An open label study to explore the feasibility and tolerability of 28 days use of intravaginal oxybutynin via the MedRing OAB system in out-patients with overactive bladder

Controlled release technologies, including sustained release of oral
medication, implants and transdermal drug delivery, have been developed to
mimic physiological concentrations and endogenous substance profiles. The
MedRing is an innovative drug delivery device designed for intravaginal drug
delivery. The MedRing contains a miniaturized electronic printed circuit board
assembly with electronics and antenna, a battery, a drug container, a miniature
peristaltic pump, and a temperature sensor; and is loaded with medicinal
product. The MedRing can wirelessly connect to a smartphone application (app)
from which drug delivery can be programmed and which receives data (dose
delivered and temperature) from the ring. The release of drug can be programmed
by the physician and has the option of *as needed* control by the patient,
within boundaries that are specified remotely by the physician. In both cases,
the delivery schedule cannot exceed pre-defined safety limits. A web
application to be used in combination with the MedRing and Smartphone app
serves as a back-end.

Overactive bladder (OAB) is a common and distressing condition which has a
significant effect on quality of life. One of the current treatment options is
the competitive muscarine receptor antagonist oxybutynin. However, after oral
administration of oxybutynin the anticholinergic side-effects oftentimes
outweigh the advantageous effects, leading to therapy non-adherence. The
formation of the metabolite N-desethyloxybutynin (DEOB), which is a result of
the extensive first pass effect of oxybutynin, has been linked to the adverse
reactions of oral oxybutynin. By administering oxybutynin intravaginally, the
first pass metabolism is avoided resulting in a favorable parent/metabolite
ratio, which is expected to lead to less side effects. In contrast to
intra-vaginal devices in which oxybutynin is released continuously, the MedRing
OAB system is developed to administer the compound pulsatile and *as-needed*.
This may result in the use of oxybutynin more in line with patients* desires:
individual flexible - possibly less - medication, only when needed. Together,
the MedRing containing oxybutynin in combination with the Smartphone (also
referred to as *Companion App*) and Web application, is referred to as MedRing
OAB system.

In a previous study, the safety, tolerability and pharmacokinetic profile of
oxybutynin upon an intravaginal single dose via the MedRing in healthy
volunteers was assessed (CHDR2032). Additionally, the pharmacokinetic profile
of oxybutynin upon administration of multiple intravaginal doses via the
MedRing was assessed and compared to oral administration and placebo in healthy
volunteers (CHDR2208). A higher parent (oxybutynin) /metabolite (DEOB) ratio
was found after intravaginal administration of oxybutynin compared to oral
administration. In this study, the safety, tolerability and feasibility of
using the MedRing system for the intravaginal delivery of oxybutynin will be
explored in patients with OAB in an outpatient setting for 28 days. The
feasibility of both a fixed and a flexible dose scheme will be explored, by
enabling patients to schedule their dose via a smartphone app.

Primary objective
• To explore the feasibility of multiple dose administration of oxybutynin via
the MedRing OAB system in an outpatient setting.
• Safety and tolerability of 28 days of intravaginal dosing of oxybutynin via
the MedRing

Secondary objective
• To confirm the functioning of the MedRing OAB system during 28 days.
• To assess patient satisfaction and quality of life using the MedRing and the
smartphone app for oxybutynin dosing.

Exploratory objective
• Preliminary assessment of clinical effect of oxybutynin delivered via the
MedRing OAB system

This is an exploratory open-label study to assess the feasibility, safety and
tolerability of 28 days of intravaginal dosing of oxybutynin via the MedRing
and the smartphone app in patients with overactive bladder (OAB) in an
outpatient setting.

The screening period for this study has a maximum duration of 42 days prior to
the insertion of the MedRing. The treatment consists of three treatment
periods, with a total duration of 28 days. The intravaginal delivery of
oxybutynin via the MedRing system will be performed in three treatment periods.

Treatment period 1 (Day 1 - 14): fixed dosing at fixed timepoints as defined
and programmed by the physician. Subjects will receive 3 doses of 2 mg per day
(total 6 mg / 24 hours) at preset times.

Treatment period 2 (Day 14 - 21): fixed dosing at flexible timepoints. Subjects
will be instructed to administer 3 doses of 2 mg oxybutynin per 24 hours via
the MedRing system at free to choose timepoints. The minimum interval between
two doses must be 3 hours.

Treatment period 3 (Day 21- Day 28): flexible dosing at flexible timepoints.
Subjects will be instructed to administer oxybutynin via the MedRing system as
needed. Oxybutynin can be administered in steps of 1 or 2 mg, with a maximum of
6 mg in 24 hours and a minimum dose interval of 3 hours.

Subjects will visit the study site on day 1, 7, 14, 21, 28 and 35. On day 1,
subjects will be trained on how to use the MedRing system, including insertion
and removal, followed by self-insertion of the MedRing. The first dosing of
oxybutynin via the MedRing will be performed at the study site. On day 1, 14
and 28, PK samples will be taken. On day 28, the MedRing will be removed,
followed by a vaginal inspection. Final follow-up visit will take place on day
35 +/- 2 days for all subjects participating in the study

OAB patients with an indication for oxybutynin treatment will be included. The
expected oxybutynin exposures to be reached in the study are within the range
of the oxybutynin exposure of the registered oral dose range. Patients will not
receive any direct benefit from this study but participation contributes to
knowledge on their disease and possibly new treatment options.

The systemic use of oxybutynin in humans is considered safe. Most of the side
effects can be explained by the anti-cholinergic mode of action. These side
effects are thought to be linked to the metabolite (DEOB), which may be reduced
by the intravaginal route of administration circumventing the hepatic
first-pass effect.
Potential issues of concern include:
- Local tolerability issues with the oxybutynin solution or the MedRing to the
vaginal cavity.
- Technical malfunction of the MedRing pump system.
- Breakage of the MedRing and releasing the reservoir of oxybutynin
intravaginally.