ABM/P-15 Bone Graft vs Traditional Bone Graft in Adult Spinal Deformity Surgery

Overview

The purpose of this prospective trial is to investigate ABM/P-15 bone graft versus traditional bone graft in patients undergoing surgery for Adult Spinal Deformity (ASD) in order to provide better clinical results through faster bone healing, no additional surgeries, fewer complications and thereby increase health-related quality of life. Main hypotheses: 1. The use of ABM/P-15 bone graft is superior to traditional bone graft treatment regarding the incidence of additional surgeries following index surgery for ASD Secondary hypotheses: 2. The investigators expect non-inferiority in patient reported outcome measures in the ABM/P-15 bone graft group compared to the control group 3. The investigators expect non-inferiority in the postoperative fusion rates (bone healing) evaluated on CT scans in the ABM/P-15 bone graft group compared to the control group 4. The investigators expect non-inferiority in postoperative incidence of asymptomatic pseudarthrosis in the ABM/P-15 bone graft group compared to the control group 5. The investigators expect non-inferiority in perioperative complications in ABM/P-15 bone graft group compared to the control group 6. The investigators expect the use of ABM/P-15 bone graft to be cost-efficient compared to the traditional treatment in the control group

2\. Description and classification of medical device i-Factor Peptide Enhanced Bone graftTM: "i-FACTOR Bone Graft is a pure, natural form of hydroxyapatite (anorganic bone mineral or ABM) containing P-15™, a synthetic peptide. It is provided in putty form, comprised of ABM/P-15 particles that are suspended in an inert biocompatible hydrogel. Hydroxyapatite is the major mineral component of bone. P-15 is a fifteen amino acid sequence polypeptide, a portion of Type-I collagen that serves as a biomimetic attachment site for bone cells. The hydrogel carrier (glycerin and carboxymethylcellulose, or CMC) forms the matrix that improves overall the handling characteristics and helps contain the i-FACTOR Bone Graft at the surgical site. The bovine-derived ABM particles within the matrix are radiopaque and sized between 250 and 425 microns. i-FACTOR Bone Graft provides a bone graft substitute that is remodeled into new bone during the natural healing process." The i-Factor Peptide Enhanced Bone graftTM is classified as a CE-marked class III medical device. i-Factor flex FRTM: "i-FACTOR Bone Graft is a pure, natural form of hydroxyapatite (anorganic bone mineral or ABM) containing P-15, a synthetic peptide. i-FACTOR Flex FR is comprised of ABM/P-15 particles that are suspended in an inert biocompatible carrier, and has been lyophylized (freeze-dried) to form flexible strips. Hydroxyapatite is the major mineral component of bone. P-15 is a fifteen amino acid sequence polypeptide, a portion of Type-I collagen that serves as a biomimetic attachment site for bone cells. The carrier (carboxymethylcellulose, glycerin, and purified silk) forms the matrix that helps contain i-FACTOR Flex FR at the surgical site. The bovine-derived ABM particles within the matrix are radiopaque and sized between 250 and 425 microns. i-FACTOR Flex FR provides a bone graft substitute that is remodeled into new bone during the natural healing process." The i-Factor flex FRTM is classified as a CE-marked class III medical device. Rationale for the project ASD is associated with excessive pain, severe disability and significantly reduces health-related quality of life. Surgical treatment is often considered the only viable option in patients with severe ASD, although surgery is associated with certain risks. In ASD surgery, the risk of revision surgery due to either postoperative mechanical failure of the implants or pseudarthrosis is common. Although several changes to treatment have been implemented in the last decade, revision surgery is still common and necessary in up to 30% of patients following the index procedure. Therefore, increased attention has been directed towards reducing the risk of pseudarthrosis, and ABM/P-15 bone graft may play a considerable role in preventing that. The effects have previously been described in patients undergoing cervical spinal discectomy with promising results. Promising results has also been found in the treatment of periodontal infrabony defects through enhanced regenerative bone capacity. Furthermore, ABM/P-15 bone graft in combination with locally harvested autograft has shown superiority compared to allogenic bone graft in non-instrumented posterolateral fusion. The use of ABM/P-15 bone graft has, however, not been assessed in patients undergoing long instrumented spinal fusion surgery which is the case in ASD surgery. The ABM/P-15 bone graft will be used as its CE-mark intends. Literature Since the introduction of iliac crest bone graft (ICBG) in 1958 leading to enhanced spinal fusion rates and lowering the rate of pseudarthrosis, bone grafts have been widely accepted as a supplement to instrumented fusion. Autologous bone graft taken from the iliac crest is often considered "gold standard" in spinal surgery due to its biomechanical