RhBMP-2 vs. Autograft for Critical Size Tibial Defects: A Multicenter Randomized Trial
Phase: PHASE4
Conditions: Tibial Fractures
Sponsor: St. Louis University

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A. 
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?  

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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. A committee of orthopaedic surgeons will 
independently adjudicate our primary outcome, fracture healing at 12 months.  Participating 
centers are part of the Major Extremity Research Consortium (METRC) and have experience 
with performing randomized clinical trials. 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 an absorbable collagen sponge (rhBMP-2/ACS) as an adjuvant to a 
freeze-dried cancellous allograft. Each patient will be separately randomized via a computer-
generated number at the Data Control Center. 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 sixteen weeks after the initial injury. 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 
sixteen 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 16 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. However, if the patient’s treatment plan does not include bone graft within 16 

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weeks of injury, the patient will not be eligible to participate. The literature supports 
interventions for non union be considered after 6 months from injury. This will guard against 
enrolling patients with “non-unions”.   Patients eligible for this study all had open fractures with 
bone defects. The soft tissue envelope needs to adequately recover from the original injury to be 
safe for additional surgery. Extending the window until 16 weeks permits time for adequate soft 
tissue recovery for the surgical procedures.  
   
The case report form provides a space to record the size of the defect as measured 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 
intra-operatively. The extent of the intra-perative defect will include area of bone loss >25% of 
the circumference to avoid measurement of small spikes that are clinically irrelevant. Intra-
operative defect size will be recorded on case report forms.  
 
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 crushed cancellous allograft packed into the defect prior to an overlay of the 
rhBMP-2/ACS.  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. 
 
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) and the Short Musculoskeletal Functional Assessment 
(SMFA) will be completed at 6 months and 12 months. Billing information will be obtained at 
the end of the 12 month study period to estimate cost of care in both treatment groups. 
 
 
Consent Procedures 
 

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Written consent will be obtained during the clinic visit when bone graft surgery is scheduled. 
Prior to bone grafting procedure, female patients will be given a pregnancy test. Those with a 
positive pregnancy test will no longer be eligible and will receive standard treatment (iliac crest 
autograft). Patients with an active infection at the operative site, purulent drainage from the 
fracture or evidence of active osteomyelitis are not eligible for the study. Active infection will be 
defined clinically by skin changes, including redness, warmth and active drainage. Additionally, 
the diagnosis can be supported by laboratory values, including elevated WBC , ESR and CRP. 
Osteomyelitis is suspected by radiographic evidence of lytic lesions .  If , at the time of surgery, 
the surgeon is concerned that the patient has a deep wound infection because of intra-operative 
findings that may include loose hardware, purulence or aninflammatory tissue reaction – the 
patient will be excluded from the study.  
 
Informed consent will be obtained before any study procedures are initiated. The consent form 
will be reviewed in its entirety with the patient by the surgeon and research coordinator and all 
questions will be answered.  Investigators will ask the subject questions to assure understanding 
before the consent for participation in the study is signed, specifically: 
1. Can you explain what it means to be involved in this study?  
2. What should you do if you no longer want to participate in the study? 
 
If the patient cannot answer these questions, the patient will be deemed by the investigator to be 
incapable of providing informed consent secondary to a lack of mental competence; the subject 
will not be enrolled into the study. 
 
 
Inclusion/Exculsion Criteria 
 
Criteria For Inclusion Of Subjects:  
 
• Patients 18-65 years old with an open tibia fracture involving diaphysis (if patient has a 
bilateral tibia fracture and both require a bone graft, then each will be randomized 
separately). 
• 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 16 weeks 
after their initial injury. 
• Patients who have no evidence of infection by clinical examination (defined as active 
infection at the operative site, purulent drainage from the fracture or evidence of active 
osteomyelitis at the time of bone graft).  
• Patients who are independent in living and ambulation prior to injury.  
• Patients who are English speaking. 
• Patients who are willing to provide consent and available for follow-up for at least 12 
months following definitive surgical procedure.  
 
