Clinical trial NCT02051933
Conditions: Equinus Contracture
Keywords: pilon tibial plafond botox ankle dorsiflexion ankle functionality ankle range of motion
Sponsor: Wake Forest University Health Sciences
Start date: 2013-01-01; Completion date: 2016-05-01
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if botulinum toxin type A (Botox) injections, at the time of surgery for pilon fractures, will improve ankle range-of-motion and functionality.

Detailed description:
To determine if the use of Botulinum toxin A intramuscular injections of the gastrocsoleus complex in patients with operatively treated tibial plafond fractures will result in:

1. increased ankle dorsiflexion when compared to controls
2. increased ankle functionality as measured by the FAAM, and quality of life as measured by the SF-36, when compared to controls
3. a higher proportion of patients achieving at least 10 degrees of dorsiflexion when compared to controls

Arms: arm 1: Botox: At the time of definitive fixation, the hospital's investigational pharmacy will provide four syringes containing 0.5mL Botulinum toxin type A. The dose of botulinum toxin will be calculated based on the patient's weight in kilograms, such that a total dose of 200U of Botox will be used for a 70kg individual. The dosage will scale linearly in proportion to the patient's body weight, such that each kilogram change results in a 3U change in Botox (rounded to the nearest 30U interval change from 200U, with a maximum of 300U).

45-55 kg: 140U 55-65 kg: 170U 65-75 kg: 200U 75-85 kg: 230U 85-95 kg: 260U 95-105 kg: 290U 105-115 kg: 300U arm 2: Placebo: At the time of definitive fixation, the hospital's investigational pharmacy will provide four syringes containing 0.5mL 0.9% sodium chloride solution . The dose of 0.9% sodium chloride will be calculated based on the patient's weight in kilograms, such that a total dose of 200U of Placebo will be used for a 70kg individual. The dosage will scale linearly in proportion to the patient's body weight, such that each kilogram change results in a 3U change in placebo(rounded to the nearest 30U interval change from 200U, with a maximum of 300U).

45-55 kg: 140U 55-65 kg: 170U 65-75 kg: 200U 75-85 kg: 230U 85-95 kg: 260U 95-105 kg: 290U 105-115 kg: 300U
Interventions: intervention 1: Botulinum toxin type A intervention 2: sodium chloride
Intervention descriptions: intervention 1: At the time of definitive fixation, the hospital's investigational pharmacy will provide four syringes containing 0.5mL Botulinum toxin type A. The dose of botulinum toxin will be calculated based on the patient's weight in kilograms, such that a total dose of 200U of Botox will be used for a 70kg individual. The dosage will scale linearly in proportion to the patient's body weight, such that each kilogram change results in a 3U change in Botox (rounded to the nearest 30U interval change from 200U, with a maximum of 300U).

45-55 kg: 140U 55-65 kg: 170U 65-75 kg: 200U 75-85 kg: 230U 85-95 kg: 260U 95-105 kg: 290U 105-115 kg: 300U intervention 2: At the time of definitive fixation, the hospital's investigational pharmacy will provide four syringes containing 0.5mL 0.9% sodium chloride solution . The dose of 0.9% sodium chloride will be calculated based on the patient's weight in kilograms, such that a total dose of 200U of Placebo will be used for a 70kg individual. The dosage will scale linearly in proportion to the patient's body weight, such that each kilogram change results in a 3U change in placebo(rounded to the nearest 30U interval change from 200U, with a maximum of 300U).

45-55 kg: 140U 55-65 kg: 170U 65-75 kg: 200U 75-85 kg: 230U 85-95 kg: 260U 95-105 kg: 290U 105-115 kg: 300U

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Study Title:  The Effect of Botulinum Toxin Injections on Ankle Dorsiflexion Following Internal Fixation 
of Tibial Plafond (Pilon) Fractures: A Pilot Study 
 
Principal Investigator: Madhav Karunakar, MD 
 
Co-Investigators:Michael Bosse, MD, James Kellam, MD, Stephen Sims, MD, Nikkole Haines, MD,  
Michael Ruffolo, MD, Bruce Cohen, MD, Kent Ellington, MD,Joseph Hsu, MD,  Rachel Seymour, PhD 
 
Version Date: 9/17/2013 
 
Protocol Version:4 
 


The Effect of Botulinum Toxin Injections on Ankle Dorsiflexion Following Internal Fixation of Tibial 
Plafond (Pilon) Fractures: A Pilot Study 
 
 
A. Specific Aims 
 
Tibial plafond fractures account for 7-10% of all tibia fractures and are potentially devastating injuries 
that continue to provide treatment challenges for orthopaedic traumatologists. While most trauma centers have 
adopted a staged protocol with initial external fixation followed by delayed internal fixation after soft tissue 
recovery, patients continue to report relatively poor physical and psychosocial outcomes. A significant 
reduction in range of motion is commonly observed after operative fixation of tibial plafond fractures, 
specifically loss of dorsiflexion. If the decrease in dorsiflexion is severe enough, it is termed equinus 
contracture and can pose functional limitations and contribute to additional lower limb pathologies in those 
suffering from it.  Botulinum toxin A has been shown to be effective in increasing dorsiflexion in children with 
equinus contracture from muscle spasticity from cerebral palsy.  More recently, promising results have been 
seen in using Botulinum toxin A in the treatment of contractures following Achilles tendon repair and total knee 
arthroplasty.  The purpose of this study is to evaluate the effect of Botulinum toxin A injections into the 
gastrocsoleus complex on ankle dorsiflexion following internal fixation of tibial plafond fractures. 
 
Specific Aim 1: To determine if the use of Botulinum toxin A intramuscular injections of the gastrocsoleus 
complex in patients with operatively treated tibial plafond fractures will result in increased ankle dorsiflexion 
when compared to controls.  
 
Hypothesis 1: The group treated with Botulinum toxin A injections will have increased ankle 
dorsiflexion when compared to controls at 6 and 12 months. 
 
Specific Aim 2: To determine if the use of Botulinum toxin A injections in patients with operatively treated 
tibial plafond fractures will lead to increased ankle functionality as measured by the FAAM, and quality of life 
as measured by the SF-36, when compared to controls.  
 
Hypothesis 2: The group treated with Botulinum toxin A injections will report more positive health-
related quality of life when compared to controls at 6 and 12 months.  
 
Specific Aim 3: To determine if the use of Botulinum toxin A injections in patients with operatively treated 
tibial plafond fractures will lead to a higher proportion of patients achieving at least 10 degrees of dorsiflexion 
when compared to controls. 
 
Hypothesis 3:  The group treated with Botulinum toxin A injections will be more likely to achieve 10 
degrees or more of ankle dorsiflexion at 6 and 12 months. 
 
We plan to enroll 20 patients (N=10 treatment, N=10 controls) in a pilot study to test procedures and collect 
preliminary data.  While this pilot study will likely not have sufficient power to definitively address the specific 
aims and hypotheses, the preliminary data collected will provide information to plan future work.  
 
