← Product Code [NOX](/productcode/NOX) · P100006S005

# AUGMENT INJECTABLE (P100006S005)

_Biomimetic Therapeutics, LLC · NOX · Jun 12, 2018 · Orthopedic · APPR_

**Canonical URL:** https://fda-staging.innolitics.com/device/P100006S005

## Device Facts

- **Applicant:** Biomimetic Therapeutics, LLC
- **Product Code:** [NOX](/productcode/NOX.md)
- **Decision Date:** Jun 12, 2018
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Orthopedic
- **Attributes:** Therapeutic, Real-World Evidence

## Real-World Evidence

| Submission | Device | Sponsor | RWD Sources | RWE Use Summary | Key Tags |
| --- | --- | --- | --- | --- | --- |
| P100006S005 · Jun 12, 2018 | AUGMENT INJECTABLE | Biomimetic Therapeutics, LLC | Medical claims database | A retrospective analysis of a medical claims database was used to compare cancer rates and mortality between patients treated with becaplermin (rhPDGF-BB) and matched comparators to assess long-term safety. | claims analysis; retrospective; cancer risk; safety |

### Clinical Evidence

| Study Design | Population | Comparator | Key Endpoints |
| --- | --- | --- | --- |
| A Cohort Study of the Risk of Cancer in Regranex (Becaplermin) Users and Matched Comparators; Retrospective cohort study; Follow-up/Duration: Up to 3 years post-treatment | 1622 patients treated with REGRANEX® Gel and 2809 matched comparators; Sample Size: 4431 | Matched comparators | Cancer incidence rates and cancer mortality |

## Indications for Use

AUGMENT® Injectable is indicated for use as an alternative to autograft in arthrodesis (i.e., surgical fusion procedures) of the ankle (tibiotalar joint) and/or hindfoot (including subtalar, talonavicular, and calcaneocuboid joints, alone or in combination), due to osteoarthritis, post-traumatic arthritis, rheumatoid arthritis, psoriatic arthritis, avascular necrosis, joint instability, joint deformity, congenital defect, or joint arthropathy in patients with preoperative or intraoperative evidence indicating the need for supplemental graft material.

## Device Story

AUGMENT® Injectable is a combination bone graft material used in ankle/hindfoot arthrodesis; replaces autograft to avoid harvest-site morbidity. Components: matrix (β-TCP granules, Type I bovine collagen) and drug (recombinant human platelet-derived growth factor-BB, rhPDGF-BB). Surgeon mixes matrix and rhPDGF-BB in OR to create flowable putty; delivered via syringe/cannula to fusion site. rhPDGF-BB recruits mesenchymal stem cells and osteoblast progenitors; stimulates angiogenesis and bone formation. Device requires metallic fixation hardware for stabilization. Healthcare providers use the graft to facilitate fusion; clinical benefit includes avoiding autograft harvest pain/complications. Stored refrigerated (2-8°C).

## Clinical Evidence

PMA approval based on three prospective, randomized, controlled clinical studies (BMTI-2006-01, BMTI-2009-01, BMTI-2010-01) using propensity score matching to compare AUGMENT® Injectable (n=132) to autograft (n=167). Primary endpoints included clinical/functional outcomes (VAS pain, FFI, AOFAS score). Results demonstrated non-inferiority of AUGMENT® Injectable to autograft at 52 weeks across all clinical/functional measures. Radiographic fusion assessment was inconclusive due to similar radiodensity of graft and bone. Safety data showed similar rates of TEAEs, serious TEAEs, and infections between groups. No deaths reported.

## Technological Characteristics

Combination product: Matrix (80% β-TCP granules 100-300μm, 20% Type I bovine collagen per ASTM F2212) and drug (rhPDGF-BB, 0.3 mg/mL). Matrix provided in 0.5g or 1.0g syringes; rhPDGF-BB in 1.5mL or 3.0mL vials. Sterilization: Gamma irradiation (matrix), ethylene oxide (vial). Connectivity: None. Energy: None.

## Regulatory Identification

The device acts as a bone void filler and consists of a filling material and a synthetic peptide.  It is intended to fill traumatic or surgically-created defects that are not intrinsic to the bony structure of the extremities, spine or pelvis.  It will be packed or placed into the defect and will resorb over time to be replaced by bone.

## Reference Devices

- AUGMENT® Bone Graft ([P100006](/device/P100006.md))
- REGRANEX® Gel

## Submission Summary (Full Text)

> This content was OCRed from public FDA records by [Innolitics](https://innolitics.com). If you use, quote, summarize, crawl, or train on this content, cite Innolitics at https://innolitics.com.
>
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# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

## I. GENERAL INFORMATION

Device Generic Name: Bone grafting material containing a therapeutic biologic

Device Trade Name: AUGMENT® Injectable

Device Procode: NOX

Applicant's Name and Address: BioMimetic Therapeutics, LLC, a wholly owned subsidiary of Wright Medical Group, N.V. 389 Nichol Mill Lane Franklin, Tennessee 37067

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P100006/S005

Date of FDA Notice of Approval: June 12, 2018

The original PMA, P100006, for AUGMENT® Bone Graft was approved on September 1, 2015, and is indicated for use as an alternative to autograft in arthrodesis (i.e., surgical fusion procedures) of the ankle (tibiotalar joint) and/or hindfoot (including subtalar, talonavicular, and calcaneocuboid joints, alone or in combination), due to osteoarthritis, post-traumatic arthritis, rheumatoid arthritis, psoriatic arthritis, avascular necrosis, joint instability, joint deformity, congenital defect, or joint arthropathy in patients with preoperative or intraoperative evidence indicating the need for supplemental graft material. The SSED to support the indication is available on the CDRH website and is incorporated by reference here. The current supplement was submitted for a new product, AUGMENT® Injectable. This new formulation incorporates a modification of the device component of AUGMENT® Bone Graft utilizing beta tricalcium phosphate ($\beta$-TCP) granules of a different particle size combined with a collagen material. This results in a 'flowable' consistency for the product, which can then be placed at the bone fusion site via a syringe.

## II. INDICATIONS FOR USE

AUGMENT® Injectable is indicated for use as an alternative to autograft in arthrodesis (i.e., surgical fusion procedures) of the ankle (tibiotalar joint) and/or hindfoot (including subtalar, talonavicular, and calcaneocuboid joints, alone or in combination), due to osteoarthritis, post-traumatic arthritis, rheumatoid arthritis, psoriatic arthritis, avascular necrosis, joint instability, joint deformity, congenital defect, or joint arthropathy in patients with preoperative or intraoperative evidence indicating the need for supplemental graft material.

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### III. CONTRAINDICATIONS

AUGMENT® Injectable **should not**:

- be used in patients who have a known hypersensitivity to any of the components of the product or are allergic to yeast-derived products.
- be used in patients with active cancer.
- be used in patients who are skeletally immature (<18 years of age or no radiographic evidence of closure of epiphyses).
- be used in pregnant women. The potential effects of rhPDGF-BB on the human fetus have not been evaluated.
- be implanted in patients with an active infection at the operative site.
- be used in situations where soft tissue coverage is not achievable.
- be used in patients with metabolic disorders known to adversely affect the skeleton (e.g. renal osteodystrophy or hypercalcemia), other than primary osteoporosis or diabetes.
- be used as a substitute for structural graft.

### IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the AUGMENT® Injectable labeling.

### V. DEVICE DESCRIPTION

AUGMENT® Injectable (AI) is a combination product bone graft material consisting of multiple components – a two-part matrix (device components) and a recombinant human protein (drug component).

#### Matrix component

The matrix component contains two constituents - β-TCP granules and a collagen matrix.

The β-TCP granules are a purified, multicrystalline, porous form of calcium phosphate with a calcium to phosphate ratio similar to human cancellous bone. The granules have a nominal diameter of 100-300μm.

The collagen matrix consists of Type I bovine collagen derived from the inner layer stratum corium of hides. All animals are sourced from a single, closed US-based herd that receives routine veterinary monitoring and feed in compliance with 21 CFR 589. The animals are slaughtered at a USDA-approved abattoir, receive pre- and post-mortem veterinary inspections and all hides are removed before the head and spinal cord. The collagen complies with ASTM F2212 (*Characterization of Type I Collagen as Starting Material for Surgical Implants and Substrates for Tissue Engineered Medical Products (TEMPS)*).

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The stratum corium is processed until an acid soluble slurry is produced. At this point the collagen is combined with the β-TCP granules to form a composite matrix that is 80% β-TCP and 20% bovine Type I collagen. The matrix is then lyophilized, mechanically shredded and sieved. The shredded β-TCP/collagen mixture is then loaded into 10ml syringes. The matrix component is provided in one of two sizes - 0.5g or 1.0g per syringe.

The filled syringes are loaded into trays that also contain an empty syringe, a female luer coupler, a blunt fill needle and a dispensing cannula. This combination of the device component and the mixing and delivery components is packaged and terminally sterilized after exposure to gamma irradiation.

# Recombinant human protein component:

The recombinant human platelet-derived growth factor B homodimer (rhPDGF-BB) component of AUGMENT® Injectable is identical to the rhPDGF-BB contained in AUGMENT® Bone Graft (P100006).

rhPDGF-BB, also referred to as becaplermin, is a recombinant form of the endogenous PDGF-BB. It is a highly purified human therapeutic protein of approximately 24.5 kDa that is expressed in the yeast, Saccharomyces cerevisiae, by recombinant DNA technology. The active ingredient is a homodimer comprising two antiparallel identical polypeptide chains of 109 amino acids that are linked by two intermolecular disulfide bonds at Cys43 and Cys52 of each chain. rhPDGF-BB supports angiogenesis by upregulating vascular endothelial growth factor (VEGF) to stimulate new capillary outgrowth, and recruits smooth muscle cells to the ends of sprouting capillaries to help stabilize the capillary bed. The protein attracts and stimulates the proliferation of mesenchymal cells at the wound site including osteoblast progenitor cells and mesenchymal stem cells (MSCs), leading to new bone formation.

