Medtronic 7510800 Instructions for Use
Infuse™ Bone Graft for Certain Oral
M704819B001E Rev. C
Maxillofacial and Dental Regenerative
Uses Important Medical Information Rx Only
2019-11-04
ENGLISH
DESCRIPTION
The Infuse™ Bone Graft consists of two components – recombinant human Bone Morphogenetic Protein-2 (rhBMP-2, known as
dibotermin alfa) placed on an absorbable collagen sponge (ACS). These components must be used as a system for the
prescribed indication described below. 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 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.
The 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.
The rhBMP-2 is provided as a lyophilized powder in vials delivering 1mg, 4.2mg or 12mg of protein. Upon reconstitution, each
milliliter of rhBMP-2 solution contains: 1.5mg of rhBMP-2; 5.0mg 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.
All the components necessary to prepare Infuse™ Bone Graft are contained in the kit: the rhBMP-2 powder; sterile water; ACS;
syringes with needles; this package insert; and instructions for preparation. The number of each item may vary depending on
the size of the kit.
After reconstitution, the solution is then applied to the provided ACS. 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 surgical site. The Infuse™ Bone Graft
Instructions for Preparation and Surgical Application contains complete details on preparation of Infuse™ Bone Graft.
Implied warranties of merchantability and fitness for a particular purpose or use are specifically excluded.
INDICATIONS
Infuse™ Bone Graft is indicated as an alternative to autogenous bone graft for sinus augmentations, and for localized alveolar
ridge augmentations for defects associated with extraction sockets.
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 pregnant women.
▪ 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 doctor of
potential risk to a fetus and informed of other possible dental treatments.
▪ Women of childbearing potential should be advised that antibody formation to rhBMP-2 or its influence on fetal development
has not been completely assessed. In the clinical trials supporting the safety and effectiveness of the Infuse™ Bone Graft
for this indication, 4/184 (2.2%) patients treated with rhBMP-2/ACS and 0/91 (0.0%) patients treated with autograft bone
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 Infuse™ Bone Graft.
▪ The safety and effectiveness of 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.
▪ 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.
▪ 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.
PRECAUTIONS
General
▪ Infuse™ Bone Graft has not been studied in extraction site(s) associated with molars or in the mandible.
▪ Infuse™ Bone Graft has not been studied in patients who are skeletally immature (<18 years of age or no radiographic
evidence of epiphyseal closure).
▪ The safety and effectiveness of repeat applications of Infuse™ Bone Graft has not been established.
▪ Infuse™ Bone Graft should only be used by surgeons or dentists who are experienced in performing dental regenerative
surgery.
▪ 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 device 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.
Bone Formation
▪ The safety and effectiveness of the Infuse™ Bone Graft device has not been demonstrated in patients with metabolic bone
diseases.
▪ While not specifically observed in the clinical studies, the potential for ectopic, heterotopic or undesirable exuberant bone
formation exists.
Antibody Formation/Allergic Reactions
▪ The safety and effectiveness of the Infuse™ Bone Graft device has not been demonstrated in patients with autoimmune
disease.
▪ The safety and effectiveness of the Infuse™ Bone Graft device 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 a component of Infuse™ Bone
Graft. The immune response to rhBMP-2/ACS components was evaluated in 184 investigational patients and 91
autogenous bone graft patients during human clinical trials of Infuse™ Bone Graft for oral maxillofacial bone grafting
procedures.
▪ Anti-rhBMP-2 antibodies: 4/184 (2.2%) patients receiving rhBMP-2/ACS component developed antibodies vs. 0/91
(0.0%) in the autogenous bone graft group.
▪ Anti-bovine Type I collagen antibodies: 37/184 (20%) of patients receiving rhBMP-2/ACS developed antibodies to bovine
Type I collagen vs. 28/91 (31%) of autogenous bone graft 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 in humans 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.
Surgeon and dentist note: although surgeons and dentists are the learned intermediary between the company and the patient,
the important medical information given in this document should be conveyed to the patient.
For US audiences only
POTENTIAL ADVERSE EVENTS
The following is a list of potential adverse events which may occur with oral maxillofacial surgery using the Infuse™ Bone Graft.
