a reference. The insertion of the investigated sensor coil
into an inferior conjunctival fornix will be done using specially designed
insert devices (see details in protocol). After insertion of the device into
the inferior conjunctival fornix by a specialist. It will be given a period of
60 minutes to stabilize the sensor where no measurements will be taken. After
that, the measurement with NovioSense device will be performed continuously for
the next 30 minutes where usual meal prior to which half the dose of their
normal short- acting insulin will be administered. In parallel to the
NovioSense measurement, blood samples will be taken and the external GCM device
will be scanned to record glucose concentration values with 15 minutes interval
and serve as a reference. The subject will be asked to wear a device for 6
hours (trial duration). The data collection will proceed for a maximum of 5
hours and following the trial the patient will undergo follow up by the
ophthalmologist, where the pictures will be taken. At the end of the study, the
subject will fill out a questionnaire.

The glucose monitor device (dummy device) has been tested in animals and humans
for up to 5 hours in the eye without any signs of irritation, infection or
damage. However, duration of the tolerability study involving the group of
subjects was influenced by the results acquired from animal tests. Sheep model
used within a study, possess a third eyelid which caused dislocation of the
device during the experiments enabling to assess tolerability only up to 5
hours. It was demonstrated in a small group of volunteers that in the human
setting dislocation did not occur. Moreover, the subjects did not report any
discomfort or pain caused by a presence of a dummy device in inferior
conjunctival fornix.
Despite positive results obtained from a dummy device in both "in vivo* and
pilot clinical settings, there still is a possibility of dislocation with
repeated rubbing or mechanical stimulation. The functional prototype device
contains external connection Pt/Ir wires (3 electrodes, see description in
section 3.1 of the protocol), firmly immobilised onto side of the face,
connected to a mechanical interlock connected to a potentiostat enabling
conducting measurement of glucose concentration in the eye. Consequently, there
is a risk of reduced comfort of a subject during the experiment. Moreover,
within the initiated study, the glucose levels in a tear fluid of human eye
will be determined by applying a small voltage (0.5 V) to the device. The
produced current, in a range from 0 to 25 micro amp will be measured. This
measurement technique is identical to that employed in all current marketed CGM
devices. The risk of short circuit occurrence has been mitigated for in the
risk assessment exercise and precautions have been undertaken to mitigate any
potential cohort circuit of the device by installing physical controls as well
as a patient operated interlock which allows them to break the contact and
terminate the measurement with minimal force if they feel a sensation which is
uncomfortable or unpleasant.
The subjects will be under continuous supervision of an ophthalmologist during
the duration of the study. In course of any failure of the device, as stated
above, or discomfort of the subject, the physician will remove the device
immediately and will conduct necessary eye examination, funds photography.
There are no direct clinical benefits for the subjects by participation in this
pilot study other than a significant contribution towards a next step in
developing a minimally invasive glucose sensor device that can help diabetic
patients to better manage their glucose levels.