A Study of INFUSE Bone Graft (BMP-2) in the Treatment of Tibial Pseudarthrosis in Neurofibromatosis Type 1 (NF1)

Study Overview
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Brief Summary
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The current study proposes adding BMP-2 (INFUSE), an anabolic agent, at the surgical site of TPA (tibial pseudarthrosis) repair in children with NF1, compared to a control group of patients treated surgically without BMP-2. The following Specific Aims will be addressed: 1) to determine if use of an osteogenic agent (BMP-2) at the time of surgical repair of TPA in NF1 patients will result in improved bone healing; 2) to document safety of BMP-2 in a pediatric NF1 population; and 3) to collect, process, and preserve biologic specimens at the time of surgery for future studies.

Detailed Description
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A randomized study will be performed by a multi-center group of the NF Consortium. A total of 54 patients will be randomized for treatment with or without INFUSE Bone Graft at the time of surgical repair. For all patients, a standard surgical procedure will be used, including: resection of pseudarthrosis tissue; placement of a rigid intramedullary rod; and placement of autogenous bone graft from iliac crest. For patients in the BMP group, the INFUSE device containing BMP-2 will in addition be applied intraoperatively to the osteotomy site. Fracture union will be determined by scoring of radiographs (RUST score) for cortical bone fusion and callus formation at the osteotomy site. RUST score at 12 months post-surgery will be the primary outcome measure to determine efficacy. Secondary measures will include determination of time to healing (months); quality of life measures; functional walking measures; and incidence of refracture after surgery. This study, once successfully completed, will determine if use of INFUSE Bone Graft improves healing of tibial pseudarthrosis in NF1 and will document safety issues. Regardless of results, the better performing of the two groups (control or BMP) will be able to serve as a much-needed control arm for future studies of additional targeted therapeutic agents for NF1-related bone disease. An international working group of orthopaedic surgeons and NF specialists has been formed and is committed to successful completion of this trial.

Official Title
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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)

Conditions
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NF1, Congenital Pseudarthrosis of Tibia

Intervention / Treatment
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* Device: INFUSE Bone Graft (BMP-2)
* Procedure: Control Group