properties of osteoconductivity, osteoinductivity, and osteogenesis. Osteoconduction is the combination of the three-dimensional structure of the bone graft and the capability of new bone formation on this particular scaffold. Moreover, availability of growth factors stimulating undifferentiated pluripotent cells into bone-forming cells is known as osteoinduction. Lastly, osteogenetic properties in bone synthesis rely on the continuous contribution of vital and established osteoprogenitor cells. Autologous bone graft consist of all three biomechanical properties however; the supply of is limited. Additionally, the use of autologous bone graft has been associated to potential donor-site complications, forcing surgeons to look for other viable options such as allogenic bone grafts or other alternatives such as demineralized bone matrix ceramics, bone morphogenetic protein, autologous growth factors, stem cell products (allogenic bone graft cellular matrix), synthetic peptides and bioactive peptides. Allogenic bone graft is described as the transfer between two genetically dissimilar individuals of the same species and is the second most transplanted tissue only surpassed by blood transfusions. Allogenic bone graft bears the properties of full osteoconduction, variably osteoinduction but completely lacks osteogenic properties due to loss of cellular elements. However, industrialized allogenic bone grafts, as well as other non-autologous bone grafts, does have some important advantages compared to autologous bone graft including decreased operative time, decreased blood loss, no donor-site morbidity and finally, almost unlimited quantities. The allogenic bone grafts (morselized femoral heads) from local bone banks are naturally with some restrictions to quantities, however; allogenic bone grafts compared to autologous bone grafts are more accessible. The use of bioactive peptides bone grafts (ABM/P-15), such as "i-FACTOR Peptide Enhanced Bone Graft" (Cerapedics, Inc., Westminister, CO), has shown similar effects in PROMs and even superiority in terms of faster formation of bridging bone within 12 months, compared to the "gold standard" autologous bone grafts. ABM/P-15 bone graft is a composite bone substitute consisting of an anorganic bovine-derived hydroxyapatite matrix (ABM) combined with a synthetic 15 amino acid peptide (P-15). The ABM/P-15 bone graft matrix bears the properties of osteconductivity, osteoinductivity and subsequent osteogenesis. The osteconductive ABM acts as a scaffold for the osteoinductive peptide P-15, acting as a binding site for the α2-β1 integrin (Type I collagen) initiating intra- and extracellular signaling pathways for increased production of growth factors, bone morphogenic proteins (BMP) and cytokines. The increased cell proliferation and differentiation ultimately results in osteogenesis. In a randomized double-blinded clinical trial, significantly increased fusion rates with the use of ABM/P-15 bone graft combined with locally harvested autograft compared to allogenic bone grafts in non-instrumented spondylolisthesis were reported. However; this did not result in overall improved PROMs in the reported 2-year follow-up period. In a systematic review, the total number of ASD surgeries in Medicare USA increased fourfold between 2000 and 2010 and additionally increasing the total costs of spinal deformity surgeries by a 16-fold from $56 million to $958 million 40. One possible explanation could be the increasing elderly population, possibly leading to increased complications and revision surgeries, imposing a major financial and clinical burden on the health care system. Several other studies also suggests the substantial increase in the frequency and expense of ASD surgery. Given the same effectiveness between two surgical index procedures, the natural choice would be to pick the less expensive procedure. However, transparency of costs (direct cost, indirect cost) may economically benefit the health care system through overall reduced patient cost. In a economic evaluation of perioperative adverse events (AE) associated with spinal surgery, an AE rate of 17.4% accounted for 16% of the total in-hospital cost. Optimally, ABM/P-15 bone grafts could reduce complications, revision surgeries and overall costs per patient. The use of autograft, allogenic bone grafts, Bone Morphogenic Protein (BMP) etc. have been extensively described in ASD patients, however; the use of the ABM/P-15 bone graft has not yet been assessed in this patient population, despite promising effects in other surgical fields. To our knowledge, only five clinical articles have been published regarding the use of ABM/P-15 bone graft in patients with spinal conditions. Of these five clinical studies, one is an annual 2-year follow-up on a previous RCT study, whereas a second study is the use of ABM/P-15 bone graft compared to allogenic bone grafts in non-instrumented lumbar fusion surgery, leaving three studies undertaken in patients undergoing instrumented spinal fusion surgery. One study (level I evidence) reported in the ABM/P-15 bone graft FDA IDE trial study similar fusion rates compared to autograft