Some of these adverse events may have been previously reported in the adverse events table below or have been reported to
the manufacturer:
▪ Allergic reaction.
▪ Death.
▪ Ectopic and/or exuberant bone formation.
▪ Fetal development complications.
▪ Itching.
▪ Scar formation.
▪ Tissue or nerve damage.
▪ Antibodies to rhBMP-2/ACS.
▪ Antibodies to bovine collagen.
▪ Antibodies to human Type I collagen.
CLINICAL RESULTS
Overview of Clinical Studies
There were five clinical studies that supported the approval of the PMA, three for sinus floor augmentation and two for extraction
socket augmentation.
The sinus floor augmentation clinical studies were:
▪ Pilot Study (short term 9409 and long-term 9410).
▪ Dosing Study (9531).
▪ Pivotal Study (9730).
The extraction socket augmentation clinical studies were:
▪ Pilot Study (short term 9411 and long-term 9412).
▪ Dosing Study (9514).
A similar study protocol was followed in each of the five studies with the treatment course consisting of study device
implantation followed by an osteoinduction phase, dental implant placement followed by an osseointegration phase, and
prosthesis placement (functional loading) followed by functional restoration. These studies involved varying dosages of
rhBMP-2/ACS and varying control groups.
A total of 312 subjects were enrolled across 5 studies. One hundred and eighty four subjects received one of three
concentrations of rhBMP-2/ACS (0.43mg/mL, 0.75mg/mL, or 1.5mg/mL); 91 subjects received bone graft, either autogenous
bone (autograft) or autogenous bone and allogeneic bone (autograft plus allograft). Two sub-groups were also treated to
evaluate no treatment (20 subjects) and a placebo consisting of ACS alone, the carrier for rhBMP-2 (17 subjects).
The five studies are summarized in the tables below.
Table 1: Sinus Floor Augmentation Study Summaries
Study Description
Number of
Subjects
Pilot Study (9409/9410) Dosing Study (9531) Pivotal Study (9730)
Short-Term (9409) Long-Term (9410)
12:
rhBMP-2/ACS
0.43mg/mL
(same subjects as
9409)
48 total subjects:
▪ Autogenous bone graft: n=13
▪ rhBMP-2/ACS 0.75mg/mL:
n=18
160 total subjects:
▪ Autogenous bone graft: n=78
▪ rhBMP-2/ACS 1.5mg/mL:
n=82
▪ rhBMP-2/ACS 1.5mg/mL: n=17
Study Design Open-label, non-
randomized, fourcenter study
Follow-Up 16 weeks post-sur-
gery
Follow-up study of
subjects enrolled in
9409
36 months postprosthesis
Randomized multi-center trial (6
centers) of two dosage levels with
ACS, or autogenous bone graft
alone
36 months post-prosthesis 24 months post-prosthesis
Multi-center trial (21 centers)
with subjects randomized to
rhBMP-2/ACS or autogenous
bone graft alone
Table 2: Extraction Socket Augmentation Study Summaries
1. Bone Grafting
Procedure
2. Bone Induction
Phase
3. Dental Implant
Placement
4. Osseointegration
Phase
6. Functional Restoration
Phase
5. Prosthesis
Placement
Study Description Pilot Study (9411/12) Dosing Study (9514)
Short-Term (9411) Long-Term (9412)
Number of Subjects
12:
rhBMP-2/ACS 0.43mg/mL
(same subjects as 9411) 80 total subjects:
▪ No treatment: n=20
▪ ACS alone (no rhBMP-2): n=17
▪ rhBMP-2/ACS 0.75mg/mL: n=22
▪ rhBMP-2/ACS 1.5mg/mL: n=21
Study Design Open-label, non-random-
ized, two-center study
Follow-Up 16 weeks post-surgery 24 months post-surgery 24 months post-prosthesis
Long-term follow-up of
subjects enrolled in 9411
Randomized multi-center trial (8 centers) of two
dosage levels with ACS, ACS alone or no treatment
Study Design/Methods
The five studies used to support this PMA application were conducted in a similar manner with similar study design and
methods used. The treatment course was the same for subjects enrolled in all of the five studies as shown in the figure below.
