Management of Traumatic Bone Defects in Tibial Plateau Fractures With Antibiotic-Impregnated Biodegradable Calcium Sulfate Beads: A Prospective Clinical Trial
Phase: NA
Conditions: Tibial Fractures, Intra-Articular Fractures, Fracture Fixation, Internal
Sponsor: Ross Leighton

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Management of Traumatic Bone Defects in Tibial Plateau Fractures with 
Antibiotic-Impregnated Biodegradable Calcium Sulfate Beads: A Prospective 
Clinical Trial 
 
 
 
 
 
 
Principal Investigator / Sponsor:  
Ross Leighton M.D. 
 
Other Investigators:   
 
Canadian Orthopaedic Trauma Society 
 
Research Coordinators: 
 
Kelly Trask 
                        
 
Shelley MacDonald 
 
Funder: 
 
 
 
Biocomposites, Ltd. 
 
Clinical Trial Registration: 
 
NCT02456194 
 
 
 

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Introduction / Background  
 
The tibial plateau is the flattened surface of the top of the tibia bone, which makes it part of the 
knee joint. It is covered with cartilage, which is critical for the smooth movement of the knee 
joint. It also houses the menisci (“shock absorbers”) of the knee joint and a number of ligaments 
that act to stabilize the knee joint. Fractures of this bone are difficult to manage since they can 
disrupt these soft tissues in addition to the bone. Fractures are classified according to their 
severity. The most common classification of tibial plateau fractures is by Schatzker (Figure 1), 
with the classification number increasing with severity1. 
 
 
Figure 1: Schatzker Classification of Tibial Plateau Fractures 
 
Tibial plateau fractures require anatomical reduction of the joint surface and stable fixation to 
allow early range of motion and progressive weight bearing to facilitate healing2. If the tibial 
plateau fracture involves a depression of the joint surface, elevating the fracture fragment can 
result in a defect, or void, in the metaphyseal bone. Standard practice is to fill this void with bone 
graft or a bone graft substitute. Autogenous Iliac Bone Grafting (AIBG) has long been 
considered the gold standard in subarticular bone defect management in conjunction with 
conventional open reduction and internal fixation techniques for unstable tibial plateau fractures3 

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although complications of graft harvest, ranging from temporary pain and numbness to long-term 
functional impairment, are well documented4-8.  These complications, along with the limited 
availability of AIBG, have led to the development of bone graft substitutes.  
Calcium sulfate has been used as a bone substitute for nearly 100 years. It is low cost, readily 
available, has a structure similar to bone allowing for osteoconductivity, and it has a proven 
safety record.  Calcium sulfate can also be used for local antibiotic delivery for the treatment or 
prevention of infection9.  
Advances in trauma care have reduced infection rates in tibial plateau fractures from 80%10 to 10 
– 14% 11, but the complex nature of the injury has been shown to be an independent risk factor 
for infection12. Preventing colonization of the bone graft used in tibial plateau fractures is 
desirable. The ability to provide antibiotics locally, rather than systemically, for the duration of 
the graft remodeling may improve outcomes of this injury if bony healing is not compromised. 
We propose a prospective clinical trial of tibial plateau fractures treated with internal fixation 
and a calcium sulfate graft which can be mixed with antibiotics and molded into various bead 
sizes for implantation into bone defects. The graft material chosen for this study is STIMULAN 
Rapid Cure (Biocomposites, UK), which is approved for use as a bone void filler and may be 
mixed with a variety of antibiotics. The combination of STIMULAN + antibiotic in bead form is 
herein referred to as the “study device”.   
Why is a Trial Needed Now? 
While studies have been done to look at prevention and treatment of infection with the study 
device13-25, there is no published evidence of its effectiveness in acute, closed, non-infected tibial 
plateau fractures. Previous studies have indicated that calcium sulfate is resorbed by three 
months after implantation and that bone has remodeled by six months26-27. These studies did not 
include the use of antibiotics in the calcium sulfate.  
Study Aims 
Our primary study aim is to look at resorption and remodeling of the study device into bone. 
Another important aim of the study is to look at subsidence, or collapse, of the joint surface. 
Secondary outcomes are those that are clinically important after this injury including time to 
bone healing, knee range of motion, knee stability, return to work and activities, infection, 
wound problems, functional outcomes, and complications.   
How Will the Results of This Trial Be Used? 

