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rhBMP-2

1.  IMPRESS

Steering Committee

2.  SOLVED

3.  rhBMP-2

4.  Femur Outcomes

5.  Damage Control

6.  Sacral Fractures

7.  Ankle Plating

Title

rhBMP-2 vs Autograft for Critical Size Tibial Defects: A Multicenter Randomized Trial

Summary

There are approximately 50,000 tibia shaft fractures annually in North America which go on to non-union.  This problem requires further invention to promote healing.  In the United States, it is estimated that 1.5 million bone grafting procedures are performed annually.  Those fractures which require additional biologic stimulants to heal are typically treated with iliac crest bone graft.  The care of  tibial shaft fractures with a critical size defect in order to heal is a challenge.   Over the past last half century the improvement in clinical outcome has been related to improved antiobiotics, change in operative techniques, use of tissue friendly techniques and the development of reliable wound coverage strategies. 
 

Delayed fracture healing is a common complication associated with high-energy tibial diaphyseal fractures.  The incidence ranges up 43% or greater especially in open tibial fractures.  When a high energy tibial shaft fracture is accompanied by bone loss; union rarely occurs without a secondary intervention. Bone grafting of the defect is commonly used to provide a stimulus for healing.  Use of autogenous bone graft 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, pain associated with the bone graft harvest site, which may range from 1-5 days to greater than 365 days.  In addition, other complications include the risk of iatrogenic fracture and damage to neurovascular structures.  Also, not all patients are suitable donors.  Previous iliac crest harvesting, poor bone quality secondary to underlying disease, smoking or medications which affect the quality of bone, and advanced age are relative contraindications to ICBG.  Finally, there is a finite amount of bone which may be obtained from the ilium and it may not be adequate in all donors to address critical size defects. The ability to restore skeletal integrity without the morbidity associated with bone graph harvesting would represent a major advantage for the patient.

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Research Design

The study will be a multicenter randomized, blinded, equivalence trial for open tibial fractures with critical sized defects. Randomization will be concealed and the study will include data collectors and analysts blinded to treatment arm. Our primary outcome will be independently adjudicated.

Each arm of the study will be separately randomized via sequentially numbered, opaque, sealed envelopes.  All data, initial demographic, surgical report, outcomes, and complications will be entered into a single computer database.  Radiographs, pre, post, and at 1 year will be stored in the same database and independently evaluated.  Outcome measures will be union, wound healing and infection, need for further surgical intervention, SF-12, MFA, and SIP at time zero, 6 months, and 1 year.  Pain will be documented using a VAS. An economic evaluation will also be performed including the costs of surgical iliac crest harvest and complications from the bone graft surgery, and the cost of complications and the biologic implant used in the experimental group. 

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Outcomes

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.

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Inclusion Criteria

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

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

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

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

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

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

7. English and Spanish speaking individuals are eligible.

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

9. 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.

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Exclusion Criteria

1. Female patients who are pregnant or lactating.

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

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

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

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

6. Patients with compartment syndrome of the affected limb.

7. Patients with immune deficiency or history of auto-immune disease,

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

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

10. 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.

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

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

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

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

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

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

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

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

19. Patients who are not treated with an intramedullary nail.
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