Subject Treatment Course Across all Five Studies
Surgery and Evaluation Procedures
Subjects enrolled across the five studies were all candidates for two-stage augmentation procedures. In the first stage, the
osteoinductive material is surgically implanted. The second stage is the placement of the dental implant, if applicable, after time
has elapsed to allow for osseointegration.
Demographics – All Patients with Infuse™ Bone Graft (1.5mg/mL Concentration of rhBMP-2/ACS)
Demographic data for the 1.5mg/mL (commercial concentration of Infuse™ Bone Graft) treatment group used for demonstration
of effectiveness are summarized below. Age, gender, and race were categorized for all study subjects.
Table 3: Demographics of Infuse™ Bone Graft (1.5mg/mL Concentration of rhBMP-2/ACS)
Characteristic Extraction Socket Dosing Study (9514) Sinus Dosing Study (9531) Sinus Pivotal Study (9730) Total
Gender
Male 52.4% 35.3% 56.1% 52.5%
Age
Mean 47.6 52.1 53.6 52.3
Age Category
<65 yrs 85.7% 88.2% 79.3% 81.7%
Race
Black 38.1% 5.9% 6.1% 11.7%
Asian 9.5% 0.0% 1.2% 2.5%
Other 0.0% 0.0% 2.4% 1.7%
Hispanic 9.5% 5.9% 6.1% 6.7%
Caucasian 42.9% 88.2% 84.1% 77.5%
Subject Disposition of All Patients in the 5 Studies
Across all five studies, the follow-up rate was ≥85%. One death was reported during the conduct of the Extraction Socket
Augmentation Dosing study. The death was determined not to be related to the study treatment. Subject withdrawals were both
voluntary and withdrawn based on missed follow-ups. As per protocol, subjects who failed to complete their scheduled follow-up
were withdrawn. Nine subjects withdrew. Subjects were analyzed in the groups to which they were assigned, not the groups in
which they were treated.
Adverse Events
The assessment of safety for both indications 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.
Adverse Events for Infuse™ Bone Graft (1.5mg/mL concentration of rhBMP-2/ACS) and Autogenous Bone Graft
The table below describes the adverse events observed in the clinical trials for the 1.5mg/mL concentration of rhBMP-2/ACS
(the commercially available concentration) used to support approval of the product. An Infuse™ Bone Graft concentration of
1.5mg/mL was implanted in 120 investigational patients and compared to 91 autogenous bone graft patients from all the
studies. 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 4: Adverse Events for Infuse™ Bone Graft (1.5mg/mL Concentration of rhBMP-2/ACS) vs. Autogenous Bone
Graft Patients: Frequent Adverse Events (>5% of Patients) by Body System and COSTART Term
Body System
COSTART Term
Body As A Whole
Accidental Injury 10 (8.3) 4 (4.4) 0.2817
Back Pain 4 (3.3) 6 (6.6) 0.3340
Dehiscence 6 (5.0) 5 (5.5) 1.0000
Edema 2 (1.7) 34 (37.4) <0.0001
Face Edema 81 (67.5) 52 (57.1) 0.1500
Flu Syndrome 3 (2.5) 5 (5.5) 0.2950
Headache 14 (11.7) 7 (7.7) 0.3652
Infection 30 (25.0) 39 (42.9) 0.0076
Pain 26 (21.7) 46 (50.5) <0.0001
Peri-Implantitis 11 (9.2) 4 (4.4) 0.2793
Cardiovascular System
Hematoma 11 (9.2) 8 (8.8) 1.0000
Hypertension 9 (7.5) 8 (8.8) 0.8011
Digestive System
Gingivitis 7 (5.8) 5 (5.5) 1.0000
Mouth Pain 102 (85.0) 76 (83.5) 0.8489
Mouth Ulceration 4 (3.3) 6 (6.6) 0.3340
Nausea 4 (3.3) 10 (11.0) 0.0470
Oral Edema 81 (67.5) 59 (64.8) 0.7688
