Biological OviTex versus synthetic graft in robotic prolapse surgery: a multicentre, phase II-III, partially randomized patient preference trial

Minimal-invasive ventral mesh rectopexy (VMR) and sacrocolporectopexy (SCRP)
are widely accepted treatments for patients suffering from pelvic
prolapse.Choice of material used in VMR or SCRP - synthetic or biologic
surgical mesh - remains subject of debate. Recent developments in usage of
transvaginal mesh to repair pelvic organ prolapse (POP) in April 2019, with the
Food and Drug Administration (FDA) ordering a direct stop in selling and
distributing this type of mesh products, have negatively influenced the
perception on surgical mesh for VMR. Currently, the most widely used mesh in
VMR is synthetic and has shown good results regarding recurrence, mesh exposure
and functional outcome. Although complication rates are low, the serious
complications of fistulation, erosion and dyspareunia are reasons to opt for a
more expensive biological mesh. High-quality evidence of synthetic versus
biological mesh is lacking, but does not stop resistance against synthetic mesh
from growing. This has even led to concerns and questions about synthetic mesh
use from the Dutch government addressed at the medical professionals and
options for alternatives are being asked.

Biologic grafts are characterized by degradation of the implant and
regeneration of host tissue. It is assumed that this process of degradation and
remodeling decreases the risk of erosion and infection. However, this
transformation may possibly lead to a higher chance of recurrence in the long
term. Rate of recurrence, but also mesh-related complications to a lesser
extent, largely depends on duration of follow-up. Since biologic graft
implementation in VMR is relatively new and its usage is restricted due to
higher costs, literature on biologic mesh with long term follow-up is limited.
In addition, there is a significant difference in various described biological
meshes. This is important to keep in mind when comparing outcome of VMR or SCP
with synthetic versus biologic mesh.

In VMR there are no randomized controlled trials on synthetic versus biologic
mesh. The biologic meshes studied thus far are Biodesign and Permacol. Erosion
rates after VMR with Biodesign and Permacol have both been studied in three
studies in total (N = 349 and N = 425 in total respectively) and show low
erosion rates of 0 to 0.1%.8,9,10. In comparison, mesh related complications
after VMR with synthetic non-resorbable mesh (like polypropylene) are around
2%.
2,3,5,8 Recurrence rates after synthetic mesh in VMR range between 2% and 14%
after a median follow-up of 12-61 months. When comparing studies on biologic
implants that report on recurrence rates there seems to be a slight difference
in favor of Biodesign. Studies on Biodesign in VMR with a median follow-up
ranging between 12 and 47 months show a recurrence rate around 5%. Literature
on Permacol shows higher recurrence rates ranging between 5 to 14% after a
median follow-up of 12 to 29 months.

In SCP allografts and xenografts have been investigated as an alternative for
polypropylene. A randomized controlled trial compared SCP using polypropylene
mesh with solvent cadaveric fascia lata.16 After one year of follow-up,
polypropylene mesh had a higher anatomical cure rate than cadaveric fascia lata
(91 percent versus 68 percent; p=0.007). Two mesh-related complications
occurred in patients who received polypropylene mesh, while none occurred in
the allograft group (p= 0.5). Another RCT with the same comparison and a
follow-up of 5 years showed similar results, with considering cadaveric fascia
not as strong of a support. Deprest et al. compared polypropylene mesh with
porcine grafts in a prospective study and found xenografts to be associated
with more apical failures and reoperations than with a polypropylene mesh (21
percent versus 3 percent; p = 0.01). However, there was no significant
difference in functional outcomes between the two groups. An erosion rate of 11
percent was described in both groups. A more recent study showed more positive
results for xenograft use.

Although Biodesign (Surgisis), Permacol and other are all grouped under the
common denominator *Biologic mesh*, each of these products is unique. There are
differences in tissue source, differences in the processes used to
decellularize the tissue and differences in the final processing steps such as
sterilization and preservation. As a result, there are significant variations
in biological and clinical performance between these products. Permacol, which
is purposely cross-linked pig dermis, behaves like a synthetic material in-vivo
and induces a permanent foreign body response, leading to encapsulation.This
prevents integration with and in the surrounding tissue. Consequently, high
rates of erosion occurwith Permacol implants. Biodesign, one of the early
biologics, is derived from small intestinal submucosa and is a non-cross-linked
mesh. Likely due to its (proprietary) processing, Biodesign in practice often
dissolves before healing and remodeling can take place.

A novelty on the surgical mesh market is OviTex. It is produced by GD medical
and exist of sterile sheep extracellular matrix (ECM) interwoven with a
(absorbable or non-absorbable) synthetic fiber. OviTex comes with a grid of
absorbable polyglycolic acid (PGA) or permanent polypropylene. Unique to OviTex
is its composition, which consists of essential components required for
regeneration of host tissue. Additionally, the coupling of an ECM with a
(absorbable) synthetic carrier ECM ensures that cross-linking is avoided but
mechanical strength is maintained. Moreover, OviTex is lower in costs than any
other biological mesh on the market. Preliminary results of a recent pilot
study at Meander MC showed that the use of an OviTex PGA (with absorbable grid)
mesh in the pelvic floor is feasible and safe. Nevertheless, 2 out of 11
patients who completed follow-up of 6 months showed an early anatomical
recurrence. This suggests that the use of permanent synthetic fiber may be
necessary for a more durable repair and fewer recurrences than using OviTex
PGA. Although resistance against synthetic grafts is growing, OviTex Permanent
contains 96% sheep ECM and only 4% polymer, compared to the standard Prolene
mesh which is 100% polymer (polymer areal density 16g/m2 OviTex 1S vs. 76g/m2
prolene). Furthermore, the polymer is embedded in the ECM which further
attenuates any inflammatory response. Observations in primates show that the
minimized amount of embedded synthetic reinforcement results in an implant
that, histologically, behaves like a biologic mesh yet maintains its functional
structure.

