Medtronic 7510800 Instructions for Use
Infuse™ Bone Graft
0381204E Rev. D
Important Medical Information
2019-11-04
ENGLISH
Caution: Federal (USA) law restricts this device to sale by or on the order of a physician with appropriate training.
DESCRIPTION
Infuse™ Bone Graft consists of two components – a recombinant human bone morphogenetic protein solution and a carrier/
scaffold for the bone morphogenetic protein solution and resulting bone. These components must be used as a system. The
bone morphogenetic protein solution component must not be used without the carrier/scaffold component or with a
carrier/scaffold component different from the one described in this document.
Infuse™ Bone Graft consists of recombinant human Bone Morphogenetic Protein-2 (rhBMP-2, known as dibotermin alfa) placed
on an absorbable collagen sponge (ACS). Infuse™ Bone Graft induces new bone tissue at the site of implantation. Based on
data from non-clinical studies, the bone formation process develops from the outside of the implant towards the center until the
entire device is replaced by trabecular bone.
rhBMP-2 is the active agent in Infuse™ Bone Graft. rhBMP-2 is a disulfide-linked dimeric protein molecule with two major
subunit species of 114 and 131 amino acids. Each subunit is glycosylated at one site with high-mannose-type glycans. rhBMP-2
is produced by a genetically engineered Chinese hamster ovary cell line.
rhBMP-2 and excipients are lyophilized. Upon reconstitution, each milliliter of rhBMP-2 solution contains: 1.5mg of rhBMP-2; 5.0
mg sucrose, NF; 25mg glycine, USP; 3.7mg L-glutamic acid, FCC; 0.1mg sodium chloride, USP; 0.1mg polysorbate 80, NF; and
1.0mL of sterile water. The reconstituted rhBMP-2 solution has a pH of 4.5, and is clear, colorless to slightly yellow and
essentially free from plainly visible particulate matter.
The ACS is a soft, white, pliable, absorbent implantable matrix for rhBMP-2. ACS is made from bovine Type I collagen obtained
from the deep flexor (Achilles) tendon. The ACS acts as a carrier for the rhBMP-2 and acts as a scaffold for new bone
formation.
Each kit contains all the components necessary to prepare Infuse™ Bone Graft: the rhBMP-2 which must be reconstituted,
sterile water, absorbable collagen sponges, syringes with needles, this package insert and instructions for preparation.
The rhBMP-2 is provided as a lyophilized powder in vials delivering 12mg of protein. After appropriate reconstitution, the
concentration of rhBMP-2 is 1.5mg/mL. The solution is then applied to the provided absorbable collagen sponge. Infuse™ Bone
Graft is prepared at the time of surgery and allowed a prescribed amount of time (no less than 15 minutes) before placement at
the fracture site. The Instructions for Preparation contain complete details on preparation of Infuse™ Bone Graft.
INDICATIONS
Infuse™ Bone Graft is indicated for treating acute, open tibial shaft fractures that have been stabilized with IM nail fixation after
appropriate wound management. Infuse™ Bone Graft must be applied within 14 days after the initial fracture. Prospective
patients should be skeletally mature.
CONTRAINDICATIONS
▪ Infuse™ Bone Graft is contraindicated for patients with a known hypersensitivity to recombinant human Bone
Morphogenetic Protein-2, bovine Type I collagen or to other components of the formulation.
▪ Infuse™ Bone Graft should not be used in the vicinity of a resected or extant tumor, in patients with any active malignancy
or patients undergoing treatment for a malignancy.
▪ Infuse™ Bone Graft should not be used in patients who are skeletally immature (<18 years of age or no radiographic
evidence of epiphyseal closure).
▪ Infuse™ Bone Graft should not be used in patients with an inadequate neurovascular status (e.g. high risk of amputation).
▪ Infuse™ Bone Graft should not be used in patients with compartment syndrome of the affected limb.
▪ Infuse™ Bone Graft should not be used in pregnant women. The potential effects of rhBMP-2 on the human fetus have not
been evaluated.
▪ Infuse™ Bone Graft should not be implanted in patients with an active infection at the operative site.
WARNINGS
▪ In an experimental rabbit study, rhBMP-2 has been shown to elicit antibodies that are capable of crossing the placenta. Re-
duced ossification of the frontal and parietal bones of the skull was noted infrequently (<3%) in fetuses of rabbit dams immunized to rhBMP-2; however, there was no effect noted in limb bud development. There are no adequate and wellcontrolled studies in human pregnant women. Women of child bearing potential should be warned by their surgeon of
potential risk to a fetus and informed of other possible orthopedic treatments.
▪ Women of childbearing potential should be advised that antibody formation to rhBMP-2 or its influence on human fetal de-
velopment has not been assessed. In the clinical trial supporting the safety and effectiveness of the Infuse™ Bone Graft in
tibia fractures, 9/149 (6.0%) patients treated with Infuse™ Bone Graft and 1/150 (0.7%) patients treated without exposure to
rhBMP-2 developed antibodies to rhBMP-2. The effect of maternal antibodies to rhBMP-2, as might be present for several
months following device implantation, on the unborn fetus is unknown. Additionally, it is unknown whether fetal expression
of BMP-2 could re-expose mothers who were previously antibody positive. Theoretically, re-exposure may elicit a more
powerful immune response to BMP-2 with possible adverse consequences for the fetus. However, pregnancy did not lead
to an increase in antibodies in the rabbit study. Studies in genetically altered mice indicate that BMP-2 is critical to fetal
development and that a lack of BMP-2 activity may cause neonatal death or birth defects. It is not known if anti-BMP-2 antibodies may affect fetal development or the extent to which these antibodies may reduce BMP-2 activity.