Oral Erythema 57 (47.5) 56 (61.5) 0.0513
Tooth Disorder 10 (8.3) 4 (4.4) 0.2817
Hemic and Lymphatic System
Anemia 4 (3.3) 9 (9.9) 0.0797
Ecchymosis 19 (15.8) 21 (23.1) 0.2157
Metabolic and Nutritional Disorders
Healing Abnormal 4 (3.3) 9 (9.9) 0.0797
Hyperglycemia 8 (6.7) 15 (16.5) 0.0270
Hypophosphatemia 2 (1.7) 9 (9.9) 0.0107
SGOT Increased 3 (2.5) 5 (5.5) 0.2950
SGOT Increased 6 (5.0) 6 (6.6) 0.7660
Musculo-Skeletal System
Arthralgia 14 (11.7) 24 (26.4) 0.0069
Bone Disorder 14 (11.7) 11 (12.1) 1.0000
Nervous System
Abnormal Gait 0 (0.0) 37 (40.7) <0.0001
Hypesthesia 5 (4.2) 15 (16.5) 0.0036
Respiratory System
Bronchitis 0 (0.0) 5 (5.5) 0.0140
Epistaxis 7 (5.8) 6 (6.6) 1.0000
Infuse™ Bone Graft Patients (n=120)
N (%) N (%)
Autogenous Bone Graft
Patients (n = 91)
p-value
Table 4: Adverse Events for Infuse™ Bone Graft (1.5mg/mL Concentration of rhBMP-2/ACS) vs. Autogenous Bone
Graft Patients: Frequent Adverse Events (>5% of Patients) by Body System and COSTART Term (continued)
Body System
COSTART Term
Rhinitis 10 (8.3) 6 (6.6) 0.7944
Sinusitis 11 (9.2) 15 (16.5) 0.1390
Skin And appendages
Rash 9 (7.5) 34 (37.4) <0.0001
The most frequent adverse events reported for both the Infuse™ Bone Graft (1.5mg/mL concentration of rhBMP-2/ACS)
treatment group and the autogenous bone graft group were: mouth pain (85.0% vs. 83.5%); oral edema (67.5% vs. 64.8%); face
edema (67.5% vs. 57.1%); and oral erythema (47.5% vs. 61.5%). Although, not statistically significant, face edema is greater in
the Infuse™ Bone Graft group and is most likely due to the recruitment of fluid and cells into the treatment area.
Subjects in the autogenous bone graft group showed a significantly greater number of adverse events versus the Infuse™ Bone
Graft (1.5mg/mL concentration of rhBMP-2/ACS) treatment group. Specifically, the following adverse events occurred
significantly more often in the bone graft group: pain (50.5% vs. 21.7%); infection (42.9% vs. 25%); abnormal gait (40.7% vs. 0);
arthralgia (26.4% vs. 11.7%); nausea (11% vs. 3.3%), hyperglycemia (16.5% vs. 6.7%); hypophosphatemia (9.9% vs. 1.7%);
edema (37. 4% vs. 1.7%); rash (erythema) (37.4% vs. 7.5%); hypesthesia (decreased sensation) (16.5% vs. 4.2%); and
bronchitis (5.5% vs. 0.0%). As noted, none of the Infuse™ Bone Graft (1.5mg/mL concentration of rhBMP-2/ACS) subjects
reported abnormal gait or gait disturbance compared to 41% of bone graft subjects.
The 120 patients in the Infuse™ Bone Graft (1.5mg/mL concentration of rhBMP-2/ACS) treatment group experienced 1184
adverse events for an average of 9.9 events/patient. 79.1% (936/1184) were mild; 18.3% (217/1184) were moderate; 2.4%
(29/1184) were severe, and 0.01% life threatening (1/1184).
The autogenous bone graft treatment group experienced 1249 adverse events in 91 patients for an average of 13.7 events/
patient. Among the 91 subjects who received an autogenous bone graft, 1249 adverse events were reported. 82.8%
(1034/1249) were mild, 14.7% (184/1249) were moderate, and 2.16% (27/1249) were severe. The increased frequencies of
these events are expected in bone graft treatments because of the harvest procedure; these adverse events reflect the
morbidity associated with the procedure which is not required with the Infuse™ Bone Graft treatment.