 
 
 


B.  Background and Significance  Defined as a fracture of the distal end of the tibia that involves a significant 
portion of the weight-bearing articular surface and overlying metaphysis, tibial pilon fractures are difficult 
orthopaedic injuries to treat.  This fracture pattern is most commonly caused by motor vehicle collisions, falls, 
and sporting accidents.1 These mechanisms produce high energy axial loads at the ankle joint causing 
significant articular comminution, bone loss, and soft tissue injury traditionally resulting in a high rate of 
unsatisfactory outcomes.1,2  
 
B.1 Management of Pilon Fractures:  Initially considered unsuitable for surgery, the treatment of tibial 
plafond fractures has evolved significantly over the last 50 years to a point where most centers are utilizing a 
staged fixation approach.2-6 The staged method employs primary external fixation to restore length and 
alignment of the extremity while allowing the soft tissues to heal. Once the tissues permit, an open approach is 
used to provide sufficient visualization of the fracture for anatomic reduction of the articular surface and 
cancellous bone grafting if necessary.   Rigid internal fixation with or without cancellous bone grafting is 
paramount in maintaining joint line congruity, preventing malunions, and allowing for early range-of-motion 
across the joint, thus providing better functional outcomes compared to other methods such as external fixation 
with or without limited internal fixation.2,4-9 
 
B.2 Current Difficulties in Treating Pilon Fractures:  Despite widespread usage of a staged protocol for this 
injury, good to excellent results are still difficult to attain. Recent studies consistently report “relatively poor 
physical and psychosocial outcomes” with persistent and severe sequelae.6,9 Pollack and colleagues noted that at 
3-year follow-up, patients presented with significantly poorer health related outcome scores than age and 
gender-matched norms.6 Large proportions of patients with this type of injury present with significant stiffness, 
swelling, pain, and difficulties with retaining employment, showing that there is still work to be done to 
improve the outcomes of this devastating injury.1,2,6,9-11 
 
B.3 Loss of Dorsiflexion:  Limited range of motion is a common and potentially debilitating result of these 
often severe articular injuries. A minimum of 10 degrees of dorsiflexion is required for normal gait mechanics 
and loss of this dorsiflexion is termed equinus contracture.12  Equinus contracture can result in functional 
limitations as well as be a contributing factor to seemingly unrelated lower limb pathologies including strains, 
plantar fasciitis, hallux valgus, stress fractures, adult-acquired flat foot, plantar fasciitis, Achilles tendonitis, 
Charcot arthropathy, diabetic foot ulceration, and metatarsalgia.12,13,14 Gait analysis studies examining limited 
dorsiflexion in the ankle joint has shown that patients with less than 10 degrees of dorsiflexion begin to 
experience abnormal stresses at multiple other lower extremity joints.13  In addition to contributing to these 
other pathologies, loss of dorsiflexion and pain are the only two independent variables shown to significantly 
limit functionality in patients recovering from ankle fractures.15 
Recent studies following outcomes on tibial plafond fractures have repeatedly shown dorsiflexion to be 
impacted. Grose and colleagues found the average dorsiflexion in their cohort to be 9 degrees with only 25% 
achieving greater than 10 degrees of dorsiflexion.16  Patients treated by Patterson and Cole achieved only 7 
degrees of dorsiflexion after staged internal fixation.5 Marsh et al. measured an average dorsiflexion of 10 
degrees with 50% of patients failing to reach at least 10 degrees of dorsiflexion, even after excluding those who 
underwent amputation or arthrodesis.11 Functional limitations such as difficulty climbing up stairs, walking up 
hills, and squatting to pick up objects are commonly reported problems following this injury, all of which 
reflect a loss of dorsiflexion.6  Clearly, stiffness is a ubiquitous problem in this population and carries with it the 
sequela of impaired functionality while contributing to other lower extremity problems.  
 


B.4 Treatment Options for Limited Range of Ankle Motion:  Once acquired, equinus contractures can be 
very difficult to treat.  Physiotherapy and stretching are the first line therapy to improve this condition, but often 
only play a limited role in the correction of this condition. Surgical options remain the mainstay treatment for 
contractures that are causing significant functional impairment.  Achilles tendon lengthening is one surgical 
option that addresses equinus contracture by lengthening the Achilles tendon by utilizing a Z-lengthening 
technique.  This procedure has a long recovery time and carries with it the risk of skin slough, Achilles tendon 
rupture, and discomfort with shoeware.17 Because the Achilles tendon accounts only for 3-5% of the 
contracture,14 there is also concern that lengthening the tendon reduces its moment-generating capacity due to 
the gastrocsoleus’ new position on the sarcomere length-strength curve, resulting in weakness in 
plantarflexion.18 Additionally, this procedure also carries with it the risk of over lengthening causing a profound 
loss of strength and resulting in a heel gait pattern.19 
Other surgical options, such as the gastrocnemius recession, have been gaining popularity as an 
alternative to Achilles tendon lengthening in the treatment of equinus contractures, because it is able to address 
the contracture without resulting in loss of strength.20  One such technique, termed the Strayer recession, is 
performed by separating the gastrocnemius from the soleus and transecting it just proximal to the 
gastrocnemius-soleus aponeurosis.21  This allows the gastrocnemius muscle to retract proximally providing 
increased dorsiflexion.21  This procedure produces excellent results by achieving an average increase in 
dorsiflexion of 14-18 degrees, but it is not without complications.20,22  Sural neuropraxia is a common 
complication of this procedure, either due to excessive retraction on the nerve at the time of surgery or proximal 
and distal tethering of the nerve within the gastrocsoleus complex during the release.23  Even though 42.5% of 
sural nerves run superficial to the facia effectively protecting them from laceration during the release, sural and 
saphenous nerve lacerations can and do occur.23  Finally a significant number of patients report dissatisfaction 
with the scar left from the surgery which can pucker due to soft tissue adhesions, and exacerbated by retraction 
of the gastrocnemius muscle belly.  Equinus contractures acquired after tibial plafond fractures are so 
problematic that some centers have advocated for performing a Strayer recession prophylactically at the time of 
fixation to prevent the development of such contractures. 
 
 
B.5 Botulinum Neurotoxin:  Botulinum toxin A (Botox) is an extremely potent neurotoxin produced by the 
bacterium Clostridium botulinum that results in transient flaccid muscle paralysis. To date, Botulinum toxin A 
and B are approved for use by the U.S. Food and Drug Administration for treatment of (1) chronic migraine 
headaches, (2) upper limb spasticity, (3) cervical dystonia, (4) strabismus and blepharospasm, (5) severe 
primary axillary hyperhidrosis, (6) and moderate to severe glabellar lines.24  In the orthopaedic literature, 
multiple potential indications have been identified including shoulder dislocations, adhesive capsulities, talipes 
equinovarus, plantar fasciitis, torticollis, knee flexion contractures, lateral epicondylitis and cerebral palsy; all 
of which are currently considered “off-label.”25,26  
 