▪ Infuse™ Bone Graft should not be used immediately prior to or during pregnancy. Women of childbearing potential should
be advised not to become pregnant for one year following treatment with the Infuse™ Bone Graft.
▪ The safety and effectiveness of the Infuse™ Bone Graft in nursing mothers has not been established. It is not known if
BMP-2 is excreted in human milk.
▪ Infuse™ Bone Graft should not be used in patients suspected of having a malignancy at the site of application.
▪ The safety and effectiveness of Infuse™ Bone Graft for non-acute fractures, with forms of internal fracture fixation other
than IM nails, implanted at locations other than the tibial shaft, or used in surgical techniques other than open reduction and
internal fixation after appropriate wound management have not been established.
▪ Inappropriate use of the product, such as preparing it differently than prescribed, compressing the rhBMP-2/ACS implant
more than necessary, or overfilling the volume intended for new bone formation, may change the concentration of the
rhBMP-2, which may inhibit the ability of the rhBMP-2/ACS to convert to bone and/or cause complications. Such use of the
rhBMP-2/ACS implant may result in radiographic evidence of resorption, fluid formation, and/or edema. These findings may
be asymptomatic or symptomatic.
▪ The formation of fluid collections (sometimes encapsulated) in some cases resulted in pain, which may require clinical
intervention (aspiration and/or surgical removal) if symptoms persist. Many of these reports have occurred when
rhBMP-2/ACS was used in conjunction with unapproved approaches/devices or in a manner inconsistent with the
instructions for use.
▪ In a clinical study in which the intramedullary canal was reamed to cortical chatter, an increased rate of infection was
observed in those patients treated with rhBMP-2/ACS compared to a control group that did not receive rhBMP-2/ACS.
Because of this, the use of rhBMP-2/ACS with reamed IM nails is not recommended.
▪ While there are currently anecdotal and literature evidence to suggest that volume overfilling and/or hyperconcentration of
the rhBMP-2 solution may lead to fluid formation and/or edema, animal models for scientifically evaluating these events do
not presently exist. A sheep model developed to test the hypothesis that volume overfilling and/or hyperconcentration of the
rhBMP-2 solution results in radiographic evidence of bone resorption has preliminarily been evaluated and appears to be
supportive of the hypothesized mechanism.
▪ Placement of rhBMP-2/ACS can cause initial resorption of trabecular bone that may be transient.
PRECAUTIONS
General
▪ The safety and effectiveness of repeat applications of Infuse™ Bone Graft has not been established.
▪ Long-bone fracture and soft-tissue management procedures should be based on standard practice including control of
infection. Physicians should achieve mechanical stability before implanting Infuse™ Bone Graft. Infuse™ Bone Graft should
not be used to fill space in the presence of compressive forces.
▪ Infuse™ Bone Graft should only be used by surgeons who are experienced in treating acute open tibial shaft fractures
involving IM nail stabilization and have undergone adequate training with this device.
▪ A single package of Infuse™ Bone Graft should be used at the fracture site.
▪ Infuse™ Bone Graft is intended for single use only. Discard unused product and use a new device for subsequent
applications. Infuse™ Bone Graft
must not be sterilized by the hospital.
▪ Prior to use, inspect the packaging, vials and stoppers for visible damage. If damage is visible, do not use the product.
Retain the packaging and vials and contact a Medtronic representative.
▪ Do not use after the printed expiration date on the label.
Hepatic and Renal Impairment
The safety and effectiveness of Infuse™ Bone Graft in patients with hepatic or renal impairment has not been established.
Pharmacokinetic studies of rhBMP-2 indicate that the renal and hepatic systems are involved with its clearance.
Geriatrics
Clinical studies of Infuse™ Bone Graft did not include sufficient numbers of patients 65 years and older to determine whether
they respond differently from younger subjects.
Bone Formation
▪ The safety and effectiveness of Infuse™ Bone Graft has not been demonstrated in patients with metabolic bone diseases,
or in pathological fractures such as those observed in Paget’s disease or in metastatic bone disease.
▪ The potential for ectopic, heterotopic or undesirable exuberant bone formation exists.
Antibody Formation/Allergic Reactions
▪ The safety and effectiveness of Infuse™ Bone Graft has not been demonstrated in patients with autoimmune disease.
▪ The safety and effectiveness of Infuse™ Bone Graft has not been demonstrated in patients with immunosuppressive
disease or suppressed immune systems resulting from radiation therapy, chemotherapy, steroid therapy or other
treatments.
Immunogenicity
▪ As with all therapeutic proteins, there is a potential for immune responses to be generated to Infuse™ Bone Graft. The
immune response to Infuse™ Bone Graft was evaluated in 149 investigational patients and 150 control patients receiving
treatment for acute open tibial shaft fractures stabilized with IM nails.