Serious Adverse Events for Infuse™ Bone Graft (1.5 mg/mL concentration of rhBMP-2/ACS)
Although there were no serious adverse events that were judged to be related to the Infuse™ Bone Graft, there were serious
adverse events that occurred during the study. The 120 patients in the Infuse™ Bone Graft (1.5mg/mL concentration of
rhBMP-2/ACS) treatment group experienced 1184 adverse events for an average of 9.9 events/patient. 79.1% (936/1184) were
mild; 18.3% (217/1184) were moderate; 2.4% (29/1184) were severe, and 0.01% life threatening (1/1184).
Adverse Events for Infuse™ Bone Graft (any concentration of rhBMP-2/ACS) and Autogenous Bone Graft
The combined Infuse™ Bone Graft treatment group experienced 1636 adverse events in 184 patients for an average of 8.9
events/patient. 80% (1309/1636) of the adverse events were mild, 17% (286/1636) were moderate, 2% (36/1636) were reported
as severe, and 0.06% (1/1636) were considered life-threatening in severity (though unrelated to rhBMP-2/ACS).
Immune Response
The presence of antibodies was assessed prior to and following use of Infuse™ Bone Graft using Enzyme-Linked
ImmunoSorbent Assay (ELISA). If there was a positive response to bovine Type I collagen, the serum was also tested for
antibodies to human Type I collagen.
Four of 184 (2.2%) rhBMP-2/ACS patients had a positive antibody response to rhBMP-2. While there is a theoretical possibility
that antibodies to rhBMP-2 could neutralize endogenous BMP-2, thereby interfering with subsequent bone healing, this was not
observed during the course of the studies. None of the autogenous bone graft patients developed these antibodies.
There were 37 of 184 (20%) rhBMP-2/ACS patients who were considered to have an authentic elevated antibody response to
bovine Type I collagen. There were 28 of 91 (31%) autogenous bone graft patients who were considered to have an authentic
elevated antibody response to bovine Type I collagen. No patients had positive responses to human Type I collagen.
There were seven pregnancies, in six women, reported in the clinical studies. Four pregnancies were reported in the
rhBMP-2/ACS group and three pregnancies in the autogenous bone graft group. All of these pregnancies resulted in the birth of
healthy babies except one in which the patient elected to terminate pregnancy for reasons unrelated to her participation in the
clinical study.
Fourteen cases of cancer were diagnosed; 3 in the Infuse™ Bone Graft group, 4 at lower concentrations of rhBMP-2/ACS, and
7 in the autogenous bone graft group. Cancers in the Infuse™ Bone Graft group included 1 gastrointestinal cancer, 1 myeloma
and 1 squamous cell carcinoma. Cancers noted at lower concentrations of rhBMP-2/ACS included 1 squamous cell carcinoma,
2 prostate cancers and 1 colon cancer. Cancers in the autogenous bone graft group included: 2 basal cell carcinomas, 2
squamous cell carcinomas, 1 brain cancer, 1 breast cancer, and 1 fibroadenoma. None of these cancers were considered
related to the treatment.
Infuse™ Bone Graft Patients (n=120)
N (%) N (%)
Autogenous Bone Graft
Patients (n = 91)
p-value
Sinus Augmentation Clinical Study Summary
Evaluation of the effectiveness for the sinus floor augmentation indication is based primarily on the sinus floor pivotal study
(9730). These data were analyzed in accordance with the endpoints and methodology from the sinus floor pivotal study
protocol. Because of similarities between studies 9730 and 9531 (sinus floor dosing study), results based on the two studies
combined are presented as well for certain endpoints.
Study Endpoints
Primary endpoint:
▪ Proportion of patients (within the rhBMP-2/ACS treatment group) who have successful dental implant borne restoration after
6 months of functional loading. Subjects who successfully received prosthesis but were lost to follow-up or withdrew
anytime thereafter were excluded from the analysis.
Secondary endpoints:
▪ Proportion of patients (within each treatment group) who have successful dental implant borne restoration after 6, 12, 18,
and 24 months of functional loading.
▪ Proportion of endosseous dental implants (within each treatment group) that once placed into the augmented maxillary
sinus(es) achieve clinical osseointegration and maintain functional restoration after 6, 12, 18, and 24 months of functional
loading (refer to the SSED for these by implant results).
