Clinical trial NCT02481869
Conditions: Fracture
Keywords: Closed unilateral pilon
Sponsor: University of Missouri-Columbia
Start date: 2015-06-01; Completion date: 2019-11-01
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patients who sustain broken ankles have a very high risk of developing arthritis soon after injury (within 2 years). This arthritis can cause increased pain and a decrease level of function, especially if the injury occurs at an early age. During and shortly after ankle injury, there is an inflammatory chemical process that takes place in the ankle that can cause damage to the cartilage in the ankle joint. The investigators want to use what is called Platelet Rich Plasma (PRP), which is produced from a small amount of the patient's own blood, to inject into the injured ankle to see if they can decrease the inflammation that happens after the injury and to see if they can decrease arthritis.

Detailed description:
Patients who sustain broken ankles have a very high risk of developing arthritis soon after their injury (within 2 years). This arthritis can cause increased pain and decreased level of function, especially if the injury occurs at an early age. During and shortly after the ankle injury, there is an inflammatory chemical processes that take place in the ankle that can cause damage to the cartilage in the ankle joint. Currently the treatment for this injury is doing surgery is a two step process. When the patient has an ankle fracture, surgeons will stabilize the fracture with an external fixation device to allow ankle swelling to decrease which has been shown improve outcomes within a few hours. After about 10 days the patient will come back for their final surgery in which surgeons will open the ankle joint and make sure that the joint lines up and fix it with plates and screws.

There is no intervention that is done with regards to the physiologic process that goes on inside the ankle joint when the ankle is injured. This is what the investigators intend to study. There is a very large destructive process that may contribute with the early development to arthritis.

The investigators would like to see the effect of this inflammatory response with the addition of platelet rich plasma (PRP) which is produced from a small vial of the patient's own blood. PRP has been used safely in patients with osteoarthritis and has been shown to slow the progression and improve pain scores. PRP is made by spinning the patient's blood in a centrifuge which separates the blood cells from each other. The bloods cells that are anti-inflammatory in nature are taken and placed in another syringe. This is a blinded randomized control study. There will be two groups in which the patients will randomize into: PRP group, or Normal Saline Group. In both groups, the investigator's plan is to withdraw joint fluid from both the injured and uninjured ankle at the time of the first surgery as to analyze the joint fluid from both ankles.

Participants who are randomized into the PRP group will receive PRP in the injured ankle at the time of the first surgery when the external fixator is placed. Participants who are randomized into the Normal Saline group will receive Normal Saline in the injured ankle at the time of the first surgery when the external fixator is placed.

After 7-14 days the participant will return and have their second surgery for definitive fixation. At the time of surgery, joint fluid will again be taken out of the joint for analysis to see if the PRP decreased the anti-inflammatory cells decreased inflammation. After the second surgery the participant will be followed up in the clinic in a regular manner.

Arms: arm 1: At the time of surgery, the participant will have both injured and uninjured ankles cleaned with surgical soap. An needle will be placed into the injured ankle joint and synovial fluid will be drawn out of the ankle and collected into a syringe. Using the same needle, the PRP will be delivered into the same arthrocentesis needle.

Next the uninjured ankle will have the same procedure as the injured ankle, except there will be no injection of PRP. There will only be a aspiration of synovial fluid from the uninjured ankle joint using a different clean needle.

Another aspiration of the synovial fluid will be done at the time of the second surgery in the same manner as before, except there will be no injection of PRP, just an aspiration of both injured and uninjured ankles. arm 2: At the time of surgery, the participant will have both injured and uninjured ankles cleaned with surgical soap. An needle will be placed into the injured ankle joint and synovial fluid will be drawn out of the ankle and collected into a syringe. Using the same needle, the Saline will be delivered into the same arthrocentesis needle.

Next the uninjured ankle will have the same procedure as the injured ankle, except there will be no injection of Saline. There will only be a aspiration of synovial fluid from the uninjured ankle joint using a different clean needle.