▪ Anti-rhBMP-2 antibodies: 9/149 (6%) patients receiving the Infuse™ Bone Graft component developed antibodies vs.
1/150 (0.7%) in the control group.
▪ Anti-bovine Type I collagen antibodies: 29/149 (20%) of patients receiving the Infuse™ Bone Graft component
developed antibodies to bovine Type I collagen vs. 9/150 (6%) of control patients. No patients in either group developed
anti-human Type I collagen antibodies.
▪ The presence of antibodies to rhBMP-2 was not associated with immune mediated adverse events such as allergic
reactions. The neutralizing capacity of antibodies to rhBMP-2 is not known.
▪ The incidence of antibody detection is highly dependent on the sensitivity and specificity of the assay. Additionally, the
incidence of antibody detection may be influenced by several factors including sample handling, concomitant medications
and underlying disease. For these reasons, comparison of the incidence of antibodies to Infuse™ Bone Graft with the
incidence of antibodies to other products may be misleading.
ADVERSE EVENTS
Table 1 describes the adverse events observed in the clinical trial used to support approval of the product. Two Infuse™ Bone
Graft doses, 0.75mg/ml and 1.5mg/ml, were evaluated. Infuse™ Bone Graft with IM nail stabilization was implanted in 300
investigational patients (149 in the 1.50mg/ml and 151 in the 0.75mg/ml groups) compared to IM stabilization alone in 150
control patients. Adverse event rates presented are based on the number of patients having at least one occurrence for a
particular adverse event divided by the total number of patients in that treatment group.
Table 1: Adverse events reported for patients enrolled in clinical trial supporting approval
# (%) of Patients
1st quarter postop 2nd quarter postop 3rd quarter postop 4th quarter postop
Ctrl
Number of patients 150 150 149 147 144 146 144 144 144 138 142 141 150 (100) 150 (99) 149 (100)
Abnormal healing
Surgical Site 64 60 53 19 19 13 7 4 7 4 2 3
Other locations 9 13 23 0 1 0 1 0 1 0 0 2 10 (7) 10 (7) 13 (9)
Abnormal lab tests
Alkaline phosphatase
Gamma glutamyl trans-
increased
Amylase increased 5 23 11 0 0 0 0 0 0 0 0 0 5 (3) 20 (13) 10 (7)
Bilirubinemia 8 9 11 0 0 0 0 0 0 0 0 0 7 (5) 9 (6) 11 (7)
BUN increased 0 3 1 0 0 0 0 0 0 0 0 0 0 (0) 3 (2) 1 (1)
Creatinine clearance
decreased
peptidase increased
Hypercalcemia 2 1 0 0 0 0 0 0 0 0 0 0 2 (1) 1 (1) 0 (1)
Hyperkalemia 2 3 3 0 0 0 0 0 0 0 0 0 2 (1) 3 (2) 3 (2)
8 8 3 0 0 0 0 0 0 0 0 0 8 (5) 8 (5) 3 (2)
2 1 2 0 0 0 0 0 0 0 0 0 2 (1) 1 (1) 2 (1)
0 1 2 0 0 0 0 0 0 0 0 0 0 (0) 1 (1) 2 (1)
Low dose
Inv
Ctrl
Low dose
Inv
Ctrl
Low dose
Inv
Ctrl
Low dose
Inv
Total Adverse Events
Ctrl
(n=150) (%)
651(43)
Low dose
(n=151) (%)
2
62 (41) 57 (38)
3
94
10 14 26
8 8 3
5 23 11
8 9 11
0 3 1
2 1 2
0 1 2
2 1 0
2 3 3
85 76
Inv
(n=149) (%)
Table 1: Adverse events reported for patients enrolled in clinical trial supporting approval (continued)
# (%) of Patients
1st quarter postop 2nd quarter postop 3rd quarter postop 4th quarter postop
Ctrl
Number of patients 150 150 149 147 144 146 144 144 144 138 142 141 150 (100) 150 (99) 149 (100)
Hypokalemia 7 9 17 1 0 0 0 0 0 1 0 0 9 (6) 9 (6) 17 (11)
Hypomagnesemia 3 11 3 0 0 0 0 0 0 1 0 0 2 (1) 11 (7) 3 (2)
Hypocalcemia 54 63 55 0 0 0 0 0 0 1 0 0 50 (33) 60 (40) 53 (36)
Lactic dehydrogenase
Accidental injuries 1 2 4 1 0 2 0 0 1 0 0 2 2 (1) 2 (1) 6 (4)
Cardiovascular
Hypercoagulability, sur-
Hypertension/hypoten-
Digestive system
Irritation and Infamma-
Nausea and vomiting 34 30 30 5 11 4 1 2 3 2 3 4 26 (17) 30 (20) 24 (16)
Hematic/lymphatic system
Immune response
Allergic reactions, sur-
Allergic reactions, sys-
Autoimmune disorders 1 0 0 0 0 0 0 1 0 0 0 0 1 (1) 1 (1) 0 (0)
Infection
Surgical site, superficial 24 20 17 4 3 3 1 5 1 2 2 1 25 (17) 22 (15) 20 (13)
increased
SGOT increased 43 47 42 0 1 0 0 0 0 0 0 0 39 (26) 46 (30) 40 (27)
SGPT increased 26 28 23 0 0 0 0 0 0 0 0 0 24 (16) 26 (17) 21 (14)
Other 134 119 117 0 0 0 0 1 0 0 0 0 80 (53) 82 (54) 77 (52)