 
B.6 Botox Use for Treating Equinus Contractures:  Among its many uses, Botox has been used in the 
treatment of a variety of range of motion limiting conditions. For many years, botulinum toxin has been used 
with great success in treating equinus deformity in children with cerebral palsy. Several double-blind 
prospective studies have reported an increase in ankle joint mobility during stance and swing phases with the 
use of Botox.27,28 
Based on the success seen in the treatment of equinus contractures in children with cerebral palsy, 
botulinum toxin has been used in the treatment of equinus contractures following Achilles tendon repair.  
Reuter and others treated 8 patients with equinus contractures after Achilles tendon repair with intramuscular 
Botox injections and physiotherapy.29  All patients experienced significant increases in dorsiflexion which 
remained present at their 2 year follow-up with no adverse events identified.29 


 
B.7 Botox Use for the Prevention of Equinus Contractures:  In addition to treating equinus contractures due 
to spasticity, Botox has been shown to prevent the occurrence of contractures in animal models.  In 1994, 
Cosgrove and Graham used a spastic mouse model commonly used to mimic cerebral palsy, to show that 
intramuscular injections into the calf muscles prevented the formation of contractures.  They found that mice 
who received placebo as opposed to intramuscular Botox had calf muscles which were 16% shorter than those 
who received Botox, supporting the theory of using Botox to prevent contracture formation.30   
 
B.8 Botox Use for Treating Flexion Contracture Following Total Knee Arthroplasty:  Recently, Botox has 
been used with great success in the treatment of flexion contractures following total knee arthroplasty.  After an 
initial report on the successful treatment of flexion contracture following total knee arthroplasty in a patient 
with Parkinson’s syndrome, Seyler and colleagues utilized botulinum toxin to treat 11 more patients with 
flexion contracture following total knee arthroplasty.31,32  Their results were extremely promising by showing 
clinical improvement in all 9 patients who had primary total knee arthroplasties.  The only two failures were in 
patients who acquired their contractures after revision total knee arthroplasties.  The patients who experienced 
the improvement maintained their increased range of motion and desirable outcomes at the time of two year 
follow-up, leading the authors to conclude that Botox therapy may be appropriate therapy for the treatment of 
flexion contractures following primary total knee arthroplasty.32  An additional investigation is currently under 
way using a larger cohort of patients and is currently showing promising preliminary results.26 
 
B.9 Botox Reduces Pain and Spasm:  Part of the theory on why Botox has been effective in alleviating these 
contractures is that the temporary muscle paralysis reduces pain and muscle spasms which can impede 
therapeutic stretching regimens.  There is also increasing evidence that Botox has anti-nociceptive properties 
that may be due to inhibiting the release of pain mediators in addition to decreasing muscle spasms.33  Muscle 
spasms are commonly experienced following fracture fixation and can be a source of significant discomfort, 
which can interfere with rehabilitation by causing pain and limiting range of motion.   Neutralization of this 
phenomenon may result in better functional outcomes due to more effective rehabilitation and stretching 
techniques employed postoperatively. 
Even after the initial spasms have subsided, Botox may aid in the prevention of contracture and help 
facilitate therapeutic stretching techniques by reducing the basal tone of the plantar flexors.  Even at rest, 
muscles exert a baseline tone to maintain posture and joint position.34  By weakening or paralyzing the 
gastrocsoleus complex, there would be an imbalance in muscular tone in the lower leg pulling the foot into a 
more dorsiflexed position even at rest.  This will also reduce voluntary and involuntary guarding during 
stretching exercises, thus improving the effectiveness of rehabilitation regimens.   
 
B.10 Summary:  Based on Botox’s ability to reduce pain and postoperative muscular spasms while at the same 
time eliminating resting basal tone of the primary plantar flexors about the ankle, it is felt that intramuscular 
injections will be beneficial in aiding therapeutic stretching exercises which is essential for maintaining ankle 
range of motion.  These exercises will be started approximately 2 weeks after the time of definitive fixation 
which is well within the 8-10 weeks of maximal effect seen with intramuscular botulinum toxin injections.29   
Botulinum toxin injections have not only been shown to prevent the development in of contractures, but also 
used to treat contractures which have already formed.27-32,35,36  The purpose of this study is to evaluate the effect 
of Botulinum toxin A injections into the gastrocsoleus complex on ankle dorsiflexion after staged internal 
fixation of tibial plafond fractures. If Botulinum toxin A proves effective, this approach could have a significant 
impact on the practice and outcomes of orthopaedic surgery and will allow for treatment and prevention of 
equinus contracture without the morbidity associated with an additional surgical procedure. 


C. Preliminary Studies  
While the investigators have not completed preliminary studies specifically addressing the effects of 
Botulinum toxin A on tibial plafond fractures, several members have had prior experience in prospective 
randomized studies in this patient population. 
The principal investigator published a multicenter study entitled:  “Indometacin as prophylaxis for 
heterotopic ossification after operative treatment of fractures of the acetabulum” which involved a similar 
prospective double-blind placebo-controlled study design.37  The experience obtained from this study provides a 
valuable resource for successfully managing the proposed study. 
The study implementation will be led by a PhD clinical researcher with experience coordinating 
randomized controlled trials funded by NIH, CDC, and the Robert Wood Johnson Foundation.38-41  The 
principal investigator’s orthopaedic clinical research team has successfully implemented and completed several 
randomized trials to date.   
 
D. Research Design and Methods 
We will use a prospective double-blind randomized placebo-controlled study design.  Subjects will be enrolled 
as inpatients or during the initial office visit by orthopaedic clinical research staff.  After routine evaluation 
reveals that a patient meets the inclusion and exclusion criteria (below), informed consent will be obtained. 
Demographic data will be recorded. Patients will be block randomized by opaque, sealed-envelope to either a 
treatment group or a placebo group (N=20; N=10 treatment, N=10 placebo). 
 
D.1 Inclusion and Exclusion Criteria 
Inclusion Criteria 
• Patients 18 and older with a tibial plafond fracture to be treated by a staged protocol involving primary 
external fixation and definitive fixation within 3 weeks from the injury.   
o Non-definitive, interval procedures such as repeat irrigation and debridement and fibular fixation 
are allowed. 
Exclusion Criteria 
• Younger than 18 years of age. 
• Significant traumatic brain injury or cognitive disability that would interfere with post-operative 
rehabilitation and study questionnaires.  
• Nerve, vascular, or tendon injury of the lower leg: injury to the tibial or peroneal motor nerves, injury to 
the posterior tibial artery requiring repair, or laceration of tendons that are involved in plantar flexion or 
dorsiflexion of the ankle which require repair. 
• History of prior lower extremity fracture to the tibia or ankle of the affected limb. 
• Incarcerated patients. 
• Patients unable or unwilling to return for follow-up examination. 
• Pregnant or lactating patients. 
• History of disease affecting the neuromuscular junction (ex: myasthenia gravis). 
• Use of aminoglycoside antibiotics at the time of definitive fixation. 
• Ipsilateral foot injury that will impair dorsiflexion exercises: Lisfranc injuries, fractures or dislocations 
of the talus, calcaneus, navicular, cuboid, cuneiforms, or metatarsals (phalanx fractures or dislocations 
will not be excluded). 
• Patients receiving Botulinum Toxin A for other reasons. 
• Patients with a known hypersensitivity to Botulinum toxin A. 
• Gustilo Anderson type III B and C. 
• Patients with a weight greater than 115 kg – to ensure proper injection locations. 