The AUGMENT drug product is formulated by diluting the rhPDGF-BB drug substance in 20 mM USP sodium acetate, pH 6.0 to a concentration of 0.3 mg/mL. This solution is aseptically filled into 1.5 or 3cc glass vials. A tray containing the vial is terminally sterilized using ethylene oxide.

When mixed at the time of surgery, the matrix combines with the rhPDGF-BB and creates a flowable putty-like consistency that allows the surgeon to place the product at the fusion site through a 14 gauge needle (included).

The components of AUGMENT® Injectable are provided as two sterile tray configurations:

o The matrix tray contains a 10 ml polypropylene syringe containing either 0.5 or 1.0 grams of a milled β-TCP/bovine Type I collagen (ratio=4:1) matrix. Also included are one 10 ml empty polypropylene syringe, one 14 gauge blunt tip needle for administration of the combination product, one 18 gauge blunt tip needle for drawing

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up the rhPDGF-BB and one female-to-female luer-lock connector for mixing of the two components. The tray is sterilized by gamma irradiation.

○ The vial tray contains one 3 cc vial, dependent on the kit configuration, aseptically filled with either 1.5 ml or 3.0 ml of rhPDGF-BB solution (0.3mg/ml). The vial tray is sterilized by ethylene oxide.

![img-0.jpeg](img-0.jpeg)

Figure 1: AUGMENT® Injectable

The two sub-assemblies are included in each kit, along with the package insert.

AUGMENT® Injectable must be used in combination with metallic fixation hardware in order to provide appropriate stabilization of the fusion site.

AUGMENT® Injectable must be stored at refrigerated temperature (2-8°C, 36- 46°F) and cannot be frozen.

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are alternatives to accomplish arthrodesis of the ankle and/or hindfoot, due to osteoarthritis, post- traumatic arthritis, rheumatoid arthritis, psoriatic arthritis, avascular necrosis, joint instability, joint deformity, congenital defect, or joint arthropathy in patients with preoperative or intraoperative evidence indicating the need for supplemental graft material. Arthrodesis procedures of the ankle and/or hindfoot may use autograft, allograft, or synthetic bone void fillers for the grafting procedure.

While autograft is the most widely used graft material, its use is associated with clinical concerns, such as graft harvesting, increased operative time, hospital stay and cost, increased blood loss, post-operative pain, risk of infection, and/or fracture. Other reported complications associated with autograft include a potential nidus for infection associated with avascular bone, limited tissue supply, and variability in cellular activity of the bone graft. In addition to these complications, a limited amount of autograft bone is available.

The supply of allograft bone is unlimited; however, the risk of disease transmission exists. While synthetic bone graft materials are also associated with unlimited supply and

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do not carry the risk of disease transmission, their effectiveness is variable and dependent on the specific material from which they are manufactured. A non-injectable granular form of AUGMENT® Bone Graft is also available (P100006).

Each of these alternative graft materials has its own advantages and disadvantages and is associated with its own set of benefits and risks which must be weighed before being used in a specific clinical situation. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

## VII. MARKETING HISTORY

AUGMENT® Injectable has been available in markets outside of the United States since 2013. The product has not been withdrawn from the market for any reason relating to the safety and effectiveness of the product. The countries in which AUGMENT® Injectable is available are as follows: Canada, Australia, New Zealand and Mexico.

## VIII. PROBABLE ADVERSE EFFECTS OF THE DEVICE ON HEALTH

As with any surgery, ankle and hindfoot arthrodesis surgery is not without risk. A variety of complications related to surgery or the use of AUGMENT® Injectable Bone Graft may occur. Patients may experience any of the following adverse events that have been reported in the literature with regard to the use of autograft or bone graft substitute products: swelling, pain, bleeding, hematoma, superficial or deep wound infection, cellulitis, wound dehiscence, incomplete or lack of osseous ingrowth, transient hypercalcemia, neuralgia and loss of sensation locally and peripherally, and anaphylaxis. Occurrence of one or more of these conditions may require an additional surgical procedure and may also require removal of the grafting material.

Below is a list of the potential adverse effects (e.g., complications) associated with the use of AUGMENT® Injectable identified from the AUGMENT® Injectable clinical trial results and published scientific literature including: (1) those associated with any surgical procedure; (2) those associated with ankle and hindfoot arthrodesis surgery; and (3) those associated with bone graft substitute products for use in ankle and hindfoot arthrodesis, such as AUGMENT® Injectable. In addition to the risks listed below, there is also the risk that surgery may not be effective in relieving symptoms, or may cause worsening of symptoms. Additional surgery may be required to correct some of the adverse effects and may also require removal of the grafting material.

1. Risks associated with any surgical procedure include: infection; pneumonia; atelectasis; septicemia; injury to blood vessels; soft tissue damage; phlebitis, thromboembolus, or pulmonary embolus; hemorrhage; respiratory distress; pulmonary edema; reactions to the drugs or anesthetic agent used during and after surgery; reactions to transfused blood; failure of the tissue to heal properly (e.g., hematoma, seroma, dehiscence, etc.) which may require drainage, aspiration, or debridement or other intervention; incisional pain; heart attack; stroke; and death.

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2. Risks associated with ankle and hindfoot arthrodesis surgery with or without the use of graft material include: swelling; bleeding; hematoma; superficial or deep wound infection; cellulitis; wound dehiscence; transient hypercalcemia; neuralgia and loss of sensation locally and peripherally; anaphylaxis; incomplete or lack of osseous ingrowth, postoperative muscle and tissue pain; surgery may not reduce the preoperative pain experienced; pain and discomfort associated with the presence of implants used to aid in the arthrodesis surgery or reaction to the metal used in the implant, as well as the cutting and healing of tissues; the ankle and/or hindfoot may undergo adverse changes or deterioration including loss of height, and/or reduction, or malalignment, and another surgery may be required; and adverse bone/implant interface reaction.
3. Risks associated with bone graft substitute products, including AUGMENT® Injectable, include: non-unions, allergies or immunogenic response to implant materials, hypersensitivity, migration of the graft material into the surrounding soft tissue, musculoskeletal and connective tissue disorders, nervous system disorders, arthralgia, pain in extremities, and infections.

For the specific adverse events that occurred in the clinical studies, please see Section X below.

### IX. SUMMARY OF NONCLINICAL STUDIES

The safety and effectiveness of the three-component product was evaluated in a series of non-clinical studies. These studies revealed that the presence of residual peroxide from the processing of the collagen component resulted in oxidation of the rhPDGF-BB component. Because this could have an impact on the effective bioactivity of the complete product and its ability to stimulate bone formation, data from the analysis of the recombinant protein combined with only the β-TCP component would not generally be representative of the behavior of the complete product under simulated clinical conditions. Some evaluations of the protein alone or protein combined with β- TCP, e.g., biocompatibility and pharmacology/toxicology studies, would be relevant to assessing the safety of the final product. The same was true for certain studies of the various components of the product in anatomic locations that differed from that of the clinical use, i.e., they were useful for addressing certain safety questions, but not product effectiveness. A separate set of studies was performed to characterize the effect of the oxidation on the bioactivity and stability of the recombinant protein component.

A series of studies were performed to evaluate the biocompatibility, toxicology, stability, and ADME/pharmacokinetics of rhPDGF-BB alone and in combination with β-TCP. The sponsor conducted a panel of biocompatibility/toxicity studies in compliance with ISO 10993 and USP guidelines. These studies evaluated β-TCP/collagen matrix, β-TCP/collagen in combination with rhPDGF-BB, as well as β-TCP from several sources with or without rhPDGF-BB. The totality of the data from the biocompatibility studies demonstrated that rhPDGF-BB combined with β-TCP is non-toxic and biocompatible. In addition, a repeat-dose toxicity study to evaluate bone tissue responses to rhPDGF-BB in

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rats and an acute toxicity study to evaluate systemic toxicity following intravenous administration of rhPDGF-BB in rats were also performed. The results from these studies showed no signs of toxicity for rhPDGF-BB administered either locally or intravenously in animal models.

## Stability

Primary analytical data of an on-going stability study were provided supporting label storage claims and drug product expiration dating for 36 months. The study was performed on lots of rhPDGF-BB stored under real-time conditions (2°C - 8°C) and accelerated aging room temperature conditions (22°C - 27°C).

## Chronic Toxicity and Carcinogenicity

A study was conducted to evaluate the chronic toxicity and carcinogenicity of rhPDGF-BB mixed with β-tricalcium phosphate (β-TCP) matrix implanted in a rat model. Sprague-Dawley rats were randomly distributed into three groups (test article (rhPDGF-BB combined with β-TCP), control article (β-TCP combined with vehicle), and sham surgery). Test or control articles were implanted adjacent to the femur underneath the overlying muscle. The test article dose administered was 30 μg of rhPDGF-BB, which is approximately four times the maximum clinical dose. Animals were treated on day 0 and euthanized after 30, 180, or 365 days. Both macroscopic and microscopic evaluations were performed to evaluate toxicity and tumor incidence. Serum was collected for hematology, coagulation, and clinical chemistry determinations. Bone marrow was also collected from all animals at all time-points. Additionally, anti-PDGF-BB antibody formation was determined using enzyme-linked immunosorbent assay (ELISA).