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This trial will provide clinical evidence on the use of antibiotics mixed with calcium sulfate in 
the treatment of acute, closed, non-infected tibial plateau fractures. This will guide orthopaedic 
surgeons in their clinical decision making for this complex injury.  
Methods  
This will be a prospective, non-randomized study. Up to four centers in Canada with extensive 
experience in the treatment of tibial plateau fractures will be selected for this multi-centre study. 
The study will be an investigator-driven study with QEII Health Sciences Centre as the lead site. 
It will be supported by an unrestricted research grant from Biocomposites Ltd. with the funds 
being distributed to all sites via the lead site. Thirty (30) consecutive patients who meet the 
inclusion criteria will be recruited for the study and followed for one year.  
Inclusion Criteria: 
Patient selection criteria will include: 
• Adult (skeletally mature) men or women; 
• Acute, closed, tibial plateau fractures, Schatzker grade 1 through 5;  
• Internal fixation and use of study device per protocol; 
• Fracture repair within 30 days of injury; 
• Signed informed consent to participate in study. 
Exclusion Criteria: 
• Uncontrolled diabetes; 
• Severe degenerative or metabolic bone disease; 
• Malignancy; 
• Severe vascular or neurologic disease; 
• Alcoholism; 
• Substance abuse; 
• Use of systemic steroids; 
• Immunosuppressive therapy;  
• Hypercalcaemia; 
• Renal-compromised patients; 
• Osteomyelitis or chronic infection in the study limb; 
• Women who are pregnant or breast-feeding. 
 
All sites will obtain approval from the institutional review board at their respective hospitals and 
participants will be required to provide informed consent prior to any study procedures. Since the 
study device is an option for treatment of this injury, informed consent may occur post-
operatively if the study device was used per protocol as the standard of care. Patients who 
consent to participate in study but do not receive the study device will not be considered study 
participants. 
 
All visits required will be those as per regular follow up visits in their institutions, so no travel 
expenses should be required. If however extra visits are required for study purposes (e.g. CT 
scan performed after hours), a small stipend will be paid to cover parking/ travel. 

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Standard open reduction and internal fixation techniques will be used to restore fracture stability. 
The implants utilized for this purpose will include locked and unlocked premolded proximal 
tibial plates and small fragment plates as per the decision of the attending surgeon. Subarticular 
grafting with the study device will be accomplished via an open procedure. The study device 
cannot be used alone or with screws only, it must be used with standard internal fixation as noted 
above. 
Preparation of the Study Device 
The study device is to be prepared with the antibiotic chosen according to the manufacturer’s 
mixing guidelines (Appendix A).  The selection of antibiotic from those in the mixing 
guidelines is left to the surgeon’s discretion. A maximum of one 10cc kit of STIMULAN Rapid 
Cure per participant is to be used. The STIMULAN is to be prepared in bead form. The selection 
of bead size is at the discretion of the surgeon.  
 
Post-operative immobilization, weight-bearing, and rehabilitation protocol will be the standard of 
care for each surgeon.  
 
Follow-up will be scheduled at 6 weeks, 3 months, 6 months, and 12 months as per the usual at 
each site. Other visits may be "clinically indicated" but would not be required as a part of this 
study. Baseline information will be collected during the initial hospital stay. 
Risks and Benefits of Study Participation 
This trial does not involve any experimental devices or procedures. The risks of participating are 
no greater than standard of care. As with any study, there is a risk of breach of confidentiality. 
There is no direct benefit to participants in this study. The results of this study will benefit future 
patients with this injury by providing more evidence on treatment with the study device. 
 
How Will The Outcome Measures Be Measured at Follow-up? 
 
Basic demographic information: At the time of study inclusion, information on basic 
demographics (age, sex), past medical history, co-morbidities, medications (i.e. bisphosphonates, 
vitamin D), pre-injury level of activity and/or employment and mechanism of injury will be 
collected for all participants. 
 