 

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Criteria For Exclusion Of Subjects:  
 
• 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 who have undergone treatment of any other investigational therapy within the 
month preceding implantation or planned within the 12 months following implantation.  
• Patients unable to return for required follow-up visits.  
• Patients who have medical co-morbidities that preclude treatment with a general 
anesthetic. 
• Patient who is pending incarceration or who is incarcerated. 
• Patients with an active infection at the operative site defined clinically by skin changes 
including redness, warmth and active draining, purulent drainage from the fracture or 
evidence of active osteomyelitis based on radiographic evidence of lytic lesions at the 
time of bone grafting. 
• Patient has segmental defects longer than 5cm in length as measured on AP and lateral 
radiographs of the injury taken after the final debridement following internal fixation 
• Patient has a segmental defect longer than 6cm as measured intraoperatively after 
debriding . 
• Patients who have segmental defects that require more than 60 cc of bone graft. 
• Patients who require more than one large kit of rhBMP-2 at time of surgery. 
• Patient’s anticipated treatment plan also includes the use of other procedures to promote 
fracture healing, e.g. ultrasound, magnetic field or electrical stimulation. 
• Patient’s tibia fracture has been treated with additional fixation beyond the 
intramedullary nail, e.g. plates, wires or screws, and additional surgical fixation, e.g. 
fibulectomy, exchange nail and dynamization of locked nail 
• Patients who have pathological fractures; a known history of Paget’s disease or known 
history of heterotropic calcification.  
• 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 that prevents placement of an intramedullary 
nail for treatment of the tibial shaft fracture. 
• Patients with prior use of INFUSE. 
 
If the patient is a female of child bearing potential: 
• Does she have a negative pregnancy test (administered within 72 hours prior to surgery)? 
• Has she agreed to use adequate contraception for a period of at least 1 year following 
implementation of rhBMP-2? 
 

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Number of Sites/Investigators/Patients 
 
There will be up to a total of twenty two (22) sites enrolling patients, all of which are familiar 
with randomized clinical trials and are part of the Major Extremity Research Consortium 
(METRC). 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 10 patients in this study. 
 
The randomization scheme is a central, computerized process using a web based, distributed data 
collection system. A block randomization scheme with no subgroups will be used for each center 
participating in the trial. Blocks will use randomly permuted sizes of even numbers only, 
consisting of an equal number of treatments in each block. The order of the treatment 
assignments in each block is random. Along with treatment allocation, each patient randomized 
is assigned an individual study number. 
 
Surgical Treatment 
 
All patients will be treated with open reduction and internal fixation consisting of an 
intramedullary nail prior to their staged bone grafting procedure.  Prior placement of a PMMA 
antibiotic spacer 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 are to be removed prior to 
the bone grafting procedure).  
 
The use of a PMMA spacers at the time of the initial injury is at the discretion of the surgeon. It 
will be recorded in the case report form.  Antibiotic PMMA spacers may be used if there is a 
significant area of tissue and bone defect in a contaminated wound 
 
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 16 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.  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 

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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.  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 
Inclusion/Exclusion 
criteria, patient 
characteristics, fracture 
characteristics, surgical 
summary, VAS 
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 
12 months 
Clinical examination, functional 
outcomes, radiographs 
Clinical follow-up data, 
VAS, SF12, SMFA 

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Measurements 
 
Effectiveness Evaluation (x-ray, 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) will be 
completed at 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. 
 
 
Safety Evaluation (complications, re-operations, adverse events) 
Wound Complications 
• Deep infections are defined as those that occur within one year from the procedure, 
involve deep soft tissue and that meet at least one of the following criteria: “purulent 
draining, a deep incision that spontaneously dehisces or is deliberately opened by a 
surgeon when the patient has at least one of the following signs or symptoms: fever (>38 
degrees C), localized pain or tenderness, unless the incision is culture negative; an 
abscess or other evidence of infection involving the deep incision is found on direct 
examination, during reoperation, or by histopathology or radiologic examination; or 
diagnosis of a deep incisional SSI by a surgeon or attending physician”  or require 
operative treatment.. All treatment and interventions will be recorded. 
• Superficial infections are defined as those that occur within 30 days after the operative 
procedure and involve only skin or subcutaneous tissue of the incision and at least one of 
the following: purulent drainage from the superficial incision; organisms isolated from an 