Another aspiration of the synovial fluid will be done at the time of the second surgery in the same manner as before, except there will be no injection of Saline, just an aspiration of both injured and uninjured ankles.
Interventions: intervention 1: Arthrocentesis/PRP intervention 2: Arthrocentesis/Saline
Intervention descriptions: intervention 1: PRP (n=20): single intra-articular injection of 5 ml of a leukocyte-reduced platelet rich plasma (ACP, Arthrex, Naples, FL) at the time of closed reduction and initial stabilization using ankle-spanning external fixation intervention 2: Control (n=20): single intra-articular injection of 5 ml of sterile 0.9% saline at the time of closed reduction and initial stabilization using ankle-spanning external fixation

Protocol documents:
Prot_000.pdf: 
IRB # 2002117 
Title:  Does early platelet rich plasma injection decrease the risk of post-traumatic 
arthritis in pilon fractures undergoing two-staged open reduction with internal fixation? 
Protocol version: 1.3 
Protocol date: 08/30/2016 
Principal Investigator: Brett Crist, MD 
NCT: 02481869 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB # 2002117 
 
A) Scientific Aims 
Specific Aim 1: Determine the effects of a single intra-articular injection of platelet rich 
plasma (PRP) for mitigating the development of post-traumatic arthritis (PTA) in patients 
being surgically treated for pilon fractures in one ankle. 
Null hypothesis: A single intra-articular injection of platelet rich plasma (PRP) will not 
be associated with significant improvements in outcome based on patient-reported 
measures of pain and function, as well as diagnostic imaging findings of PTA in patients 
being surgically treated for pilon fractures in one ankle. 
Specific Aim 2: Assess the discriminatory potential of a synovial fluid biomarker panel 
for categorizing presence and severity of PTA based on patient-reported outcome 
measures of pain and function, as well as diagnostic imaging findings in patients being 
treated for pilon fractures in one ankle. 
Null hypothesis: Synovial fluid biomarkers will not have high discriminatory 
capabilities for categorizing presence and severity of PTA in patients being treated for 
pilon fractures in one ankle. 
  
B) Background and Significance 
Pilon fractures are common and are associated with a 75% chance for symptomatic post-
traumatic arthritis (PTA).1 Although the mechanisms for initiation and progression of 
PTA after pilon fracture are incompletely understood, articular fracture is known to 
induce pro-inflammatory cytokines and degradative enzymes, which can result in 
chondrocyte death, accelerate cartilage degradation, and drive synovitis after injury. 
These pathologic processes appear to be especially important in the early phases of 
disease.2-4 Current treatments for articular fractures are focused on biomechanical issues: 
anatomic reduction, rigid stability, and limb alignment. These are critical issues to 
address for optimal healing, early limb use, and joint function. However, the biologic 
components of articular fracture are likely as, or even more important, with respect to 
development of PTA. As such, research efforts also need to focus on these important 
aspects in order to mitigate the development and progression of joint pathology after 
articular fracture. 
In an in vitro study, antioxidant treatment delivered hours after articular cartilage injury 
was reported to prevent progression of PTA-related pathology.5 Using canine models of 
PTA, our group has noted significant benefits after intra-articular injection of platelet rich 
plasma (PRP) in decreasing pain, improving limb use, maintaining joint range of motion, 
and mitigating progression of osteoarthritis. Beneficial results associated with PRP 
treatment of OA have also been reported in clinical veterinary patients.6 Based on this 
translational evidence in conjunction with the regulatory status and availability of PRP 
for clinical use in trauma patients, this orthobiologic therapy appears to have strong 
potential for providing a practical means of mitigating development of PTA in patients 
suffering ankle fracture. Importantly, we will be able to use a synovial fluid biomarker 
panel that has been shown to have high discriminatory potential for categorizing presence 
and severity of OA in dogs9, to assess patients for PTA after pilon fracture – which 
provides critical data regarding disease mechanisms7,8 – and treatment monitoring for 
development and assessment for novel therapeutic strategies for this pervasive problem. 
  


IRB # 2002117 
C) Previous Work on the Study 
 There has been little published work on this particular treatment strategy for post 
traumatic arthritis of the ankle 
  