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of NF1 using the NIH Consensus Conference criteria. In addition to tibial pseudarthrosis, one or more of the following diagnostic criteria for NF1 must be present: Six or more cafe'-au-lait spots (≥ 0.5cm prepubertal; ≥ 1.5cm postpubertal) Freckling in the axilla or groin Optic pathway glioma Two or more iris Lisch nodules Two or more neurofibromas or one plexiform neurofibroma A first-degree relative with NF1 Patients must have tibial pseudarthrosis that has the potential to cause significant morbidity. Radiographic findings (AP & lateral leg radiographs) must support the diagnosis of tibial pseudarthrosis with chronic non-union. Age between 2 years and 18 years of age at time of study entry. Performance Level: Karnofsky ≥ 50 percent for patients > 10 years of age and Lansky ≥ 50 percent for patients or ≤ 10 years of age. Prior Therapy: 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. Patients who have had 2 or more prior surgeries for pseudarthrosis repair are ineligible Absence of Tumors: Patients must undergo thorough physical examination of the leg undergoing surgery. If physical exam is equivocal for presence of tumors, then a normal MRI of the lower extremity will be required before eligibility is met. If there is evidence of plexiform neurofibroma or nodular neurofibroma of > 3 cm diameter on the ipsilateral leg, then they are ineligible for the study. Organ Function Requirements Adequate bone marrow function defined as: Absolute neutrophil count (ANC) > 1500/ µl Platelet count > 100,000/ µl Hemoglobin ≥ 10.0 gm/dL Adequate renal function defined as: maximum serum creatinine of 1.5 mg/dL OR a creatinine clearance≥70ml/min/1.73m2. Adequate renal function defined as: maximum serum creatinine of 1.5 mg/dL OR a creatinine clearance ≥ 70ml/min/1.73m2. Adequate liver function defined as: Total bilirubin < 1.5 X upper limit of normal for age, and SGPT (serum glutamic pyruvic transaminase, ALT) < 2 X upper limit of normal for age Serum Vitamin D level ≥ 10 ng/ml Exclusion Criteria: Lack of documentation for a diagnosis of NF1 Tibial fracture without evidence of pseudarthrosis or tibial dysplasia Tibial dysplasia/bowing without fracture or pseudarthrosis Plexiform neurofibroma of any size, or nodular neurofibroma of > 3 cm diameter involving the ipsilateral leg, including the hip If presence of plexiform is suspected but not certain on physical exam, MRI of the leg may be indicated to rule this out. History of MPNST (malignant peripheral nerve sheath tumor) or any malignancy other than asymptomatic and stable optic nerve glioma Optic nerve glioma that has resulted in precocious puberty or visual impairment of any degree Visual impairment from any cause Precocious puberty from any cause Hypertension other than mild essential hypertension controlled with medication Metastatic disease of any kind Inadequate neurovascular status in the involved limb that may jeopardize healing Active or known prior infection at the pseudarthrosis site Active systemic infection Other injury or condition that prevents ambulation or completion of study assessments Two or more prior surgeries for tibial pseudarthrosis Bilateral tibial dysplasia Selection of a surgical approach that does not include prescribed surgical intervention, which must include removal of pseudarthrosis tissue, placement of an intramedullary rod using the Williams approach, and autogenous bone graft from the iliac crest distributed at the osteotomy site Normal ipsilateral fibula without planned fibular osteotomy at time of surgery Allergy to bone morphogenetic protein Allergy to bovine collagen products Positive antibody titers to BMP-2, bovine collagen, or BMP-2 neutralizing antibodies prior to surgery History of using any of the following medications, regardless of dose, for at least 1 month, within 3 months of enrollment: Anabolic agents, Glucocorticoids (does not include inhaled glucocorticoids), Growth hormone, Parathyroid hormone (PTH) Need for postoperative medications that could interfere with bone healing of the implant, such as steroids, (but not including low-dose aspirin or routine perioperative anti-inflammatory drugs) Untreated endocrine abnormality, such as hypothyroidism, parathyroid hormone disorder Severe Vitamin D deficiency with serum 25-OH (hydroxy) Vitamin D < 10 ng/ml (25 nmol/l) Patients with Vitamin D levels < 10 ng/ml may be treated with Vitamin D and reconsidered for enrollment when levels are sufficient Females who are sexually active without use of effective contraception Females who are pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: INFUSE Bone Graft (BMP-2)<br>Children with NF1 and tibial pseudarthrosis who require surgery will have the INFUSE bone graft added to their surgical protocol. After a standard surgical approach of resection of abnormal pseudarthrotic tissue, placement of a rigid intramedullary rod (of the surgeon's choice) and placement of autogenous bone graft from the iliac crest; in addition, the INFUSE bone graft in the form of a collagen sponge will be wrapped around the tibia during the surgical process. | Device: INFUSE Bone Graft (BMP-2)<br>* The INFUSE bone graft, containing BMP-2 on a collagen sponge, will be wrapped around the tibia during the surgical process.<br>|
| Placebo Comparator: Control Group<br>Children with NF1 and tibial pseudarthrosis who require surgery will receive the standard surgical protocol only. This includes resection of abnormal pseudarthrotic tissue, placement of a rigid intramedullary rod (of the surgeon's choice) and placement of autogenous bone graft from the iliac crest. | Procedure: Control Group<br>* The control group will receive the standard surgical protocol, without addition of the INFUSE device.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RUST Score | The RUST scale (Radiographic Union Score for Tibial fractures; RUST) was developed in 2010 as a measure of tibial fracture healing and has been validated in the NF1 population. This was used as the primary outcome measure in this trial. The score is based on radiographic evaluation of the bone cortex based on AP (anterior-posterior) and lateral xrays. Four cortices of tibial bone seen in these views are each given a score of 1 to 3, with 1 representing no healing, 2 representing some callus present, and 3 representing healing of the bone cortex. The 4 scores are totaled, to give a total score range of 4 to 12. For the purpose of this study, a total RUST score of 9 to 12, with at least 2 evaluable cortices having a score of 3, is considered to be healed. Scores of 5 to 8 are considered to represent partial healing, and a score of 4 is considered to be no healing. | 12 mos post surgery. The score at 12 mos post surgery will be used to determine success of healing and is the score reported. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Time to Healing in Months | Time to healing is determined by RUST scores calculated at 3 month intervals after surgery. The first time point at which a score of 9 to 12 is achieved on the RUST Scale will be considered the time to complete healing. One time point is reported which is the time point of first healing. | Baseline through 12 months post-surgery. | 