• Patients taking non-depolarizing neuromuscular blocking agents (not including those used for general 
anesthesia). 
 
D.2 Outcome Variables 
Primary Outcome Variable (objective): 
Ankle Dorsiflexion of Injured Extremity.  The primary outcome variable will be ankle 
dorsiflexion of the injured extremity as measured by a  goniomemeter and radiographs.   
 
Ankle Dorsiflexion of Uninjured Extremity.  In patients with a unilateral lower extremity injury, 
the ankle dorsiflexion of the uninjured extremity will be measured in the same fashion as the 
injured extremity.   
Secondary Outcome Variables (self-report):  
The Short-Form 36 (SF-36) will be used to measure health related quality of life. The SF-36 is a 
commonly used general health status measure and assessment of function, which allows 
individuals to describe their own health status. It allows for the comparison between individuals 
with the same condition as well as to the general population. Subscale scores measure various 
domains of health and quality of life, while the physical (PCS) and mental (MCS) component 
summary scores represent the main dimensions of health.  The PCS and MCS scores range from 
0 to 100 points and are standardized to population norms with higher scores indicating higher 
function. The mean score for the PCS and MCS in the general population is 50 points 
with 10 points representing one standard deviation from the mean.52 
 
Pain.  Overall Study limb as well as ankle specific pain intensity will be measured using the 0-10 
visual analogue scale used in the Brief Pain Inventory. Pain intensity will be measured both at 
rest and during ambulation.53 The Brief Pain Inventory (BPI) will be administered to patients at 6 
and 12-month follow-up appointments. The BPI is a widely used, 15-item measure of pain 
intensity and interference with daily life.53,54 The questionnaire assesses three key pain domains: 
pain intensity, pain interference, and efficacy of pain treatments or medications. 
 
The Foot and Ankle Ability Measure (FAAM) is a well validated instrument that consists of 29 
items measuring 2 broad categories: activities of daily living (84 points) and sports (32 points).55 
The scores are normalized to 100 for each category and are reported separately. The FAAM will 
be obtained at 6 and 12 months to assess the functional status of the affected ankle. 
 
Independent Variables 
Group Assignment: Participants assigned to the control group will receive normal saline 
injections following definitive fixation of their tibial plafond fracture (N=10).  Patients assigned 
to the treatment group will receive Botulinum toxin A injections following definitive fixation of 
their tibial plafond fracture (N=10).    
 
Covariates 
Demographics 
• Age 
• Race/ethnicity 
• Gender  
• BMI 


• Co-morbidities 
• Fracture classification 
• Time until definitive fixation 
• Tobacco use 
• Workers compensation status 
• Level of education 
• Marital status 
• Personal income 
• Health insurance 
• Working status before injury 
These data will be abstracted from the medical record by the research staff.  
Additional Outcomes 
• Time until full weight bearing 
• Time until return to work 
• Compliance with weight bearing status 
• Compliance with prescribed treatment 
These data will be patient reported 
Complications 
• Nonunion 
• Malunion 
• Infection: Deep 
• Infection: Superficial 
• Osteomyelitis 
• Wound breakdown 
• Skin slough: partial thickness 
• Skin slough: full thickness 
• Additional surgeries: Strayer recession, Achilles lengthening, hardware removal, 
amputation, or arthrodesis. 
• Rehospitalizations 
These data will be captured during clinical exam at each office visit 
 
D.3 Methods 
Orthopaedic surgery attendings and residents will identify potential study candidates during the initial 
consultation based on the presence of a tibial plafond fracture.  If the patient meets the inclusion and exclusion 
criteria (noted above), a member of the treatment team will discuss the study with eligible patients.  If the 
patient expresses interest in the study, the physician will notify the research staff.  Orthopaedic Clinical 
Research staff will describe study procedures in detail and go through the informed consent process to enroll the 
patient in the study.  Patients will be informed of the “off-label” usage of botulinum toxin injections as well as 
the potential side effects. 
Once informed consent is obtained and the patient is enrolled in the study, the attending surgeon will 
classify the fracture based on the AO/OTA classification system (Figure 1).  Study participants will then be 
block randomized and assigned by sequentially numbered sealed opaque envelopes to one of the two treatment 
groups based on computerized selection: those who receive intramuscular botulinum toxin injections at the time 
of definitive fixation, and those who receive placebo.  Patients with bilateral pilon fractures and no other lower 
extremity injuries of the tibia, ankle, or foot that would further impair dorsiflexion stretching or other 


rehabilitation exercises will have each extremity randomized and evaluated separately.  Patients with a 
unilateral tibial plafond fracture and no injury of the contralateral tibia, ankle, or foot will be placed in a 
subgroup of patients who will have their unaffected extremity examined for comparison.  Patients with an injury 
to the contralateral extremity that would exclude them from this subset will have only the extremity with the 
pilon fracture analyzed.  
 
 
Figure 1.56 
 
All patients will be treated by a fellowship trained orthopaedic surgeon who has completed advanced 
training in either trauma or foot and ankle surgery.  Patients will all undergo a staged fixation approach which 
involves primary external fixation with irrigation and debridement if necessary, followed by open reduction and 
internal fixation when soft tissues allow.  Additional procedures on the injured extremity that take place 
between external fixation and definitive fixation (ex: ORIF of the fibula or repeat irrigation and debridement) 
do not disqualify the patient from the study as long as definitive fixation takes place within 3 weeks (21 days) of 
the injury.  All definitive operations will take place at either Carolinas Medical Center – Main, or Carolinas 
Medical Center – Mercy.   
At the time of definitive fixation, the hospital’s investigational pharmacy will provide a blinded solution 
of either Botulinum toxin A or 0.9% sodium chloride solution for injection intraoperatively following skin 
closure. Four syringes containing 0.5 ml 0.9% sodium chloride, with or without Botulinum toxin type A based 
on the patient’s randomization, will be provided and refrigerated until they are ready to be administered. Both 
the physician and the patient will be blinded to the contents of the syringe.  Once reconstituted, botulinum toxin 
type A will only last for 4 hours at room temperature so it will be necessary to not allow the solution to sit at 
room temperature for an extended period of time.  All patients in the study group will receive 
onabotulinumtoxinA, Botox® (Allergan, Irvine, California) provided by the investigational pharmacy. The total 
dose of botulinum toxin will calculated based on the patient’s weight in kilograms, such that a total dose of 
200U of Botox will be used for a 70 kg individual (see Table 1 below).  The dosage will scale linearly in 


proportion to the patient’s body weight, such that each kilogram change results in a 3U change in Botox 
(rounded to the nearest 30U interval change from 200U, with a maximum of 300U).  This dosing regimen was 
chosen based on the effective dose for an average gastrocnemius from other studies.26 
 
Table 1:  Botox Dosing by Weight 
45-55 kg:  
140 U 
55-65 kg:   
170 U 
65-75 kg:   
200 U 
75-85 kg:   
230 U 
85-95 kg:   
260 U 
95-105 kg: 
290 U 
105-115 kg:  
300 U 
 