in single-level anterior cervical discectomy and fusion (ACDF). Another study (level III evidence) reported similar fusion rates compared to autograft in posterior lumbar interbody fusion (PLIF). Lastly, the third study (level IV evidence) reported satisfactory fusion rates for patients who underwent anterior lumbar interbody fusion (ALIF). Conclusively, our study will be the first to examine the use of ABM/P-15 bone graft both in patients undergoing more than one level of instrumented fusion and in ASD patients. The current findings supplemented with the results of this study will be of significant value, since spinal surgery often involves multiple levels of fusion. Furthermore, our study will merely be the second level I next to the FDA IDE trial study performed in 2016. The use of ABM/P-15 bone graft has, furthermore, been used in the field of odontology regarding periodontal regeneration. Several studies showed significantly enhanced regenerative bone capacity and provided overall better clinical results in the treatment of periodontal infrabony defects. 4\. Main Purposes In a prospective trial, patients undergoing surgery for Adult Spinal Deformity (ASD) will be randomized into two groups. One group receiving the standard bone graft which is a mix of locally autologous harvested bone and a morselized femoral head (allogenic) and the other group will receive bone graft of anorganic bovine bone mineral coated with a bioactive peptide (ABM/P-15). The following parameters across groups will be assessed: 1. The incidence of revision surgery 2. Patient reported outcome measures (PROMs) preoperatively, at 3 months, at 1-year and 2-year follow-up 3. Evaluation of fusion based on CT-scans at 1-year follow-up e. Perioperative adverse events f. Cost-effectiveness Main hypotheses 1. The use of ABM/P-15 bone graft is superior to traditional treatment with a mix of locally autologous harvested bone and a morselized femoral head (allogenic) regarding incidence of revision surgery following index surgery for ASD Secondary hypotheses 2. The investigators expect non-inferiority in PROMs in the ABM/P-15 bone graft group compared to the control group 3. The investigators expect non-inferiority in the postoperative fusion rates evaluated on CT scans in the ABM/P-15 bone graft group compared to the control group 4. The investigators expect non-inferiority in postoperative incidence of asymptomatic pseudarthrosis in the ABM/P-15 bone graft group compared to the control group 5. The investigators expect non-inferiority in perioperative adverse events in ABM/P-15 bone graft group compared to the control group 6. The investigators expect the use of ABM/P-15 bone graft to be cost-efficient compared to the traditional treatment in the control group 5\. Materials and methods Study design Prospective, single-blinded, randomized, controlled clinical trial at a quaternary specialized spine unit covering all deformity surgery in eastern Denmark. Methods of analysis A prospective, single-blinded, randomized, controlled clinical, single center study where patients scheduled for elective ASD surgery are randomized to receive either bone grafts of ABM/P-15 or the standard locally harvested autograft combined with allogenic bone graft. Group A: bone graft of anorganic bovine bone mineral coated with a bioactive peptide (ABM/P-15) mixed with locally harvested bone graft. Will be placed directly on the lamina and or in between transverse processes if no lamina. It will be contained by the muscle layer. Group B: standard bone-grafting which is a mix of locally harvested bone and a morselized femoral head (allogenic) Patient data will be recorded in RedCap, which will generate a random generic identifier number (ID). All patients will receive the following examinations at the described time: Questionnaires (30 min): 14 days prior to surgery, 3 months postop, 1 year postop and 2 years postop X-rays (30 min): 14 days prior to surgery, 7 days postop, 3 months postop, 1 year postop and 2 years postop CT-scan (30 min): 1 year postop Incidence of revision surgery will be defined as revision surgery due to any of the following: * Implant failure (e.g rod breakage, screw breakage, cage displacement/subsidence) * Pseudarthrosis assessed by CT-scan Posterolateral fusion will be defined according to the Lenke fusion grading system (Type A-D). Type A and type B will be defined as having fusion, whereas type C and type D will be defined as non-fusion. Radiographic signs of pseudarthrosis (in accordance to the above) in combinations with patient reported complaints, including pain, will be defined as symptomatic pseudarthrosis, and asymptomatic pseudarthrosis in cases of radiographic pseudarthrosis without patient reported complaints. The need for accessory anterior support will be assessed for each individual patient, and utilized through ALIF/PLIF. These patients will receive ABM/P-15 bone graft inside the cage. Radiographic non-fusion of ALIF/PLIF will be defined as one of the following: * Lack of substantial sclerotic changes in the recipient bone bed * Lack of visible bridging bone either through the cage or surrounding it as observed on