The results of this study demonstrated that implantation of the test article was not associated with any unexpected mortality, clinical findings, or changes in body weight or food consumption. In addition, implantation of the test article was not associated with any treatment-related changes in hematology, coagulation, clinical chemistry, or bone marrow parameters. Upon necropsy and histopathologic evaluation, no differences were noted in tissue response between the sham or control treated animals and the test article implanted animals. The results of this study demonstrated that implantation of the test article did not result in any toxicity or tumorigenicity and, in addition, demonstrated that the test article was biocompatible.

## Pharmacokinetics

Two animal studies were performed to characterize pharmacokinetics of ¹²⁵I-rhPDGF-BB, its metabolism and excretion, and tissue distribution in a rat model. Both studies indicated that rhPDGF-BB is cleared rapidly from the blood (mainly in the urine), with lesser amounts eliminated in the feces following intravenous administration.

There is limited systemic exposure to the protein following intramuscular implantation of ¹²⁵I- rhPDGF-BB combined with β-TCP and clearance is again mainly in the urine. Overall, the toxicology and pharmacokinetic data demonstrated that rhPDGF-BB combined with β-TCP does not lead to any signs of acute or chronic toxicity and the protein is eliminated rapidly from the body following administration with limited

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systemic exposure. However, while the evaluations provide information regarding the relative clearance rates of injected or implanted rhPDGF-BB, they only approximate how the product will be implanted in ankle or hindfoot bone grafting procedures.

The characterization of the release kinetics, biological potency, and biochemical integrity of rhPDGF-BB combined with β-TCP from different sources was also studied. Both in vivo and in vitro preclinical data demonstrated that rhPDGF-BB is released rapidly from β-TCP alone, AUGMENT® Injectable β-TCP/collagen matrix and other sources of β-TCP in a similar fashion. The protein retains its biological potency and is biochemically intact following release from β-TCP matrices as determined by in vitro, cell-based analyses. Thus, the data support AUGMENT® Injectable Bone Graft's β-TCP/collagen matrix as an appropriate device component of this combination product.

## Reproductive Development/Teratology

A reproductive development/teratology study in female Sprague-Dawley rats was conducted at two dose levels (1x - 0.04 mg/ml rhPDGF-BB 40 μg/kg/day and 10x - 0.4 mg/ml rhPDGF-BB 400 μg/kg/day the maximum single, clinical dose) repeated daily over 21 days starting on day zero of gestation, i.e., the low dose group received 21 times (21 days of 1x dose amounts) and the high dose group 210 (21 days of 10x dose amounts) times the maximum clinical dose during the extended period of administration. Detailed examinations, which included measurement of body weight and food consumption, were performed on gestation days 0, 3, 6, 9, 12, 15, 18, and 21. Maternal blood sampling was performed on gestation days 0 and 21, and fetal blood sampling was performed on day 21 of gestation.

No visceral or skeletal anomalies were observed in the control or the low dose rhPDGF-BB groups; no visceral anomalies were found in the first generation fetuses. There were indications of somewhat accelerated ossification of the interparietal and hyoid bones and slight (not significant) increase in the presence of a rudimentary 14th rib in first generation fetuses from maternal rats (dams) receiving rhPDGF-BB. The low dose group had a higher incidence of incomplete ossification of the hyoid bone, while the high dose group had lower incidence of incomplete ossification of the interparietal bone. However, this finding was not dose-dependent; the incidence of incomplete ossification of the hyoid bone in the high dose group was not different from the control group. These observations were made in comparison to the control group.

No detectable amount of rhPDGF-BB was found in the maternal and fetal plasma samples. Anti-rhPDGF-BB antibodies were detected in one out of 15 dam pretreatment samples analyzed. All dam and fetal post-treatment samples analyzed were negative for antibodies to rhPDGF-BB. The administration of rhPDGF-BB at 0.040 and 0.40 mg/kg/day, by intravenous injection, resulted in neither maternal toxicity, nor adverse effects on embryo-fetal development, in this study. Based on these results, 0.40 mg/kg/day (i.e., the highest dose tested in this study) was the no-observed-effect-level (NOEL) for maternal toxicity and the no observed-adverse-effect-level (NOAEL) for embryo-fetal development.

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Table 1 summarizes the biocompatibility studies and Table 2 summarizes the preclinical animal studies performed. See below.

Table 1: Biocompatibility Studies

|  Test | Standard | Methods | Result | Pass  |
| --- | --- | --- | --- | --- |
|  Genotoxicity of β-TCP/collagen matrix | ISO 10993 Part 3 | Reverse Mutation Assay using NaCl and CSO Extracts (Salmonella typhimurium and Escherichia coli) | Nonmutagenic to Salmonella typhimurium tester strains TA98, TA100, TA1535, and TA1537, and to Escherichia coli strain WP2uvrA | Pass  |
|  Genotoxicity of AUGMENT Injectable Bone Graft | ISO 10993 Part 3 | Reverse Mutation Assay using NaCl and CSO Extracts (Salmonella typhimurium and Escherichia coli); conducted with 10x concentration of rhPDGF-BB (3.0 mg/ml) combined with β-TCP/collagen | Nonmutagenic to Salmonella typhimurium tester strains TA98, TA100, TA1535, and TA1537, and to Escherichia coli strain WP2uvrA | Pass  |
|  Intracutaneous Reactivity of β-TCP/collagen matrix | ISO 10993 Part 11 | Intracutaneous Injection Test using NaCl and CSO Extracts in New Zealand White Rabbits | Negligible irritant | Pass  |
|  Intracutaneous Reactivity of AUGMENT Injectable | ISO 10993 Part 10 | Intracutaneous Injection Test using NaCl and CSO Extracts in New Zealand White Rabbits | Negligible irritant | Pass  |
|  Sensitization of β-TCP/collagen | ISO 10993 Part 10 | Kligman Maximization Test using NaCl and CSO Extracts in Guinea Pigs | Grade I Reaction (0% sensitization) | Pass  |
|  Sterilization of AUGMENT Injectable | ISO 10993 Part 10 | Kligman Maximization Test using NaCl and CSO Extracts in Guinea Pigs | Grade I Reaction (0% sensitization) | Pass  |
|  Cytotoxicity of β-TCP/collagen | ISO 10993 Part 5 | L929 MEM Elution Test | Non-cytotoxic Grade 1 Reaction | Pass  |
|  Cytotoxicity of AUGMENT Injectable Bone Graft | ISO 10993 Part 5 | L929 MEM Elution Test | Non-cytotoxic Grade 1 Reaction (slight) | Pass  |
|  Intramuscular Reactivity of β-TCP/collagen matrix | ISO 10993 Part 6 | Intramuscular Implantation Test (4 Week Implantation) in New Zealand White Rabbits | Bioreactivity Rating of 0.5 | Negative. No signs of toxicity. Toxicity rating of 0.5 (non-toxic)  |

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|  Test | Standard | Methods | Result | Pass  |
| --- | --- | --- | --- | --- |
|  Intramuscular Reactivity of AUGMENT Injectable Bone Graft | ISO 10993 Part 6 | Intramuscular Implantation Test (4 Week Implantation) in New Zealand White Rabbits | Bioreactivity Rating of 0.5 | Negative. No signs of toxicity. Toxicity rating of 0.5 (non-toxic)  |
|  Acute Toxicity of β-TCP/collagen matrix | ISO 10993 Part 11 | Systemic Injection Test in Swiss Albino Mice | No biological response when compared to control | Pass  |
|  Acute Toxicity of AUGMENT Injectable Bone Graft | ISO 10993 Part 11 | Systemic Injection Test in Swiss Albino Mice | No biological response when compared to control | Pass  |
|  Hemolytic β-TCP/collagen matrix | ISO 10993 Part 4 | Hemolysis - Rabbit Blood using NaCl Extract | Non-hemolytic | Pass  |
|  Hemolytic Assessment of AUGMENT Injectable Bone Graft | ISO 10993 Part 4 | Hemolysis - Rabbit Blood using NaCl Extract | Non-hemolytic | Pass  |
|  TCP/collagen matrix | ISO 10993 Part 11 | Rabbit Pyrogen Test in New Zealand White Rabbits | Non-pyrogenic | Pass  |
|  Pyrogenicity of AUGMENT Injectable Bone Graft | ISO 10993 Part 11 | Rabbit Pyrogen Test in New Zealand White Rabbits | Non-pyrogenic | Pass  |

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Table 2: Pre-Clinical Animal Studies

|  Test | Methods | Result  |
| --- | --- | --- |
|  Acute Toxicity of rhPDGF-BB Following Intravenous Administration in Rats (Acute, single dose Systemic Toxicity) | Treatment groups: • 0.2 mg rhPDGF-BB/kg body mass • 4.0 mg rhPDGF-BB/kg body mass Model: Normal rats; single IV tail-vein injection Timepoints: 2 and 15 days Dose rationale: The high dose (4.0 mg/kg), was approximately 100 times the maximum human clinical dose (39 μg/kg body mass) | • Intravenous rhPDGF-BB at 0.2 mg/kg and 4.0 mg/kg did not elicit significant toxicity in rats • rhPDGF-BB has a high margin of safety in this assay when administre intravenously  |
|  Evaluation of the chronic toxicity and carcinogenicity of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) mixed with β-tricalcium phosphate (β-TCP) matrix implanted in a rat model (Chronic Local Toxicity and carcinogenicity) | Treatment groups: • Single parafemoral, intramuscular implantation of 0.175 mg/kg of rhPDGF-BB + β-TCP; Timepoints: 30, 180 and 365 days Dosing rationale: Dose in this study of 150 ug/kg body mass exceeded maximum human clinical dose by 4 times (39 ug/kg body mass) | • No evidence of carcinogenicity • No treatment-related mortality or effects on body weight, hematology, coagulation, clinical chemistry, bone marrow parameters, or histopathology • No differences in local tissue response between groups • No anti-PDGF-BB antibodies seen in the rhPDGF-BB + β-TCP test group  |
|  Bone Response to Intramuscular Injections of rhPDGF-BB (Acute Local Toxicity; Repeated dose) | Treatment groups: 13.9; 41.2 and 138.8 μg/kg/day every other day for 2 weeks Model: Normal rats; repeat intramuscular injections next to femur and first metatarsal bones in each animal Timepoints: 2 and 8 weeks Dosing rationale: Single dose in study of 160 ug/kg body mass was 4 times the maximum human clinical dose (39 ug/kg body | • Effects at the high dose for both soft tissue and bone were consistent with the mechanism of action of PDGF-BB • The responses were transient and not present 6 weeks after the last dose  |