Primary Endpoint Analysis
Table 5: Primary Effectiveness Endpoint Results for Sinus Augmentation Studies 9730 and 9531 with Infuse™ Bone
Graft (1.5mg/mL Concentration of rhBMP-2/ACS)
9531
Subjects
(n=17)
(N=%) (N=%) (N=%)
Received dental implants into newly induced
15 (88.2) 67 (81.7) 82 (82.8)
bone without additional augmentation
Received prosthesis (functionally loaded) 14 (82.4) 65 (79.3) 79 (79.8)
After 6 months functionally loaded
N 17 81 98
Success
a,b
95% CI of Success
c
14 (82.4) 64 (79.0) 78 (79.6)
(56.6, 96.2) (68.5, 87.3) (70.3, 87.1)
9730
(n=82)
Combined 9730/9531
(n=99)
After 12 months functionally loaded
N 17 80 97
Success
a,b
95% CI of Success
c
14 (82.4) 63 (78.8) 77 (79.4)
(56.6, 96.2) (67.0, 86.6) (69.1, 86.5)
After 24 months functionally loaded
N 17 75 92
Success
95% CI of Success
a
Success is defined as a subject who received implant(s) into newly induced bone for any teeth under study and none required
a,b
c
14 (82.4) 57 (76.0) 71 (77.2)
(56.6, 96.2) (64.7, 85.1) (67.3, 85.3)
additional maxillary sinus floor augmentation.
b
For subjects who missed a functional loading visit but whose status at flanking visits was known, the known status at the last
visit was imputed.
c
2-sided 95% exact confidence interval.
Secondary Endpoint Analysis: Patient-level success rates after functional loading
Table 6: Number (%) of Subjects Who Received Prosthesis and Maintained Functional Loading in the Sinus
Augmentation Pivotal Study (9730)
Subjects
Autogenous Bone Graft
(n=78)
Infuse™ Bone Graft
(1.5mg/mL)
Difference
(n=82)
Received dental implants into newly induced bone without
74 (94.9%) 67 (81.7%)
additional augmentation
Received prosthesis (functionally loaded) 72 (92.3%) 65 (79.3)
a
After 6 months functionally loaded
N 76 81
Success
b,c
69 (90.8%) 64 (79.0%) -11.8
Table 6: Number (%) of Subjects Who Received Prosthesis and Maintained Functional Loading in the Sinus
Augmentation Pivotal Study (9730) (continued)
Subjects
Autogenous Bone Graft
(n=78)
Infuse™ Bone Graft
(1.5mg/mL)
Difference
(n=82)
95% CI
d
(81.9, 96.2) (68.5, 87.3) (-22.8, -0.8)
After 12 months functionally loaded
N 76 80
Success
95% CI
b,c
d
69 (90.8%) 63 (78.8%) -12.0
(81.9, 96.2) (68.2, 87.1) (-23.1, -1.0)
After 18 months functionally loaded
N 76 77
Success
95% CI
b,c
d
69 (90.8%) 60 (77.9%) -12.9
(81.9, 96.2) (67.0, 86.6) (-24.2, -1.5)
After 24 months functionally loaded
N 76 75
Success
95% CI
a
Difference = Infuse™ – autogenous bone graft.
b
Success is defined as a subject who received implant(s) into newly induced bone for any teeth under study and none required
b,c
d
69 (90.8%) 57 (76.0%) -14.8
(81.9, 96.2) (64.7, 85.1) (-26.4, -3.1)
additional maxillary sinus floor augmentation.
c
For subjects who missed a functional loading visit but whose status at flanking visits was known, the known status at the last
visit was imputed.
d
Exact confidence intervals for success rates in both groups; approximate confidence intervals for the difference.
