A Phase III Randomized, Controlled, Superiority Study Evaluating the Fibrin Pad Versus Standard of Care Treatment in Controlling Parenchymal Bleeding During Elective Hepatic Surgery

Bleeding during surgical procedures may manifest in many forms. It can be
discrete or diffuse from a large surface
area. It can be from large or small vessels* arterial (high pressure) or venous
(low pressure) of high or low volume. It
may be easily accessible or it may originate from difficult to access sites.
The bleeding tissues may be firm or friable.
For challenging severe bleeding, immediate control may be necessary to avoid
unwanted haemodynamic
consequences.

Conventional methods to achieve control of bleeding (haemostasis) include use
of surgical techniques, sutures,
ligatures or clips, and energy*based coagulation or cauterisation. When these
conventional measures are ineffective
or impractical, adjunctive haemostasis techniques and products are typically
utilised, including topical absorbable haemostats
(agents used to control bleeding which are applied to the surface of the
tissue) such as oxidised regenerated
cellulose, gelatin, or collagen and active haemostats such as topical thrombin
or fibrin sealants.

While fibrin sealants have proven efficacious in controlling slowly bleeding
foci, diffuse oozing, bleeding from needle
puncture sites, and diffuse parenchymal organ haemorrhage they are not as
effective in the control of severe or active
bleeding. The requisite preparation time for lyophilised products can be
impractical and furthermore the use of fibrin
sealants can complicate the application of pressure to the bleeding site, in
that applied pressure can disrupt the
sealant bond or cause the sealant to adhere to gloves or gauze. Application of
fibrin sealants to actively bleeding sites
can result in the sealant lifting or floating off the target site, particularly
in high volume or high pressure bleeding.
There is a need for products or techniques to rapidly control challenging
severe and active bleeding when treatment
with conventional surgical techniques or conventional adjunctive haemostatic
products is either ineffective or
impractical. The ideal agent would be effective in a wet field, with active
bleeding, would rapidly and effectively control
severe bleeding of high or low pressure, and would afford ease of operative
handling and storage.

This clinical study is the third pivotal clinical trial for FP, and is designed
to determine the safety and efficacy of FP when
used in controlling bleeding from the liver during hepatic surgery.

The objective of this study is to evaluate the safety and hemostatic
effectiveness of FP versus SoC
treatment in controlling parenchymal bleeding during hepatic surgery.

This is a randomized, controlled, superiority, study evaluating the
effectiveness of the FP compared with SoC methods utilized to control bleeding
in hepatic parenchyma for which standard methods of achieving hemostasis are
ineffective, impractical or inappropriate. Qualified subjects are stratified
based on the typeof hepatic parenchyma (Normal vs. Abnormal) and are randomized
on a 1:1 basis, FP vs. SoC control.

The appropriate TBS will be identified following transection of the hepaticpar
enchyma. This will be the site assessed for hemostatic effectiveness.


FOR SUBJECTS TO BE TREATED WITH FIBRIN PAD
After placement of the treatment article, firm manual compression sufficient to
stem all bleeding at the TBS will be applied continuously and will be
maintained until 4 minutes post-randomization. The surgeon may use a surgical
sponge (laparotomy pad or surgical gauze) to assist in providing adequate
pressure over the entire FP surface area (including pressure over the area of
FP overlap).
Hemostasis will be assessed at 4 minutes following randomization by carefully
releasing manual compression and removing the surgical sponge (if used) without
disturbing the hemostatic product. The FP should not be removed once bleeding
has been stopped.
If breakthrough bleeding occurs at the TBS during the 4-minute treatment
period, the surgeon may re-treat with FP if clinically appropriate. After
re-treatment application, manual compression must be applied for 2-3 minutes,
after which hemostasis will be assessed. Under any circumstance, hemostasis
must be assessed at 4 minutes post-randomization. If breakthrough bleeding
requiring treatment other than FP occurs at anytime, the surgeon will revert to
SoC and the subject will be considered a treatment failure for the primary
efficacy parameter.
If hemostasis is achieved at 4 minutes post randomization with FP but the
surgeon feels that additional treatment is required to assure durability of
hemostasis then such treatment should be applied. This will be considered a
treatment failure.

Hemostasis at the TBS will be assessed again at 10 minutes from randomization.
The TBS will be observed until completion of the surgery immediately prior to
initiation of final fascial closure.
FP may be used in other areas of the resected plane of the parenchyma. These
additional areas treated with FP will not be assessed for TTH. A maximum of
four units (4 x 4 inches) of FP may be implanted (left in place at the bleeding
site/s) per subject assigned to be treated with FP.


FOR SUBJECTS RANDOMIZED TO STANDARD OF CARE (SoC)
SoC will be initiated with 4 minutes of continuous firm manual compression
following randomization with or without gauze or sponge and with or without a
topical absorbable hemostat (TAH) i.e. SURGICEL
Patient safety in this control SoC group is protected since during manual
compression there should be no ongoing blood loss based upon this TBS
definition and if break through bleeding requiring treatment occurs at anytime,
the surgeon will revert to whatever his/her standard treatment would be. This
will be considered as a treatment failure for the primary efficacy parameter.
Hemostasis will be assessed at 4 minutes post-randomization. If hemostasis has
not been achieved at 4 minutes, the surgeon will continue to treat the bleeding
according his/her SoC. Hemostasis at the TBS will be assessed again at 10
minutes following randomization. The TBS will be observed until completion of
the surgery and immediately prior to initiation of final fascial closure. If
hemostasis is achieved at 4 minutes post randomization with manual
compression but the surgeon feels that additional treatment is required to
assure durability of hemostasis then such treatment should be applied. This
will be considered a treatment failure.
If bleeding requiring re-treatment at the TBS occurs anytime after the 4-minute
assessment, the surgeon should control bleeding according to his/her SoC and
the subject will be considered a treatment failure for the primary efficacy
variable.

The additional burden for patients participating in this study is minimal.
Study-related examinations are generally done during the visits associated with
the standard treatment of this patient group, with the exception of perhaps the
30 and 60 day visits.
The risks involved in the study are the same as patients who undergo standard
liver surgery. The additional risk that participants have is the chance of
developing a viral infection because of the use of the investigational product.
As described elsewhere, this product is manufactured under the strictest safety
measures but can not guarantee 100% certainty that no viruses are transmitted.
A viral safety test is taken from every patient.

However, the small chance of developing a viral infection outweights, in the
perspective of the researcher, the
adverse effects of CSF leakage, i.e. need for renewed surgical intervention,
wound infection, meningitis and
delayed wound healing.

The risks associated with participation are the same as those noted in section
E9, which are:

Possible risks and discomforts that may be expected include any of the standard
risks and discomforts associated with the elective surgical procedure each
subject is undergoing.

In addition the possibility of passing on infection by using the Fibrin Pad
cannot be totally excluded because this medicine is made from human blood.