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|  Recombinant Human Platelet-derived Growth Factor-BB (rhPDGF-BB): an Intravenous Injection Teratology Study in the Rat (Reproductive and developmental Toxicity) | Treatment groups: • 40 ug/kg body mass per injection 400 ug/kg body mass per injection Model: Normal gravid, female rats; repeat IV tail-vein injections daily on gestation days 0-20 Timepoint: 21 days Dosing rationale: The maximum cumulative dose for this study exceeded the maximum human clinical dose (39 ug/kg body mass) by 210 -fold. Outcomes: Assessment of maternal and fetal toxicity | • No maternal toxicity • No adverse effects on embryo- fetal development • Minor transitory increases in the rate of ossification in the high dose fetuses. • No detectable neutralizing antibodies against rhPDGF-BB • NOAEL for maternal toxicity is 400 μg/kg/day • NOAEL for embryo fetal development is 400 μg/kg/day  |
| --- | --- | --- |
|  New Zealand white rabbit 6-month paravertebral muscle implantation study | Treatment groups: • β-TCP/collagen combine with 20 mM sodium acetate vehicle • β-TCP/collagen combined with 0.3 mg/ml rhPDGF-BB (AUGMENT® Injectable) • β-TCP-collagen combined with 1.0 mg/ml rhPDGF-BB (AUGMENT® Injectable) Model: Rabbit paravertebral intramuscular implantation Timepoints: 28 and 180 days | • No signs of acute or chronic toxicity • All animals survived to scheduled endpoint • Fine to 30 x 20 μm “black specks” of material observed histologically after 180 days in rabbit intramuscular sites  |
|  Geriatric non-human primate (baboon) spine vertebral body injection safety study | Treatments: • β-TCP/collagen combined with 1.0 mg/ml rhPDGF-BB (AUGMENT® Injectable) • β-TCP/collagen combined with 20 mM sodium acetate, pH 6.0 vehicle • Vehicle alone Model: Geriatric, non-human primate (baboon) percutaneous injection of 3 lumbar vertebra per animal Timepoint: 9 months | • All animals survived to their scheduled endpoint • No signs of acute or chronic toxicity • 9-months post-injection, was moderate to marked new bone formation in the injected areas of the vertebral bodies with or without rhPDGF-BB • No signs of local toxicity or neurotoxicity in neighboring lumbar spinal cord segments  |

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|  Acute Toxicity of rhPDGF-BB Following Intravenous Administration in Rats (Acute, single dose Systemic Toxicity) | Treatment groups: • 0.2 mg rhPDGF-BB/kg body mass • 4.0 mg rhPDGF-BB/kg body mass Model: Normal rats; single IV tail-vein injection Timepoints: 2 and 15 days Dose rationale: The high dose (4.0 mg/kg), was approximately 100 times the maximum human clinical dose (39 μg/kg body mass) | • Intravenous rhPDGF-BB at 0.2 mg/kg and 4.0 mg/kg • did not elicit significant toxicity in rats • rhPDGF-BB has a high margin of safety in this assay when administered intravenously  |
| --- | --- | --- |
|  Evaluation of the chronic toxicity and carcinogenicity of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) mixed with β-tricalcium phosphate (β-TCP) matrix implanted in a rat model (Chronic Local Toxicity and carcinogenicity) | Treatment groups: • Single parafemoral, intramuscular implantation of 0.175 mg/kg of rhPDGF-BB + β-TCP; Timepoints: 30, 180 and 365 days Dosing rationale: Dose in this study of 150 μg/kg body mass exceeded maximum human clinical dose by 4 times (39 μg/kg body mass) | • No evidence of carcinogenicity • No treatment-related mortality or effects on body weight, hematology, coagulation, clinical chemistry, bone marrow parameters, or histopathology • No differences in local tissue response between groups • No anti-PDGF-BB antibodies seen in the rhPDGF-BB + β-TCP test group  |
|  Bone Response to Intramuscular Injections of rhPDGF-BB (Acute Local Toxicity; Repeated dose) | Treatment groups: • 13.9; 41.2 and 138.8 μg/kg/day every other day for 2 weeks; Model: Normal rats; repeat intramuscular injections next to femur and first metatarsal bones in each animal Timepoints: 2 and 8 weeks Dosing rationale: Single dose in study of 160 μg/kg body mass was 4 times the maximum human clinical dose (39 μg/kg body mass) | • Effects at the high dose for both soft tissue and bone were consistent with the mechanism of action of PDGF-BB • The responses were transient and not present 6 weeks after the last dose  |
|  Recombinant Human Platelet-derived Growth Factor-BB (rhPDGF-BB): an Intravenous Injection Teratology Study in the Rat (Reproductive and developmental Toxicity) | Treatment groups: • 40 μg/kg body mass per injection 400 μg/kg body mass per injection Model: Normal gravid, female rats; repeat IV tail-vein injections daily on gestation days 0-20 Timepoint: 21 days Dosing rationale: The maximum cumulative dose for this study exceeded the maximum human clinical dose (39 μg/kg body mass) by 210-fold. | • No maternal toxicity • No adverse effects on embryo-fetal development • Minor transitory increases in the rate of ossification in the high dose fetuses. • No detectable neutralizing antibodies against rhPDGF-BB • NOAEL for maternal toxicity is 400 μg/kg/day • NOAEL for embryo fetal development is 400 μg/kg/day  |

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|  New Zealand white rabbit 6-month paravertebral muscle implantation study | Treatment groups: • β-TCP/collagen combine with 20 mM sodium acetate vehicle • β-TCP/collagen combined with 0.3 mg/ml rhPDGF-BB (AUGMENT® Injectable) • β-TCP-collagen combined with 1.0 mg/ml rhPDGF-BB (AUGMENT® Injectable) Model: Rabbit paravertebral intramuscular implantation Timepoints: 28 and 180 days | • No signs of acute or chronic toxicity • All animals survived to scheduled endpoint • Fine to 30 x 20 μm “black specks” of material observed histologically after 180 days in rabbit intramuscular sites  |
| --- | --- | --- |
|  Geriatric non-human primate (baboon) spine vertebral body injection safety study | Treatments: • β-TCP/collagen combined with 1.0 mg/ml rhPDGF-BB (AUGMENT® Injectable) • β-TCP/collagen combined with 20 mM sodium acetate, pH 6.0 vehicle • Vehicle alone Model: Geriatric, non-human primate (baboon) percutaneous injection of 3 lumbar vertebra per animal Timepoint: 9 months | • All animals survived to their scheduled endpoint • No signs of acute or chronic toxicity • 9-months post-injection, was moderate to marked new bone formation in the injected areas of the vertebral bodies with or without rhPDGF-BB • No signs of local toxicity or neurotoxicity in neighboring lumbar spinal cord segments  |
|  Bacterial Mutagenicity Test - AMES Assay (Genotoxicity) | • Potential of rhPDGF-BB to induce: – histidine (His) reversion in S. typhimurium – tryptophan reversion in E. coli • Six dose levels with the top dose tested at 10 mg/mL (1.0 mg/plate) | The highest dose tested: 10 mg/mL (1.0 mg/plate) rhPDGF-BB was non-mutagenic  |

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|  Fracture Healing of the Tibia in Geriatric-Osteoporotic Rats | • Treatment groups (n=110 rats): – 1.0 mg/mL rhPDGF-BB + collagen/β-TCP (AUGMENT® Injectable) – 0.3 mg/mL rhPDGF-BB + collagen/β-TCP (AUGMENT® Injectable) – sodium acetate + collagen/β- TCP – untreated fracture • Model: Unilateral fracture model (osteotomy model) • Outcomes: MicroCT and Histology- 3 and 5 weeks (n=16) Radiographs and Biomechanical testing – 3 and 5 weeks post fracture (n=64) Histomorphometry – 12 weeks post-fracture (n=18) | • At five weeks, the mechanical strength of AUGMENT® Injectable -treated tibias was not different from the non-fractured contralateral tibia • There were no untoward tissue responses  |
| --- | --- | --- |
|  Diabetic Rat Fracture Model | • Treatment groups (n=110 rats): 1.0 mg/mL rhPDGF-BB + collagen/ β-TCP (AUGMENT® Injectable); 0.3 mg/mL rhPDGF-BB + collagen/ β-TCP (AUGMENT® Injectable) sodium acetate + collagen/ β-TCP untreated fracture • Model: Unilateral fracture model (Einhorn model) • Outcomes: Cellular proliferation – 4 days post-fracture (n=26) Biomechanical testing – 6 and 8 weeks post fracture (n=66) Histomorphometry – 12 weeks post-fracture (n=18) | AUGMENT® Injectable treatment in diabetic rats resulted in: • Increased cell proliferation at 4 days • Increased biomechanical strength as early as 6 weeks • Increased bone content of the fracture callus at 12 weeks • No evidence of either abnormal or ectopic bone formation  |

