Investigational plan



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rhBMP-2/ACS vs. Autograft for Critical Size Tibial Defects

  1. INVESTIGATIONAL PLAN


Purpose

Fractures of long bones constitute the majority of emergency operating room procedures in most trauma centers. Of these long bone injuries, tibial fractures are the most common. The National Center for Health Statistics reports an annual incidence of 492,000 fractures of the tibia and fibula per year in the United States. Patients with tibial fractures remain in the hospital for a total of 569,000 hospital days and incur 825,000 physician visits per year in the United States. Delayed fracture healing is a common complication associated with high-energy tibia fractures. Open tibia fractures with bone loss rarely unite without a secondary intervention. Delayed bone grafting of the defect is commonly used to provide stimulus for healing. The use of an autogenous iliac crest bone graft (ICBG) has remained the gold standard in the treatment of tibial non-unions with a bone defect. However, there are significant limitations to autogenous bone grafting, including the increased risk of infection from a second surgical incision and pain associated with the bone graft harvest site, which may range from 1-5 days to more than a year. Additional risks include iatrogenic fracture and damage to neurovascular structures. Also, not all patients are suitable donors. Relative contraindications to ICBGs include previous iliac crest harvesting; poor bone quality secondary to underlying disease, smoking or medications that affect the quality of bone; and advanced patient age. Finally, there is a finite amount of bone that may be obtained from the ilium, and it may not be adequate in all donors to address critical size defects. Recent technological advances with the advent of recombinant bone morphogenetic proteins emerging as a viable bone graft substitute may offer a viable alternative for patients.


The purpose of our study is to evaluate the use of one such recombinant protein in patients at a high risk for nonunion. We will evaluate open, tibial shaft fractures treated with an intramedullary nail and a circumferential bone defect of at least one centimeter in length compromising at least 50% of the circumference of the bone. Patients with critical sized defects who undergo a planned, secondary grafting or whose fractures fail to demonstrate progression towards union over three consecutive months of radiographic and clinical evaluation will be included. Patients will be randomized to the use of recombinant human bone morphogenetic protein 2 (RhBMP-2) or standard ICBG to stimulate healing. The ability to restore skeletal integrity without the morbidity associated with bone graft harvesting would represent a major advantage for the patient. As a secondary evaluation, given that rhBMP-2 has been associated with decreased infections when used in open tibia fractures, we will also determine if patients with these severe fractures have a decreased infection rate with the use of rhBMP-2/ACS relative to the control group. In addition, the overall economic impact of the 2 treatment groups will be evaluated with a cost effectiveness evaluation.
Research Question:
Primary:

What is the relative effect of rhBMP-2/ACS versus autogenous ICBG on rates of union in patients with critical size defects following tibial shaft fractures?


Null hypothesis: rhBMP-2/ACS has the same union rate when used in

critical-sized defects as does ICBG.
Secondary:

What is the relative effect of rhBMP-2 versus autogenous ICBG on infection rates in patients with nonunion or critical size defects following tibial shaft fractures?


Null hypothesis #2: The infection rate in open tibias with critical-sized defects treated with rhBMP-2 and autogenous ICBG are the same.

What is the economic impact of the use of RhBMP 2 for tibial fractures with critical sized defects?


Null hypothesis #3: There will be no difference in the economic cost of the treatment of critical sized defects using the RhBMP-2 versus iliac crest bone graft.

This investigation is a prospective, stratified, parallel, randomized, blinded multicenter trial to evaluate the use of rhBMP-2/ACS in 25 patients versus a control group of 25 patients who have tibial fractures with critical size defects. Randomization will be concealed and the study will include data collectors and analysts blinded to treatment arm. Our primary outcome, fracture healing at 12 months, will be independently adjudicated by a committee of orthopaedic surgeons at 12 months. Only Level 1 Trauma Centers will participate, all of which are familiar with randomized clinical trails and have Orthopaedic Trauma Association (OTA) members participating. Approval by each center’s institutional review board will be obtained prior to commencing the study and we will follow the research guidelines set forth by each site.