anterior-posterior or lateral radiographs * Vertebral body translation of \<3 mm on lateral radiographs Bone graft migration at 3-months follow-up will be evaluated on radiographs. Comparison will be made to the immediate postoperative radiographs. Statistical analysis: All statistical analyses will be performed by the primary investigator using R (R Development Core Team, 2011, Vienna). P \< 0.05 will be considered significant. Patient characteristics 1. Continuous data will be compared using Student's t-test (Gaussian distributed data) or Wilcoxon's sum rank test (non-Gaussian data) 2. Categorical variables will be compared using Chi squared or Fisher's exact test Randomization procedure Group A: bone graft of anorganic bovine bone mineral coated with a bioactive peptide (ABM/P-15) Group B: standard bone graft which is a mix of locally harvested bone and a morselized femoral head (allogenic) The cohort will be block randomized (10 in each block) according to the above mentioned two groups. Patients will be informed about the possibility of receiving ABM/P-15 bone graft or standard locally harvested autograft combined with allogenic bone graft. The primary investigator will be responsible for the randomization without bias through block randomization of ten patients in each block. The primary investigator will make ten identical envelopes, five with the text "Group A" and five with the text "Group B". The envelopes will be shuffled, and the surgeon will hereafter be presented the ten envelopes and randomly select one. At the next ASD surgery for a new patient, the surgeon will be presented the remaining nine envelopes. When all ten envelopes have been picked for surgery, ten new ones will be made. This randomizes the selection of bone graft bias-free with a fifty-fifty percent chance of ending in either group A or group B. The practical completion and investigation of the study Patients evaluated at a multidisciplinary conference and afterwards scheduled for ASD surgery will be identified in the electronic medical records system (Sundhedsplatformen). Patients eligible for inclusion will at first outpatient visit to plan further final surgery (approx. 2 weeks prior to surgery), be informed about the study both in written form and orally. This information will be given by the primary investigator and/or the spine surgeon in a closed separate room after initial surgery planning. All patients have the right to an assessor to all outpatient visits and also during the written and oral information regarding the clinical study. If the patient wishes to bring an assessor to the information meeting regarding the clinical study, a new appointment can be made 3-10 days prior to the surgery date. Therefore, participating in this study will in no way impact the date of the surgery and further treatment. On the day of surgery, a written informed consent will be obtained should the patient decide to participate in this study. No patient will have less than 48 hours to answer, complied with the Helsinki declaration. After the patient agrees to participate in the study the primary investigator will randomize the patient to receive either ABM/P-15 bone graft or the standard of locally harvested autograft combined with allogenic bone graft according to the above mention section "randomization procedure". Deviations from standard treatment There will be no deviations from standard treatment since patients will receive either ABM/P-15 bone graft or the similar standard of locally harvested autograft combined with allogenic bone graft. All patients will be treated with a posterior spinal instrumentation and fusion (PSF) procedure and anterior support whenever deemed necessary at the surgeon's discretion. Choice of implants, osteotomies, numbers of levels fused will be decided prior to randomization at the multidisciplinary conference where final indication for surgery is confirmed. Cost-effectiveness analysis The overall cost per patient undergoing ASD surgery (incl. pre-, peri- and postoperative costs) can be estimated, using: diagnosis codes, procedural codes incl. supplemental codes in conjunction with data extraction from electronic medical records (Sundhedsplatformen). The total cost is calculated using diagnosis-related group (DRG) rates (this include for example: cystitis, pneumonia etc.). In the preoperative phase, the investigators will mainly analyze the ABM/P-15 bone graft (i-FACTOR Peptide Enhanced Bone Graft, Cerapedics) purchase price per patient compared to the cost of allogenic morselized femoral head. Furthermore, the investigators will note if extra clinical controls are required. In the perioperative phase the investigators will look at surgery time (incision time), time in theater, personnel involved, use of surgery equipment, planning time, waste time etc. The postoperative phase will be divided into cost during admission and cost after discharge from the hospital. Here, the investigators will analyze, in particular, the rate of revision surgery and other adverse events during admission. Additionally, length of hospital stay, complications to surgery, readmission to hospital following discharge, including readmission reason, department, time and length of readmission will be analyzed. Moreover, the investigators will look at the total cost of rehabilitative care and use of pain medication following discharge. All reimbursed prescription medicine is recorded in The Danish National Health Service Prescription Database (DNHSPD). These data will be gathered and analyzed as part of the total cost of rehabilitative care. Finally, information regarding reimbursed physiotherapy will also be gathered and analyzed. 