A randomized prospective clinical trial comparing OsteoActivator-P coated membranes vs Collagen Membrane-P uncoated for accelerated localized alveolar ridge preservation.

Guided bone regeneration (GBR) is achieved by placing a collagen barrier
membrane (e.g. obtained from porcine pericardium) onto a bone defect. GBR is a
surgical procedure that uses barrier membranes with or without particulate bone
grafts and/or bone substitutes and is widely applied for dental implant
therapies. In general, osseous regeneration by GBR is performed using CE
certified collagen membranes and depends on the migration of pluripotent and
osteogenic cells (e.g. osteoblasts derived from the periosteum and/or adjacent
bone and/or bone marrow) to the bone defect site and exclusion of cells
impeding bone formation (e.g. epithelial cells and fibroblasts). To accomplish
the regeneration of a bone defect, the rate of osteogenesis extending inward
from the adjacent bony margins must exceed the rate of fibrogenesis growing in
from the surrounding soft tissue. After GBR procedures, bone regeneration
follows a specific sequence of events. Within the first 24 hours after a bone
graft, the graft material/barrier created space is filled with the blood clot
which releases growth factors (e.g., platelet derived growth factor) and
cytokines (e.g., IL-8) to attract neutrophils and macrophages. The clot is
absorbed and replaced with granulation tissue which is rich in newly formed
blood vessels. Through these blood vessels, nutrients and mesenchymal stem
cells capable of osteogenic differentiation can be transported and contribute
to osteoid formation. Mineralization of osteoid forms woven bone, which later
serves as a template for the apposition of lamellar bone. This transformation
of primary sponge work would eventually constitute both compact and reticular
bone with mature bone marrow. These events occur 3 to 4 months post-surgery.
A pericardial collagen membrane provides the optimal condition for GBR by
simultaneously limiting the ingrowth of epithelial cells and facilitating the
generation of a blood clot (due to bleeding at the site). This provides the
optimal conditions for mesenchymal cells to differentiate into active
osteoblast cells due to the barrier function of the membrane. The principal
mode of action of a collagen membrane is therefore a barrier membrane that
shields against epithelial cell ingrowth from the surroundings of the fracture
and that retains and guides, in a mechanical way, the new structures that will
differentiate into a new bone. Unlike so-called microfibrillar collagen, which
is a partially water-insoluble acid salt of purified porcine corium collagen
and capable to directly activate platelet aggregation (Sundaram & Keenan,
2010), no interaction between the (pericardial) collagen membrane and blood
platelets has been described in the literature. As such there is no indication
that there is a pharmacological process initiated by the membrane. Also, no
immunological or metabolic actions have been ascribed to a (pericardial)
collagen membrane in the literature (Elgali, et al., 2017) (Lee & Kim, 2014)
(Stoecklin-Wasmer, et al., 2013) (Dimitriou, et al., 2012) (Bunyaratavej &
Wang, 2001) (Schwartzmann, 2000) (Wang & Carroll, 2000).
The use membranes for GBR is widely used in the field of periodontal bone
regeneration, not only for reconstructive surgery but most importantly to
create a sufficient amount of bone to allow for osteointegration of dental
implants, often in combination with bone grafts or bone graft substitute.
Following teeth extraction, healing of extraction sockets is impaired due
increased resorption of bone in the socket, applying the principle of GBR in
alveolar extraction sockets resulted in significant less vertical and
horizontal bone loss compared to control sites of un-augmented extraction
sockets (Iasella et al., 2003; Lekovic et al., 1998). Collagen membranes are
also applied for augmentation of the alveolar ridge if the amount of bone is
insufficient for implant placement. Augmentation by GBR can either be applied
before implant placement, creating sufficient stable bone for the implant
integration or at the time of implant placement. Both approaches resulted in
successful augmentation and increased success rates of implant placement over
non-augmented sites (Parodi et al., 1998; Von Arx et al., 2006; Chiapasco and
Zaniboni, 2009). GBR is also used to treat other dental defects, as intrabony
defects, furcation defects or root coverage procedures. As a consequence,
collagen membranes have become the standard of care in reconstruction of dental
bone defects.
Attempts have been made to accelerate bone formation in the treatment of
periodontal bone by the application of growth factors, either directly applied
or loaded on membranes or bone graft substitute (Gothard et al., 2014; Carreira
et al., 2014). These growth factors include recombinant human bone
morphogenetic protein 2 (rhBMP-2), rhBMP-7, recombinant human growth
differentiation factor 5 (rhGDF-5) and recombinant human platelet-derived
growth factor-BB (rhPDGF-BB) and have been tested in a several dental
procedures, including alveolar reconstruction, sinus augmentation, tooth
extraction socket healing, implant guided bone regeneration, and periodontal
bone repair (Gothard et al., 2014; Carreira et al., 2014). Despite the large
number of studies conducted, no consensus has been reached on the clinical
efficacy of growth factors in orofacial bone regeneration. A systemic review by
Li et al. (2019) addressing this problem, indicate that all application of
rhBMP-2 are insufficient in promoting tooth extraction socket healing, sinus
augmentation or reconstruction of alveolar clefts as tested in randomized
clinical trials. Only a marginal effect of rhPDGF-BB was suggested for tooth
extraction socket healing (a non-significant 2.16% increase of new bone
formation) (Geurs et al., 2014, Ntounis et al., 2015).
In this context, Osteo-Pharma intends to clinically evaluate the application of
OsteoActivator coated pericardial membranes for periodontal bone regeneration.
OsteoActivator coating consists of ancillary amounts of testosterone and
alendronate encapsulated in PLGA. Both compounds have been extensively
clinically tested and have authorized by the EMA and FDA for various
applications. It should be mentioned though that the use of OsteoActivator-P
membranes will not result in any systemic exposure of either testosterone or
alendronate due to the use of ancillary amounts of these compounds.
Testosterone activates bone forming osteoblast cells whereas alendronate
inhibits bone resorbing osteoclast cells resulting in a net effect of bone
growth and thereby improving the process of GBR.
The nonclinical package for OsteoActivator - P comprises pharmacodynamic
studies to support proof-of-concept and local tolerance, and biocompatibility
studies with the porcine pericardial membrane. Information on pharmacokinetic
characteristics and the (systemic) safety profile of ancillary substances
testosterone and alendronate is based on published data and has been included
in the relevant sections of the Investigator Brochure (6). Information on the
safety of PLGA applied as the carrier for the ancillary substances is likewise
based on published data.

