A pilot study to investigate the functionality of intra-vaginal glucose sensor in vagina.

Continuous Glucose Monitoring (CGM) has been shown to improve glucose
regulation in patients with type 1 diabetes (Special issue on CGM in clinical
practice, Diabetes Technology& Therapeutics, volume 9, 2017). Current CGM
systems are devices that measure glucose in the subcutaneous fluid and are
applied to the skin. The disadvantages of the present systems are that they
give skin irritations in about 9% of patients and are visible on the outside. A
lot of patients (especially, but not only young women) don*t like the
visibility of the device. Also, because glucose is measured in the subcutaneous
fluid there is a *lagtime* between capillary glucose and subcutaneous glucose,
especially when glucose values are rapidly changing. LiGalli BV is developing
an intelligent intra-vaginal ring for drug delivery and diagnostics. The
incorporation of a glucose sensor and insulin reservoir would provide
flexibility in dosage, schedule and timing. To the best of our knowledge there
is only one study in the open literature measuring glucose from vaginal wall
transudation. In this study the change of glucose was measured in vaginal
secretions during glucose tolerance testing (Ehrström et al., Obstetrics &
gynecology, 2006, 108, 1432*1437). According to Ehrström et al. the median
level of glucose in vagina secretions of healthy women was 5.2 mM before and
3.7 mM after oral glucose tolerance test, while plasma glucose was 5 mM before
and 5.8 mM after oral glucose tolerance test. Also, one women with
insulin-dependent diabetes was analyzed in this research. Although the plasma
glucose of this women was equal to 14.3 mM, the level of glucose in vaginal
secretion was only 6.2 mM. The results of this small study suggest that there
is no correlation between blood glucose and vaginal fluid glucose
concentrations. Yet, it should be noted that glucose concentration was measured
from the pool of vaginal fluid in the deepest part of the vagina (fornix
posterior) which is composed of past secretion of cervical mucus and
transudate. Moreover, the measurement was done by use of a sterile, weighted
strip of filter paper, thus glucose was not measured directly from the vaginal
mucosa.
To the best of our knowledge there are no data on the correlation between the
concentration of glucose in blood and vaginal wall transsudate. The current
embodiment is in direct contact with the mucosal wall only a few millimeters
away from the very richly vascularized area of the vagina. Glucose can pass
these anatomical borders easily. It is plausible that vaginal wall transsudate
glucose might reflect the actual changes in blood glucose concentrations. The
ring and measuring sensor are placed directly against the vaginal wall in a
flexible manner and do not penetrate the tissue itself.
NovioSense and LiGalli have combined technologies to develop an intravaginal
glucose sensor to determine glucose levels in vaginal wall transudate. A
vaginal ring developed by LiGalli, housing components developed by NovioSense
BV and Philips Medimetrics is placed into vagina and by its design offers a
stable contact positioning of the glucose sensor to the vaginal wall. The
device uses the NovioSense glucose sensing platform to determine the glucose
concentration of vaginal wall transsudate.
This pilot study will evaluate the ability of the intravaginal device to
measure vaginal wall glucose and correlate that value to blood glucose and
subcutaneous measured glucose by currently used CGM systems.
The tolerability of the ring shaped silicone device has been assessed as a
dummy device in 6 patients who could easily insert and remove the ring
themselves. Two of them wore the ring for 4 weeks. The pilot was carried out at
Maxima Medisch Centrum Veldhoven, the Netherlands in August 2015. The ring was
found to be comfortable and did not illicit irritation from the surrounding
tissue.
The functionality of the device was assessed in a second small pilot study
performed in 1 healthy volunteer, carried out at Maxima Medisch Centrum
Veldhoven, the Netherlands on the 20th of October 2016 (see summary of the
report NS 12-2016 and NS 13- 2016). A Boston
Scientific explorer 360 electrocardiology catheter was retrofitted into the
Ligalli ring and coated with NovioSense coating to form the intravaginal
glucose sensor. The device was placed into the vagina in contact with the
vaginal wall by a gynecologist and was examined for approximately 1 hour 20 min
period. The in vivo pilot work demonstrated that the intravaginal device can
function and give a stable and clear response in the vagina. Also, it was shown
that the device can measure a shift in a glucose concentration following
flushing near the sensor with different concentrations of glucose.
This pilot study will evaluate the ability and efficacy of the intravaginal
device to measure glucose proximal to the vaginal wall. Moreover, it will give
an answer if glucose sampled from the upper vaginal tract close to the cervix
reflects levels of glucose found in blood as was seen in the previous study.
The results will also be compared by those of currently used CGM devices.