D) Methods 
With IRB approval and informed consent, patients (n=40) will be included who sustain 
closed pilon fracture of one ankle and are undergoing initial reduction with spanning 
external fixation, followed by open reduction with internal fixation (ORIF). Up to 50 
patients will be enrolled in order to account for expected attrition in this patient 
population. Patients will be randomized to one of two treatment groups: 
- PRP (n=20): single intra-articular injection of 5 ml of a leukocyte-reduced platelet rich 
plasma (ACP, Arthrex, Naples, FL) at the time of closed reduction and initial 
stabilization using ankle-spanning external fixation 
- Control (n=20):  single intra-articular injection of 5 ml of sterile 0.9% saline at the time 
of closed reduction and initial stabilization using ankle-spanning external fixation  
Study candidates will be identified as they present to the University Hospital emergency 
room or clinics and will be recruited for enrollment.  Informed consent will be obtained 
as per IRB protocol.  The patients will be approached by an orthopedic resident 
physicians, attending, or study staff to present the current study. Patients will be told of 
the details of the study and what is required of them if they chose to participate. The 
patients will be randomized by envelop to one of two groups, the PRP or control group. 
The patients will be blinded to which treatment they receive. Patients will be treated 
according to current standard of care, Following initial reduction and placement of ankle-
spanning external fixation, synovial fluid will be aseptically obtained via arthrocentesis 
from both ankles and saved for subsequent biomarker analysis at the Comparative 
Orthopedic Laboratory. For the injured ankle, the PRP injection will be performed 
through the same needle used for arthrocentesis. PRP will be isolated from venous blood 
drawn from a peripheral vein. When appropriate, ORIF will be performed for definitive 
fracture treatment likely 7-14 days following external fixator placement. Prior to 
capsulotomy for ORIF, synovial fluid will again be aseptically obtained via arthrocentesis 
from both ankles and saved for subsequent biomarker analysis. 
  
Follow-up assessments will be performed at 3 weeks, 6 weeks, 12 weeks, 6 months, 12 
months, and 18 months after surgery for all patients. Radiographs will be obtained at 6 
weeks and each subsequent visit. Patient reported outcomes (PRO) including AOFAS, SF 
12 and VAS for pain and level of function will be recorded at all follow-up assessments 
starting at 3 weeks. At 18 months, MRI of the affected ankle will be performed and used 
for whole-joint assessment of OA.10 
Number of patients per group was determined from a pre-study power analysis using 
previously published data on prevalence of PTA after pilon fracture – the assumption 
being that a 10% reduction in percentage of patients experiencing symptomatic PTA 
would be clinically significant. Patients and all patient evaluators will be kept blinded to 
treatment until all data are collected and analyzed by the co-investigator responsible for 


IRB # 2002117 
all data analyses. For data analysis, PTA presence will be defined based on a diagnosis of 
OA, or findings consistent with OA, reported for either imaging modality at any 
assessment time point. PTA severity will be determined from whole-joint MRI scoring 
and patient reported outcomes at 18 months after surgery and categorized as mild, 
moderate or severe. To test the first hypothesis, we will compare treatment groups for 
statistically significant (p<0.05) differences in proportions with PTA, proportions within 
each severity category, and PRO scores using Fisher’s exact tests, t-Tests, and rank sum 
tests. To test the second hypothesis, we will perform receiver operator characteristic 
curve analyses to determine the discriminatory capabilities (area under the curve (AUC)) 
of the panel for distinguishing the presence and severity of PTA. The injured ankle will 
be compared to the normal, contralateral ankle and AUC>0.8 will be considered to 
represent high and clinically useful discriminatory capability. In addition, patient age, 
gender, BMI, tobacco use, and co-morbidities, as well as the CT scan injury severity 
score11 will be assessed as variables for predicting likelihood of presence and severity of 
PTA using Fisher’s exact test and odd’s ratios. 
Based on its mechanisms of action and preliminary data, we expect to reject our null 
hypotheses and show that a single injection of PRP is associated with significant 
improvements in outcomes. We also expect that our synovial fluid OA biomarker panel 
will have high discriminatory capabilities for categorizing presence and severity of PTA 
in patients being treated for pilon fractures in one ankle. 
  
Subject Selection 
Inclusion criteria: 
-Patients with closed unilateral pilon fractures 
-Patients undergoing staged pilon procedures with an external fixator index procedure 
 
Exclusion criteria: 
- Patients who are younger than 18 years of age 
- Open pilon fracture 
- Patients with contralateral lower extremity injury 
- Patients unable to comply with the follow-up appointments 
- Patients who had previous ankle injury to the currently injured ankle 
- Patients who are pregnant 
- Prisoners 
 
 E) Re-consent of previously incompetent subjects 
Subjects who are consented while in an incompetent state will be approached after the 
procedure if and when they become competent.  During the re-consent process, the 
subject will again be informed of the study details and be given as much time as needed 
to make their decision to continue enrollment in the study. 
F) Quality Assurance of Data Collection: 
Patient confidentiality will be maintained by adherence to the rules of HIPAA and the 
University of Missouri IRB.  All patients will have a de-identified Patient Study ID 


IRB # 2002117 
number and the data will be maintained in a secured environment within the Department 
of Orthopaedic Surgery.  Additionally, copies of study documents will be maintained in a 
secured location in a locked suite in the Department of Orthopaedic Surgery, with access 
granted only to the designated research personnel. 
 
