title: Efficacy of i-Factor Bone Graft versus Autograft in Anterior Cervical Discectomy and Fusion: Results of the Prospective, Randomized, Single-blinded Food and Drug Administration Investigational Device Exemption Study.
abstract: METHODS
  A prospective, randomized, controlled, parallel, single-blinded noninferiority multicenter pivotal FDA IDE trial.
  
  
  OBJECTIVE
  The objective of this study was to investigate efficacy and safety of i-Factor Bone Graft (i-Factor) compared with local autograft in single-level anterior cervical discectomy and fusion (ACDF) for cervical radiculopathy.
  
  
  BACKGROUND
  i-Factor is a composite bone substitute material consisting of the P-15 synthetic collagen fragment adsorbed onto anorganic bone mineral and suspended in an inert biocompatible hydrogel carrier. P-15 has demonstrated bone healing efficacy in dental, orthopedic, and nonhuman applications.
  
  
  METHODS
  Patients randomly received either autograft (N = 154) or i-Factor (N = 165) in a cortical ring allograft. Study success was defined as noninferiority in fusion, Neck Disability Index (NDI), and Neurological Success endpoints, and similar adverse events profile at 12 months.
  
  
  RESULTS
  At 12 months (follow-up rate 87%), both i-Factor and autograft subjects demonstrated a high fusion rate (88.97% and 85.82%, respectively, noninferiority P = 0.0004), significant improvements in NDI (28.75 and 27.40, respectively, noninferiority P < 0.0001), and high Neurological Success rate (93.71% and 93.01%, respectively, noninferiority P < 0.0001). There was no difference in the rate of adverse events (83.64% and 82.47% in the i-Factor and autograft groups, respectively, P = 0.8814). Overall success rate consisting of fusion, NDI, Neurological Success and Safety Success was higher in i-Factor subjects than in autograft subjects (68.75% and 56.94%, respectively, P = 0.0382). Improvements in VAS pain and SF-36v2 scores were clinically relevant and similar between the groups. A high proportion of patients reported good or excellent Odom outcomes (81.4% in both groups).
  
  
  CONCLUSIONS
  i-Factor has met all four FDA mandated noninferiority success criteria and has demonstrated safety and efficacy in single-level ACDF for cervical radiculopathy. i-Factor and autograft groups demonstrated significant postsurgical improvement and high fusion rates.
  