Altered function 3 0 2 0 0 0 0 0 0 0 0 2 3 (2) 0 (0) 4 (3)
Altered rhythm 3 10 19 2 1 1 0 0 1 2 0 0 6 (4) 11 (7) 10 (7)
gical site
Hypercoagulability,
general
Other, surgical site 1 3 2 0 0 0 0 0 1 0 0 0 1 (1) 3 (2) 3 (2)
Other, general 1 1 8 0 1 1 0 0 0 0 0 0 1 (1) 2 (1) 5 (3)
Altered function 11 5 9 1 1 2 0 1 0 0 0 0 10 (7) 6 (4) 8 (5)
Bleeding episodes 0 1 0 0 0 0 0 1 0 0 0 0 0 (0) 2 (1) 0 (0)
Constipation 20 31 30 0 1 0 0 0 0 0 0 1 20 (13) 29 (19) 27 (18)
Dyspepsia 2 2 3 0 0 0 0 0 1 0 0 0 2 (1) 2 (1) 4 (3)
Other 9 6 14 1 1 3 0 0 0 1 0 0 10 (7) 7 (5) 14 (9)
Anemia 85 85 86 2 1 0 0 1 1 1 0 1 79 (53) 75 (50) 74 (50)
Other 14 20 14 1 0 0 0 0 0 0 0 0 12 (8) 17 (11) 12 (8)
gical site
Surgical site, deep 15 10 14 2 3 0 1 2 1 0 1 1 16 (11) 13 (9) 14 (9)
30 34 32 0 1 0 0 0 0 0 0 0 29 (19) 33 (22) 26 (17)
2 2 1 0 0 0 0 0 0 0 0 0 2 (1) 2 (1) 1 (1)
3 5 2 0 0 1 0 0 0 0 0 0 3 (2) 4 (3) 3 (2)
7 10 6 2 2 0 0 1 0 2 0 0 8 (5) 12 (8) 6 (4)
sion
5 4 2 2 2 3 2 0 1 0 1 0 5 (5) 7 (5) 5 (3)
tion
12 11 7 0 4 5 1 4 2 1 1 2 12 (8) 16 (11) 11 (7)
13 13 24 3 2 1 0 0 0 0 1 0 14 (9) 12 (8) 16 (11)
temic
Low dose
Inv
Ctrl
Low dose
Inv
Ctrl
Low dose
Inv
Ctrl
Low dose
Inv
Total Adverse Events
Ctrl
(n=150) (%)
Low dose
(n=151) (%)
9 9 17
3 11 3
54 63 55
30 35 32
43 48 42
26 28 23
134 120 117
2 2 9
3 0 4
7 11 21
2 2 1
3 5 3
11 13 6
1 3 3
1 2 9
12 7 11
0 2 0
20 32 31
2 2 4
9 7 6
42 46 41
11 7 17
88 87 88
15 20 14
14 20 16
16 16 25
1 1 0
31 30 22
18 16 16
Inv
(n=149) (%)
Table 1: Adverse events reported for patients enrolled in clinical trial supporting approval (continued)
# (%) of Patients
1st quarter postop 2nd quarter postop 3rd quarter postop 4th quarter postop
Ctrl
Number of patients 150 150 149 147 144 146 144 144 144 138 142 141 150 (100) 150 (99) 149 (100)
Inflammation
Kidney 0 1 4 0 0 0 0 0 0 0 0 0 0 (0) 1 (1) 2 (1)
Liver, other 0 0 3 0 0 0 0 0 0 0 0 0 0 (0) 0 (0) 1 (1)
Metabolic & nutritional
Neuromuscularskeletal
Altered mental status 63 56 70 1 1 4 1 0 1 1 1 3 47 (31) 40 (26) 41 (28)
Altered sensory status,
Altered sensory status,
Altered motor status,
Altered motor status,
Respiratory system 31 45 39 0 2 1 0 1 0 0 1 0 30 (20) 38 (25) 32 (21)
Skin and appendages
Urogenital
General 8 9 18 4 0 1 2 0 1 3 1 1 13 (9) 8 (5) 15 (10)
Systemic 64 74 78 6 5 5 2 0 4 0 0 0 47 (31) 53 (35) 56 (38)
Surgical site 72 79 67 30 24 16 6 8 10 8 3 5 78 (52) 78 (52) 71 (48)
12 13 10 1 2 0 0 1 0 1 0 0 11 (7) 14 (9) 7 (5)
general
surgical site
general
surgical site
Other, surgical site 160 157 158 127 92 86 33 51 37 41 33 33 121 (81) 111 (74) 109 (73)
Other, general 68 59 71 9 7 19 14 5 8 11 4 7 54 (36) 43 (28) 44 (30)
Surgical area 2 1 3 1 1 1 0 0 0 0 0 0 3 (2) 2 (1) 4 (3)
General 3 0 1 0 0 1 1 0 0 0 0 1 4 (3) 0 (0) 3 (2)
Dysfunction 6 8 10 1 0 2 1 0 1 0 1 0 7 (5) 7 (5) 8 (5)
Hematuria 0 2 3 0 0 1 0 0 0 0 0 0 0 (0) 2 (1) 4 (3)
Infection 1 4 4 0 0 2 0 0 1 0 0 0 1 (1) 4 (3) 6 (4)
10 8 11 0 1 3 1 0 1 0 1 0 10 (7) 5 (3) 10 (7)
16 22 27 2 4 6 2 1 0 3 1 1 18 (12) 21 (14) 28 (19)
4 7 4 1 1 0 0 0 0 0 0 0 5 (3) 8 (5) 4 (3)
13 11 11 2 1 1 0 0 0 1 0 0 10 (7) 10 (7) 11 (7)
Low dose
Inv
Ctrl
Low dose
Inv
Ctrl
Low dose
Inv
Ctrl
Low dose
Inv
Total Adverse Events
Ctrl
(n=150) (%)
Low dose
(n=151) (%)
17 10 21
72 79 87
116 114 98
0 1 4
0 0 3
14 16 10
66 58 78
11 10 15
23 28 34
5 8 4
16 12 12
361 333 314
102 75 105
31 49 40
3 2 4
4 0 3
8 9 13
0 2 4
1 4 7
Inv
(n=149) (%)
1
No. of patients with event
2
Percent of patients with event
3
Total number of events
A post-approval clinical study was designed to evaluate the performance of reamed IM nails in treating open tibia fractures in
which the intramedullary canal was reamed to cortical chatter compared to the standard of care. This study was terminated prior
to completion of enrollment due to safety concerns. Specifically, an increased rate of infection was observed in the rhBMP-2/
ACS-treated group versus the standard of care control group (19% versus 9%, respectively). In pre-approval studies evaluating
