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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02718131
Registration number
NCT02718131
Ethics application status
Date submitted
7/03/2016
Date registered
24/03/2016
Date last updated
27/10/2021
Titles & IDs
Public title
A Study of INFUSE Bone Graft (BMP-2) in the Treatment of Tibial Pseudarthrosis in Neurofibromatosis Type 1 (NF1)
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Scientific 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)
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Secondary ID [1]
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W81XWH-12-1-0155
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Secondary ID [2]
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NF107
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Universal Trial Number (UTN)
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Trial acronym
NF107-BMP2
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
NF1
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Congenital Pseudarthrosis of Tibia
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Condition category
Condition code
Neurological
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Other neurological disorders
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Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Skin
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Dermatological conditions
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Cancer
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Other cancer types
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Injuries and Accidents
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Fractures
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Musculoskeletal
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Other muscular and skeletal disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Devices - INFUSE Bone Graft (BMP-2)
Treatment: Surgery - Control Group
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.
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.
Treatment: Devices: 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.
Treatment: Surgery: Control Group
The control group will receive the standard surgical protocol, without addition of the INFUSE device.
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Intervention code [1]
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Treatment: Devices
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Intervention code [2]
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Treatment: Surgery
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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RUST Score
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Assessment method [1]
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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.
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Timepoint [1]
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12 mos post surgery. The score at 12 mos post surgery will be used to determine success of healing and is the score reported.
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Secondary outcome [1]
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Average Time to Healing in Months
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline through 12 months post-surgery.
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Secondary outcome [2]
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Refracture Rate
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Assessment method [2]
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Numbers of patients with refracture within 1 year after surgery.
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Timepoint [2]
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12 months post-surgery
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Secondary outcome [3]
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Long-term Refracture
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Assessment method [3]
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Numbers of patients with refracture over long-term follow up of up to 10 years.
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Timepoint [3]
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annually, up to 10 years post-surgery
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Secondary outcome [4]
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Ten Meter Timed Walk
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Assessment method [4]
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Time (seconds) to perform the Ten Meter Timed Walk. Assessed at 6 and 12 months after surgery. Both 6 month and 12 month reported.
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Timepoint [4]
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Assessed at 6 and 12 months after surgery. Month 12 reported.
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Secondary outcome [5]
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Pain Intensity
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Assessment method [5]
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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.
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Timepoint [5]
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measured at post-op visits at 6 weeks, 3 mos, 6 mos, and 12 mos after surgery
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Secondary outcome [6]
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Quality of Life Score - The Upper Extremity and Physical Function Core Scale
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Assessment method [6]
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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.
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Timepoint [6]
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Assessed at 6 and 12 months after surgery. Month 12 reported.
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Secondary outcome [7]
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Quality of Life Score - The Transfer and Basic Mobility Core Scale
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Assessment method [7]
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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.
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Timepoint [7]
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Assessed at 6 and 12 months after surgery. Month 12 reported.
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Secondary outcome [8]
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Quality of Life Score - The Sports and Physical Functioning Core Scale
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Assessment method [8]
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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.
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Timepoint [8]
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Assessed at 6 and 12 months after surgery. Month 12 reported.
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Secondary outcome [9]
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Quality of Life Score - The Pain/Comfort Core Scale
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Assessment method [9]
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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.
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Timepoint [9]
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Assessed at 6 and 12 months after surgery. Month 12 reported.
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Secondary outcome [10]
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Quality of Life Score - The Happiness Core Scale
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Assessment method [10]
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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.
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Timepoint [10]
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Assessed at 6 and 12 months after surgery. Month 12 reported.
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Secondary outcome [11]
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Quality of Life Score - The Global Functioning Scale
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Assessment method [11]
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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.
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Timepoint [11]
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Assessed at 6 and 12 months after surgery. Month 12 reported.
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Eligibility
Key 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
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Minimum age
2
Years
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Maximum age
18
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
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Intervention assignment
Parallel
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Other design features
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Phase
Not Applicable
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Terminated
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/03/2016
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
1/06/2020
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Sample size
Target
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Accrual to date
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Final
5
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Recruitment in Australia
Recruitment state(s)
NSW
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Recruitment hospital [1]
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The Children's Hospital at Westmead - Westmead
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Recruitment postcode(s) [1]
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2145 - Westmead
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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Alabama
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United States of America
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State/province [2]
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California
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United States of America
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State/province [3]
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District of Columbia
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United States of America
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Illinois
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United States of America
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Indiana
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United States of America
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State/province [6]
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Maryland
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Country [7]
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United States of America
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Massachusetts
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Country [8]
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United States of America
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Missouri
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United States of America
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New York
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United States of America
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Ohio
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United States of America
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Pennsylvania
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United States of America
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Texas
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United States of America
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State/province [13]
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Utah
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Funding & Sponsors
Primary sponsor type
Other
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Name
University of Alabama at Birmingham
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Address
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Other collaborator category [1]
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Other
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Name [1]
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The Children's Tumor Foundation
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Address [1]
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Other collaborator category [2]
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Commercial sector/Industry
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Name [2]
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Medtronic
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Address [2]
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Ethics approval
Ethics application status
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Summary
Brief summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02718131
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Bruce R. Korf, MD, PhD
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Address
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Univ. of Alabama at Birmingham
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Fax
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Email
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Contact person for public queries
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02718131
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