Protocol
The patients who provide informed consent will be randomized to one of two treatment groups: Patients in the control group (C) will not receive the rhBMP-2, but instead will be treated with an autogenous iliac crest bone graft. Patients in the treatment group (T) will receive 1.50 mg/ml -12 mg of rhBMP-2 soaked on a absorbable collagen sponge (rhBMP-2/ACS) as an adjuvant to a freeze-dried cancellous allograft. Each arm of the study will be separately randomized via a computer-generated number at the Data Control Center at University of Texas-Southwestern. The grafting material for both groups will be surgically implanted on a delayed basis. For our study, patients will be bone grafted between six and ten weeks after the initial injury. This time-frame is consistent with bone grafting in the previous IDE study (G990226). In an acute fracture setting, autogenous bone graft is not indicated for at least the first six weeks as the factors present in the fracture hematoma and in the fracture region would lead to consumption of the autogenous bone graft. It is not appropriate for anyone to be considered for acute bone grafting in tibial shaft fractures until at least six weeks after the initial injury. Time intervals for the bone graft surgery are between six and ten weeks after injury with no evidence of fracture healing on the radiographs. In addition, sometimes the soft tissue injury which accompanied the tibial shaft fracture may be so extensive that even at ten weeks it may not be an appropriate soft tissue envelope in order to operate through. We leave that to the discretion of the surgeons when it is safe for intervention to promote healing.

The case report form provides a space to record the size of the defect radiographically from the AP and lateral x-rays. The measurement should be recorded as a total of the length, width and depth of the defect. Because an intramedullary nail is in place, the depth of the defect is to be recorded as the cortical thickness. In addition, there should be measurements made of the defect volume pre and post debridement intra-operatively and recorded on the case report form.
The patients in the control group will undergo iliac crest bone graft surgery per the surgeon’s usual practice. The treatment group will be managed in a similar fashion, with the rhBMP-2/ACS placed at the site of bone defect on a collagen sponge carrier per manufacturer’s instructions. The patients will receive allograft chips (between 15 cc to 60 cc) packed into the defect prior to an overlay of the rhBMP-2/ACS. Freeze dried cancellous allograft will be provided in prepackaged containers of 15 cc chips. The chips will be implanted in the fracture defect in 15 cc increments until the fracture defect is filled as determined by the surgeon. The maximum amount of allograft chips is 60 cc to be used to fill the defect. The allograft chips will be loosely packed to fill the cortical defect flush to the cortical bone. After the allograft is implanted into the site and there is an adequate hemostasis, the RhBMP2 sponge will be applied as an overlay covering the allograft and bridging the proximal and distal tibial fragment of the defect; that is laying flat on the surface. The sponge is not to be folded, rolled or placed in any other configuration. The sponge requires no sutures to be held in place. If the patient requires more than one large pack of Infuse, they will be excluded from the study. This RhBMP2/ACS implant will be placed directly adjacent to viable muscle bed. A drain will not be used. Wound closure will commence when hemostasis is obtained. The amount of cancellous chips and brand used will be recorded on the case report form.

Medtronic Sofamer Danek markets rhBMP-2/ACS as INFUSE Bone Graft. They have agreed to provide kits of rhBMP-2 to the 25 patients randomized to the treatment group. This donation is unrestricted. Medtronic Sofamer Danek will not be a participant in the study, nor will have any access to patient or study data or any input into data analysis, results and presentations.


Data on the cost of care will be collected on the day they receive the bone grafting procedure (control and treatment groups). This will include the charges associated with the surgical procedures for bone grafting (control and treatment), days hospitalized, costs for subsequent admissions for complications and post-operative care throughout the study period up to 1 year follow-up.
Measurements

The patients in both groups will be evaluated at 2 weeks, 6 weeks, 12 weeks, 18 weeks, 6 months and 12 months. Outcome measures will be “union,” “wound healing and infection,” and “need for further intervention.” Pain will be documented using the Visual Analogue Scale (VAS) at each visit. Short Form-12 (SF-12), Short Musculoskeletal Functional Assessment (SMFA) and Sickness Impact Profile (SIP) will be completed at time of surgery, 6 months and 12 months.