the use of rhBMP-2/ACS in combination with reamed or unreamed IM nails to treat open tibia fractures, this difference in
infection rates was not observed.
Potential Adverse Events
The following is a list of potential adverse events which may occur with treatment of open tibial fractures requiring stabilization
with an IM nail. Some of these adverse events may have been previously reported in the adverse events table. As with any
surgery, surgical treatment of a fracture is not without risk. A variety of complications related to surgery or the use of Infuse™
Bone Graft can occur. These may occur singly or in combination. Some of these may be severe, affecting patient outcome.
▪ Bone fracture.
▪ Bowel, bladder, or gastrointestinal problems.
▪ Change in mental status.
▪ Damage to blood vessels, bleeding (which may require a blood transfusion) or cardiovascular system compromise.
▪ Damage to nearby tissues.
▪ Death.
▪ Development of respiratory problems.
▪ Disassembly, bending, breakage, loosening, and/or migration of IM nail components.
▪ Ectopic and/or exuberant bone formation.
▪ Fetal development complications.
▪ Foreign body (allergic) reaction.
▪ Incisional complications.
▪ Infection.
▪ Neurological system compromise.
▪ Non-union (or pseudarthrosis), delayed union, mal-union.
▪ Pain or discomfort.
▪ Rash or allergic reaction.
▪ Scar formation.
▪ Side effects from anesthesia or the surgical approach.
▪ Swelling.
▪ Tissue or nerve damage.
Note: additional surgery may be necessary to correct some of these potential adverse events.
CLINICAL RESULTS
Premarket Study Results
Safety and effectiveness of Infuse™ Bone Graft were evaluated as part of a prospective, randomized, controlled, multinational
(11 countries), multi-center (49 sites) study. Subjects were randomized into one of three groups – control or one of two
investigational groups (0.75 or 1.50mg/ml rhBMP-2). All subjects received wound management and fracture stabilization with an
IM nail, while the investigational subjects also received Infuse™ Bone Graft at the fracture site. No restrictions were placed on
the type of IM nail used or whether it was reamed or non-reamed. The use of bone wax, Gelfoam, or other collagen hemostatic
agents, corticosteroids, bone growth stimulators (electrical, ultrasound, or magnetic) was specifically prohibited.
Only the subjects and an independent radiology panel were blinded with respect to treatment. The investigators were aware of
the treatment assignment.
The enrolled patients had been diagnosed with an acute, open tibia fracture of Gustilo Grade I, II, IIIA or IIIB with the major
component of the fracture being diaphyseal. Patients with isolated tibia fractures and those with multiple injuries were included.
Clinical and radiographic effectiveness parameters
Subjects were followed for 12 months after definitive wound closure (DWC). Evaluations were performed postoperatively at 6,
10, 14, 20, 26, 39, and 50 weeks. Adverse events, device-related or not, were evaluated over the course of the clinical trial. At
each evaluation timepoint, the primary and secondary clinical and radiographic outcome parameters were evaluated. Success
was determined from data collected during the initial 12 months of follow-up. Antibodies to rhBMP-2 and bovine Type I collagen
were assessed preoperatively and at timepoints post-operatively. Antibodies to human Type I collagen were assessed if the
antibody response to bovine Type I collagen was positive.
Clinical and radiographic fracture assessments were performed at each postoperative visit. However, the protocol did not
provide the specific objective criteria that were used to determine fracture healing. The “Assessment of Fractured Limb” case
report form provided for the documentation of the following parameters, but did not indicate how these were to be used to
determine fracture status or how many needed to be present in order for a complete evaluation to have occurred:
▪ Wound (healed, not healed, not evaluated).