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aseptically obtained culture of fluid or tissue from the superficial incision; at least one of 
the following signs or symptoms of infection- pain or tenderness, localized swelling, 
redness or heat and the superficial incision is deliberately opened by surgeon unless the 
incision is culture=negative; or diagnosis of superficial incisional SSI by the surgeon or 
attending physician” and that are treated only with local antibiotics and wound care, and 
no operative treatment for the infection (Horan TC et al, 1992).   
Swelling: Swelling will be defined as the absence of skin wrinkling. 
Fracture Healing 
Radiographic union will be measured by evidence of fracture healing defined by the 
Radiographic Union Scale in Tibial fractures (RUST) score, 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 evaluation will be assessed by blinded orthopaedic surgeons and will use 
consensus adjudication to determine union measured by the RUST score. 
 2. Clinical healing is defined as pain free, full unsupported weight bearing 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.   
 
 
 
Economic Outcomes 
An economic evaluation will also be performed including the costs of iliac crest bone graft 
harvest and complications from the bone graft surgery and the cost of the Rh-BMP 2 and the 
biologic implant used in the treatment group. Billing information from CMS forms UB04 and 
1500 along with discharge abstracts will be obtained for treatment received by study participants 
at the pTOG study site hospital(s) and clinics at the end of the 12 month follow-up period. 
Billing records will not be collected for treatment received at hospitals or clinics not affiliated 
with the pTOG study.  However, it will be important to document the types of treatment received 
so that costs for non-study site admissions and outpatient visits can be estimated during the final 
analysis. Therefore, during scheduled follow-up visits, patients will be asked about medical care 
received since the prior study visit.  Responses as documented in the case report forms will 
provide a basis for estimating treatment costs.    
 
 
 
Statistical Analyses/Data Presentation 

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Sample Size Justification 
 
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. 
 
Final Analysis 
 
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.  
 
Data will be analyzed on an intent to treat basis (patient data included in the treatment group and 
stratum to which randomized). Fishers exact test will be used to compare categorical variable 
and the Student t test will be used for continuous variables for comparisons between the two 
groups. 
 
Quality of life data will be coded and scored according to the guidelines provided with the 
SMFA (Coding Key Manual, Musculoskeletal Function Assessment, Injury and Arthritis 
Survey) and the SF-12 (Coding Manual for the SF-12 Health Survey). 
 
 
Data Security and Protection Plan 
 
All data will be collected on Case Report Forms provided to the participating sites by the 
Coordinating Center. The research coordinators at each site will obtain the information necessary 
to complete the case report forms (CRFs) from several sources including the patient's medical 
record, clinical evaluations and patient interviews. These forms will NOT contain the patient’s 
name, SSN, or hospital medical record number; they will be identified only by a unique patient-
specific study number.    
 
The Site Research Coordinator will enter non-personally identifiable information into a central 
and secured web-based data management system being implemented for all Consortium studies, 
known as REDCap. This data management system has incorporated state-of-the-art features for 
electronic data collection and is configured in accordance with best practices for information 
technology and research data management 
 

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Hard copy documents containing subject data and patient identifiers (and contact information) 
will be stored in secure document containers (file cabinets, lockers, drawers, etc.) in accordance 
with standard document management practices. The data collection forms will be destroyed 
within five years after study completion, as will the file linking study numbers with personally 
identifiable information. Paper forms will be shredded and the file containing personally 
identifiable data at each site will be deleted from local site computers. Each site will provide the 
Coordinating Center a signed verification that these data have been destroyed. 
 
All research data, in hard copy or electronic form, will be stored and managed in a secure 
manner following applicable federal regulations and guidelines and according to institutional 
policies and practices.  
 
At all times, only listed key personnel specifically designated and authorized by the Principal 
Investigator shall have access to any research related documents, including electronic data.  All 
such personnel will be properly trained and supervised regarding the management and handling 
of confidential materials. The Principal Investigator assumes full responsibility for such training, 
supervision, and conduct 
 
Risk Analysis 
Risks Associated with Experimental Treatment: 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.  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.   
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 
 

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It is possible for women of child bearing age to develop antibodies 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.  Women who are able to have children 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. 
 