  
  METHODS
  1.
authors.affiliation: University of Kansas Medical Center, Kansas City, KS.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Arnold
authors.affiliation: Indiana Spine Group, Carmel, IN.
authors.forename: Rick C
authors.initials: RC
authors.lastname: Sasso
authors.affiliation: Center for Spine Disorders, Thornton, CO.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Janssen
authors.affiliation: University of Toronto Spine Program and Toronto Western Hospital, Toronto, Ontario, Canada.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fehlings
authors.affiliation: Indiana Spine Group, Carmel, IN.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Smucker
authors.affiliation: Rothman Institute at Jefferson, Philadelphia, PA.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Vaccaro
authors.affiliation: Rutgers-New Jersey Medical School, Newark, NJ.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Heary
authors.affiliation: Kennedy-White Orthopaedic Center, Sarasota, FL.
authors.forename: Ashvin I
authors.initials: AI
authors.lastname: Patel
authors.affiliation: Montreal Neurological Institute, Montreal, Quebec, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Goulet
authors.affiliation: Cleveland Clinic, Cleveland, OH.
authors.forename: Iain H
authors.initials: IH
authors.lastname: Kalfas
authors.affiliation: University of Washington, Seattle, WA.
authors.forename: Branko
authors.initials: B
authors.lastname: Kopjar
mesh_terms: D000328:Adult; D016025:Bone Transplantation / Q000379:methods / Q000592:standards*; D002574:Cervical Vertebrae / Q000601:surgery*; D018795:Device Approval; D017586:Diskectomy / Q000379:methods / Q000592:standards*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011843:Radiculopathy / Q000175:diagnosis / Q000453:epidemiology / Q000601:surgery*; D016037:Single-Blind Method; D013123:Spinal Fusion / Q000379:methods / Q000592:standards*; D014182:Transplantation, Autologous / Q000379:methods / Q000592:standards; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology; D014486:United States Food and Drug Administration
references.citation: Bohlman HH. Cervical spondylosis and myelopathy. Instr Course Lect 1995; 44:81–97.
references.citation: Bohlman HH, Emery SE, Goodfellow DB, et al. Robinson anterior cervical discectomy and arthrodesis for cervical radiculopathy. Long-term follow-up of one hundred and twenty-two patients. J Bone Joint Surg Am 1993; 75:1298–1307.
references.citation: Emery SE, Fisher JR, Bohlman HH. Three-level anterior cervical discectomy and fusion: radiographic and clinical results. Spine (Phila Pa 1976) 1997; 22:2622–2624.
references.citation: Ebraheim NA, Elgafy H, Xu R. Bone-graft harvesting from iliac and fibular donor sites: techniques and complications. J Am Acad Orthop Surg 2001; 9:210–218.
references.citation: St John TA, Vaccaro AR, Sah AP, et al. Physical and monetary costs associated with autogenous bone graft harvesting. Am J Orthop (Belle Mead NJ) 2003; 32:18–23.
references.citation: Silber JS, Anderson DG, Daffner SD, et al. Donor site morbidity after anterior iliac crest bone harvest for single-level anterior cervical discectomy and fusion. Spine (Phila Pa 1976) 2003; 28:134–139.
references.citation: De Long WG Jr, Einhorn TA, Koval K, et al. Bone grafts and bone graft substitutes in orthopaedic trauma surgery. A critical analysis. J Bone Joint Surg Am 2007; 89:649–658.
references.citation: Epstein NE. A preliminary study of the efficacy of beta tricalcium phosphate as a bone expander for instrumented posterolateral lumbar fusions. J Spinal Disord Tech 2006; 19:424–429.
references.citation: Epstein NE. An analysis of noninstrumented posterolateral lumbar fusions performed in predominantly geriatric patients using lamina autograft and beta tricalcium phosphate. Spine J 2008; 8:882–887.
references.citation: Epstein NE. Beta tricalcium phosphate: observation of use in 100 posterolateral lumbar instrumented fusions. Spine J 2009; 9:630–638.
references.citation: Finkemeier CG. Bone-grafting and bone-graft substitutes. J Bone Joint Surg Am 2002; 84-A:454–464.
references.citation: Gosain AK, Song L, Riordan P, et al. A 1-year study of osteoinduction in hydroxyapatite-derived biomaterials in an adult sheep model: part I. Plast Reconstr Surg 2002; 109:619–630.
references.citation: Gunzburg R, Szpalski M. Use of a novel beta-tricalcium phosphate-based bone void filler as a graft extender in spinal fusion surgeries. Orthopedics 2002; 25:s591–s595.
references.citation: Hardenbrook MA, Lombardo SR. Silicate-substituted calcium phosphate as a bone void filler after kyphoplasty in a young patient with multiple compression fractures due to osteogenesis imperfecta variant: case report. Neurosurg Focus 2006; 21:E9.
references.citation: Lerner T, Bullmann V, Schulte TL, et al. A level-1 pilot study to evaluate of ultraporous beta-tricalcium phosphate as a graft extender in the posterior correction of adolescent idiopathic scoliosis. Eur Spine J 2009; 18:170–179.
references.citation: Linovitz RJ, Peppers TA. Use of an advanced formulation of beta-tricalcium phosphate as a bone extender in interbody lumbar fusion. Orthopedics 2002; 25:s585–s589.
references.citation: Mastronardi L, Ducati A, Ferrante L. Anterior cervical fusion with polyetheretherketone (PEEK) cages in the treatment of degenerative disc disease. Preliminary observations in 36 consecutive cases with a minimum 12-month follow-up. Acta Neurochir (Wien) 2006; 148:307–312.
references.citation: Neen D, Noyes D, Shaw M, et al. Healos and bone marrow aspirate used for lumbar spine fusion: a case controlled study comparing healos with autograft. Spine (Phila Pa 1976) 2006; 31:E636–E640.