The SF-12 questionnaire was developed from the Medical Outcomes Study. It is a self-administered, 12-item questionnaire that measures health-related quality of life in 8 domains. Both physical and mental summary scores can be obtained. Each domain is scored separately from 0 (lowest level) to 100 (highest level). The instrument has been extensively validated and has demonstrated good construct validity, high internal consistency, and high test-retest reliability. Our decision to use the SF-12 over other available instruments was based on its widespread use in orthopaedics, its use in previous studies evaluating fracture outcomes, and the strong evidence of validity.
The SMFA is a shorter version of the 101 item Musculoskeletal Function Assessment (MFA) questionnaire. The SMFA is a 46 item questionnaire consisting of the dysfunction and bother index. The dysfunction index has 34 items for assessment of patient function, while the bother index consists of 12 items designed to detect how much patients are bothered by functional items. The SMFA has been evaluated for reliability, validity and responsiveness in patient populations. We chose this scale because it is a short, validated instrument to provide us with information regarding the patient’s functional status.
The SIP is a quality of life scale developed in the United States in 1972 designed to measure health status or the resulting dysfunction due to disease. The instrument is a 136 item questionnaire divided into 12 categories of daily activity including: emotional behavior, body and movement, social behavior, sleep and rest, home management, mobility, work, recreation, ambulation, alertness behavior, communication and eating. It is a self administered questionnaire. The SIP was developed with information from over 1000 people on dysfunctions of behavioral changes that were related to health. It has been validated with the score relating to sickness and self-assessment of dysfunction. In addition, the SIP was a useful tool in providing information for patients in the LEAP study. Our patient population will have a similar degree of injury as those enrolled in the LEAP study.
Inclusion/Exculsion Criteria

CRITERIA FOR INCLUSION OF SUBJECTS:


  • All patients age 18-65 with open tibia fractures involving the diaphysis will be eligible for inclusion.

  • Tibia fractures with a circumferential bone defect of at least one centimeter in length compromising at least 50% of the circumference of the bone.

  • The definitive treatment of the tibia fracture must be with an intramedullary nail (may have temporary external fixation prior to IM nail placement).

  • Patients whose treatment plan includes placement of a bone graft between 6 to 10 weeks after their initial injury.

  • Patients must not have evidence of infection by clinical examination.

  • Patients who are independent living and ambulation prior to injury.

  • English and Spanish speaking individuals are eligible.

  • Patients with bilateral tibia fracture; if both fractures require a bone graft, then each will be randomized separately.

  • The patient, or a designated appointee, must be willing to provide consent. The patient must be available for follow-up for at least 12 months following definitive surgical procedure.

  • Patients who smoke are not excluded from the study.

A female of childbearing potential must have a negative pregnancy test within 72 hours prior to surgery and must agree use adequate contraception for a period of at least 1 year following implantation of rhBMP-2. Written, informed consent will be obtained from the patient or legal guardian.


CRITERIA FOR EXCLUSION OF SUBJECTS:


  • Female patients who are pregnant or lactating.

  • Patients with known hypersensitivity to rhBMP-2 or bovine type I collagen.

  • Patients with a history of tumor, a resected or extant tumor, an active malignancy, or patients undergoing treatment for malignancy.

  • Patients who are skeletally immature (>18 years of age or no radiographic evidence of epiphyseal closure).

  • Patients with inadequate neurovascular status, e.g. high risk of amputation.

  • Patients with compartment syndrome of the affected limb.

  • Patients with immune deficiency or history of auto-immune disease,

  • Patients undergoing treatment of any other investigational therapy within the month preceding implantation or planned within the 12 months following implantation.

  • Patients with the inability to return for required follow-up visits and/or medical co morbidities which preclude treatment with a general anesthetic.

  • Patients with an active infection at the operative site, purulent drainage from the fracture or evidence of active osteomyelitis at the time of bone grafting. In addition, patients with intraoperative positive gram stain or an elevated CRP after laboratory screening for infection will be excluded.

  • Patients with segmental defects longer than 5 cm in length.

  • Patients with segmental defects who require more than 60 cc of bone graft.

  • Patients who require more than one large kit of rh-BMP 2 at time of surgery.

  • Patients whose anticipated treatment plan also includes the use of other procedures to promote fracture healing, e.g. ultrasound, magnetic field or electrical stimulation.

  • Patients whose tibia fracture has been treated with addition fixation beyond the intramedullary nail, e.g. plates, wires, or screws

  • Patients with pathological fractures; a known history of Paget’s disease or known history of heterotopic ossification.

  • Patients with a Glasgow Coma Scale less than 15 (less than fully awake) at the time of informed consent.

  • Patients with previous hardware in place which prevents placement of an intramedullary nail for treatment of the tibial shaft fracture.

  • Patients who are not treated with an intramedullary nail.