 
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 

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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. 
Risks Associated with Standard Treatment 
The risk of standard treatment with iliac crest bone graft harvest includes infection, bleeding, 
donor site pain, and possible increased length of hospital stay.  
Risks Associated with Both Treatments 
With any surgical procedure, there is a small risk of having an infection in the bone, and small 
risk of having complications from anesthesia. This injury is severe and known to cause stiffness, 
pain, nerve paralysis, and physical limitations regardless of the treatment one receives. 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 
 
• Sensitive Questions. Some of the questions asked as part of this study may make 
participants feel uncomfortable.  Participants may refuse to answer any of the questions, 
take a break or stop participation in this study at any time. 
• Loss of Confidentiality. Any time information is collected; there is potential risk for loss 
of confidentiality. 
• Risks of Radiation from the Diagnostic Tests. Radiation dose received from diagnostic 
tests is medically indicated for participant’s condition and it is the same that they would 
get if they were not involved in this research study. 
• Risks of Blood Drawing Risks associated with drawing blood from the arm include 
minimal discomfort and/or bruising.  Infection, excess bleeding, clotting, and/or fainting 

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 also are possible, although unlikely. All patients will have about a tablespoon of blood 
drawn to rule out infection. Females of child bearing age will have an additional 
tablespoon of blood collected for a pregnancy test. 
 
Steps to Minimize Risk 
 
There may be unknown risks/discomforts involved. Study staff will update the participant’s in a 
timely way on any new information that may affect the patient’s health, welfare, or decision to 
stay in this study. The risks of participation in this study if one is randomized to the Rh-BMP 2 
group are documented from previous studies. If there is an accelerated healing rate in those 
patients who receive rhBMP-2 versus the autograft, the patient benefits may include less pain, a 
decrease in the need for secondary interventions, and improved functional outcome. If there is no 
healing with the use of the Rh-BMP 2 group, the patient will still be able to receive autograft to 
promote healing. 
 
The patient’s physician and the study investigators will share responsibility for patient safety. 
They will ensure patient confidentiality throughout trial management. The investigator and 
designated study staff will be responsible for adhering to institutional standards for ensuring 
patient safety and confidentiality.  
 
At each clinical visit, assessment will be made based on vital signs, physical evaluation of the 
limb including skin inspection, pain, swelling, infection, neurovascular status and radiographic 
evaluation of the involved tibia. There will be close monitoring of the occurrences of adverse 
events. In addition, certain vulnerable patient populations have been excluded from this study.  
 
Every effort will be made to keep patient information confidential. 
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). 
 

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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 Life 
Sciences 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 
Life Sciences 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 
 
This study is being conducted under the umbrella of the Major Extremity Trauma Research 
Consortium (METRC). The Consortium has developed an independent Data Safety Monitoring 
Board (DSMB) charged with the task of safety monitoring of all Consortium studies. 
 
At its first meeting the DSMB will review definition of all outcomes, adverse events and serious 
adverse events and revisions to the protocol will be made as appropriate. Summary data on 
adverse events (together with study outcomes) will be monitored by the DSMB at its semiannual 
meetings or more frequently, as needed. These summaries will include analyses comparing rates 
of adverse events by blinded treatment group, by clinic, or in other subgroups requested by the 
DSMB. 
 
After each meeting, the DSMB will issue a written summary of its review of the study data, 
including adverse events, for transmission to the IRBs at Johns Hopkins Bloomberg School of 
Public Health and each of the study centers. 
 

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The MM is responsible for providing medical guidance and overseeing patient safety for the 
pTOG clinical research study. The MM participates in determining the course of action 
necessary to meet the goals and objectives of the DSMB.  This is achieved through the review of 
safety reports; resolving safety issues; interacting with Principal Investigators, and reporting to 
the DSMB. 
 
Marc Swiontkowski, MD  
Professor of Orthopaedic Surgery 
University of Minnesota  
2512 South 7th Street 
Suite R200 
Minneapolis, MN 55454 
 
. 
 
 
Plan for reporting unanticipated problems/adverse events:   
 
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. 
 