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|  Partial arthrodesis of the carpus in dogs | • Treatment groups (n=30 dogs): Autologous bone graft: 0.3 mg/ml rhPDGF-BB + Autologous bone graft β-TCP: 0.3 mg/ml rhPDGF-BB + β-TCP Collagen/β-TCP: 0.3 mg/ml rhPDGF-BB + Collagen/β-TCP (AUGMENT® Injectable) • Model: Two-level arthrodesis of the carpus • Outcomes: Manual palpation – 5 and 12 weeks post-surgery (n=7; n=3) Radiograph – 5 and 12 weeks post surgery (n=7; n=3) Histology – 12 weeks post- surgery (n=13) | • Addition of rhPDGF-BB to the graft materials increased the number and extent of fused joints compared to the materials alone • New bone formed was normal • No evidence of ectopic bone formation • No evidence of acute or chronic toxicity  |
| --- | --- | --- |
|  Biological Assessment of a Bone Repair Model (Rabbit Tibial Osteotomy) | • Unicortical 5-mm osteotomies • Treated with cylinders of: β-TCP β-TCP + 25 μg rhPDGF-BB β-TCP+ 75 μg rhPDGF-BB • Histomorphometric analysis at 4 and 8 weeks post-implantation | • Residual β-TCP detected at four weeks was significantly reduced by eight weeks • No statistically significant differences among the treatment groups  |
|  Tissue distribution and mass balance of radioactivity in Sprague-Dawley rats following an intravenous injection of ¹²⁵I-rhPDGF-BB | • Single IV Injection 0.31 mg/kg • Whole body autoradiography, blood, urine, feces and cage residue collected for radioactivity analysis at different time points up to 7 days | • rhPDGF-BB is widely distributed and cleared rapidly from the circulation. Tmax: 30 min 18% of Cmax at 4 hours • Radioactivity was excreted in urine and feces primarily as unbound ¹²⁵I with smaller amounts of bound ¹²⁵I also excreted in feces  |
|  Pharmacokinetics of radioactivity in Sprague-Dawley rats following intravenous administration or intramuscular implantation of ¹²⁵I-labeled recombinant human Platelet-Derived Growth Factor-BB (rhPDGF-BB) combined with β-Tricalcium Phosphate (β-TCP) | • Single IV Injection 0.31 mg/kg • Single IM Implantation of rhPDGF + β-TCP adjacent to femur 0.29 mg/kg • blood, urine, feces and cage residue collected for radioactivity analysis at different time points up to 7 days | • The systemic bioavailability of the test article was similar by both routes of administration • rhPDGF-BB is rapidly released from the β-TCP matrix over the 24 hours following IM implantation, and is nearly depleted from the implant site by 168 hours post-dose: Tmax: 8 hours t½: 30.3 hours 3% of Cmax at 168 hours  |

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|  Evaluation of In Vivo Release of ^{125}I- Recombinant Human Platelet-Derived Growth Factor (^{125}I-rhPDGF-BB) from β-TCP/COLLAGEN and β-TCP Matrices Implanted in a Rat Calvarial Bone Defect | - Single implantation in calvarial defect     - – β-TCP: 56 µg/kg     - – β-TCP /Collagen: 112 µg/kg - Radioactivity at implantation site measured at different intervals up to 7 days | - Rapid release of 50% in the first 60 minutes and 80% in the first 24 hours - Only 2% of input counts at 7 days - No differences between groups  |
| --- | --- | --- |
|  Evaluation of In Vivo Release of ^{125}I- Recombinant Human Platelet-Derived Growth Factor (^{125}I-rhPDGF-BB) from β-TCP and β- TCP/Human Bone Allograft Matrices Implanted in a Rat Calvarial Bone Defect | - Single implantation in calvarial defect     - – β-TCP (1000 – 2000 µm): 182.4 µg/kg     - – β-TCP (250 – 1000 µm): 187.5 µg/kg     - – Allograft+β-TCP (250 – 1000 µm): 237.6 µg/kg - Radioactivity at implantation site measured at different intervals up to 3 days | - Rapid release of 50% in the first 30 minutes - Only 10% of the initial radioactivity was present at the implantation site at 72 hours (3 days) - No differences among groups  |

### Summary of Human Pharmacokinetic Study

The pharmacokinetic profile was evaluated by implanting of 0.3 mg/ml rhPDGF-BB combined with β-TCP compared to autograft control subjects in the human hindfoot or ankle. A total of 11 subjects were treated: 4 subjects received standard rigid fixation plus autologous bone graft, and 7 subjects received standard rigid fixation plus 0.3 mg/ml rhPDGF-BB combined with β-TCP. Blood samples were collected from each subject prior to treatment and at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 2 days, 3 days, and 7 days. The blood samples were processed to obtain serum, which was frozen and stored until analysis of the PDGF-BB concentration. Serum PDGF-BB levels after the administration of 6-9 cc of rhPDGF-BB combined with β-TCP used in this study fell within the PDGF-BB concentration range of the autograft control subjects receiving comparable volumes of autologous bone graft. Seventeen of the 119 serum samples tested showed quantifiable levels of PDGF-BB (above 7.8 ng/mL). The 17 samples with quantifiable levels of PDGF-BB were found in three subjects; two of three subjects received autograft. The data suggested a low systemic exposure to rhPDGF-BB following one- time implantation of rhPDGF-BB combined with β-TCP (up to 2.7 mg of rhPDGF-BB) in the human hindfoot or ankle. Caution should be taken when interpreting these data because the assay for measuring rhPDGF-BB in human serum has not been fully validated.

## **X. SUMMARY OF PRIMARY CLINICAL STUDIES**

The submission consists of data from three sources that the sponsor has identified as BMTI-2006-01, BMTI-2009-01 and BMTI-2010-01. These numbers correspond to three different clinical studies that incorporated different inclusion/exclusion criteria, endpoints, etc. The first dataset (BMTI-2006-01) evaluated the behavior of a different graft substitute compared to the other two datasets. The investigational graft material in this study was AUGMENT® Bone Graft which consists of β-TCP granules and rhPDGF-BB. The investigational graft

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material in the other two studies (BMTI-2009-01 and BMTI-2010-01) was AUGMENT® Injectable, consisting of different β-TCP granules, bovine collagen and the identical recombinant protein. Because of differences in the granule components, the presence of the collagen component and the action of the collagen component causing complete oxidation of the recombinant protein component, AUGMENT® Bone Graft and AUGMENT® Injectable are considered to be different products whose clinical outcome cannot be combined into a single dataset. As a result of these significant differences between the investigational product in the first study and the investigational product in the second and third studies, only the control data from the first dataset were considered in the discussion described below. Relevant details of these studies are as follows:

### A. Study Designs

#### 1st data source - BMTI-2006-01 (AUGMENT® Bone Graft clinical study performed in the US under IDE G050118)

The data from the control population of this study were used to supplement the control population data from the clinical study that evaluated AUGMENT® Injectable.

This study was designed as a prospective, randomized, controlled, non-inferiority trial. A total of 396 subjects were to be randomized 2:1 investigational:control with the control subjects receiving autograft and the investigational subjects receiving the investigational graft material. All subjects had the joints to be fused stabilized by screw fixation. Subjects requiring foot (hindfoot) or ankle fusions were eligible.

Subjects were enrolled in accordance with the following inclusion/exclusion criteria:

*inclusion*

- at least 18 years of age and considered to be skeletally mature
- bone defect in the hindfoot or ankle requiring fusion using open surgical technique with supplemental bone graft/substitute, requiring one of the following procedures - ankle joint fusion, subtalar fusion, calcaneocuboid fusion, talonavicular fusion, triple arthrodesis (subtalar, talonavicular and calcaneocuboid joints) OR double fusions (talonavicular and calcaneocuboid joints)
- fusion site able to be rigidly stabilized with no more than 3 screws across the fusion site
  - supplemental pins allowed
  - supplemental screws external to the fusion site(s) allowed
  - plate fixation not allowed.
- signed informed consent document, independent, ambulatory, and can comply with all post-operative evaluations and visits

*exclusion*

- has undergone previous surgery of the proposed fusion site
- fusion site requires plate fixation, more than three (3) screws across the fusion site to achieve rigid fixation, or more than 3 kits/9cc of graft

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- radiographic evidence of bone cysts, segmental defects or growth plate fracture around the fusion site that may negatively impact bony fusion
- current untreated malignant neoplasm(s) at the surgical site or currently undergoing radio- or chemotherapy
- pregnant or intending to become pregnant during the study period
  - a urine pregnancy test will be administered within 21 days of the surgical visit to any female unless post-menopausal, has been sterilized or is practicing a medically accepted method of contraception.
- morbidly obese defined as BMI > 45 kg/m²
- pre-existing sensory impairment, e.g., diabetics with baseline sensory impairment, which limits ability to perform objective functional measurements and may be at risk for complications. For the purpose of this protocol, diabetics not sensitive to the 5.07 monofilament (Semmes-Weinstein) are to be excluded.
- metabolic disorder known to adversely affect the skeleton other than primary osteoporosis or diabetes, e.g., renal osteodystrophy or hypercalcemia
- use of chronic medications known to affect the skeleton, e.g., glucocorticoid usage > 10mg/day. NSAID use excluded during the first 6 weeks post-op.
- pre-fracture neuromuscular or musculoskeletal deficiency which limits ability to perform objective functional measurements
- physically or mentally compromised, e.g., current treatment for a psychiatric disorder, senile dementia, Alzheimer's disease, etc., to the extent that the Investigator judges the subject to be unable or unlikely to remain compliant
- allergic to yeast-derived products
- received an investigational therapy within 30 days of proposed surgery or during the follow-up phase of the study
- is a prisoner, known or suspected transient or a history of drug/alcohol abuse within the 12 months prior to screening

Subject evaluation consisted of a series of clinical and radiographic assessments. These were collected at up to 21 days pre-op (if not collected within 6 months of surgery), 7 to 21 days post-op, 6 weeks ± 7 days, 9 weeks ± 7 days, 12 weeks ± 7 days, 16 weeks ± 7 days, 24 weeks ± 14 days, 36 weeks ± 14 days and 52 weeks ± 14 days.