Number of Sites/Investigators/Patients

There will up to a total of ten (10) sites enrolling patients, Currently five Level 1 Trauma Centers have been identified to participate (see table below), all of which are familiar with randomized clinical trails and have Orthopaedic Trauma Association (OTA) members participating. Future sites will be identified after IDE approval by the FDA and the FDA will be notified in the annual report. Approval by each center’s institutional review board will be obtained prior to commencing the study and we will follow the research guidelines set forth by each site. A total 50 patients will be enrolled in this study. The definitive treatment of the tibia fracture in all patients must be with an intramedullary nail. The number of patients enrolled at each site will be dependant on the random nature of the admission to hospital of eligible patients. No one site will enroll more than 6 patients in this study.


Currently Identified Study Sites

Principal Investigator:

Lisa K. Cannada




Associate Professor

St. Louis University Hospital

Co-Principal Investigator:

Paul Tornetta III




Professor

Orthopaedic Surgery-Boston Univ.

Michael J. Bosse

Director of Orthopaedic Clinical Research

Orthopaedic Surgery

Carolinas Medical Center



Theodore Miclau, III



Professor/Vice Chair

Orthopaedic Surgery

Univ. of California, SF



Alan L. Jones

Director of Orthopaedic Trauma

Orthopaedic Surgery

Baylor Univ. Hospital



The randomization scheme is a computerized randomization scheme. We will use a standard 4 block randomization scheme that will be pre-programmed into the Online Randomizer for each center participating in the trial. The scheme is a standard 4 block scheme with no subgroups. Each site will be assigned 2 blocks with an even number of treatments in each block. The order of the treatment assignments in each block are random. Along with treatment allocation, each patient randomized is assigned an individual study number.


Surgical Treatment

All patients will be treated with open reduction internal fixation consisting of an intramedullary nail prior to their staged bone grafting procedure. Prior placement of antibiotic beads may be performed at the discretion of the surgeon to temporarily occupy the tibia fracture defect site and preserve space for the bone graft (these beads are to be removed prior to the bone grafting procedure).



The use of antibiotic beads at the time of the initial injury is at the discretion of the surgeon. It will be recoded in the case report form. Antibiotic beads may be used if there is a significant area of tissue and bone defect in a contaminated wound. The criteria for inclusion in this study is not an open fracture, thus antibiotic beads would not be appropriate for closed tibial shaft fractures with bone defect. Because all patients are being cultured prior to insertion of the rhBMP-2/ACS implant, we will know if there is any infection. If our short term results are significant for those patients with antibiotic beads not having positive cultures versus control, we will consider a change in protocol.

Patients in the control group will receive the standard of care, cancellous autogenous bone graft harvested from the iliac crest using a standard surgical technique. Patients in the investigational treatment group will receive one INFUSE Bone Graft Large II kit (12 mg) in combination with freeze-dried cancellous allograft bone chips. Regardless of treatment assignment, the grafting material will be surgically implanted between 6 and 10 weeks after initial injury.


Autogenous Bone Graft Preparation

For the autograft group, autogenous bone graft will be harvested from the iliac crest in the standard surgical fashion. For insertion of the autogenous bone graft, the recipient site will be exposed and cultures obtained. We will await the results of the intraoperative gram stain to ensure that the recipient fracture site is free of infection. If the recipient fracture site is free of infection, we will prepare the recipient site to expose bleeding bone. The approach chosen by the surgeon will be an anterior or posterior approach depending on the position of the fracture defect and the condition of the surrounding soft tissues. The autograft will be implanted within the fracture defect and to fill the fracture defect and along the proximal and distal margin.


INFUSE Bone Graft Preparation

The INFUSE Bone Graft should be prepared according to the manufacturer’s instructions listed on the product; briefly 8.4 mL of Sterile Water for Injection is mixed to reconstitute the rhBMP-2 to a concentration of 1.50 mg/mL, 8.0 mL of this rhBMP-2 solution is then uniformly distributed onto the 3” by 4” bovine collagen sponge supplied in the kit, allow the wetted collagen sponges to stand for a minimum of 15 minutes before implantation.