▪ Pain (absent, present, not evaluated).
▪ Swelling (absent, present, not evaluated).
▪ Tenderness (absent, present, not evaluated).
▪ Neurovascular status (intact, impaired, not evaluated).
▪ Infection (absent, present, not evaluated).
▪ Weight-bearing status (non-, touch down, partial, full, not evaluated).
Radiographic assessments (AP and lateral radiographs) were performed at each post-op visit. Oblique radiographs were to be
used if the standard views did not adequately visualize the fracture. The radiographs were evaluated by the investigator and the
radiology panel.
Investigators were to evaluate radiographic healing by assigning a score of “united”, “not united”, “uncertain union” or
“uninterpretable”. No definitions for these terms were provided in the protocol.
The protocol for the independent radiology panel stated that "…fracture union was determined if there was cortical bridging
and/or disappearance of the fracture lines were visible on 3 of the 4 bone aspects (anterior, posterior, medial, and lateral)…."
These definitions were not available to the investigators. The first visit at which these criteria were met was considered the time
of union radiographically. The independent radiographic evaluation protocol called for the review of each radiograph by all three
members of the panel. An agreement of 2 of the 3 reviewers was necessary for a determination of fracture union. The
independent radiographic evaluation was performed on all available radiographs.
Adverse events were assessed for relatedness to the device and severity was based on the WHO recommendations.
Investigators were provided with the following definitions:
▪ "…Nonunion – considered to be established when a minimum of 9 months has elapsed since injury and the fracture site
showed no visibly progressive signs of healing for a minimum of 3 months (no change of fracture callus)."
▪ Delayed union – insufficient fracture healing determined by radiographic and clinical assessment. A specific time point at
which delayed union was defined was not provided.
▪ Secondary intervention for delayed union – any intervention, surgical or non-surgical, that was performed to induce or
accelerate fracture union after DWC. Examples included use of autograft, allograft or bone graft substitutes; IM nail
dynamization; exchange nailing; or noninvasive modalities, e.g., ultrasound, magnetic field, or electrical stimulation.…" The
decision to perform a secondary intervention for delayed union was dependent on the definition of delayed union above.
Investigators determined fracture union based on clinical judgement. The protocol did not provide the specific objective criteria
that were used to determine fracture healing or deciding whether to recommend secondary interventions to promote fracture
healing.
Patient demographics and accountability
The sample size estimation called for 150 subjects per treatment group. A total of 149 investigational and 150 control patients
were enrolled in the study and received treatment. Only the results from the control patients and investigational patients
receiving the 1.5mg/ml dose device are described below.
The demographics of the patient population were similar across all study groups except for the parameter of age, specifically the
mean and range. The subjects in the investigational group were younger (mean = 33.4 years, range 18-77 years) compared to
the control group (mean = 36.8 years, range = 17-87 years). Patients in the control group had a slightly larger percentage of
nails that were unreamed and/or less than 9mm, while the investigational group had a higher percentage of reamed nails
and /or nails that were greater than 11mm. Nail type did affect the number of secondary interventions (i.e. patients with
unreamed nails had a higher incidence of secondary interventions compared to patients receiving reamed nails).
Clinical and radiographic effectiveness evaluation
The primary efficacy endpoint was defined as the proportion of subjects who required a secondary surgical intervention to
promote fracture healing within 12 months of DWC. The secondary efficacy endpoints included the following:
▪ The proportion of subjects healed at 6 months without a secondary intervention as determined by the investigator’s clinical
and radiographic assessment.
▪ The independent radiology panel’s assessment of time to fracture union.
▪ The pharmacoeconomic impact of the treatment.
Primary effectiveness endpoint
The rate of secondary interventions was significantly lower in the Infuse™ Bone Graft group (p=0.001) as described in the table
below. Interventions were categorized in one of three ways – recommended by the investigator and performed, recommended
by the investigator and not performed, or not recommended by the investigator but performed anyway. If any of these occurred,
the patient was considered to have failed the primary endpoint and, therefore, was considered a study failure. In addition,
patients who experienced screw breakage resulting in self-dynamization were also considered treatment failures.
α
Table 2: Number of patients with secondary interventions
Recommended/performed 38 19
Recommended/not performed 3 5
Not recommended/performed 6 7
Self-dynamizations 19 7
Total failures/patients (%) 66/150 (44) 38/149 (26)
α
Includes bone grafting, fibula osteotomies, exchange nailing, plate fixation, Ilizarov frame removal, external fixation placement,
bone transport, IM nail dynamizations, exchange to a functional brace and electrical stimulation.
Control
(n=150)
Investigational
(n=149)
Safety and immune response evaluation
The assessment of safety consisted of an evaluation of the reported adverse events, as well as an evaluation of antibodies to
rhBMP-2, bovine Type I collagen and human Type I collagen. The complete list of adverse events is described in the Adverse
Events section above. Refer to this section for a description of the rates associated with infection and abnormal clinical lab
values. Adverse events of special interest are discussed below.
fracture healing
The rates of hardware failure in the investigational and control groups were 18/149 (14%) and 32/150 (24%), respectively.
