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A Study of INFUSE Bone Graft (BMP-2) in the Treatment of Tibial Pseudarthrosis in Neurofibromatosis Type 1 (NF1) (NF107-BMP2)

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ClinicalTrials.gov Identifier: NCT02718131
Recruitment Status : Recruiting
First Posted : March 24, 2016
Last Update Posted : July 25, 2017
Information provided by (Responsible Party):

Study Description
Brief Summary:
The current study proposes adding BMP-2 (INFUSE), an anabolic agent, at the surgical site of TPA 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.

Condition or disease Intervention/treatment Phase
NF1 Congenital Pseudarthrosis of Tibia Device: INFUSE Bone Graft (BMP-2) Procedure: Control Group Phase 2

Detailed Description:
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.

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 54 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: 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)
Study Start Date : March 2016
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : December 2021

Arms and Interventions

Arm Intervention/treatment
Active Comparator: INFUSE Bone Graft (BMP-2)
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)
The INFUSE bone graft, containing BMP-2 on a collagen sponge, will be wrapped around the tibia during the surgical process.
Placebo Comparator: Control Group
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
The control group will receive the standard surgical protocol, without addition of the INFUSE device.

Outcome Measures

Primary Outcome Measures :
  1. RUST score [ Time Frame: 12 mos post surgery. The score at 12 mos post surgery will be used to determine success of healing ]
    Radiographic Union Score of Tibia (RUST) calculated from X-rays.

Secondary Outcome Measures :
  1. Average time to healing in months [ Time Frame: X-rays obtained at 3, 6, 9, and 12 mos. post-surgery ]
    Time to healing is determined by RUST scores calculated at 3 month intervals after surgery. A score of 9/12 is considered to be complete healing.

  2. Refracture rate [ Time Frame: 12 months post-surgery ]
    Numbers of patients with refracture within 1 year after surgery.

  3. Long-term refracture [ Time Frame: annually, up to 10 years post-surgery ]
    Numbers of patients with refracture over long-term follow up of up to 10 years.

  4. Ten Meter Timed Walk [ Time Frame: 6 and 12 mos. after surgery. ]
    Time (seconds) to perform the Ten Meter Timed Walk.

  5. Pain intensity [ Time Frame: measured at post-op visits at 6 weeks, 3 mos, 6 mos, and 12 mos after surgery ]
    Pain intensity as assessed by the patient with the Faces Pain Scale-Revised (FPS-R).

  6. Quality of life score [ Time Frame: 6 and 12 mos. after surgery ]
    QOL measured by the Pediatric Outcome Data Collection Instrument (PODCI), filled out by patient and parent.

  7. Adverse Events [ Time Frame: measured at post-op visits at 6 weeks, 3 mos, 6 mos, and 12 mos after surgery ]
    Numbers of participants with treatment-related adverse events as assessed by CTCAE v4.0.

Eligibility Criteria

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Ages Eligible for Study:   2 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 (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 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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02718131

Contact: Elizabeth Schorry, MD 513-636-4760 elizabeth.schorry@cchmc.org
Contact: Karen A Cole-Plourde, BS 205.934.5140 kcole@uab.edu