The following clinical and radiographic evaluations were performed:

- pain using VAS
  - general pain
  - pain at fusion site on weight-bearing (if applicable)
  - pain at the autograft harvest site (control subjects only)
- motion at the fusion site (+ or -)
- warmth at the fusion site (none, mild, moderate, severe)
- swelling (none, mild, moderate, severe)
- tenderness at the surgical site (+ or -)
- neuro status (intact or impaired)
- infection (+ or -)

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- weight-bearing status (nonweight-bearing, touchdown, partial weight-bearing, full weight-bearing)
- clinical/radiographic assessment of healing by the investigator (union, evidence of progressive healing (≤ 6 months), delayed union (≤ 6 months), nonunion (@ 36 weeks), uninterpretable at 24 and 36 weeks)
- hardware complications (none, fractured hardware, developing lucency surrounding screws)

Quality of life assessments included SF-12, American Orthopaedic Foot and Ankle Society (AOFAS) Outcomes Scores (Ankle-Hindfoot Scale) and the Foot Function Index (FFI) at 6, 12, 24, 36, and 52 weeks, post-op.

In addition to the investigator's general radiographic evaluation, a more detailed radiographic assessment was performed by an independent reviewer. This assessment was based on anterior-posterior (AP), lateral, and oblique views of the ankle and AP, lateral, and oblique views of the foot, as well as axial heel views only for subjects receiving subtalar or triple arthrodesis. Plain films were taken at each visit to assess standard clinical healing parameters, while computed tomography (CT) scans were only collected at 9, 16, 24, and 36 weeks post-op to determine the degree of fusion. A baseline CT scan was not collected. Radiographs were also obtained before and after re-reduction maneuvers, if necessary.

Serum was collected at baseline (prior to grafting procedure), the 7-21 day post-op visit and at 6, 12 and 24 weeks post-op for the presence of neutralizing and non-neutralizing antibody formation to rhPDGF-BB. Subjects testing positive for anti-rhPDGF-BB antibodies were tested for neutralizing activity.

The primary effectiveness endpoint was defined as the percent of subjects achieving fusion (≥ 50% osseous bridging on CT scans at 24 weeks post-op). A composite endpoint consisting of clinical and radiographic endpoints was also created. Individual subject success was defined as:

- surgical treatment completed per protocol
- subject determined to have union or progressive evidence of healing (as per the Investigator assessment)
- evidence of fusion >25% on CT Scan
- less than 20mm on VAS pain assessment at bone graft harvest site beyond 30 days post-study surgery
- no serious AEs possibly related to treatment
- no second surgical intervention

Fusion success was based on the independent radiographic review of bone formation (fusion) across the treated joints. Greater than or equal to 50% fusion across the joint space was defined as fusion success. For the subtalar joint, the review was isolated to the posterior facet. For procedures involving multiple joints, e.g., triple or double arthrodesis, fusion success was determined by assessment of bone bridging as a percentage of the total fusion construct. Subjects who were categorized as a fusion success at 24 weeks had a confirmatory CT scans taken at 36 weeks. If 36-week CT scans were not available, the

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fusion endpoint was considered to have been achieved at 24 weeks if there was no evidence to the contrary that fusion was not sustained after 24 weeks.

Safety was assessed by the evaluating the frequency and severity of reported AEs.

## 2nd data source - BMTI-2009-01 (AUGMENT® Injectable clinical study performed in Canada)

This study was originally intended to incorporate an identical investigational plan (IP) to that of a US study conducted under an approved Investigational Device Exemption (IDE) application; however, it was approved by Health Canada prior to approval of the US IDE and did not incorporate modifications to the inclusion/exclusion criteria, study endpoints, or definitions of success that had been approved for the IP of the US IDE study. This Canadian study evaluated subjects undergoing foot (hindfoot) and ankle fusions.

This study was designed as a prospective, randomized, controlled, non-inferiority trial. The intent was to enroll a total of 180 subjects randomized 5:1 investigational:control resulting in 150 prospective, randomized investigational subjects and 30 prospective, randomized control subjects. These control subjects were to be combined with 120 control subjects from the original AUGMENT® Bone Graft clinical study described above (BMTI-2006-01). Enrollment was terminated after only 75 total prospective subjects had been enrolled (63 investigational and 12 control).

The control population received autograft bone and the investigational subjects received the investigational AUGMENT® Injectable graft material. All subjects had the joints to be fused stabilized by screw fixation. Subjects requiring foot (hindfoot) or ankle fusions were eligible.

Subjects were enrolled in accordance with the following inclusion/exclusion criteria:

inclusion

- at least 18 years of age and considered to be skeletally mature
- bone defect in the hindfoot or ankle requiring fusion with supplemental bone graft/substitute, requiring one of the following procedures - ankle joint fusion, subtalar fusion, calcaneocuboid fusion, talonavicular fusion, triple arthrodesis (subtalar, talonavicular and calcaneocuboid joints) OR double fusions (talonavicular and calcaneocuboid joints)
- fusion site able to be rigidly stabilized with no more than 3 screws across the fusion site
  - supplemental pins or staples allowed
  - supplemental screws external to the fusion site(s) allowed
- signed informed consent document, independent, ambulatory, and can comply with all post-operative evaluations and visits

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# *exclusion*

- • has undergone previous fusion surgery of the proposed fusion site or revision of failed total ankle arthroplasty
- • fusion site requires plate fixation, more than three (3) screws across the fusion site to achieve rigid fixation, or more than 3 kits/9cc of graft
- • structural bone graft, allograft, bone graft substitute, platelet-rich plasma (PRP) or bone marrow aspirate required
- • requires a pankalar fusion, i.e., fusion of the ankle plus all hindfoot joints (talonavicular, subtalar, and calcaneocuboid) or a tibiotalocalcaneal (ankle and subtalar) fusion
- • radiographic evidence of bone cysts, segmental defects or growth plate fracture around the fusion site that may negatively impact bony fusion
- • current untreated malignant neoplasm(s) at the surgical site or currently undergoing radio- or chemotherapy or has been diagnosed with hypercalcemia
- • pre-existing sensory impairment, e.g., diabetics with baseline sensory impairment, which limits ability to perform objective functional measurements and may be at risk for complications
  - – diabetics not sensitive to the 5.07 monofilament (Semmes-Weinstein) are to be excluded
- • metabolic disorder known to adversely affect the skeleton other than primary osteoporosis or diabetes, e.g., renal osteodystrophy or hypercalcemia
- • use of chronic medications known to affect the skeleton, e.g., glucocorticoid usage > 10mg/day
- • physically or mentally compromised, e.g., current treatment for a psychiatric disorder, senile dementia, Alzheimer's disease, etc., to the extent that the Investigator judges the subject to be unable or unlikely to remain compliant
- • allergic to yeast-derived products or bovine collagen or other bovine-sourced products
- • received an investigational therapy within 30 days of proposed surgery or during the follow-up phase of the study
- • is a prisoner, known or suspected transient or a history of drug/alcohol abuse within the 12 months prior to screening
- • pregnant or intending to become pregnant during the study period
  - – A urine pregnancy test will be administered within 21 days of the surgical visit to any female unless post-menopausal, has been sterilized or is practicing a medically accepted method of contraception.
- • morbidly obese defined as BMI > 45 kg/m$^{2}$
- • currently has an acute infection at the surgical site
- • history of anaphylaxis or of multiple non-environmental allergies that have precipitated an anaphylactic reaction

Subject evaluations consisted of a series of clinical and radiographic assessments. Data were collected according to the following schedule: within 21 days of scheduled surgery, intra-op,

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7-21 days post-op, 6 weeks ± 7 days, 9 weeks ± 7 days, 12 weeks ± 7 days, 16 weeks ± 7 days, 24 weeks ± 14 days, 36 weeks ± 14 days and 52 weeks ± 14 days.

The following clinical and radiographic evaluations were performed:

- pain using VAS
  - general pain
  - pain at fusion site on weight-bearing (if applicable)
  - pain at the autograft harvest site (control subjects only)
- motion at the fusion site (+ or -)
- warmth at the fusion site (none, mild, moderate, severe)
- swelling (none, mild, moderate, severe)
- tenderness at the surgical site (+ or -)
- neurological status (intact or impaired)
- infection (+ or -)
- weight-bearing status (nonweight-bearing, touchdown, partial weight-bearing, full weight-bearing)
- clinical/radiographic assessment of healing by the investigator (union, evidence of progressive healing (≤ 6 months), delayed union (≤ 6 months), nonunion (@ 36 weeks), uninterpretable at 24 and 36 weeks)
- hardware complications (none, fractured hardware, developing lucency surrounding screws)

Quality of life assessments included SF-12, AOFAS Outcomes Scores (Ankle-Hindfoot Scale) and the Foot Function Index (FFI) at 6, 12, 24, 36, and 52 weeks, post-op.

Serum was collected at baseline (prior to the grafting procedure), the 7-21 day post-op visit and at 6, 12 and 24 weeks post-op for the presence of neutralizing and non-neutralizing antibody formation to rhPDGF-BB. Subjects testing positive for anti-rhPDGF-BB antibodies were tested for neutralizing activity.