references.citation: Peterson B, Whang PG, Iglesias R, et al. Osteoinductivity of commercially available demineralized bone matrix. Preparations in a spine fusion model. J Bone Joint Surg Am 2004; 86-A:2243–2250.
references.citation: Schizas C, Triantafyllopoulos D, Kosmopoulos V, et al. Posterolateral lumbar spine fusion using a novel demineralized bone matrix: a controlled case pilot study. Arch Orthop Trauma Surg 2008; 128:621–625.
references.citation: Thalgott JS, Fritts K, Giuffre JM, et al. Anterior interbody fusion of the cervical spine with coralline hydroxyapatite. Spine (Phila Pa 1976) 1999; 24:1295–1299.
references.citation: Vaccaro AR, Stubbs HA, Block JE. Demineralized bone matrix composite grafting for posterolateral spinal fusion. Orthopedics 2007; 30:567–570.
references.citation: Wang JC, Alanay A, Mark D, et al. A comparison of commercially available demineralized bone matrix for spinal fusion. Eur Spine J 2007; 16:1233–1240.
references.citation: Hanks T, Atkinson BL. Comparison of cell viability on anorganic bone matrix with or without P-15 cell binding peptide. Biomaterials 2004; 25:4831–4836.
references.citation: Bhatnagar RS, Qian JJ, Gough CA. The role in cell binding of a beta-bend within the triple helical region in collagen alpha 1 (I) chain: structural and biological evidence for conformational tautomerism on fiber surface. J Biomol Struct Dyn 1997; 14:547–560.
references.citation: Bhatnagar RS, Qian JJ, Wedrychowska A, et al. Construction of biomimetic environments with a synthetic peptide analogue of collagen. Mater Res Soc Symp Proc 1998; 530:43–54.
references.citation: Cerapedics. i-Factor Bone Graft Technology. Available at: http://www.cerapedics.com/intl/technology. Accessed May 20, 2015.
references.citation: Yang XB, Bhatnagar RS, Li S, et al. Biomimetic collagen scaffolds for human bone cell growth and differentiation. Tissue Eng 2004; 10:1148–1159.
references.citation: Schwartz Z, Goldstein M, Raviv E, et al. Clinical evaluation of demineralized bone allograft in a hyaluronic acid carrier for sinus lift augmentation in humans: a computed tomography and histomorphometric study. Clin Oral Implants Res 2007; 18:204–211.
references.citation: Yukna RA, Krauser JT, Callan DP, et al. Multi-center clinical comparison of combination anorganic bovine-derived hydroxyapatite matrix (ABM)/cell binding peptide (P-15) and ABM in human periodontal osseous defects. 6-month results. J Periodontol 2000; 71:1671–1679.
references.citation: Yukna RA, Mellonig JT. Histologic evaluation of periodontal healing in humans following regenerative therapy with enamel matrix derivative. A 10-case series. J Periodontol 2000; 71:752–759.
references.citation: Gomar F, Orozco R, Villar JL, et al. P-15 small peptide bone graft substitute in the treatment of non-unions and delayed union. A pilot clinical trial. Int Orthop 2007; 31:93–99.
references.citation: Kubler A, Neugebauer J, Oh JH, et al. Growth and proliferation of human osteoblasts on different bone graft substitutes: an in vitro study. Implant Dent 2004; 13:171–179.
references.citation: Scarano A, Iezzi G, Petrone G, et al. Cortical bone regeneration with a synthetic cell-binding peptide: a histologic and histomorphometric pilot study. Implant Dent 2003; 12:318–324.
references.citation: Thorwarth M, Schultze-Mosgau S, Wehrhan F, et al. Enhanced bone regeneration with a synthetic cell-binding peptide–in vivo results. Biochem Biophys Res Commun 2005; 329:789–795.
references.citation: Vernon H, Mior S. The Neck Disability Index: a study of reliability and validity. J Manipulative Physiol Ther 1991; 14:409–415.
references.citation: McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 1993; 31:247–263.
references.citation: Odom GL, Finney W, Woodhall B. Cervical disk lesions. J Am Med Assoc 1958; 166:23–28.
references.citation: Blackwelder WC. Proving the null hypothesis” in clinical trials. Control Clin Trials 1982; 3:345–353.
references.citation: Food and Drug Administration. Draft Guidance for Industry and Food and Drug Administration Staff. Adaptive Designs for Medical Device Clinical Studies. GUD1500005. May 18, 2015. Available at: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM446729.pdf. Accessed June 9, 2015.
references.citation: Carreon LY, Glassman SD, Campbell MJ, et al. Neck Disability Index, short form-36 physical component summary, and pain scales for neck and arm pain: the minimum clinically important difference and substantial clinical benefit after cervical spine fusion. Spine J 2010; 10:469–474.
references.citation: Artzi Z, Kozlovsky A, Nemcovsky CE, et al. Histomorphometric evaluation of natural mineral combined with a synthetic cell-binding peptide (P-15) in critical-size defects in the rat calvaria. Int J Oral Maxillofac Implants 2008; 23:1063–1070.
references.citation: Lallier TE, Yukna R, St Marie S, et al. The putative collagen binding peptide hastens periodontal ligament cell attachment to bone replacement graft materials. J Periodontol 2001; 72:990–997.
references.citation: Luszczyk M, Smith JS, Fischgrund JS, et al. Does smoking have an impact on fusion rate in single-level anterior cervical discectomy and fusion with allograft and rigid plate fixation? Clinical article. J Neurosurg Spine 2013; 19:527–531.
references.citation: Karikari IO, Jain D, Owens TR, et al. Impact of subsidence on clinical outcomes and radiographic fusion rates in anterior cervical discectomy and fusion: a systematic review. J Spinal Disord Tech 2014; 27:1–10.