United States, Alabama
The University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35294
Contact: Bruce Korf, MD    205-934-9411    bkorf@uab.edu   
Principal Investigator: Bruce Korf, MD, PhD         
United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Tena Rosser, MD    323-361-5825    trosser@chla.usc.edu   
Principal Investigator: Tena Rosser, MD         
United States, District of Columbia
Children's National Medical Center Not yet recruiting
Washington, D.C., District of Columbia, United States, 20010
Contact: Roger Packer, MD    202-884-2120    rpacker@cnmc.org   
Principal Investigator: Roger Packer, MD         
United States, Illinois
Children's Lurie Hospital Recruiting
Chicago, Illinois, United States, 60611
Contact: Stewart Goldman, MD    312-227-4823    sgoldman@luriechildrens.org   
Contact: Robert Listernick, MD    312-227-6841    rlisternick@luriechildrens.org   
University of Chicago Not yet recruiting
Chicago, Illinois, United States, 60637
Contact: James Tonsgard, MD    773-702-6488    tonsgard@midway.uchicago.edu   
Contact: Cynthia MacKenzie    773.702.6487    cmackenzie@peds.bsd.uchicago.edu   
Principal Investigator: James Tonsgard, MD         
United States, Indiana
Indiana Unversity Not yet recruiting
Indianapolis, Indiana, United States, 46202
Contact: Wade Clapp, MD    317-278-9290    kcole@uab.edu   
Contact: Cindy Dwight    317-274-4928    cdwight@iu.edu   
Sub-Investigator: Chie Shih, MD         
United States, Maryland
Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21287
Contact: Jaishri Blakeley, MD    410-502-6732    jblakel3@jhmi.edu   
United States, Massachusetts
Children' Hospital Boston and Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Nicole Ullrich, MD    617-355-3193    nicole.ullrich@childrens.harvard.edu   
Sub-Investigator: Scott Plotkin, MD         
Sub-Investigator: Mark Kieran, MD         
Children' Hospital Boston Recruiting
Boston, Massachusetts, United States, 02115
Contact: Nicole Ullrich, MD    617-355-3193    nicole.ullrich@childrens.harvard.edu   
United States, Missouri
Washington University in St. Louis Recruiting
Saint Louis, Missouri, United States, 63130
Contact: David Gutmann, MD, PhD    314-362-7379    gutmann@wustl.edu   
Contact: Hannah Zabriskie       Zabriskieh@wudosis.wustl.edu   
United States, New York
New York University Medical Center Not yet recruiting
New York, New York, United States, 10016
Contact: Jeffrey C Allen, MD    212-263-9907    jeffrey.allen@nyumc.org   
Contact: Anna Yaffe    212-263-9907    anna.yaffe@nyumc.org   
Sub-Investigator: Matthias Karajannis, MD         
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Elizabeth Schorry, MD    513-636-4760    Elizabeth.Schorry@cchmc.org   
Principal Investigator: Elizabeth Schorry, MD         
United States, Pennsylvania
Children's Hospital of Philadelphia Not yet recruiting
Philadelphia, Pennsylvania, United States, 19096
Contact: Michael Fisher, MD    215-590-5188    fisherm@email.chop.edu   
Contact: Ratnakar Patti    215.590.5188    ratnakarp@email.chop.edu   
Principal Investigator: Michael Fisher, MD         
United States, Texas
Texas Scottish Rite Hospital for Children Recruiting
Dallas, Texas, United States, 75235
Contact: Stephens Richards, MD, PhD       Steve.Richards@tsrh.org   
United States, Utah
University of Utah Not yet recruiting
Salt Lake City, Utah, United States, 84132
Contact: David Viskochil, MD    801-581-8943    dave.viskochil@hsc.utah.edu   
Australia, New South Wales
The Children's Hospital at Westmead Not yet recruiting
Westmead, New South Wales, Australia, 2145
Contact: David Little, MD    61-9845-1906    david.little@health.nsw.gov.au   
Contact: Belinda Barton, MD    61.2.9845.3698    belinda.barton@health.nsw.gov.au   
Sub-Investigator: Kathyrn North, MD         
Sponsors and Collaborators
University of Alabama at Birmingham
The Children's Tumor Foundation
Study Chair: Bruce R. Korf, MD, PhD Univ. of Alabama at Birmingham
More Information

Responsible Party: Bruce Korf, MD, Principal Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT02718131     History of Changes
Other Study ID Numbers: NF107
W81XWH-12-1-0155 ( Other Grant/Funding Number: Department of Defense, US Army )
G140004 ( Other Identifier: FDA IDE )
507821 ( Other Identifier: Medtronic )
First Posted: March 24, 2016    Key Record Dates
Last Update Posted: July 25, 2017
Last Verified: July 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Bruce Korf, MD, University of Alabama at Birmingham:
Tibial Pseudarthrosis

Additional relevant MeSH terms:
Neurofibromatosis 1
Nerve Sheath Neoplasms
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Peripheral Nervous System Diseases
Neuromuscular Diseases
Fractures, Ununited
Fractures, Bone
Wounds and Injuries