| Refracture Rate | Numbers of patients with refracture within 1 year after surgery. | 12 months post-surgery | 
| Long-term Refracture | Numbers of patients with refracture over long-term follow up of up to 10 years. | annually, up to 10 years post-surgery | 
| Ten Meter Timed Walk | Time (seconds) to perform the Ten Meter Timed Walk. Assessed at 6 and 12 months after surgery. Both 6 month and 12 month reported. | Assessed at 6 and 12 months after surgery. Month 12 reported. | 
| Pain Intensity | Pain Intensity was measured using the Faces Pain Scale-Revised (FPS-R) for patients aged 4 years and older. This is a self-report pain scale, where children chose one of 6 faces to indicate their current pain. Scores range from 0 to 10, with 0 representing no pain (happy face) and 10 representing the most pain. | measured at post-op visits at 6 weeks, 3 mos, 6 mos, and 12 mos after surgery | 
| Quality of Life Score - The Upper Extremity and Physical Function Core Scale | Quality of Life (QOL) was measured during the study using the Pediatric Outcome Data Collection Instrument (PODCI), a validated scale developed by the American Academy of Orthopaedic Surgeons to measure outcomes in orthopedic interventions. The Parent-report form, which was used for this study, consists of 86 Likert-format questions, covering 5 domains (Upper extremity and physical function; transfer and basic mobility; sports/physical functioning; pain/comfort; and happiness scales). In addition, a Global Functioning Scale is computed. Scores for each subscale range from 0 to 100, with lower scores representing better quality of life. | Assessed at 6 and 12 months after surgery. Month 12 reported. | 
| Quality of Life Score - The Transfer and Basic Mobility Core Scale | Quality of Life (QOL) was measured during the study using the Pediatric Outcome Data Collection Instrument (PODCI), a validated scale developed by the American Academy of Orthopaedic Surgeons to measure outcomes in orthopedic interventions. The Parent-report form, which was used for this study, consists of 86 Likert-format questions, covering 5 domains (Upper extremity and physical function; transfer and basic mobility; sports/physical functioning; pain/comfort; and happiness scales). In addition, a Global Functioning Scale is computed. Scores for each subscale range from 0 to 100, with lower scores representing better quality of life. | Assessed at 6 and 12 months after surgery. Month 12 reported. | 
| Quality of Life Score - The Sports and Physical Functioning Core Scale | Quality of Life (QOL) was measured during the study using the Pediatric Outcome Data Collection Instrument (PODCI), a validated scale developed by the American Academy of Orthopaedic Surgeons to measure outcomes in orthopedic interventions. The Parent-report form, which was used for this study, consists of 86 Likert-format questions, covering 5 domains (Upper extremity and physical function; transfer and basic mobility; sports/physical functioning; pain/comfort; and happiness scales). In addition, a Global Functioning Scale is computed. Scores for each subscale range from 0 to 100, with lower scores representing better quality of life. | Assessed at 6 and 12 months after surgery. Month 12 reported. | 
| Quality of Life Score - The Pain/Comfort Core Scale | Quality of Life (QOL) was measured during the study using the Pediatric Outcome Data Collection Instrument (PODCI), a validated scale developed by the American Academy of Orthopaedic Surgeons to measure outcomes in orthopedic interventions. The Parent-report form, which was used for this study, consists of 86 Likert-format questions, covering 5 domains (Upper extremity and physical function; transfer and basic mobility; sports/physical functioning; pain/comfort; and happiness scales). In addition, a Global Functioning Scale is computed. Scores for each subscale range from 0 to 100, with lower scores representing better quality of life. | Assessed at 6 and 12 months after surgery. Month 12 reported. | 
| Quality of Life Score - The Happiness Core Scale | Quality of Life (QOL) was measured during the study using the Pediatric Outcome Data Collection Instrument (PODCI), a validated scale developed by the American Academy of Orthopaedic Surgeons to measure outcomes in orthopedic interventions. The Parent-report form, which was used for this study, consists of 86 Likert-format questions, covering 5 domains (Upper extremity and physical function; transfer and basic mobility; sports/physical functioning; pain/comfort; and happiness scales). In addition, a Global Functioning Scale is computed. Scores for each subscale range from 0 to 100, with lower scores representing better quality of life. | Assessed at 6 and 12 months after surgery. Month 12 reported. | 
| Quality of Life Score - The Global Functioning Scale | Quality of Life (QOL) was measured during the study using the Pediatric Outcome Data Collection Instrument (PODCI), a validated scale developed by the American Academy of Orthopaedic Surgeons to measure outcomes in orthopedic interventions. The Parent-report form, which was used for this study, consists of 86 Likert-format questions, covering 5 domains (Upper extremity and physical function; transfer and basic mobility; sports/physical functioning; pain/comfort; and happiness scales). In addition, a Global Functioning Scale is computed. Scores for each subscale range from 0 to 100, with lower scores representing better quality of life. | Assessed at 6 and 12 months after surgery. Month 12 reported. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tibial Pseudarthrosis