At the completion of surgery, the gastrocsoleus complex will be injected in four locations (superior 
medial, superior lateral, inferior medial, and inferior lateral) prior to the application of short leg splint, per the 
recommendation of prior studies.57  At each injection site, ¼ of the total dose of botulinum toxin A or normal 
saline will administered in approximately 0.5 ml injections.  The use of EMG or other imaging modalities has 
been recommended to ensure accuracy of botulinum toxin injection at the target muscle motor end plates, 
however it is not necessary when injecting the gastrocsoleus complex, even in small children due to its large 
size and superficial location.58  The injection sites are illustrated in the figure 2 below:  
 
 
Figure 257 
 
Following definitive fixation and study injections, patients will be placed in a well-padded splint in at 
least neutral dorsiflexion for two weeks to allow for wound healing. Following wound healing, patients will 
transition to a removable orthosis and begin range of motion exercises and stretching techniques. All patients 
will undergo a structured exercise regimen.  Each patient will receive a pamphlet at an 8th grade reading level 
containing a standardized exercise protocol which clearly states the exercises to be utilized, the frequency, and 
duration.  As long as there are no adverse events, patients will proceed to touch down weight bearing at roughly 
6 weeks postoperatively and continue their exercise program.  Patients will then advance to partial weight 
bearing at approximately eight weeks and full weight bearing as tolerated at 10 to 12 weeks, as long as no 
adverse events occur precluding this progression. 


Study participants will return to regularly scheduled follow-up appointments to monitor their progress. 
At each follow-up appointment (2 weeks, 6 weeks, 12 weeks, 6 months, and 1 year), patients will be monitored 
for signs and symptoms of Botox toxicity.  All patients will be seen in follow-up at one of two clinic locations.  
At each site, research staff familiar with the study will be present along with a device for measuring 
dorsiflexion in a standardized fashion.   
Clinical assessment will be accomplished by physical exam and questionnaires for subjective complaints 
described above with a member of the Orthopaedic Clinical Research staff. Patients will be asked to complete 
SF-36, BPI, and FAAM questionnaires at their 6 month and 12 month follow-up visits.   Time to full weight 
bearing, time to return to work, compliance with weight bearing status, and compliance with rehabilitation 
protocol will all be noted at 6 and 12 months. 
At the end of the 6 and 12-month follow-up appointments, ankle dorsiflexion will be assessed using a 
device to measure dorsiflexion and radiographcs in a standardized manner.   
Routine radiographs taken as part of standard of care will be used to assess the quality of fracture 
alignment, range of motion and to follow for boney union or malunion.  Radiographic data will be reviewed by 
a group of three independent observers blinded to the patient and the treatment group. Malunion will be 
assessed by drawing a line along the subchondral bone of the tibial plafond and a line drawn through the center 
of the tibial shaft.  Deviation of >5 degrees from 90 in either the AP or lateral plane will be considered varus, 
valgus, or sagittal plane malunion.   Clinical union will be defined as the patient’s ability to bear full weight on 
the injured extremity with evidence of boney bridging in at least 2 of 4 cortices.  The determination of nonunion 
will be determined by the attending surgeon’s assessment based on radiographic and clinical findings consistent 
with nonunion, such as hardware failure, failure of boney bridging, and persistent pain at the fracture site 
beyond what would be expected in a healed fracture. 
Study volunteers will be provided with a $70 patient incentive for their time in completing the health 
assessment questionnaires and dorsiflexion measurements at 6 months.  An additional $100 will be provided to 
those who return at 1 year for examination and health assessment questionnaires.  
The results of the patients receiving Botox will be compared to those who received placebo.  Average 
dorsiflexion will be determined and compared between the two groups as well as the percentage of patients who 
achieve 10 degrees or more of dorsiflexion.  If applicable, the average dorsiflexion in the injured extremity will 
also be compared to the uninjured extremity to determine the average difference in dorsiflexion between the two 
groups. For statistical analysis, differences with a p value of <0.05 will be considered statistically significant.  
 
 
D.4 Data Management 
All data will be entered into REDCap, a web-based data entry and management system that provides 
logic checks on input and checks for invalid entries. Data will be entered continuously as they are collected and 
stored in univariate form. We will also run standard checks for outliers, duplicates and other types of errors 
which may occur within a complex data file. All data files will be password protected and hard copies of 
blinded patient records will be maintained in locked cabinets in the research office. 
Data Analysis: In order to determine that the randomization process produced comparable groups, we 
will use t-tests and cross-tabulations to compare patients in the treatment group to patients in the placebo group 
on the following variables: age, race, gender, BMI comorbidities, fracture classification, time until definitive 
fixation, tobacco use, workers compensation status, level of education, marital status, personal income, health 
insurance, working status before surgery, compliance with weight-bearing restrictions, compliance with 
prescribed treatment, time until full weight bearing and return to work. 
Analyses will follow the intent-to-treat paradigm, under which all patients will be analyzed according to 
the treatment group to which they were randomized.  Intention to treat analyses of outcomes will be conducted 
in two stages. First, we will conduct a bivariate analysis to examine relationships between assigned treatment 


group, primary and secondary outcomes, and potential covariates and confounders (demographics, injury 
characteristics, co-morbidities). We will then use the results to build a multivariate model to predict primary and 
secondary outcomes based on treatment type. 
 
D.5  Pilot Data 
Currently, no previous work has been done on this project and therefore no pilot data is available.  If 
funding for the entire study is unable to be secured, partial funding will be used for the procurement of pilot 
data.  A pilot study will consist of 20 patients, 10 randomized to each group, and will be executed in the same 
manner as the full trial.  A pilot study will show that the investigators and research staff are capable of 
implementing this prospective, double-blind, placebo controlled trial which will serve to strengthen further 
external grant proposals.   At the conclusion of the pilot study, blinding will be broken and the data will be 
analyzed.  Those data will be used to support or modify the power analysis for the full study and will eventually 
be incorporated into to the full study cohort.  If clearly inferior results are observed in the intervention group, 
those data will be published and the full trial will not be conducted.  
 
D.6 Estimated Timeline 
 
Due to the large number of trauma patients treated at our institution, a retrospective review of the 
number of cases indicates an incidence of 108 tibial plafond fractures treated per year.  With an expected 
enrollment rate of 60% and a goal sample size of 20 patients, we expect enrollment to take 4 months, making 
this study quite feasible.   
  
Year 1 
Year 2 
Year 3 
  
Q1 
Q
2 
Q
3 
Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 
Train research staff on study procedures 
  
  
  
  
  
  
  
  
  
  
  
  
Train surgeons on dorsiflexion measuring 
device 
  
  
  
  
  
  
  
  
  
  
  
  
Patient Enrollment 
  
  
  
  
  
  
  
  
  
  
  
  
Patient Follow-up at 6 and 12 months 
  
  
  
  
  
  
  
  
  
  
  
  
Data Analysis 
  
  
  
  
  
  
  
  
  
  
  
  
Manuscript development, submission, and  
preparation of final report 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
D.7 Potential Problems 
 
In a busy trauma center, the enrollment of patients in prospective randomized study can be difficult. We 
will train the attendings, fellows, residents, and our research staff to identify potential candidates for the study. 
Information about the study including the inclusion/exclusion criteria will be readily available online or on 
study information cards provided to the staff and residents.  Additionally, all surgical staff will receive an in-
service training session so that they are aware of the study protocol to be followed in the operating room.  There 
will be approximately 14 days between the time of injury and definitive fixation giving ample time for patient 
identification and obtaining informed consent. 
 