6\. Statistical considerations Using: \- Alpha = 5% \- Statistical power = 80% \- Estimated revision rate in the non-intervention group: 30% \- Estimated revision rate in the intervention group: 15% Sample size calculation resulted in a sample size of n = 102 in each group. In the study the investigators have planned to include and randomize (block-randomization with 10 in each block) a total of 240 patients. This will secure a high statistical power even if some of the participants should drop out during the study. 7\. Patients The participants of the study will be 240 patients that have been scheduled for elective ASD surgery using the usual indications for ASD at the Spine Unit, Department of Orthopedic Surgery, Rigshospitalet. ASD with indication for surgery will be defined as any spinal procedure requiring posterior instrumented fusion at a minimum of 5 levels to the sacrum. Patients who have undergone previous lumbar spine surgery for a degenerative condition will be eligible for inclusion. 8\. Risks, side effects and disadvantages The main risks of ASD surgery involve infection, blood-loss, embolism, paresthesia, paralyses or even death. Based on previous studies with ABM/P-15 bone graft, participation in the present study will not expose the patients to any added risks of these complications. Side effects and disadvantages that may occur in this clinical trial study (approved in accordance to the regulation rules of medical devices), will be reported to the "Danish Medicines Agency". Radiographs: Patients will follow the department's routine regarding long standing radiographs pre- and postoperatively after 1 week, 3, 12 and 24 months. The standard procedure at our institution is that patients undergoing surgical treatment for ASD are scheduled for a CT-scan 1-year postoperatively. In the present study, the investigators will use this opportunity and analyze the already planned CT-scans in our study. In the written consent form patients are asked (yes:no) in regards of recieving information about the clinical study results as well as any consequences the study might have for the individual patient. In case of any secondary findings on the radiographs, patients who replied "no" on the form will not be informed about these findings. Patients who replied "yes" on the form will be informed about any secondary findings on radiographs and proper treatment will hereafter be initiated. The treatment includes referral to the proper department responsible for treating the specific secondary finding. 10\. Information via electronic medical records (Sundhedsplatformen) Variables collected: ● Name ● CPR-number ● Address and phone number * Birthdate * Sex * Diagnosis * Lifestyle factors such as alcohol consumption, caffeine intake, smoking habits, weight, height and exercise * Comorbidities and a ASA score, including medical treatments (including, but not limited to, hypertension, hypercholesterolemia, diabetes mellitus/HbA1C, dialysis dependence, chronic venous insufficiency, end-stage renal disease, liver disorder, congestive heart failure, osteoporosis, ostemalacia, Paget's disease, disseminated cancer diseases, severe psychiatric diseases) All above mentioned information gathered via electronic medical records will be used before patient consent and are essential to the clinical study in terms of the recruitment of patients. This information will hereafter be passed on to the primary investigator. All below mentioned information gathered via electronic medical records will be used after patient consent. This information is essential to the clinical study in order to proper analyze differences among patients and thereby, conclude on these findings the differences between the ABM/P-15 bone graft versus the traditional bone graft in Adult Spinal Deformity surgery. This information is in particular of relevance in spine surgery when evaluating differences in bone graft treatment. Furthermore, in order to analyze correlations between the two groups, the investigators believe that the below mentioned information are essential in order to make the correlations analysis. ● Previous surgical procedures of the spine (date, type and implants) ● Surgical parameters, including blood-loss, surgery time, fluid-replacement therapy, levels of surgery, implant types. ● Complications to surgery * Adverse events during admission * Readmission to hospital following discharge, including readmission reason, department, time and length of readmission * Mortality * Previously filed patient-reported outcome measures * Length of hospital stay From phone conversations or outpatient clinic visits the following information are collected: * Occupation * Current use of pain medication * Rehabilitative care (expenditures) All radiographs will be analyzed which is the standard procedure for all patients undergoing ASD surgery at our institute. After written consent from the patient, the primary investigator and Spine unit, Department of Orthopedic Surgery 6011C, Rigshospitalet, will get direct access to the patient's electronic medical records in order to collect the above mentioned variables as a part of this clinical trial study. 