A Post-Market Clinical Follow-up Study to Investigate the Usability of the CollaGUARD Adhesion Barrier following Hysteroscopic Adhesiolysis

The development of intrauterine adhesions (IUA) following gynecological
surgery is a major
complication which may cause a range of severe clinical symptoms in
women. IUA*s can result in menstrual abnormalities, dysmenorrhea and
infertility. IUA*s are thought to develop as a result of trauma to the uterine
cavity, related to, for instance, curettage, infections and surgical
hysteroscopy. Post-operative adhesions are classified as *de novo *when
they develop at sites that did not have adhesions before, and are
considered *reformed* when they develop at sites where previous adhesiolysis
has been performed. Corrective surgery is often needed to resolve
adhesion-related complications, and prevention of adhesions is therefore
considered important.

The insertion of an intrauterine device has been shown by many studies as an
effective method of preventing adhesion reformation. Post-operative use of an
IUD keeps the surfaces of the uterus separated during the initial healing
phase, and reduces the chance that the surfaces will adhere. IUDs include,
among others, Foley-balloons and barrier gels. The Foley balloon has been shown
to prevent reformation of IUA*s. However inserting a Foley balloon catheter
carries a risk of infection spread from the vagina and the inflated balloon may
cause a decreased blood flow to the uterine walls, slowing regeneration.
Additionally, the method can cause discomfort the patient. When using a barrier
gel, the application of it prevents adhesions by forming a protective coating
on the uterine wall. A disadvantage of gel formulations is the fact that in
case of bleeding they may be washed out of the uterine cavity, losing its
efficacy. Other adhesion barriers have been developed, including
barriers consisting of collagen. Collagen is a fully biodegradable and
bioactive material and has been shown to act as an effective adhesion barrier
in isolation and in combination with polymers. The CollaGUARD adhesion barrier
is such a collagen adhesion barrier.

CollaGUARD adhesion barrier is a transparent bioresorbable film of 100% type I
purified equine collagen. CollaGUARD is approved in Europe for the prevention
of postoperative adhesions in patients undergoing abdomino-pelvic laparotomy or
laparoscopy and has a CE certification since October 2011. CollaGUARD can be
implanted at the time of surgery and serves as a temporary barrier to separate
adhesiogenic surfaces throughout the normal tissue repair process. can be
easily rolled for insertion through a trocar when implanted
laparoscopically. CollaGUARD is fully resorbed by the human body by
means of enzymatic degradation by collagenases. The resorption time is about
4 weeks. A pre-clinical study using CollaGUARD adhesion barrier in a
rat-abrasion model showed that CollaGUARD increased the probability of
remaining adhesion free by more than six-fold (P < 0.001) and significantly
reduced the extent and severity of adhesions (P < 0.001). Safety of
the CollaGUARD adhesion barrier was evaluated in this study by
histopathological analysis of acute and/or chronic inflammation reaction.
Results showed good local tolerance of the CollaGUARD adhesion barrier. Based
upon this data and extensive clinical experience with collagen-based products
in other fields of application, CollaGUARD was determined to have a positive
risk-benefit ratio. Furthermore, there have been no spontaneous reports of any
adverse device effects since launch. CollaGUARD is expected to reduce adhesion
reformation and formation of de novo adhesions.

This study is designed to determine the usability of the CollaGUARD adhesion
barrier in gynecological surgery. The aim is to collect qualitative and
quantitative data in a small number of subjects (pilot study) to gain
information on the usability and implantation procedures of the CollaGUARD
adhesion device in hysteroscopic surgery. Results from this study can be used
to design statistically powered clinical trials for the investigation of
efficacy parameters.

This is a multicenter post-marketing pilot study. In total, 10 patients will be
implanted at two investigational sites in the Netherlands. Patients deemed
eligible after screening, and who gave written consent for participation in the
trial, will be treated with the CollaGUARD adhesion barrier according to the
Instructions for Use during the hysterscopic adhesiolysis. Directly after
surgery, an ultrasound will be done to assess the position of the device. The
Investigator will complete a series of questions regarding the usability of the
device. Also, he will classify the adhesion severity before and after the
surgery (using ESGE and mAFS scales). Subjects are prescribed medication to
induce withdrawal bleeding, and are followed up as following:

1 week post-op: safety phone call. If deemed necessary by the investigator, a
control visit in the hospital can be scheduled.

2 week post-op: control visit. An additional ultrasound will be done to assess
the location and degradation of the device.

3 week post-op: safety phone call. If deemed necessary by the investigator, a
control visit in the hospital can be scheduled.

4 week post-op: control visit. An additional ultrasound will be done to assess
the location and degradation of the device.

9 week post-op: control visit. A follow-up hysteroscopy will be performed to
classify adhesion reformation and de novo formation. This hysteroscopy is
according standard practice.

The clinical investigation is expected to take approximately 8 months: an
estimated 3-5 months recruitment period and 9 weeks of follow-up for each
patient.

Possible risks of participating in this trial are associated with the
hysteroscopic procedure and with non-active implants that are left in situ.
These anticipated risks are the following and are not considered unique for the
CollaGUARD device:
- Blood loss
- Perforation of the uterus wall
- Allergic reaction
- Infection of the uterus
- Formation of granulomas

Potential risks associated with the CollaGUARD device are:
- Allergic reactions due to hypersensitivity to collagen
- Blood and/or fluid accumulation in uterus (due to blockage of flow by the
device)
- Infection

Besides these anticipated risks, patients can experience extra burden by the
two additional visits and ultrasounds at the 2 and 4 week FU visits, which are
not standard of care. Potential benefits are expected for the patient by means
of reduced de novo and reformation adhesions, and consequently reduced
symptoms. Because the additional burden and risks compared to the standard care
are minimal, the potential benefits for the patients and the advantage for
future research outweigh the potential risks posed to the participating
subjects.