Delayed union was the most frequent serious adverse event reported at one year; occurring in 39 (26%) control and 26 (17%)
investigational patients.
The rate of nonunion was lower in the investigational group as compared to control. A total of 80/150 (53.3%) control and
56/149 (37.6%) investigational patients did not require a secondary intervention and were not radiographically healed at 12
months as determined by the independent radiology panel. For the control patients who required a secondary intervention,
18/66 (27%) reported nonunions at 12 months compared to 19/38 (50%) investigational patients. Investigational patients who
required a secondary intervention were considered healed later than control patients.
abnormal bone formation
Heterotopic ossification (HO) was not a significant concern and no ectopic ossification was reported. Because only the involved
tibia was evaluated radiographically, it is not clear if abnormal bone formation occurred in other anatomical locations. Although
twice as many investigational patients reported hypertrophic callus formation compared to controls (8 vs. 4), no action was
required to treat any of these events. A total of 12 patients experienced at least one event classified as hypertrophic callus, with
the investigational group having the highest number (8) and percentage (6%) of patients with HO. No interventions were
required to treat any of the HO-related events.
infections
The combined rate of deep and superficial infections of the injured limb was lower in patients with Gustilo IIIA and B fractures of
the investigational group as compared to the control group [16/66 (24%) and 26/61 (43%), respectively].
immune response
The presence of antibodies was assessed using ELISA. If there was a positive response to bovine Type I collagen, the serum
was also tested for antibodies to human Type I collagen. The screening ELISA cutpoint for positive antibody responses was set
to 2 times the signal generated by pooled normal human sera in each ELISA. Subjects were considered to have an elevated
immune response if the preoperative test was negative (titer<50) and postoperative test was positive (titer≥50) or if the
preoperative test was positive and the postoperative test was positive with a three-fold higher titer than the preoperative test.
There were detectable rhBMP-2 antibodies in 1 control patient and 9 investigational patients after treatment. Of the 9
investigational patients with elevated post-treatment antibody titers, 2 were elevated at visit 6 (20 weeks), the last planned
assessment and data from 1 patient were unavailable for visit 6. An additional sample from 1 of these patients was collected
and tested following the positive test at visit 6, and the titers decreased to <50. (No follow-up data were available for the other
patient.) Anti-rhBMP-2 antibody responses were determined to be transient in 6/9 patients by 20 weeks, and in 7/9 patients after
follow-up testing (samples from 2 patients were unavailable to confirm transience of the antibody response). Because of the
small numbers involved, it was not possible to determine if a correlation existed between the immune response and clinical
outcome.
There were 38 patients who developed antibodies to bovine Type I collagen - 9 (6%) control and 29 (20%) investigational
patients. Approximately half of the patients had persistently elevated antibody titers at evaluations 20 weeks and more after
DWC. Thirty categories of adverse events that may have been manifestations of an immune response were identified and all
were observed to have a comparable incidence across all groups. Although there were 4 patients with an adverse event termed
“allergic event”, the investigators believed that there was no evidence of allergic response to the investigational treatment.
Table 3: Immune response
Control
[n (%)]
Anti-rhBMP-2 antibodies 1 (1) 9 (6)
Anti-bovine Type I collagen antibodies 9 (6) 29 (20)
Anti-human Type I collagen antibodies 0 (0) 0 (0)
# healed patients with antiBMP-2 antibody response (successes) 1 6
# secondary intervention patients with antiBMP-2 antibody response (failures) 0 3
The rates of authentic antibody response to rhBMP-2 were higher than that observed for another application of rhBMP-2/ACS.
When rhBMP-2/ACs was placed inside of a metallic spinal fusion cage for anterior interbody fusion treatment of degenerative
disc disease, the antiBMP-2 antibody response in the investigational group was 0.7%. This compares to a 6% rate in the
investigational group in the trauma study. The contribution of the trauma setting to this outcome is unknown, as is the clinical
significance of the antibody response.
Investigational
[n (%)]
Post-market study results (Study 400)
As a condition of its Marketing Authorization in Europe, Wyeth Research conducted a post-market study to evaluate the safety
and effectiveness of rhBMP-2/ACS (Infuse™ Bone Graft) when used specifically with reamed intramedullary (IM) nails in the
treatment of open tibial shaft fractures. This study, which had a prospective, randomized, single-blind design, was conducted at
28 sites throughout Europe and South Africa. Within 14 days after the initial injury, subjects were randomized (1:1) into one of
two treatment groups, which were stratified according to the Gustilo-Anderson classification of the wound at the time of the
injury. All subjects received standard of care wound management and fracture stabilization with a statically-locked reamed IM
nail, while the investigational subjects also received rhBMP-2/ACS (1.5 mg/ml) at the fracture site.
The study was originally designed for 300 subjects to receive one of the study treatments. A total of 277 subjects (224 men and
53 women) were randomized into one of the two treatment groups, and of these, 271 received treatment prior to the study being
stopped due to an observed increase in the rate of infection in the investigational group. Study subjects ranged in age from 18
to 85 years, with an average age of 39 years. The study population was found to be comparable between treatment groups with
respect to baseline demographics, morbidity, and fracture and treatment characteristics.