11\. Sensitive patient data All sensitive patient data gathered in this project are protected under "General Data Protection Regulation" and "The Data Protection Act". All data will be anonymized. No personally identifiable information will be shared with Cerapedics. Only a gathered anonymized data pool with all patients included could potentially be shared and will in no circumstances include sharing of patient data on individual level. In short, no patient will be identifiable. 14\. Recruitment of patients and informed consent The primary investigator/or surgeon will preoperatively inform potential ASD patients about this scientific study regarding the use of ABM/P-15 bone graft versus locally harvested autograft combined with allogenic bone graft at first outpatient visit to plan further final surgery (approx. 2 weeks prior to surgery). All information regarding the scientific study will be given in a closed separate undisturbed room. The patient has the right to an assessor at the conversation. If the patient wishes to bring an assessor to the information meeting regarding the clinical study, a new appointment can be made 3-10 days prior to the surgery date. Therefore, participating in this study will in no way impact the date of the surgery and further treatment. Patients will be thoroughly informed about this clinical trial, handed the "Participation information", "Before participating" and "Participants rights in a scientific researh project" sheets and all questions regarding the study will be answered to the best of spine surgeons abilities. Furthermore, patients will be informed that no participants will have to have to make a final decision at this time and that cancelation of participation in the study will not influence treatment pre-, peri- or postoperatively. No participants will have less than 48 hours to answer, complied with the Helsinki declaration. However, if the patient agrees to participate in this study by signing a written consent, the primary investigator will inform the surgeon on whether to use ABM/P-15 bone graft or the standard locally harvested autograft and allogenic bone graft on the day of surgery as described. It is the primary investigators responsibility and duty to make sure the above mentioned criteria are met. Copies of information and informed consent will be given to subjects in this trial. 15\. Publication of results All results, including positive, negative or inconclusive results will be published in peer-reviewed scientific journals. Publications will be done as follows: 1year follow-up study of the interim results 2year follow-up study of the final results 16\. Ethical considerations The investigators do not expect that patients participating in the study will experience any special side effects or complications directly related to the specific use of ABM/P-15 bone graft. Patients in both groups will receive the needed amount of bone graft evaluated by the surgeon. The purpose of giving ABM/P-15 bone graft is to provide better clinical results through faster fusion and higher fusion rates, fewer complications, no additional surgeries and improved overall PROMs postoperatively. There has not been performed any fundamental changes in the overall surgery with this new bone graft type. Additionally, a cost-effectiveness analysis of ABM/P-15 bone graft will be performed and might optimize resources in the health care system. This analysis will have no impact on the treatment of patients in this study. The study will not be started until approval from the Scientific Ethical Committee of the Capital Region of Denmark and the Danish Data Protection Agency has been obtained, and it will be registered at clinicaltrials.gov. All patients will receive both oral and written information before informed consent to participate is obtained. The significant usefulness of the present study is to gather new knowledge concerning further optimization of clinical result postoperatively from ASD surgeries. Knowledge from our study will benefit society in general and optimize utilization of resources, in terms of best treatment for future patients. In case of serious adverse preliminary results, data will be analyzed and if this treatment is found to cause significant critical problems compared to other bone grafts (p\<0.05), the study will be ended. This preliminary analysis will be performed after the inclusion of 5% of the patients in order to validate the effect of treatment and adverse events. The study is thus designed to minimize unnecessary risk to the patients. 17\. Information regarding compensation The participants are covered by the Danish Patient Compensation Association.