Functional outcomes: The Knee injury Osteoarthritis Outcome Score (KOOS)28 is a validated 
self-administered questionnaire which will be completed at the designated follow-up visits. The 
questionnaire completion time is approximately 15 minutes. Return to work and return to pre-
injury activities will be measured in weeks. 
 

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Clinical outcome: Range of motion will be evaluated and will include active and passive flexion 
and extension. Knee stability will be assessed. The surgical site will be examined for progression 
in healing, wound issues (drainage, dehiscence, etc.) or signs of infection.  
 
Radiological outcome: Evaluation will be performed at each participating centre and all 
radiographs will be sent to the principal investigation centre with all identifiers removed. Exams 
at each study visit will be the standard AP and lateral radiographs. Amount of study device 
remaining and percent remodeled will be measured on plain radiographs. Time to union will be 
defined as bridging callus evident on two x-rays. Our previous study on tibial plateau fractures 
indicated that subsidence occurs between three and six months after surgery29.  Therefore, at six 
months a CT scan will be performed to determine if any study device remains and to measure 
any subsidence of the joint surface. 
 
Adverse Events: Since the study device is being used according to the indications for use, 
monitoring of adverse events will be according to standard clinical practice. Reporting of serious 
adverse events will be according to the REB policy at participating sites, with copies sent to the 
lead site and the Quality Department at Biocomposites. Adverse events of interest in the study 
are those associated with the surgical procedure and healing of the injury.   
Data Collection, Management, and Retention 
Each study participant will be assigned a unique Subject ID to safeguard confidentiality. The 
Subject ID will be used on all data collection forms. Subject IDs will be assigned consecutively 
at each site. Participating sites will be provided with a site number and all the required Case 
Report Forms prior to initiation. Completed CRFs and questionnaires from each study site will 
be sent via Fax or e-mail to the lead site after each patient follow-up visit, according to the data 
transfer and/or sub-site agreement in effect. Sites will also be given the option to enter de-
identified data directly into REDCap.  Study sites will keep the originals and file them in the 
subject binder at each site. Radiographic images (x-rays and CT) for each subject will be de-
identified and copied onto a compact disc (CD) and submitted to the lead site at the end of the 
study. See Appendix B for schedule of events. 
 
Data management will be coordinated from the lead site (QEII Health Sciences Centre).  Study 
data will be managed using REDCap electronic data capture tools hosted by Nova Scotia Health 
Authority. REDCap (Research Electronic Data Capture) is a secure, web-based application 
designed to support data capture for research studies, providing 1) an intuitive interface for 
validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) 
automated export procedures for seamless data downloads to common statistical packages; and 
4) procedures for importing data from external sources. Sites will be given a choice to either 
continue to send CRF’s to the lead site or they will be given dedicated login information and 
training on how to access the REDCap tool and enter data directly into REDCap.   
 

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Study documents will be retained for seven (7) years. Sites will store and maintain all study-
related documents according to local policies, guidelines, and standards. Destruction of study 
records will be in accordance with local policies. 
Analysis of Results  
All analysis will be performed at the lead site. Descriptive statistics will be used to describe the 
study sample. Patients will be evaluated as to union, subsidence, loss of graft or premature 
resorption, percent of graft remaining at each visit, knee range of motion, knee stability, loss of 
fixation or fixation failure, infection, functional recovery (outcome scores and return to work, 
return to activity) and effect of tobacco use, age, sex, fracture classification. The sample size of 
thirty participants was chosen based on the expected recruitment rate at this site and others 
planning to participate in the interest of providing objective evidence of the healing potential 
with this device in patients with this injury.  
 