After receiving the assigned study treatment and being discharged from acute-care hospitalization, subjects were followed on an
outpatient basis for a total of nine visits over a 52-week time period (at 6, 10, 13, 16, 20, 24, 32, 41, and 52 weeks after the
baseline visit). At these protocol-specified time points, the condition of the fractured tibia and the surrounding tissues were
assessed, radiographs of the fracture were evaluated, the healing status of the fracture was determined, and treatment
recommendations were made. Safety evaluations were also conducted at these time points (or as reported) and included
recording of adverse events (AEs) and concomitant treatments, as well as laboratory evaluations. In addition, antibody
formation to BMP-2 and Type I collagen were evaluated at certain time points during the study (6, 20, and 52 weeks).
The study’s primary efficacy endpoint was the proportion of subjects having a healed fracture, as demonstrated by radiographic
and clinical assessment, at 13 and 20 weeks after treatment. At week 13, the rate of fracture healing was higher in the
rhBMP-2/ACS group (60%) than in the SOC group (48%), but this difference failed to reach the threshold for statistical
significance (p=0.0541). At week 20, there was no discernible difference in the proportion of subjects with healed fractures (68%
in the rhBMP-2/ACS group and 67% in the SOC group).
With respect to safety, most study subjects (90%) had at least one treatment-emergent adverse event (TEAE), which is
consistent with the morbidity associated with an open tibia fracture and the surgical treatment required. The most frequent
TEAEs reported in the region under study were pain, peripheral edema, hardware failure, and infections. With the exception of
infection, these events occurred with similar frequency in both treatment groups. Twenty-seven (27) subjects (19.4%) in the
rhBMP-2 group and 15 subjects (10.9%) in the SOC group reported infections. While this difference was not statistically
significant (p=0.0645; difference in infection risk = 0.09 [95% confidence interval, 0.0 to 0.17]), it was determined to be clinically
significant by the Sponsor and was the basis for early termination of the study.
Thirty-one (22%) subjects in the rhBMP-2 group and 25 (18%) in the SOC group reported serious adverse events, four of which
were deemed related to rhBMP-2. One death was reported in each treatment group during the study, but neither was thought to
be related to treatment. No difference in laboratory measurements between the two groups were observed, and the rate of antiBMP-2 and anti-bovine Type I collagen antibody formation was low and not clinically significant. No neutralizing BMP-2
antibodies and no anti-human type I collagen antibodies were found in the subjects presenting with elevated anti-BMP-2 titers
and anti-bovine type I collagen antibodies, respectively.
HOW SUPPLIED
Infuse™ Bone Graft is supplied in a kit containing all the components necessary to prepare the device (i.e. the collagen sponge,
a vial with the lyophilized rhBMP-2, a vial with the sterile water for reconstituting the rhBMP-2, syringes and needles).
STORAGE CONDITIONS
Store Infuse™ Bone Graft at room temperature [15–30°C (59 to 86°F)].
DOSAGE AND ADMINISTRATION
Infuse™ Bone Graft is prepared immediately prior to use from a kit containing all necessary components. Once prepared,
Infuse™ Bone Graft contains rhBMP-2 at a concentration of 1.5mg/mL. The instructions for preparation must be followed and
the rhBMP-2 must be reconstituted to this solution concentration of 1.5mg/ml and then distributed uniformly across the entire
ACS.
Only a single Infuse™ Bone Graft kit should be used for each patient.
Infuse™ Bone Graft is implanted after the completion of IM nail fracture stabilization and wound management (i.e. at the time of
soft tissue coverage). The number of Infuse™ Bone Graft kits and the volume of Infuse™ Bone Graft to be implanted is
determined by the fracture anatomy. Generally, the fracture is treated with one kit. The accessible surface area of the fracture
(fracture lines and defects) should be covered with Infuse™ Bone Graft. Because very few patients in the clinical trial received
more than one Infuse™ Bone Graft kit (specifically, 2 kits) the response to the use of more than one kit is unknown. When
determining the specific volume and placement for Infuse™ Bone Graft, the potential to induce compartment syndrome should
be considered.
DIRECTIONS FOR USE
For directions for using the Infuse™ Bone Graft for tibia fractures, see the brochure entitled “Instructions for Preparation and
Surgical Application.”
PRODUCT COMPLAINTS
Any health care professional (e.g. customer or user of this system of products), who has any complaints or who has
experienced any dissatisfaction in the product quality, identity, durability, reliability, safety, effectiveness and/or performance of
this product, should notify the distributor or Medtronic. Further, if any of the implanted INFUSE® Bone Graft ever “malfunctions,”
(i.e. does not meet any of its performance specifications or otherwise does not perform as intended), or is suspected of doing
so, the distributor should be notified immediately. If any Medtronic product ever “malfunctions” and may have caused or
contributed to the death or serious injury of a patient, the distributor should be notified immediately by telephone, fax or written
correspondence. When filing a complaint, please provide the component(s) name and number, lot number(s), your name and
address, the nature of the complaint and notification of whether a written report from the distributor is requested.
©2019 Medtronic Sofamor Danek USA, Inc. All rights reserved.
Covered by patents U.S. 5,013,649, U.S.5,618,924, U.S.5,166,058 and U.S.5,631,142
Loading...