References 
  
1. Marsh JL, Weigel DP, Dirschl DR: Tibial Plafond Injuries: How do these ankles 
function over time? JBJS American 2003; 85(2): 287-295. 
2. Martin JA, Buckwalter JA: Post-traumatic osteoarthritis: The role of stress induced 
chondrocyte damage. Biorheology 2006; 43(3-4):517-521. 
3. Green DM, Noble PC, Ahuero JS, Birdsall HH: Cellular events leading to chondrocyte 
death after cartilage impact injury. Arthitis Rheum 2006; 54(5):1509-1517. 
4. Guilak F, Fermor B, Keefe FJ, et al: The role of biomechanics and inflammation in 
cartilage injury and repair. Clinical Orthopedic & Related Research 2004; 423:17-26. 
5. Martin JA, McCabe D, Walter M, Buckwalter JA, McKinley TO: N-aceytlcysteine 
inhibits post-impact chondrocyte death in osteochondral explants. JBJS Am 
2009;91(8):1890-1897. 
6. Franklin SP and Cook JL. Prospective trial of autologous conditioned plasma versus 
hyaluronan plus corticosteroid for elbow osteoarthritis in dogs. Can Vet J 2013;54:881-
884. 
7. Waters NP, Stoker AM, Carson WL, Pfeiffer FM, and Cook JL.  Biomarkers affected 
by impact velocity and maximum strain of cartilage during injury. J Biomech 2014 
8. Waters NP, Stoker AM, Pfeiffer FM and Cook JL.  Biomarkers affected by impact 
severity during osteochondral injury. J Knee Surg 2014 
9. Garner BC, Stoker AM, Kuroki K, Evans R, Cook CR and Cook JL. Using animal 
models in osteoarthritis biomarker research. J Knee Surg 2011;24:251-264 
10. Golditz T, Steib S, Pfeifer K, Uder M, Gelse K, Janka R, Hennig FF, Welsch 
GH. Functional ankle instability as a risk factor for osteoarthritis: using T2-mapping to 
analyze early cartilage degeneration in the ankle joint of young athletes. 
OsteoarthritisCartilage. 2014 Oct;22(10):1377-85. 
11. Thomas, et al. Objective CT-based Metrics of Articular Fracture Severity to Assess 
Risk for Posttraumatic Osteoarthris. JOT;24:764-69.Chris James 
 

SAP_001.pdf: 
Title:  Does early platelet rich plasma injection decrease the risk of post-traumatic arthritis in pilon 
fractures undergoing two-staged open reduction with internal fixation? 
Date: 08/30/2016 
Principal Investigator: Brett Crist, MD 
NCT: 02481869 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sample Size Determination 
Number of patients per group was determined from a pre-study power analysis using previously 
published data on prevalence of PTA after pilon fracture – the assumption being that a 10% reduction in 
percentage of patients experiencing symptomatic PTA would be clinically significant. 
  
Data Analysis 
For data analysis, PTA presence will be defined based on a diagnosis of OA, or findings consistent with 
OA, reported for either imaging modality at any assessment time point. PTA severity will be determined 
from whole-joint MRI scoring and patient reported outcomes at 18 months after surgery and 
categorized as mild, moderate or severe. To test the first hypothesis, we will compare treatment groups 
for statistically significant (p<0.05) differences in proportions with PTA, proportions within each severity 
category, and PRO scores using Fisher’s exact tests, t-Tests, and rank sum tests. To test the second 
hypothesis, we will perform receiver operator characteristic curve analyses to determine the 
discriminatory capabilities (area under the curve (AUC)) of the panel for distinguishing the presence and 
severity of PTA. The injured ankle will be compared to the normal, contralateral ankle and AUC>0.8 will 
be considered to represent high and clinically useful discriminatory capability. In addition, patient age, 
gender, BMI, tobacco use, and co-morbidities, as well as the pre-operative CT scan injury severity 
score11 will be assessed as variables for predicting likelihood of presence and severity of PTA using 
Fisher’s exact test and odd’s ratios.