 
 

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References  
 
1. Schatzker J, McBroom R, Bruce D. (1979). The tibial plateau fracture. The Toronto 
experience 1968--1975. Clin Orthop Relat Res. Jan-Feb 138:94-104. 
2. Koval KJ, Helfet DL. (1995). Tibial plateau fractures: evaluation and treatment. J Am 
Acad Orthop Surg. 3:86-94. 
3. Segal, D., A. V. Franchi, et al. (1985). "Iliac autograft for reconstruction of severely 
depressed fracture of a lateral tibial plateau. Brief note." J Bone Joint Surg Am 67(8): 
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4. Younger, E., Chapman, MW (1989). "Morbidity at bone graft donor sites."  J. Orthop 
Trauma 3: 192-195.  
5. Goulet, J. A., L. E. Senunas, et al. (1997). "Autogenous iliac crest bone graft. 
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6. Fowler, B. L., B. E. Dall, et al. (1995). "Complications associated with harvesting 
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8. St John, T. A., A. R. Vaccaro, et al. (2003). "Physical and monetary costs associated with 
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9. Beuerlein MJ, McKee MD. (2010). Calcium sulfates: what is the evidence? J Orthop 
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10. Young MJ, Barrack RL. (1994). Complications of internal fixation of tibial plateau 
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11. Berkson EM, Virkus WW. (2006). High-Energy Tibial Plateau Fractures. J Am Acad 
Orthop Surg. Jan 14(1):20–31. 
12. Bachoura A, Guitton TG, Smith RM, Vrahas MS, Zurakowski D, Ring D. Infirmity and 
Injury Complexity are Risk Factors for Surgical-site Infection after Operative Fracture 
Care. Clin Orthop Relat Res. 2010 Dec 16; DOI: 10.1007/s11999-010-1737-2. 
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15. McPherson EJ, Dipane MV, Sherif SM. (2013). Dissolvable antibiotic beads in treatment 
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hip and knee arthroplasty. Joint Implant Surgery & Research Foundation, 3(3):28-29. 

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17. Kallala R, Nizam I, Haddad F. (2013, October). Outcomes following use of antibiotic-
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18. Nayar D, Duffy P, Aldridge C, Longstaff L, Shaw N, Scott S. (2013, September). 
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19. Saghieh S, Murtada A, Sheikh Taha AM, Masrouha K. (2011). Treatment of infected 
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20. Maale GE, Eager J. (2012, February). Local elution profiles of a synthesized CaSO4 
pellet, loaded with vancomycin and tobramycin for infected total joints. Paper presented 
at the American Academy of Orthopaedic Surgeons, San Francisco, CA, USA.  
21. Swords K, Martinez DR, Lockhart JL, Carrion R. A preliminary report on the usage of an 
intracorporal antibiotic cast with synthetic high purity CaSO4 for the treatment of 
infected penile implant. J Sex Med. 2013;10(4):1162-1169. 
22. Roche AJ, Selvaratnam V, Mukhopadhava S, Unnikrishnan N, Abiddin Z, Narayan B, 
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23. Whitlark JD, Rotondo LD, Su A. (2013, August). Management of below the knee 
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24. Parihar M, Ahuja D. (2012). Infected non-union of radius and ulna – Strategy of 
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PN. Calcium sulphate delivery system with tobramycin for the treatment of chronic 
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26. Kelly CM, Wilkins RM, Gitellis S, et al. The use of a surgical grade calcium sulfate as a 
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27. Yu HK, Ma H, Zhang C, Su J, Zhao J, Li J, Bai Y, Tang H. Treatment of tibial plateau 
fractures with high strength injectable calcium sulphate. Int Orthop. 2009 
Aug;33(4):1127-33.  
28. Roos EM, Lohmander LS. Knee injury and Osteoarthritis Outcome Score (KOOS): from 
joint injury to osteoarthritis. Health Qual Life Outcomes 2003;1:64 
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calcium phosphate cement for defect augmentation in tibial plateau fractures. A 

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multicenter, prospective, randomized study. J Bone Joint Surg Am. 2008; 90(10):2057-
61. 
 

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APPENDIX A 
 
STIMULAN Antibiotic Mixing Guidelines (Stimulan Rapid Cure Instructions for Use) 
 
 

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APPENDIX B 
 
Schedule of Events 
 
 
 
Baseline 
6 weeks 
3 months 
6 months 
12 
months 
 
Informed Consent 
 
 
X 
 
 
 
 
 
Clinic Visit and 
CRF Completion 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Range of Motion 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
KOOS 
questionnaire 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Assess for 
Adverse Events 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X-ray (AP & lat) 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
CT scan 
 
 
 
 
 
X