The sponsor defined a series of primary and secondary radiographic and clinical effectiveness endpoints:

*primary radiographic effectiveness endpoint*

- 24-week fusion rate (%) by CT scans

*secondary radiographic effectiveness endpoints*

- mean time to clinical healing, determined by investigator's clinical/radiographic assessment
- supplemental radiographic parameters for healing as determined by the independent radiologist
- overall assessment of osseous bridging based on CT at 9, 16, 24 and 36 weeks post-op
- presence of heterotopic bone formation
- assessment of β-TCP resorption

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- hardware (screw) complications

*secondary clinical endpoints*

- 36-week fusion rate (%) based on CT scans
- 36-week composite success
- time to fusion based on CT scan
- 36-week fusion rate based on clinical assessments
- clinical success defined as improvement in pain on weight-bearing and lack of revision surgery
- time to radiographic healing as determined by the independent radiologist
- pain on weight-bearing
- pain at graft harvest site
  - this was to be assessed prior to all other functional assessments and rehabilitation procedures at each visit
- operative time
- quality-of-life assessments based on the SF-12 (Physical Composite Score [PCS] component only), AOFAS outcomes score and the Foot Pain and Disability Index

The primary safety endpoint was defined as pain scores at any secondary surgical site. Secondary safety endpoints included total operating room time and surgical wound infection rate. In addition, all subjects were monitored over the initial 12-month post-op period for incidence of loss of reduction, infection, non-union, need for revision fusion surgery, and complications associated with hindfoot and ankle fusion procedures, as well as any other AEs that were reported.

The primary effectiveness endpoint was defined as the percent of subjects achieving fusion (≥ 50% osseous bridging on CT scans at 24 weeks post-op). Secondary effectiveness endpoints included:

- fusion rate (%) at 36 weeks based on CT scans
- radiographic assessments
- time to healing
- pain on weight-bearing
- graft harvest site pain
- quality of life evaluations
- a composite success endpoint

The composite endpoint consisted of clinical and radiographic endpoints. Success for the composite endpoint was defined as:

- surgical treatment completed per protocol
- subject determined to have union or progressive evidence of healing (as per the Investigator assessment)
- evidence of fusion >25% on CT scan
- less than 20 mm on VAS pain assessment at bone graft harvest site ≥ 6 weeks post-op
- no serious AEs possibly related to treatment

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- no second surgical intervention

Fusion success was based on the independent radiographic review of bone formation (fusion) across the treated joints. Greater than or equal to 50% fusion across the joint space was defined as fusion success. Multiple fusions were to be assessed based on a defined index joint. The index joint for multiple fusions was defined as the talonavicular joint if a talonavicular joint fusion was performed. The subtalar joint was defined as the index joint if a talonavicular fusion was not performed. For the subtalar joint, the review was to be isolated to the posterior facet because this is traditionally considered the most significant area of interest for this procedure. For multi-joint fusions, e.g., triple or double arthrodesis, fusion of the index joint was to be used for the purpose of determining the primary endpoint. The independent radiologist was also instructed to assess the fusion status of each individual joint. All subjects were to have a 36-week CT scan. If the 36-week CT scans were unavailable, the fusion endpoint was considered to have been achieved at 24 weeks unless there was evidence to the contrary.

Safety was assessed by the evaluating the frequency and severity of reported AEs.

### **3rd data source - BMTI-2010-01 (AUGMENT® Injectable clinical study performed in the US under IDE G090133)**

This study was designed as a prospective, randomized, concurrently-controlled, multi-center trial to assess the use of AUGMENT® Injectable in fusions stabilized with screw fixation compared to the same treatment using autograft bone in treating foot joint degeneration in adult subjects. The objective of the study was to demonstrate the non-inferiority of the synthetic AUGMENT® Injectable graft compared to autograft bone. Clinical (pain using a Visual Analog Scale (VAS) and function using the Foot Function Index (FFI)) and radiographic (x-rays with secondary assessments using CT scans to demonstrate presence of fusion) endpoints were assessed out to 24 months post-op. Due to the nature of the surgical procedure, i.e., the need to harvest an autograft from a site away from the fusion in the control subjects, it was not possible to blind the investigators, surgical assistants or subject with respect to treatment assignment. Subject masking existed only until the immediate post-op period. The radiographic reviewers, on the other hand, remained blinded with respect to treatment for the entirety of the study.

This study was originally approved for a total of 201 subjects randomized 2:1 investigational:control (134 investigational and 67 control) at a total of 25 sites. The investigational plan was subsequently modified by increasing enrollment to a total of 300 subjects randomized 2:1 (200 investigational and 100 control) at a total of 30 sites. The study was not designed to incorporate any control subject data from any other study. Because enrollment in this study was never completed, a total of 104 subjects were enrolled. Of these subjects, 96 were enrolled under the US IDE (G090133, 64 investigational:32 control subjects) and the remainder in Canada. There were 18 US sites and 4 Canadian sites.

The control population received autograft bone and the investigational subjects received the investigational AUGMENT® Injectable graft material. All subjects had the joints to be fused stabilized by screw fixation. Unlike the subjects eligible for the studies defined in BMTI-

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2006-01 and BMTI-2009-01, the subjects eligible for enrollment in this study were determined to only need a foot fusion. Because of differences in subject selection and treatment, subjects requiring a foot fusion are not the same as those requiring an ankle fusion. In addition, subjects undergoing a primary procedure are not equivalent to those undergoing a revision procedure.

Subjects were enrolled in accordance with the following inclusion/exclusion criteria:

*inclusion*

- at least 21 years old and considered skeletally mature
- minimum baseline VAS full weight-bearing without assistive devices pain score of 40mm on a 100mm scale
- diagnosed with degenerative joint disease (DJD) affecting the hindfoot due to a congenital or acquired deformity, osteoarthritis, rheumatoid arthritis, post- traumatic arthritis or ankylosing spondylitis of the subtalar, calcaneocuboid, and/or talonavicular joints
- requires one of the following hindfoot fusion procedures with supplemental bone graft/substitute: subtalar fusion (talocalcaneal), calcaneocuboid fusion, talonavicular fusion, triple arthrodesis (subtalar, talonavicular and calcaneocuboid joints) OR double fusions (any combination of any two of the following: subtalar, talonavicular and calcaneocuboid joints)
- fusion site able to be rigidly stabilized with no more than 3 screws across the fusion site
  - supplemental pins or staples allowed
  - supplemental screws external to the fusion site(s) allowed
- signed informed consent document, independent, ambulatory, and can comply with all post-operative evaluations and visits

*exclusion*

- undergone previous fusion surgery at the proposed location, i.e., revision of a failed fusion
- previous hindfoot surgery
  - previous procedures that do not have significant compromise of the peri-articular soft tissues are allowed. Examples include:
    - diagnostic arthrotomy and debridement
    - arthrotomy for removal of osteophytes
    - open reduction internal fixation for tibial fractures or foot fracture
    - ligament/ tendon repair or reconstruction
    - hardware removal
- more than one previous procedure at the involved joints
- retained hardware spanning the joint(s) intended for fusion
- procedure anticipated to require plate fixation (including claw plates), intramedullary (IM) nails or more than 3 screws to achieve rigid fixation based on pre-op planning
- procedure expected to require more than 9cc of graft material based on pre-op planning

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- procedure expected to require structural bone graft, allograft, bone graft substitute, platelet rich plasma (PRP) or bone marrow aspirate
- procedure expected to require a pantalar fusion, i.e., fusion of ankle plus all hindfoot joints (talonavicular, subtalar, and calcaneocuboid) or an ankle fusion in combination with any hindfoot fusion
- expectation of performing a subsequent surgery of the concomitant hindfoot within 12 months of the investigational procedure
- presence of bilateral degenerative joint disease that may require fusion or surgical repair of the contralateral hindfoot with 12 months of enrollment
- radiographic evidence of bone cysts, segmental defects or growth plate fracture near the fusion site that could negatively impact the proposed fusion procedure
- tested positive or been treated for a malignancy in the past or is suspected of having a malignancy or currently undergoing radio- or chemotherapy treatment for a malignancy anywhere in the body, whether adjacent to or distant from the proposed surgical site
- pre-existing sensory impairment, e.g., diabetics with baseline sensory impairment, which limits ability to perform objective functional measurements and may be at risk for complications
  - diabetics not sensitive to the 5.07 monofilament (Semmes-Weinstein) are to be excluded
- metabolic disorder known to adversely affect the skeleton other than primary osteoporosis or diabetes, e.g., renal osteodystrophy or hypercalcemia
- use of chronic medications known to affect the skeleton, e.g., glucocorticoid usage > 10mg/day
- pre-fracture neuromuscular or musculoskeletal deficiency which limits the ability to perform objective functional measurements
- has vascular insufficiency (large or small vessel disease) or kidney insufficiency
- diagnosis or history of bi-polar disorder, schizophrenia, suicidal ideation, post-traumatic stress disorder, senile dementia or Alzheimer's disease as defined via standard, recognized methods such as the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria, to the extent that the investigator judges the subject to be unable or unlikely to remain compliant
- allergic to yeast-derived products or bovine collagen or other bovine-sourced products
- received an investigational therapy within 30 days of proposed surgery or during the follow-up phase of the study
- is a prisoner, known or suspected transient or a history of drug/alcohol abuse within the 12 months prior to screening
- pregnant or intending to become pregnant within 12 months of the study procedure
  - A urine or blood pregnancy test will be administered within 2 days of the surgical visit to any female unless post-menopausal, has been sterilized or is practicing a medically accepted method of contraception.
- morbidly obese defined as BMI > 45 kg/m²
- currently has an acute infection at the surgical site
- history of anaphylaxis or of multiple non-environmental allergies

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- refuses to discontinue tobacco use prior to surgery
- medical history that contraindicates use of surgical tourniquet

Subject evaluations consisted of a series of clinical and radiographic assessments. Data were collected according to the following schedule: within 21 days of scheduled surgery, intra-op, 7-21 days post-op, 6 weeks ± 7 days, 9 weeks ± 7 days, 12 weeks ± 7 days, 16 weeks ± 7 days, 24 weeks ± 14 days, 36 weeks ± 14 days, 52 weeks ± 14 days and 104 weeks ± 14 days. Annual follow-up visits occurred until the last subject enrolled had returned for their 104 week visit.

