rhBMP-2 Versus Autograft in Critical Size Tibial Defects

Study Overview
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Brief Summary
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The purpose of our study is to evaluate the use of recombinant human bone morphogenetic protein 2 (RhBMP-2) as compared to standard ICBG in the treatment of severe open tibia fractures with a critical size bone defect (at least one centimeter in length compromising at least 50% of the circumference of the bone).

Detailed Description
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Open tibia fractures have a 15% or higher rate of not healing. Those fractures which do not heal are typically treated with bone from the hip (iliac crest autograft; or ICBG). The use of ICBG bone with the treatment of delayed unions/non-unions with critical defect, although successful, has its drawbacks. The bone graft sources are limited and the procedure is associated with additional operating room time plus a second incision with increased risk of infection, post operative pain and increased hospital stay. The purpose of this study is to determine if Rh-BMP2, a new bone graft substitute, is at least as effective as using bone from the hip (autograft) to help promote healing of open, tibia (shin bone) fractures. Research Questions: Primary: What is the relative effect of rhBMP-2 versus autogenous ICBG on rates of union in patients with critical size defects following tibial shaft fractures? Null hypothesis #1: rhBMP-2 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 Rh-BMP 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.

Official Title
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RhBMP-2 vs. Autograft for Critical Size Tibial Defects: A Multicenter Randomized Trial

Conditions
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Tibial Fractures

Intervention / Treatment
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* Device: recombinant bone morphogenetic protein 2
* Procedure: Autogenous iliac crest bone graft


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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, purulent drainage from the fracture or evidence of active osteomyelitis at the time of bone grafting. Patient has intraoperative positive gram stain or an elevated CRP after laboratory screening for infection. Patient has segmental defects longer than 5cm in length. 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. 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?

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: recombinant bone morphogenetic protein 2<br>The patient will receive rhBMP-2 plus allograft chips in the bone defect site. Intervention type: surgical | Device: recombinant bone morphogenetic protein 2<br>* Patients 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<br>* Other names: (rhBMP-2) (INFUSE);|
| Active Comparator: Autogenous iliac crest bone graft<br>Bone will be harvested from the iliac crest and placed in the bone defect. | Procedure: Autogenous iliac crest bone graft<br>* Patients will undergo autogenous iliac crest bone graft surgery per the surgeon's usual practice.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fracture Healing (Union) at 12 Months | Union will be defined by: 1. Radiographic union as defined by the Radiographic union scale in tibia fractures (RUST) score, Radiographic evaluation will be assessed by blinded orthopaedic surgeons. | 12 months post op | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infection | Infection will be assessed based on the CDC criteria for deep and superficial infection. | 12 months post op. | 
| Medical Cost | 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. | 12 mos post op | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Open tibia fractures, rhBMP-2, critical size defects, bone grafting