Bone Grafting Procedure

Up to 60 cc of bone graft (cancellous autograft bone or allograft bone) will be used to fill the tibia fracture defect. The grafting approach should be selected according to the position of the fracture and the condition of the surrounding soft tissues. Either an anterior or posterior approach is acceptable as long as the graft is placed in an area surrounded by a viable muscle mass. For insertion of bone graft, the recipient site will be exposed and cultures obtained. We will await the results of the intraoperative gram stain to ensure that the recipient fracture site is free of infection. The proximal and distal margins of the defect site may be roughened with a burr or osteotome to expose bleeding bone. The bone graft is applied in and around the area surrounding the defect site until the defect is full. For the investigational patients, the INFUSE Bone Graft will be applied as an overlay after the defect has been first filled with cancellous allograft bone chips, the collagen sponge should bridge from proximal to distal end and cover the defect as much as possible based on the surgical opening.


Duration/Follow-up Schedule

It is anticipated that the required patients will be enrolled into this study during an 18-month period and will be followed for one year. Thus, the data collection time is anticipated to be a 2.5 year period. The patients will be evaluated at 2 weeks, 6 weeks, 12 weeks, 18 weeks, 6 months and 12 months according to the following schedule:




Follow-Up Schedule

Process

Data Collected

Enrollment

Clinical examination

VAS, SF12, SMFA, SIP

2 weeks

Clinical examination, functional outcomes

Clinical follow-up data, VAS

6 weeks

Clinical examination, functional outcomes, radiographs

Clinical follow-up data, VAS

12 weeks

Clinical examination, functional outcomes, radiographs

Clinical follow-up data, VAS

18 weeks

Clinical examination, functional outcomes, radiographs

Clinical follow-up data, VAS

6 months

Clinical examination, functional outcomes, radiographs

Clinical follow-up data, VAS, SF12, SMFA, SIP

12 months

Clinical examination, functional outcomes, radiographs

Clinical follow-up data, VAS, SF12, SMFA, SIP



    1. Effectiveness Evaluation (x-ray, Ct Scan, weight bearing, 2nd procedures)

Outcome measures will be “radiographic union,” “clinical union”, “wound healing and infection,” and “need for further intervention.”
Pain will be documented using the Visual Analogue Scale (VAS) at each visit. Short Form-12 (SF-12), Short Musculoskeletal Functional Assessment (SMFA) and Sickness Impact Profile (SIP) will be completed at time of surgery, 6 months and 12 months.


    1. Safety Evaluation (complications, re-operations, adverse events)

Wound Complications

*Superficial wound infection-There is erythema and warmth around wound. There is no purulent drainage. The patient is not febrile (Temperature less than 39 degrees Celsius). Treatment is with PO antibiotics. The condition resolves without additional intervention.

*Deep wound infection: The patient has the wound characteristics as described above and has drainage. Cultures will be obtained. All treatment and interventions will be recorded.

Swelling: Swelling will be defined as the absence of skin wrinkling.


    1. Patient/Study Success

Union: Time to union will be determined radiographically by the number of cortices bridged by bone. There are no validated measures to grade fracture healing based on radiographs. The number of cortices was chosen based on the work of Whelan et al on the interobserver and intraobserver variation in the assessment of fracture healing of tibia fractures treated with an intramedullary nail. Clinical union will be defined by: 1. Pain free full weight bearing and/or 2. The absence of pain to palpation at the fracture site.

Clinical Success will be determined by the clinical investigators on the basis of both: 1. Radiographic union will be measured by evidence of fracture healing which is defined as extra-cortical bridging callus on three of four cortices on anterior- posterior and lateral radiographs and 2. Clinical healing is defined as pain free, full weightbearing and lack of tenderness at the fracture site on palpation. The fracture will be considered to be a Clinical Success (e.g. healed) when radiographic union is confirmed and both clinical parameters listed above for healing has been met.



    1. Statistical Analyses/Data Presentation

STATISTICS:

To address our primary objective, a comparison of healing rates between BMP and Autogenous Bone Grafts, we assume at 20% higher healing rate in BMP treated patients ( Jones et al, 2006), with a baseline healing rate of 65% (with autogenous bone graft). Stipulating a study power of 80% and an alpha level=0.05, and a non-inferiority margin of 20% our study will require at least 14 patients per treatment arm. If we stipulate our non-inferiority margin to be 10%, we will require 25 patients per group. Thus, to be most conservative, our study will recruit 50 patients total (25 patients per treatment arm). We will complete an interim evaluation of results once 25 patients have been enrolled, including a power analysis.

A statistician will subject the data to a statistical analysis and the results will be reported comparing the outcomes in the groups at each follow-up period. It is anticipated that the required patients will be entered into the investigation during an 18-month period and will be followed for one year. Thus, the data collection time will be a 2.5- year period. We believe that at that time, the results of the study will reveal whether any differences exist with this high-energy disabling fracture in terms of outcomes, union rates, times to union, soft-tissue complications and infection rates.