The objective of this pilot study is to investigate if glucose measurement on
the vaginal wall can be an alternative for capillary and subcutaneous glucose
measurement. The present study will look at the efficacy of an intravaginal
device to measure glucose in the vagina up to 4.5 hours and to investigate if
glucose sampled from vaginal wall transsudate reflects levels of glucose found
in capillary blood and interstitial fluid measured with a currently used
subcutaneous device.

This is a, nonrandomized, single-center, sponsor initiated pilot study.
The selected subjects will report on the day of the trial fasted on normal
basal insulin and will be asked to wear the vaginal device throughout the trial
for up to 4.5 hours in which the glucose measurements with the sensor from the
vaginal wall will be taken. The capillary blood samples will be collected from
finger stick glucose tests during the experiment time points for quantitative
analysis of glucose levels and serve as a reference. Additionally, the glucose
values from interstitial fluid will be measured by a CGM (continues glucose
monitoring) sensor as a supporting control to the acquired data and given to a
subject at least one day prior the trial. After insertion of the device by a
gynecologist, the basal evaluation of glucose measurements will be performed
for 30 minutes. Next, the patients will take their own usual breakfast prior to
which half the dose of their normal short-acting insulin will be
administered.Half the dose of the short-acting insulin is chosen to increase
the glucose value after the meal up to a level of about 15 mmol/L, a value that
is not uncommon in everyday practice for patients with type 1 diabetes. Blood
samples to measure glucose values during the experiment time points will be
taken with Point-Of-Care system and serve as a reference. Additionally,
patients should wear a commercially available CGM (continuous glucose monitor)
sensor to serve as a supporting control to the acquired data. Data collection
will proceed for a maximum of 4 hours and following the trial the patient will
undergo follow up by the gynecologist.

The intravaginal ring device (dummy device) has been tested in women for up to
28 days and the functional device tested for 1 hour 20 min in vagina without
any signs of irritation or an acute response. In both studies subjects did not
report any discomfort or pain caused by a presence of the device in vagina.
The functional intravaginal device contains external connection to a
potentiostat enabling electrochemical measurement of glucose concentration in
vagina. Despite positive results obtained from previously conducted pilot
trails, the tolerability was assessed on a small number of subjects recruited,
thus there is still a possibility to sense a reduced comfort during wearing the
device within time of the trial. Therefore a physician will be present
throughout the trial and will remove the device immediately if any discomfort
is experienced by the subject.
Moreover, as part of the initiated pilot study, the glucose levels in vagina
will be determined by applying a small potential to the device (0.5 V). The
produced current, in a range from 0 to 15 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 by
physical separation of the electrodes, 100% inspection and testing of devices.
The risk assessment exercise and precautions have been undertaken to mitigate
any potential short circuit of the device. The patient can ask to terminate the
measurement if they feel a sensation which is uncomfortable or unpleasant at
any point. Additionally, in course of the trial (up to 4.5 hours), the subject
will experience reduced mobility caused by external connection between device
and the potentiostat.
In course of any failure of the device, as stated above, or any other
unforeseen adverse event, the physician will remove the device immediately and
will conduct necessary examination.
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 intravaginal glucose sensor device that could answer fundamental
questions if there is a correlation between vagina wall glucose and blood
glucose.