There are no studies comparing OviTex to the current standard (Prolene, PMN3,
Ethicon Inc Johnson & Johnson, The Netherlands) Therefore, a comparative study
should be conducted before OviTex is used as a biologic alternative for
polypropylene in VMR on a larger scale. Following the OviTex pilot study, we
aim to conduct a follow-up study (ProTex trial) in which, both in the short and
longer term, the efficacy of the OviTex mesh in pelvic floor surgery will be
assessed in comparison with the current standard polypropylene, by means of a
non-inferiority test.

Main study parameter/endpoint phase II
- Post-operative morbidity measured by reoperations, reinterventions,
re-admissions, serious adverse events, Clavien Dindo classification and CTS
classification.
- The rate of rectal prolapse recurrence and complications (complaints,
physical examination, addition research, re-operation and readmission).

Main study parameter/endpoint phase III
Constipation, incontinence and urogenital functioning (questionnaire, validated
scoring system: Fecal Incontinence Severity Index (FISI), Altomare obstructive
defecation score (ODS)) and Pelvic Floor Distress Inventory-20 (PFDI-20).

Secondary Objective(s):
- Quality of life (QoL) pre- and postoperatively objectified primarily by the
Patient Assessment of Constipation-Quality of Life Questionnaire (PAC-QoL),
Fecal Incontinence Quality of Life Scale (FIQL), Pelvic Floor impact
Questionnaire (PFIQ-7), Patient Global Impression of Improvement (PGI-I),
Patient Global Impression of Severity (PGI-S) and European Quality of Life Five
Dimension (EQ-5D).
- Post-operative morbidity measured by reoperations, reinterventions,
re-admissions, and serious adverse advents.
- Anatomic recurrence of the prolapse, measured by defecogram or MR
defecography in rest and during Valsalva maneuver.
- Rate of rectal prolapse recurrence and complications (complaints, physical
examination, addition research, re-operation and readmission).
- Anatomic recurrence of pelvic organ prolapse (POP) using the simplified
Pelvic Organ Prolapse Quantification (sPOPQ)
- Sexual functioning pre- and postoperatively by the questionnaire Prolapse
Incontinence Sexual Inventory Questionnaire (PSIQ-12).
- Length of hospital stay, peri-operative and post-operative in hospital
mortality and morbidity.
- Rate of extra outpatient visits because of complaints.

This study aims to investigate the efficacy of the OviTex mesh in pelvic floor
surgery in comparison with the currently used polypropylene mesh, by means of a
multi-center, phase II-III, partly randomised patient-preference,
non-inferiority study.

In the phase II study, in the experimental arm 10 patients for each operation
indication (30 in total) will be included:
- Full thickness external rectal prolapse (ERP) (n=10);
- Internal rectal prolapse (IRP) Oxford grade 3 or 4 with symptoms (n=10);
- Any of the above indications combined with a sPOPQ stage >= 2 for which
concomitant surgery is required (SCR or cervicopexy) (n=10).

After the total of 30 participants completed a follow-up of 90 days, an interim
analysis takes place. (see chapter 9)

In the subsequent phase III follow-up of the patients will be performed
according to routine postoperative follow-up with some minor adjustments. After
the standard 6 weeks follow-up visit at the outpatient visit, the patients will
be asked to fill in a questionnaire after 90 days. Recurrence, complications
and pelvic floor function will be assessed at 6, 12 and 24 months
post-operatively by means of an outpatient visit and questionnaires. Compared
to standard care, the last visit has been added in relation to the study. If
symptoms persist or recur the responsible physician may be decided to carry out
additional imaging.

The primary aim of this study is to compare prolapse surgery with OviTex
instead of the current standard polypropylene mesh (Prolene, Ethocin Inc,
Johnson & Johnson, Hamburg, Germany; weight 80-85 g/m2) in adult patients with
a rectal prolapse and/or pelvic prolapse performed by experienced surgeons.
Study participants will have 2 additional follow-up moments (each including the
questionnaire and outpatient visits) in addition to standard practice. Further
treatment will be the same for patients undergoing current VMR or SCR with
polypropylene mesh.

In VMR and SCR a mesh implant is used to reinforce weakened tissue of the
pelvic floor (the rectovaginal septum). Ovitex is a CE certified surgical mesh
and its usage in VMR and SCP falls under the intended use. A recent pilot study
on safety and feasibility concluded that the usage of Ovitex in VMR is safe.

Disadvantages of participating in the study are:
- The participant will spend extra time filling in the questionnaires during
follow-up (usually 10-30 minutes).
- The participant has two extra outpatient visits to which he or she must
attend as much as possible.
- The participant may find the questionnaires confronting.