    1. Patient Report Forms: See attached in Appendix

Risk Analysis

POTENTIAL RISKS: The study has several risks. It is possible that the subject will get the BMP-2 treatment but do less well than he/she would have done with standard care alone. Also because the treatment is relatively new, we may not yet know the side effects: something unexpected could happen.

The use of rhBMP-2 in the staged bone grafting of a tibial shaft fractures with a bone defect is currently off-label. BMP-2 is approved for extremity trauma for open tibial shaft fractures within the first 14 days after injury. However, we are not intending to support a new indication for its use or not intending to support a significant change in advertising for the product; the route and dosing of administration and subject population is the same as currently used according to FDA approvals; the study will be conducted in compliance with IRB review and informed consent and also in compliance with the requirements concerning the promotion and sale of the drug and it does not intend to invoke the Humanitarian Device Exemption. Based on the result of animal and human studies, rhBMP-2 may help bone to heal faster than it normally would without rhBMP-2.



BMP-2 Group: If you are a woman who is able to have children, it is possible that you may develop antibodies (a reaction form your immune system) to BMP. In clinical experience, antibodies develop in approximately 1-5% of patients who receive the treatment. The effect of a mother’s antibodies on an unborn baby is not known, both when the antibodies are detected and later. If you are a woman who is able to have children, you will need to take measures to prevent pregnancy for one year after treatment with BMP. Examples of birth control methods include, but are not limited to, birth control pills, intrauterine device (IUD), birth control implant, birth control patch and diaphragm. Your doctor can further discuss birth control options with you.
Possible risks of rhBMP-2 (the side effects reported by 1% to 10% of all patients studied) were:

  • Headache

  • Increased amount of amylase (an enzyme used in digestion), in the blood without obvious signs of pancreatitis (inflammation of the pancreas)

  • Tachycardia (fast heart beat)

  • Decreased magnesium in the blood


Unforeseen risks: RhBMP-2 may not help your bone to heal faster than it normally would with your own bone.

SPECIAL PRECAUTIONS: The investigator and designated study staff will be responsible for adhering to institutional standards for enduring patient safety and confidentiality. The PI will maintain telephone contact and will at regular intervals perform investigational site monitoring visits. To monitor safety and unanticipated toxicity, the following measures will be taken as part of the planned evaluation. The fracture site will be monitored radiographically for skeletal abnormalities, heterotopic bone formation, resorption, malunion, delayed union or nonunion fracture. The soft tissue will be evaluated for any signs of skin breakdown, swelling (absence of skin wrinkling), warmth, erythema (redness) and/or drainage at each visit by the physician. In addition certain patient populations have purposely been excluded from the study, as outlined in the inclusion and exclusion criteria.

PREGNANCY: The following boxed warning is present on the current labeling for INFUSE® Bone Graft:

  • In an experimental rabbit study, rhBMP-2 has been shown to elicit antibodies that are capable of crossing the placenta. Reduced 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 well-controlled studies in human pregnant women. Women of child bearing potential should be warned by their surgeon of potential risk to a fetus and informed of other possible orthopedic treatments.

  • Women of childbearing potential should be advised that antibody formation to rhBMP-2 or its influence on human fetal development has not been assessed. In the clinical trial supporting the safety and effectiveness of the INFUSE Bone Graft in tibia fractures, 9/149 (6.0%) patients treated with INFUSE Bone Graft and 1/150 (0.7%) patients treated without exposure to rhBMP-2 developed antibodies to rhBMP-2. The effect of maternal antibodies to rhBMP-2, as might be present for several months following device implantation, on the unborn fetus is unknown. Additionally, it is unknown whether fetal expression of BMP-2 could re-expose mothers who were previously antibody positive. Theoretically, re-exposure may elicit a more powerful immune response to BMP-2 with possible adverse consequences for the fetus. However, pregnancy did not lead to an increase in antibodies in the rabbit study. Studies in genetically altered mice indicate that BMP-2 is critical to fetal development and that a lack of BMP-2 activity may cause neonatal death or birth defects. It is not known if anti-BMP-2 antibodies may affect fetal development or the extent to which these antibodies may reduce BMP-2 activity.