The following clinical and radiographic evaluations were performed:

- pain using VAS
  - pain at fusion site, non weight-bearing
  - pain at fusion site on weight-bearing without assistive devices, starting at 6 weeks post-op
  - pain at the autograft harvest site (control subjects only)
- motion at the fusion site (+ or -)
- warmth at the fusion site (none, mild, moderate, severe)
- abnormal swelling (none, mild, moderate, severe)
- tenderness at the surgical site (+ or -)
- neurological status (intact or impaired)
- infection (+ or -)
- weight-bearing status (non weight-bearing, touchdown, partial weight-bearing, full weight-bearing)
- clinical/radiographic assessment of healing by the investigator (union, evidence of progressive healing (@ 24 weeks), delayed union (@ 24 weeks), nonunion (≥ 36 weeks), uninterpretable (day 7-21), secondary therapeutic intervention required)

Quality of life assessments included SF-12, AOFAS Outcomes Scores (Ankle-Hindfoot Scale) and the Foot Function Index (FFI) at 6, 12, 24, 36 and 52 weeks, post-op.

Serum was collected at baseline (prior to grafting procedure), the 7-21 day post-op visit and at 6, 12, 24, 36, 52 and 104 weeks post-op then annually until the last subject enrolled had returned for their 104 week evaluation. Serum was assessed for the presence of neutralizing and non-neutralizing antibody formation to rhPDGF-BB or to bovine Type I collagen. Subjects testing positive for anti-rhPDGF-BB or anti-bovine Type 1 collagen antibodies were tested for neutralizing activity. Subjects who tested positive for antibodies to rhPDGF-BB or bovine Type 1 collagen at their last scheduled blood draw were required to provide additional samples at 3 month intervals until titers returned to baseline.

The sponsor defined a series of primary and secondary effectiveness and safety endpoints that consisted of clinical and radiographic parameters.

*primary effectiveness endpoint*

The sponsor defined a composite effectiveness endpoint as follows:

- radiographic evidence of fusion at 24 weeks

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- absence of significant pain defined as:
  - absence of weight-bearing pain, i.e., pain less than 20mm on a 100mm VAS scale AND graft site harvest pain, i.e., pain less than 20mm on a 100mm VAS scale
- improvement in function as demonstrated by at least a 10 point reduction in the Foot Pain and Disability Index (also referred to as the Foot Function Index or FFI); Budiman-Mak, 1991
- absence of any secondary interventions

*secondary effectiveness endpoints*

The sponsor defined a series of secondary effectiveness endpoints:

- CT fusion based on full complement of joints at 24 weeks post-op
- Subject Performance Composite plus CT fusion based on full complement of joints at 24 weeks post-op
- Subject Performance Composite exclusive of radiographic success
- CT fusion based on individual joints
- radiographic union (3-aspects) based on full complement of joints
- radiographic union (3-aspects) based on individual joints
- radiographic union (2-aspects) based on full complement of joints
- radiographic union (2-aspects) based on individual joints
- clinical healing at the subject level
- clinical healing at the joint level
- clinical success
- composite success
- functional success as determined by:
  - weight-bearing pain
    no pain or mild pain defined as ≤ 20mm on VAS scale in the absence of ambulatory assist devices.
  - maintenance or improvement in function; and
  - no need for a secondary surgical intervention
- therapeutic failure
- time to the binary endpoints listed above
- SF-12
- FFI
- AOFAS
- VAS pain scores (fusion site, graft harvest site, weight bearing pain)
  weight-bearing pain success defined as ≥ 20mm reduction on VAS pain
  assessment of fusion site (performed prior to all other functional assessments and rehabilitation procedures at each visit)
- assessment of β-TCP resorption
- hardware complications (i.e., screws)
- presence of heterotopic bone formation

*primary safety endpoints*

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- surgical site complications associated with injury or standard surgical treatment, including non-union
- product-related AEs categorized as anticipated and unanticipated

secondary safety endpoints

- operative time
- wound infection rate
- pain scores at any secondary surgical site
- overall AEs
- pain at graft harvest site (assessed prior to collection of other functional assessments and rehab)

Subjects were also monitored over the course of the study for the loss of reduction, infection, non-union, need for revision fusion surgery, and associated complications with hindfoot fusion procedures, in addition to the incidence of other AEs. Like the effectiveness assessments, safety assessments continued annually after the 104-week visit until the last enrolled subject had their 104-week evaluation.

Safety was assessed by the evaluating the frequency, severity and relatedness of reported AEs.

### B. Accountability of Combined PMA Cohort

Because each of the three datasets described above incorporated different inclusion/exclusion criteria and endpoints, e.g., foot fusion alone versus foot and ankle fusion and minimum VAS pain score for eligibility, a propensity score matching analysis was performed in order to identify a single set of investigational and control subjects derived from the three datasets that were comparable and could be evaluated for the purpose of assessing the safety and effectiveness of AUGMENT® Injectable. Propensity score analysis involves matching and statistical adjustment for measured confounders. The sources of data and the number of eligible subjects from each dataset are outlined in Figure 2 below:

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![img-1.jpeg](img-1.jpeg)

Figure 2: Subject Accounting Tree for Clinical Studies

Throughout the 52 week follow-up period for all three studies there was a high rate of subject follow up, with approximately 90% of subjects having outcome data available at 52 weeks. For the AUGMENT® Injectable group, 91.7% of subjects had endpoint data available for all assessments at 52 weeks. For the autograft group, the 52 week follow up rate for all assessments was 91.0%.

#### Study withdrawals prior to randomization

Table 3 presents the number of subjects who withdrew prior to randomization for each study.

Table 3: Study Withdrawals Pre-randomization

|  Pre-randomization withdrawal | Subjects  |
| --- | --- |
|  BMTI 2009-01 | 6  |
|  BMTI 2010-01 | 5  |
|  BMTI 2006-01 | 21  |
|  Total subjects withdrawn prior to randomization | 32  |

#### Randomized but not treated

Table 4 presents the number of subjects in each study who withdrew following randomization but prior to treatment.

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Table 4: Study withdrawals post-randomization/pre-treatment

|  Post-Randomization Withdrawal | AUGMENT® Injectable | Autograft  |
| --- | --- | --- |
|  BMTI 2009-01 | 0 | 0  |
|  BMTI 2010-01 | 0 | 2  |
|  BMTI 2006-01 | - | 7  |
|  Total subjects withdrawn after randomization/prior to treatment | 0 | 9  |

The primary study withdrawals post randomization and prior to treatment occurred in BMTI 2006-01. In the AUGMENT® Injectable group, there were no subjects who withdrew after randomization but prior to treatment.

### C. Study Population Demographics and Baseline Parameters in Combined Dataset

The baseline demographic factors for the treated subjects in the combined dataset are presented in Table 5. Overall, the baseline subject demographics in the investigational and control groups were similar, a consequence of the propensity score matching algorithm.

Table 5: Demographics and Clinical Factors

|   | AUGMENT Injectable (AI) N=132 | Autograft N=167 | AI vs Autograft P-value*  |
| --- | --- | --- | --- |
|  Sex |  |  | 0.816  |
|  Male | 70 (53.03%) | 86 (51.5%) |   |
|  Female | 62 (46.97%) | 81 (48.5%) |   |
|  Affected Foot/Ankle |  |  | 0.131  |
|  Ankle fusion | 31 (23.48%) | 46 (27.54%) |   |
|  Subtalar fusion | 52 (39.39%) | 59 (35.33%) |   |
|  Calcaneocuboid fusion | 3 (2.27%) | 0 (0.0%) |   |
|  Talonavicular fusion | 6 (4.55%) | 9 (5.39%) |   |
|  Double fusion^{1} | 21 (15.91%) | 17 (10.18%) |   |
|  Triple arthordesis^{2} | 19 (14.39%) | 36 (21.56%) |   |
|  Ankle-Hindfoot fusion | 0 (0.0%) | 0 (0.0%) |   |
|  Ever smoked |  |  | 0.562  |
|  No | 61 (46.21%) | 83 (49.7%) |   |
|  Yes | 71 (53.79%) | 84 (50.3%) |   |
|  Obese (BMI >= 30) |  |  | 0.061  |
|  No | 68 (51.52%) | 68 (40.72%) |   |
|  Yes | 63 (47.73%) | 99 (59.28%) |   |
|  Older (>= 65 yo) |  |  | 0.133  |
|  No | 97 (73.48%) | 109 (65.27%) |   |

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|  Yes | 35 (26.52%) | 58 (34.73%) |   |
| --- | --- | --- | --- |
|  **Baseline Weight Bearing Pain > 40mm** |   |   | 0.569  |
|  No | 12 (9.09%) | 19 (11.38%) |   |
|  Yes | 120 (90.91%) | 145 (86.83%) |   |
|  **Graft Material Used^{3}** |   |   | 0.000  |
|  Not recorded | 0 (0.0%) | 1 (0.6%) |   |
|  1-3cc | 78 (59.09%) | 49 (29.34%) |   |
|  4-6cc | 40 (30.30%) | 77 (46.11%) |   |
|  7-9cc | 14 (10.61%) | 40 (23.95%) |   |

*Fisher's exact test p-value for categorical v…

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**Source:** [https://fda-staging.innolitics.com/device/P100006S005](https://fda-staging.innolitics.com/device/P100006S005)

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