D.8  Future Directions 
At the conclusion of this pilot study, the data collected will be unblinded and analyzed.  Those data will 
be used to aid in a power analysis to determine the sample size needed for a full trial.  This protocol will then be 
amended to include the appropriate number of patients needed to be enrolled in order to have the appropriate 


power.  If no changes are made to the protocol, the data from this pilot will be combined with the data of the 
full study cohort. 
 
E.  Human Subjects 
 
E.1  IRB Statement 
As this study involves the inclusion of live human subjects and their personal information, we will 
strictly follow the guidelines and procedures outlined by our institutions IRB.  Ensuring patient safety and 
maintaining patient confidentiality are of paramount importance and taken extremely seriously by the 
investigators of this study. 
 
E.2  Study Population 
All subjects involved in this study will be ages 18 and older who have sustained a fracture of the tibial 
plafond.  All patients will have their injury treated in a staged protocol, meaning primary external fixation 
followed by definitive fixation within 3 weeks of the injury.   
Inclusion Criteria 
• Patients 18 and older with a tibial plafond fracture to be treated by a staged protocol involving primary 
external fixation and definitive fixation within 3 weeks from the injury.   
o Non-definitive, interval procedures such as repeat irrigation and debridement and fibular fixation 
will be allowed 
Exclusion Criteria 
• Younger than 18 years of age. 
• Significant traumatic brain injury or cognitive disability that would interfere with post-operative 
rehabilitation and study questionnaires.  
• Nerve, vascular, or tendon injury of the lower leg: injury to the tibial or peroneal motor nerves, injury to 
the posterior tibial artery requiring repair, or laceration of tendons that are involved in plantar flexion or 
dorsiflexion of the ankle which require repair. 
• History of prior lower extremity fracture to the tibia or ankle of the affected limb. 
• Incarcerated patients. 
• Patients unable or unwilling to return for follow-up examination. 
• Pregnant or lactating patients. 
• History of disease affecting the neuromuscular junction (ex: myasthenia gravis). 
• Use of aminoglycoside antibiotics at the time of definitive fixation. 
• Ipsilateral foot injury that will impair dorsiflexion exercises: Lisfranc injuries, fractures or dislocations 
of the talus, calcaneus, navicular, cuboid, cuneiforms, or metatarsals (phalanx fractures or dislocations 
will not be excluded). 
• Patients receiving Botulinum Toxin A for other reasons. 
• Patients with a known hypersensitivity to Botulinum toxin A. 
• Gustilo Anderson type III B and C. 
• Patients with a weight greater than 115 kg – to ensure proper injection locations. 
• Patients taking non-depolarizing neuromuscular blocking agents (not including those used for general 
anesthesia). 
 
E.3  Inclusion of Women and Minorities in Study 


The study population will be representative of the typical trauma population seen at Carolinas Medical 
Center – Main.  Carolinas Hospital System is the largest provider in the region with a large catchment area 
encompassing western North Carolina and South Carolina.  As the region’s busiest trauma center, patients of all 
ages, genders, ethnicities, and backgrounds present to CMC, which is representative of the diverse population 
enjoyed by this region of the country.  Women and minority groups will all be included in the study.  Based on 
previous clinical series of patients at our institutions, we expect that 70% of our patients will be men and 25% 
minority patients.  
 
E.4  Description of the Screening Procedures and Recruitment Process 
Potential patients will be recruited during the index hospitalization or as a referral from an outside 
physician.  Patients that may be eligible for the study will be evaluated by the attending physician to determine 
whether the inclusion and exclusion criteria are met.  An attending surgeon will approach patient about 
volunteering for the research study, and if patient expresses interest, the formal education and consent process 
will be initiated by research staff. The research assistant or coordinator will then discuss the research and 
enrollment process and consent patients expressing willingness to participate. 
 
E.5  Description of the Informed Consent Process 
Once a patient has expressed interest in the study, a member of the treatment team will provide each 
patient with sufficient time and information to make a well-informed decision on whether or not to enroll in the 
study based on the risks and benefits imposed.  There are strong ethical and practical reasons for striving for 
quality in the consent process and is taken seriously by all those involved in this study.  Decisions made hastily 
or without accurate and adequate information are not in the patient’s or the investigators’ interest.  Materials to 
inform prospective participants and to obtain consent will be developed in conjunction with the Steering 
Committee and consultants as required to ensure that they are accessible, informative and culturally sensitive.   
 
Persons who meet the initial eligibility criteria for the study will be told of the trial, its purpose, and the general 
expectations of those enrolled.  Those interested in further screening and willing to participate will be given a 
copy of the consent.  Formal consent, as represented by the act of signing and dating an IRB approved consent 
statement for the trial, will occur after the final evaluation for eligibility and a review of what is involved in the 
trial.  Persons will be reminded of the expectations placed on them if they enroll.  They will be advised not to 
enroll if they are uncertain that they would be willing to accept treatment as assigned by a random process.  
Ambivalent subjects should not be enrolled.  Persons will be given an opportunity to query study personnel on 
issues needing clarification.  Patients who no longer wish to be involved in the study will be withdrawn 
immediately at their request and continue to receive the standard of care. 
 
E.6  Risk/Benefits Assessment 
E.6.a  Foreseeable Risks: There are minimal risks inherent in this study.  Both study arms will receive the 
current standard of care in the treatment of their tibial plafond fractures.  The treatment group, however, will 
receive intramuscular injections of botulinum toxin A; an indication which is considered “off-label” as it is not 
an FDA approved indication of the product.  Botox has been used safely and effectively for many years for 
similar “off-label” indications in the orthopaedic literature.  Great care was taken to ensure that Botox is used 
safely and correctly in this study.  All effects of Botox are completely reversible if given enough time, and it is 
felt that botulinum toxin injections will pose minimal risk to patients when used correctly. 
 