  • INFUSE® Bone Graft should not be used immediately prior to or during pregnancy. Women of childbearing potential should be advised not to become pregnant for one year following treatment with the INFUSE® Bone Graft.

  • The safety and effectiveness of the INFUSE® Bone Graft in nursing mothers has not been established. It is not known if BMP-2 is excreted in human milk.

Safety data has not been established in females who are pregnant or nursing, and these patients will be excluded from this study. Females will undergo serum pregnancy testing in order to rule out pregnancy prior to implantation of INFUSE® Bone Graft. Informed Consent will inform subject’s that INFUSE® Bone Graft has not been tested in pregnant or nursing women. Female subjects with child-bearing potential will be advised to use oral contraceptives and/or refrain from becoming pregnant for 12 months following implantation. These precautions should minimize any potential risk to female patients and/or their fetus. If a subject becomes pregnant after implantation of INFUSE® Bone Graft the Investigator will document pregnancy as an AE, advise the subject to notify their obstetrical physician, monitor for occurrence of additional AEs, and report findings related to pregnant and/or nursing females in the annual and final report.



The following risks are related to the anesthesia/surgery used to place a bone graft and expected to be equal for both groups:

  • Bowel, bladder or gastrointestinal problems

  • Change in mental status

  • Damage to blood vessels, bleeding (which may require a blood transfusion) or cardiovascular system compromise

  • Damage to nearby tissues

  • Development of respiratory problems

  • Disassembly, bending, breakage, loosening and/or migration of IM nail components

  • Incisional complications

  • Neurological system compromise

  • Pain or discomfort

  • Side effects from anesthesia or the surgical approach

  • Tissue or nerve damage



    1. Post-Operative Regimen

See schedule attached in #6 for follow-up


    1. Retrieval Study

Should a patient fail to heal with the use of Bone Morphogenetic protein-2, salvage would be attempt of autogenous bone graft. As the sponge is dissolved within 14 days and the product thus would not be retrievable at salvage surgery.
Device Description

The INFUSE® Bone Graft component consists of recombinant human Bone Morphogenetic Protein-2 (rhBMP-2) soaked onto an absorbable collagen sponge (ACS) carrier. BMP-2 is a natural human protein that has been shown in animal studies to induce bone formation. The human BMP-2 protein sequence has been cloned and expressed in mammalian cells to yield large quantities of highly purified rhBMP-2.


INFUSE® Bone Graft is commercially available for use with the LT-CAGE® Lumbar Tapered Fusion Device in anterior lumbar spine interbody fusion procedures (P000058), for use in acute open tibial shaft fractures (P000054), and for use in sinus augmentations and localized alveolar ridge augmentations for defects associated with extraction sockets in oral maxillofacial procedures (P050053).
The carrier component, the absorbable collagen sponge (ACS), provides the matrix for the delivery of rhBMP-2. The ACS is commercially available and is marketed by Integra LifeSciences Corporation under the trade name HELISTAT® Absorbable Collagen Hemostatic Agent. That product is covered by a U.S. Food and Drug Administration Premarket Approval Application and is “approved for use in surgical procedures (other than neurological, ophthalmological, and urological surgery) as an adjunct to hemostasis when control of bleeding by ligature or conventional procedures is ineffective or impractical” (Colla-Tec, Inc. – an Integra LifeSciences Company).
For the purposes of this study, a commercially-available INFUSE® Bone Graft (rhBMP-2/ACS) Large II kit (Ref. #7510800) will be used for the investigational group. The rhBMP-2 is provided as a lyophilized powder in vials delivering 12 mg of protein. After appropriate reconstitution, the concentration of rhBMP-2 is 1.50 mg/mL. The solution is then applied to the provided absorbable collagen sponge. INFUSE Bone Graft is prepared at the time of surgery and allowed a prescribed amount of time (no less than 15 minutes) before placement at the fracture site. Investigational patients will receive freeze-dried allograft chips (15 cc) wrapped in the rhBMP-2 soaked collagen sponge. Freeze-dried allograft chips will be obtained from the local/regional tissue bank at each site.
The INFUSE® Bone Graft kit contains the following components:


  • One (1) vial of sterile rhBMP-2 (12mg);

  • One (1) package of one (1) sterile ACS 3" x 4" (7.5 cm x 10 cm);

  • One (1) vial of sterile water for injection (10 mL);

  • Two (2) sterile 10 mL syringes with 20G 1 ½" needles;


Monitoring Procedures

The Principle Investigator at each site will be responsible for the safety monitoring. The PI will report all safety issues to the Sponsor (Lisa K. Cannada, MD).