a
Table 7: Number (%) of Subjects Who Received Prosthesis and Maintained Functional Loading in the Sinus
Augmentation Pivotal Study (9730) and Dosing Study (9531) Combined
Subjects
Autogenous Bone Graft
(n=91)
Infuse™ Bone Graft
(1.5mg/mL)
Difference
(n=99)
Received dental implants into newly induced
87 (95.6) 82 (82.8)
bone without additional augmentation
Received prosthesis (functionally loaded) 85 (93.4%) 79 (79.8%)
After 6 months functionally loaded
N 89 98
Success
95% CI
b,c
d
80 (89.9%) 78 (79.6%) -10.3
(81.7, 95.3) (70.3, 87.1) (-20.4, -0.2)
After 12 months functionally loaded
N 87 97
Success
95% CI
b,c
d
77 (88.5%) 77 (79.4%) -9.1
(79.9, 94.4) (70.0, 87.0) (-19.6, 1.4)
After 18 months functionally loaded
N 87 94
Success
95% CI
b,c
d
76 (87.4%) 74 (78.7%) -8.7
(78.5, 93.5) (69.1, 86.5) (-19.5, 2.2)
a
After 24 months functionally loaded
N 87 92
Table 7: Number (%) of Subjects Who Received Prosthesis and Maintained Functional Loading in the Sinus
Augmentation Pivotal Study (9730) and Dosing Study (9531) Combined (continued)
a
Subjects
Autogenous Bone Graft
(n=91)
Infuse™ Bone Graft
(1.5mg/mL)
Difference
(n=99)
Success
95% CI
a
Difference = Infuse™ – autogenous bone graft.
b
Success is defined as a subject who received implant(s) into newly induced bone for any teeth under study and none required
b,c
d
76 (87.4%) 71 (77.2%) -10.2
(78.5, 93.5) (67.3, 85.3) (-21.2, 0.9)
additional maxillary sinus floor augmentation.
c
For subjects who missed a functional loading visit but whose status at flanking visits was known, the known status at the last
visit was imputed.
d
Exact confidence intervals for success rates in both groups; approximate confidence intervals for the difference.
Sinus Augmentation Clinical Data Summary
In the Pivotal Study (9730), 79.0% of patients in the Infuse™ group (95% confidence interval: 68.5% – 87.3%) successfully
received dental implants without additional augmentation, received a prosthesis, and maintained functional loading for at least
six months. The observed success rate at six months post-loading in the autogenous bone graft group was higher by 11.8
percentage points (95% confidence interval: 0.8% – 22.8%). Combining the Pivotal Study (9730) with the Dosing Study (9531)
yielded similar results.
However, as seen in the adverse events sections, the autogenous bone graft group had a statistically significant higher number
of adverse events than the Infuse™ group.
Extraction Socket Clinical Study Summary
The evaluation for the extraction socket augmentation procedure is based on the results of the Dosing Study (9514). The
treatment groups included:
▪ No treatment – the extraction socket was allowed to heal on its own.
▪ Infuse™ Bone Graft (1.5mg/mL rhBMP-2/ACS) – ACS with commercial dose of rhBMP-2.• Infuse™ Bone Graft (1.5mg/mL
rhBMP-2/ACS) – ACS with commercial dose of rhBMP-2.
Study Endpoints
The protocol of study 9514 specifies the following endpoints.
Primary endpoint:
▪ Proportion of patients within each treatment group that have adequate bone formation to support the placement of
endosseous dental implants at four months.
Secondary endpoints:
▪ Proportion of patients that have a prosthesis placed onto the dental implants placed into the study treatment area.
▪ Proportion of patients that maintain a successful prosthesis at 6, 12, 18, and 24 months following loading.
Primary Endpoint Analysis
Table 8: Number of Patients (%) within each Treatment Group who underwent Dental Implant Placement without
Additional Augmentation at 4 months
No Treatment Infuse™ Bone Graft
1.5mg/mL
Needed augmentation 8 (40%) 2 (10%)
Failed 2 (10%) 1 (5%)
Withdrew 1 (5%) 0
Succeeded 9 (45%) 18 (85%)
Total 20 21
Because of a withdrawn patient in the No Treatment group, different statistical analyses are possible depending on how this
patient is handled. Counting the withdrawn patient as a failure leads to a Fisher exact p-value of 0.0088 for comparing Infuse™
Bone Graft (1.5mg/mL rhBMP-2/ACS) to No Treatment. If the withdrawn patient is assumed to be missing completely at
random, then it can be excluded from the analysis and the resulting Fisher exact p-value is 0.0171 for comparing Infuse™ Bone
Graft (1.5mg/mL rhBMP-2/ACS) to No Treatment.
