A Study of INFUSE Bone Graft (recombinant human Bone Morphogenetic Protein-2/absorbable collagen sponge) in the treatment of Tibial Pseudarthrosis in Neurofibromatosis 1 (NF1)

GOALS

To determine if use of an osteogenic agent (rhBMP-2) at the time of surgical treatment for tibial pseudarthosis in NF1 patients will result in improved bone healing when compared to NF1 patients treated with the same surgical treatment but without BMP-2.

DRUGS

Bone morphogenetic proteins (BMPs) are naturally occurring substances that are involved in bone formation of the transforming growth factor-beta superfamily, and their mechanism of action involves the recruitment and differentiation of mesenchymal progenitor cells into osteoblasts. When applied to bone at the time of surgery, BMPs induce mesenchymal stem cells to infiltrate the fracture zone and to differentiate into osteoblasts, which subsequently form new bone. The application of these substances at the time of surgery may increase the chance of tibial fracture healing. Bone morphogenetic protein-2 (BMP-2), as a collagen sponge device marketed as INFUSE, has shown efficacy in healing of complex traumatic tibial fractures in adult populations. The current study proposes adding BMP-2 (INFUSE), an anabolic agent, at the surgical site of tibial pseudarthosis repair in children with NF1, compared to a control group of patients treated surgically without BMP-2.

ELIGIBILITY

The target population for this study is patients with NF1 between the ages of 2 and 18 who have tibial pseudarthrosis that requires surgical intervention with intramedullary rod and autogenous bone graft. Patients who have undergone 1 previous surgery for tibial pseudarthrosis repair will be eligible to enter the study if they have refracture. Use of BMP-2 in the prior surgery is permitted, however patients with prior exposure must be screened for antibodies to BMP-2, bovine collagen, and rhBMP-2 neutralizing antibodies. Prior use of BMP-2 is allowed but will be recorded as a possible compounding factor. Evidence of adequate bone marrow function must be available as well.

PROTOCOL

Children with NF1 and tibial pseudarthrosis whose primary orthopedic surgeon deems surgical intervention is required are eligible for this trial. At time of enrollment, participants will be randomized to either the BMP-2 or control group. Surgery must take place at one of the participating consortium sites, and the standard surgical approach will include: extensive resection of abnormal pseudarthrotic material, tibial osteotomy, placement of an intramedullary rod, and autogenous bone graft from the iliac crest to the osteotomy tibial gap. Those in the BMP-2 group will in addition have INFUSE in a collagen sponge wrapped around the tibia during the surgical process.

All patients will be immobilized for a minimum of 3 months after surgery in either a spica or above knee cast; surgeons will use clinical discretion to determine if further casting is needed on an individual basis. After the cast is removed, patients will be permanently braced (24 hours per day) in a custom-made-above or below-the-knee orthosis. The rate of tibial healing will be assessed at 6 weeks, 3 months, 6 months, 9 months, and 12 months after surgery. Quality of life will be assessed by the Pediatric Outcome Data Collection Instrument, and walking function will be assessed by the 10 meter timed walk, performed at baseline, 6 mos, and 12 mos. Biologic specimens including discarded pseudarthrosis tissue and bone fragments from the iliac crest will be collected at the time of surgery and sent to a central lab. Patients will be followed up to 12 months, with a one month follow-up on this study.

PROTOCOL CHAIRS

• Elizabeth K. Schorry, MD, Chair
• B. Stephens Richards, MD, Co-Chair
• David. H. Viskochil, MD, PhD Co-Chair
• David G. Little, MBBS, FRACS, PhD, Co-Chair

CURRENT STATUS

This study is complete and closed. Please see trial results via publications or by visiting clinicaltrials.gov/ct2/show/study/NCT02718131