5.6.a.1 Botulinum Toxin Safety 


Botulinum Toxin A has been approved by the FDA for more than 20 years and has a long-
established safety profile.  When used correctly, the side effects of Botulinum Toxin type A injections 
are uncommon and usually mild and transient.59  Local side effects are the most common and are usually 
mild pain at the injection site and adjacent muscle weakness due to diffusion of the toxin across fascial 
barriers.25  Systemic side effects are very rare and include mild generalized weakness, urinary 
incontinence, constipation, and dysphagia; all of which are typically seen in susceptible individuals.25  
Botox is contraindicated in patients with a history of neuromuscular disorder such as myasthenia gravis, 
and in patients receiving aminoglycoside antibiotics or non-depolarizing neuromuscular blocking agents, 
as these can all potentiate the effects of the toxin.  It is also relatively contraindicated in patients with a 
history of pseudobulbar palsy and frequent chest infections for concern over aspiration pneumonia, an 
exceedingly rare, but serious side effect.  These adverse events are not expected to cause problems based 
on our study design and patient population.   
Of the local side effects, pain at the injection site is unlikely to be noticed by the patient as 
injections will be administered under general anesthesia and the patient’s co-committent injury will 
likely dwarf any residual pain from the injection.  The diffusion of Botox into adjacent muscle groups is 
not only inconsequential, but in-fact desired based on our study design.  Although all injections will be 
made in the muscle belly of the gastrocnemius, diffusion into the deeper soleus muscle would provide 
additional weakness of the gastrocsoleus complex and potentially result in better outcomes without 
causing additional functional impairment 
In order to minimize the occurrence of systemic side effects, the amount of Botox utilized in this 
study will be well below the maximum safe dose for Botox, 12U/kg, even if bilateral pilon fractures are 
both randomized to the treatment group.57  In addition, patients with a history of a neuromuscular 
disorder, who are receiving aminoglycoside antibiotics or non-depolarizing neuromuscular blocking 
agents, or women who are or may become pregnant will be excluded from this trial.  Patients reporting 
dysphagia or aspiration are typically those undergoing injections for cervical dystonia, and may be 
considered a local side effect rather than a systemic one. Based on the remote injection site utilized for 
this study, dysphagia and aspiration are unlikely to be experienced. The average total dose of 200U of 
Botulinum Toxin A will be injected into the gastrocnemius of the effected extremity and was chosen 
based on the effective dose for the average gastrocnemius from other studies.26   
 
E.6.a.2 Duration of Botox 
An intramuscular injection of Botox results in flaccid paralysis that gradually improves over an 
average of 2 to 4 months.25,60,61  Although the effects are temporary, paralyzing the primary plantar 
flexors in the lower leg could prove problematic and result in gait disturbances contributing to 
subsequent falls.  For this reason, pilon fractures have been chosen for this study because it is an injury 
which not only commonly results in ankle stiffness, but it also requires a non-weight bearing status for 
approximately 3 months, allowing the botulinum toxin to run its course without interfering with return to 
normal function.  The effects of Botox are entirely reversible over time, and long term effects are 
unlikely to be experienced. 
 
 
E.6.b Foreseeable Benefits:  The specific aims of this study are to provide improved outcomes of operatively 
treated tibial plafond fractures by using Botox to improve ankle dorsiflexion.  Patients randomized to the Botox 
arm of the study have the potential to experience increased ankle dorsiflexion, which will result in improved 
gait and lower limb functionality, as well as reduce the risk of developing other lower extremity pathologies.  
 


E.7  Patient Safety Monitoring 
A data safety monitor will be appointed for this study.  This person will otherwise be uninvolved in the planning 
or execution of this trial but will have the ability to unblind the collected data to analyze and determine if 
subjects experiencing an unacceptably high level of adverse events.  The adverse effects of Botox are typically 
mild, transient, and well tolerated by most patients.  Additionally, most side effects of Botox are commonly 
seen at baseline in the trauma population being studied (ex: generalized weakness, constipation, difficulty with 
urination, etc).  For this reason, only adverse events outside of what would reasonably be expected for a typical 
post-operative trauma patient will be considered.   These adverse events will be assessed by the treating 
physicians at every follow-up appointment (2 weeks, 6 weeks, 3 months, and 6 months), who will notify the 
data safety monitor within 24 hours.  If deemed necessary, the data safety monitor will unblind the collected 
data and determine if the study group is experiencing adverse events at a significantly higher rate or with greater 
severity than the control group.   If the risk to patients is deemed unacceptably high by the data safety monitor, 
the study will be terminated and the results will be published. 
 
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ICF_001.pdf: 
Botox Use in Pilon Fractures 
Date: June 20, 2012 
Revised: 4/15/2013 
Expiration: June 19, 2013  
Page 1 of 7 
 
 
 
 
 
 
 
 
 
CAROLINAS HEALTHCARE SYSTEM 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
 
 
The Effect of Botulinum Toxin Injections on Ankle Dorsiflexion Following Internal 
Fixation of Pilon Fractures 
 
INTRODUCTION 
Drs. Karunakar and his colleagues are asking you to participate in this research study of pilon 
fractures at OrthoCarolina and Carolinas HealthCare System (CHS).  You are being asked to take 
part because you have a pilon fracture.  The purpose of this study is to determine if botulinum toxin 
type A (Botox) injections at the time of surgery for your injury will improve ankle range-of-motion 
and functionality.  You will be one of approximately 20 people involved in this research project at 
CHS, and your participation will last for 12 months. 
 
Botox is not Food and Drug Administration (FDA) approved at this time for this particular 
indication, however it is currently being used “off-label” in a similar manner. 
 
HOW THE STUDY WORKS 
If you agree to participate, you will receive an injection of either Botox or saline placebo into your 
calf muscle while your injury is surgically repaired. You will be assigned by chance (like flipping a 
coin) to one of the two types of treatment being studied (this is called randomization): 
x
Group A: Injection Botox into calf muscle in operating room 
x
Group B: Injection of saline (the placebo or inactive medicine) into your calf muscle in 
operating room 
Neither you, nor your physician will know the contents of the injection. We are using 
this method because it is not clear at the present time whether Botox improves ankle 
range-of-motion and functionality. Although you and your doctor will not know which 
treatment you are receiving, this information can be determined in the event of an 
emergency. 
 
 
After you sign this informed consent and agree to be part of the study, the following things will 
happen: 
x
You will be assigned one of the two treatments 
x
You will be asked your demographic information 
 
You will be placed in a splint for 2 weeks to allow your incisions to heal.  After 2 weeks, the splint 
will be removed and you will begin a standardized rehabilitation protocol with stretching and range-
of-motion exercises clearly outlined.  Physical therapy is not mandated, but is available for patients 
who request it.  You will return for regularly scheduled follow-up appointments with your surgeon to 
assess your progress consistent with current practices.   
At 6 and 12 months following your surgery,  


Botox Use in Pilon Fractures 
Date: June 20, 2012 
Revised: 4/15/2013 
Expiration: June 19, 2013  
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x
You will be asked to complete two short questionnaires to assess your quality-of-life and 
ankle functionality.   
x
You will also have your ankle range-of-motion measured with a device specifically designed 
to do so accurately.   
  
You will then undergo the same rehabilitation protocol plan currently used as standard of care for 
this injury.   
At the conclusion of the study, the results of the information we gather will be compared between 
the two study groups. 
 
 
 
 
 
 
RISKS 
The study has several risks.  First, you may be in the placebo (inactive medicine) group and have no 
active medicine.  Currently, your injury is treated without this medicine and you will be treated 
exactly how we treat all patients with your injury.  Being randomized into the placebo group is the 
same as not participating in the study at all.  Second, it is possible that you will get the new treatment 
but do less well than you have been doing.  Third, because the treatment is new, we may not yet 
know all of the side effects: something unexpected could happen.  The known side effects are: 
 
Likely  
 
 
x
Pain at the injection site 
o
You will be asleep for all injections.  Any residual pain will be minor if 
noticeable at all. 
 
x
Surrounding muscle weakness 
o
Botox can spread in to closely associated muscles.  This is a desired effect for 
this study.  You will not begin using your lower leg until well after the effects 
of Botox have worn off. 
 