Secondary Endpoint Analyses
Table 9: Number of Patients (%) within each Treatment Group who underwent Prosthesis Placement without Additional
Augmentation (Baseline - Time 0 Functional Loading)
No Treatment Infuse™ Bone Graft
1.5mg/mL
Needed augmentation 8 (40%) 2 (10%)
Table 9: Number of Patients (%) within each Treatment Group who underwent Prosthesis Placement without Additional
Augmentation (Baseline - Time 0 Functional Loading) (continued)
No Treatment Infuse™ Bone Graft
1.5mg/mL
Failed 2 (10%) 3 (14%)
Withdrew 3 (15%) 0
Succeeded 7 (35%) 16 (76%)
Total 20 21
Again, different methods exist for handling the withdrawn patients. The Fisher exact p-value for comparing Infuse™ Bone Graft
(1.5mg/mL rhBMP-2/ACS) to No Treatment is 0.0122 if the patients who withdrew or missed a visit are counted as failures or
0.0458 if those patients are excluded from the analysis.
The table below shows the proportion of patients that maintain a successful prosthesis at 6 months following loading.
Table 10: 6-Month Functional Loading
No Treatment Infuse™ Bone Graft
1.5mg/mL
Needed augmentation 8 (40%) 2 (10%)
Failed 2 (10%) 3 (14%)
Withdrew 3 (15%) 0
Succeeded 6 (30%) 14 (66%)
Total 20 21
The Fisher exact p-value for comparing Infuse™ Bone Graft (1.5mg/mL rhBMP-2/ACS) to No Treatment is 0.0294 if the patients
who withdrew or missed a visit are counted as failures or 0.0442 if those patients are excluded from the analysis.
Extraction Socket Clinical Data Summary
In the Dosing Study (9514), 85% of the Infuse™ Bone Graft (1.5mg/mL rhBMP-2/ACS) group had grown enough bone at 4
months to receive implants without additional augmentation. Sixty six percent (66%)of the patients in the Infuse™ Bone Graft
(1.5 mg/mL rhBMP-2/ACS) group successfully received dental implants without additional augmentation, received a prosthesis,
and maintained functional loading for at least six months. Ten percent (10%) of the patients required augmentation at the time of
dental implant placement through six months, 14% of the patients failed through six months, and 10% of the patients missed
their 6-month visit. The observed success rate at six months post-loading in the No Treatment group was 30%. There was a
statistically significant difference between the number of patients who were successful in the No Treatment and Infuse™ groups
at 6 months post-loading.
HOW SUPPLIED
Infuse™ Bone Graft is supplied in a kit containing all the components necessary to prepare the device (a vial with the lyophilized
rhBMP-2, a vial with Sterile Water for Injection to reconstitute the rhBMP-2, the ACS, syringes and needles). Packages for each
of the components should be intact upon receipt. Damaged packages or products should not be used, and should be returned
to Medtronic.
STORAGE CONDITIONS
Store Infuse™ Bone Graft at room temperature (15 to 30ºC, 59 to 86º F).
DOSAGE AND ADMINISTRATION
Infuse™ Bone Graft is prepared immediately prior to use from a kit containing all necessary components. Once prepared, the
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 the solution concentration of 1.5mg/mL and then distributed uniformly across the entire
ACS.
Infuse™ Bone Graft is implanted after the surgeon or dentist prepares the implant site utilizing standard surgical techniques.
The Infuse™ Bone Graft kit size is selected depending on volume requirement of the implant site.
DIRECTIONS FOR USE
Infuse™ Bone Graft component is prepared at the time of surgery in the surgical suite by reconstituting the lyophilized rhBMP-2
with sterile water (see the Infuse™ Bone Graft Instructions for Preparation and Surgical Application*), and then uniformly
applying the reconstituted rhBMP-2 solution to the ACS. If the Infuse™ Bone Graft is not used within two hours after
reconstitution, it must be discarded. The Infuse™ Bone Graft must not be sterilized by the hospital.
*To obtain a copy of the Instructions for Preparation and Surgical Application, contact Medtronic.
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, should notify
the distributor or Medtronic. If any Medtronic product ever “malfunctions” and may have caused or contributed to the death or
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