Unanticipated problems involving risk to volunteers or others, serious adverse events related to 
participation in the study and all volunteer deaths related to participation in the study will be 
promptly reported by phone (301-619-2165), by e-mail (hsrrb@amedd.army.mil), or by facsimile 

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(301-619-7803) to the U.S. Army Medical Research and Materiel Command’s Office of Research 
Protections, Human Research Protections Office.  A complete written report should follow the 
initial notification.  In addition to the methods above, the complete report can be sent to the U.S. 
Army Medical Research and Materiel Command, ATTN:  MCMR-RPH, 504 Scott Street, Fort 
Detrick, Maryland  21702-5012 
 
Department of Defense Reporting Requirements 
 
The following are reporting requirements and responsibilities of the Principal Investigator to the 
United States Army Medical Research and Materiel Command’s (USAMRMC) Office of 
Research Protections (ORP), Human Research Protection Office (HRPO). 
 
        (1)  The protocol will be conducted in accordance with the protocol submitted to and 
approved by the USAMRMC ORP HRPO and will not be initiated until written 
notification of approval of the research project is issued by the USAMRMC ORP 
HRPO.   
        (2)  Accurate and complete study records will be maintained and made available to 
representatives of the U.S. Army Medical Research and Materiel Command as a part 
of their responsibility to protect human subjects in research.  Research records will be 
stored in a confidential manner so as to protect the confidentiality of subject 
information.   
        (3)  All unanticipated problems involving risk to subjects or others, serious adverse events 
related to participation in the study and subject deaths related to participation in the 
study will be promptly reported by phone (301-619-2165), by email 
(hsrrb@.amedd.army.mil), or by facsimile (301-619-7803) to the USAMRMC, Office 
of Research Protections, Human Research Protection Office.  A complete written 
report will follow the initial notification.  In addition to the methods above, the 
complete report will be sent to the U.S. Army Medical Research and Materiel 
Command, ATTN: MCMR-RP, 504 Scott Street, Fort Detrick, Maryland 21702-5012.   
 
        (4)  Suspensions, clinical holds (voluntary or involuntary), or terminations of this research 
by the IRB, the institution, the Sponsor, or regulatory agencies will be promptly 
reported to the USAMRMC ORP HRPO. 
 
        (5)  Any deviation to the protocol that may have an adverse effect on the safety or rights of 
the subject or the integrity of the study will be reported to the USAMRMC ORP 
HRPO as soon as the deviation is identified.   
 
        (6)  Major modifications to the research protocol and any modifications that could 
potentially increase risk to subjects will be submitted to the USAMRMC ORP HRPO 
for approval prior to implementation.  All other amendments will be submitted with 
the continuing review report to the USAMRMC ORP HRPO for acceptance. 

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        (7)  A copy of the approved continuing review report and the local IRB approval 
notification will be submitted to the USAMRMC ORP HRPO as soon as these 
documents become available.  A copy of the approved final study report and local IRB 
approval notification will be submitted to the USAMRMC ORP HRPO as soon as these 
documents become available.   
 
        (8)  The knowledge of any pending compliance inspection/visit by the FDA, OHRP, or 
other government agency concerning this clinical investigation or research, the issuance 
of Inspection Reports, FDA Form 483, warning letters or actions taken by any 
Regulatory Agencies including legal or medical actions and any instances of serious or 
continuing noncompliance with the regulations or requirements that relate to this 
clinical investigation or research will be reported immediately to USAMRMC ORP 
HRPO.   
 
Payment:   
 
Participants will receive $10 for the first four follow up visit, and $25 for completing the final two 
visits at -6 and 12 months after surgery in appreciation for their time and effort.   
There are no additional costs for participating in this research study outside of standard of care.  
The patient and their insurance company will be billed for standard of care costs for treating an 
open tibia fracture with bone loss (i.e. rehospitalization and surgical procedure to address the 
bone loss). The Rh-BMP 2 will be provided should the patient randomize to this study arm and 
neither the patient, nor their insurance company will be billed for the device. 
 
The Rh-BMP2 is being provided at no cost to the patients randomized to that group. 
INFUSE® Bone Graft is a currently approved medical device marketed by Medtronic Sofamor    
Danek USA, Inc. INFUSE® Bone Graft (rhBMP-2/ACS) will be provided by Medtronic free of 
charge for all investigational participants, this therefore does not constitute commercialization of 
the device.