Collagen barrier membranes are widely used for ridge preservation applications.
Once an extraction socket is filled with a bone filler and covered by a
collagen membrane, guided bone regeneration (GBR) is observed due to the
barrier function of the membrane, allowing implant placement after a certain
time period. Due to the addition of a PLGA coating containing ancillary amounts
of alendronate and testosterone to a collagen membrane, bone formation is
stimulated, which is expected to further accelerate GBR allowing implants to be
placed at an earlier timepoint.

This is a prospective, randomized, standard of care controlled clinical trial.

In this study, surgery and placement of a collagen membrane are considered
standard of care. All subjects will receive standard of care. In the context of
this study, the application of a collagen membrane, whether coated
(experimental) or non-coated (control) is considered an intervention.

Currently, based on the data available and control measures defined, no risks
have been found to be unacceptable in the context of a first in human clinical
trial. Based on the data described in the IB it is concluded that (i) no
adverse effects were observed in the biocompatibility study, (ii) the risk of
clinically relevant pharmacokinetic drug interactions is estimated to be
negligible, (iii) preclinical studies revealed no adverse effects as determined
by detailed histology and (iv) the risk of adverse systemic effects related to
the ancillary substances is estimated to be minimal under the proposed
conditions of clinical use.
OsteoActivator-P is potentially beneficial to dental ridge preservation and is
not associated with any specific safety concern under the proposed conditions
of clinical use. As faster bone regeneration in a dental defect would ensure
that patients can receive an implant at an earlier stage, it has the added
benefit that accelerated healing will be accompanied by more rapid resumption
of other daily and leisure activities, with the obvious benefits for quality of
life.
It is important to note that all control measures for the clinical trial batch
have been validated. The tests are in place and have been verified and found to
be effective for product release.