This clinical study will be properly monitored to protect the human subjects and assure compliance with approved protocol. For each study site the investigator will designate their study coordinator as the local study monitor. The monitor will assure that the investigators are complying with their signed agreements, the investigational plan, the IDE requirements, any other applicable FDA regulations, or any conditions of approval imposed by the reviewing IRB or FDA.
Prior to the start of study, the monitor will:
• Ensure that the Investigator, Sub-Investigator and research team members understand that the use of INFUSE® in this study is “off label”;

• Ensure that the Investigator, Sub-Investigator and research team members understand the nature of the study protocol;

• Ensure that the Investigator, Sub-Investigator and research team members understand the requirements of accuracy and control of study;

• Ensure that the Investigator, Sub-Investigator and research team members understand the requirement to obtain informed consent in accordance with 21 CFR Part 50, from all subjects before being enrolled into the study;

• Ensure that the Investigator, Sub-Investigator and research team members understand the obligation to obtain IRB review and approval before beginning the study and the obligation to obtain ongoing review in accordance with 21 CFR Part 56.

• Confirm that the Investigator has access to an adequate number of suitable subjects to conduct the investigation as determined by review of the Investigator’s practice database;

• Confirm that the Investigator and Center has adequate facilities for conducting the study;

• Ensure that the Investigator, Sub-Investigator and research team members have adequate time to conduct the study.


These assurances will be documented by the Monitor and kept with study documents. All study documents and case report forms will be in paper format.
Throughout the course of the study, the Monitor will document all protocol deviations, adverse events or issues pertaining to the conduct of study. All such documentation will be kept with the study documents.
Each investigator will maintain accurate and complete records relating to the investigation. These records include;

  • all correspondence including required reports,

  • records of receipt, use, or disposition of the investigational device,

  • records of each subject's case history and exposure to the device,

  • the protocol and documentation (date and reason) for each deviation from the protocol

Each investigator will provide the following reports in a timely manner to the sponsor and/or the IRB.



  • Adverse Events

  • Withdrawal of IRB Approval

  • Progress Reports

  • Deviations from the Investigational Plan

  • Informed Consent

  • Final Report

The physician/ sponsor will obtain a signed agreement from each participating investigator that includes;




    • the investigator's curriculum vitae,

    • a statement of the investigator's relevant experience, including the dates, location, extent, and type of experience, where applicable,

    • an explanation of the circumstances that led to termination of a study if the investigator was involved in an investigation or other research that was terminated,

    • a statement of the investigator's commitment to:

      • conduct the investigation in accordance with the agreement, the investigational plan, the IDE and other applicable FDA regulations, and conditions of approval imposed by the reviewing IRB or FDA,

      • supervise all testing of the device involving human subjects.

      • and ensure that the requirements for obtaining informed consent are met.

Adverse Event (“AE”), Serious Adverse Event (“SAE”) and Unanticipated Adverse Event (“UAE”) monitoring will be conducted at all intervals (including those additional intervals not mandated by the protocol).


AE will be defined as any adverse event, whether or not that event is felt to be implant related, occurring at the time of or following time of implant through the remainder of study. AE’s will be treated in accordance with accepted medical standards and documented in the subject’s study binder and monitored by the Investigator and research team. AE’s will be reported to the FDA and the site IRB in the annual report and the final report.
SAE will be defined as any significant adverse experience, including death or those events which may be either life-threatening or involve permanent or long term injuries, but excluding injuries that are non life-threatening and that are temporary and reasonably reversible. SAE’s will be treated in accordance with accepted medical standards and documented in the subject’s study binder and reported to the site IRB, the sponsor and Medtronic Customer Service Division (1-800-933-2635) within 1 business day of known occurrence. SAE’s will be included in the annual and final report.
UAE will be defined as any event that could not be reasonably foreseen or had not been previously reported by MSD in the product package insert as a potential adverse event related to use of implant. UAE’s will be treated in accordance with accepted medical standards and reported to the site IRB, the sponsor and Medtronic Customer Service Division (1-800-933-2635) within 5 business days after the Principal becomes aware of the event. UAE’s will also be included in the annual and final report.


CONFIDENTIAL PROTOCOL – IDE G080034 VERSION C; December 2008

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