Less Likely   
x
Generalized Weakness (rare) 
x
Flu-Like Symptoms (rare) 
x
Allergic Reactions (rare) 
x
Constipation (rare) 
x
Urinary Incontinence (rare) 
 
Rare but serious 
x
Difficulty swallowing  (extremely rare) 
x
Aspiration Pneumonia (extremely rare) 
x
Anaphylaxis (extremely rare) 
 
As with all medications, side effects may include allergic reaction.  Allergic reactions 
may range from minor itching or rash to major reactions which can result in death.  A 


Botox Use in Pilon Fractures 
Date: June 20, 2012 
Revised: 4/15/2013 
Expiration: June 19, 2013  
Page 3 of 7 
 
 
 
 
 
 
serious reaction would occur during your first hospital stay where you can be adequately 
supported. 
 
Reproductive Risks 
Botox has not been studied in pregnant women.  For this reason, we are excluding women who are 
pregnant or without a pregnancy test on file from this study.  There is no foreseeable risk for 
women who become pregnant more than 1 week after the study injections as Botox remains 
primarily at the site where it is injected.  Although systemic spread has been documented, it is very 
uncommon and cleared from the system in several days. 
 
If you have problems that might be related to the drug, your doctor may "break the code" to find 
out which group you are in.  You would then no longer be in the study, but you would still get $70-
$100 per visit for the appointments you have kept. 
 
 
EXCLUSION CRITERIA 
x
Younger than 18 years of age. 
x
Significant traumatic brain injury or cognitive disability that would interfere with post-
operative rehabilitation and study questionnaires.  
x
Nerve, vascular, or tendon injury of the lower leg: injury to the tibial or peroneal motor 
nerves, injury to the posterior tibial artery requiring repair, or laceration of tendons that are 
involved in plantar flexion or dorsiflexion of the ankle which require repair. 
x
History of prior lower extremity fracture to the tibia or ankle of the affected limb. 
x
Incarcerated patients. 
x
Patients unable or unwilling to return for follow-up examination. 
x
Pregnant or patients who are breastfeeding. 
x
History of disease affecting the neuromuscular junction (ex: myasthenia gravis). 
x
Use of aminoglycoside antibiotics at the time of definitive fixation. 
x
Ipsilateral foot injury that will impair dorsiflexion exercises: Lisfranc injuries, fractures or 
dislocations of the talus, calcaneus, navicular, cuboid, cuneiforms, or metatarsals (phalanx 
fractures or dislocations will not be excluded). 
x
Patients receiving Botulinum Toxin A for other reasons. 
x
Patients with a known hypersensitivity to Botulinum Toxin A. 
x
Gustilo Anderson type III B and C. 
x
Patients with a weight greater than 115 kg – to ensure proper injection locations. 
 
 
BENEFITS 
This study may or may not improve your condition.  The information gained from your case may 
benefit others with your condition.  There is the potential for those in the treatment group to 
experience improved ankle range-of-motion, but this has never been shown.  You should not enter 
the study with this expectation. 
 


Botox Use in Pilon Fractures 
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Revised: 4/15/2013 
Expiration: June 19, 2013  
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ALTERNATIVE PROCEDURE/TREATMENT 
There are no alternative procedures to prevent the loss of ankle range-of-motion for your injury at 
this time.  By participating in this study, you are not forgoing any other treatment options that may 
be beneficial.  The alternative to being in the study is to not participate. This would in no way 
harm your relationship with your doctor or CHS. 
 
ADDITIONAL COST 
There are additional costs associated with receiving Botox injections for this study.  You will not 
be responsible for the cost of Botox injections as these will be paid for by funds from our research 
grant. You will however be responsible for charges for the cost of care for your injury, as you 
would if you did not participate in this study. 
 
COMPENSATION 
In the event that you are harmed as a direct result of your participation in this study, we will 
provide or arrange for treatment as necessary.  This treatment, as well as other medical expenses, 
will be billed to you or your insurance company in the usual manner. 
 
You will also be provided financial compensation for your time in completing questionnaires and 
having your ankle range-of-motion measured.  You will receive $70 for your 6-month visit and 
$100 for your 12-month visit. 
 
WITHDRAWAL  
Your participation in this study is completely voluntary. You should feel under no 
pressure to be in the study.  If you decide not to be in the study, it will not in any way 
harm your relations with your doctors or with Carolinas HealthCare System.  You are 
free to withdraw from the study if you change your mind after entering it.  This would 
not harm your relations with your doctors or Carolinas HealthCare System. 
 
We will tell you about new medical findings that may affect your willingness to continue in the 
study. 
 
CONFIDENTIALITY:  
The records of this study will be kept private.  In any sort of report we might publish, we will not 
include any information that will make it possible to identify a patient.  However, your record for 
this study may be reviewed and/or photocopied by Carolinas HealthCare System, or by 
representatives of the Food and Drug Administration or other government agencies.  To that 
extent, confidentiality is not absolute. A description of this clinical trial will be available on 
www.ClinicalTrials.gov, as required by U.S. law. This website will not include information that can 
identify you. At most, the website will include a summary of the results. You can search this 
website at any time. 
 
 
AUTHORIZATION: 
If you wish to take part in this clinical study, you will be asked to sign this consent form.  It allows 
the study sponsor and the study investigator to collect, process and pass on to the sponsor 


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organizations any relevant personal health information collected from you during the study.  These 
are activities routinely carried out during all clinical studies. 
 
You have been told that personal information about you (including sensitive personal health 
information, such as your medical history and your racial/ethnic origin if relevant to the study) will 
be reviewed, collected on a computer database, stored in electronic or manual files, audited, and/or 
otherwise processed by: 
 
the clinical study investigators (Karunakar, Cohen, Ellington, Ruffolo, Bosse, Kellam, Sims,Hsu  
Haines), and research staff 
 
regulatory or other governmental authorities of the United States and other countries, 
Carolinas HealthCare System employees, 
other persons or agencies as required by law or allowed by federal regulations. 
 
You have been told that your personal data are being collected and processed to: 
 
check your suitability to take part in the study, 
monitor your treatment with the study medication, 
compare and pool treatment results with those of other subjects in clinical studies. 
 
You have been told that your personal information may be processed within the U.S. or elsewhere in 
the world or transferred to or from the U.S. for review, processing and/or storage by an associated 
company or a carefully selected third-party organization.  By signing this document, you explicitly 
consent to the transfer of your personal information, including sensitive personal information, 
collected during this clinical study, for review, processing and/or storage.  Your personal health 
information may be further shared by the groups above.  If shared by them, the information will no 
longer be covered by the Privacy Rule.  However, the groups are committed to keeping your 
personal health confidential. 
 
You may refuse this authorization to transfer your personal information.  If you choose not to agree 
to this authorization, you might be ineligible to participate in the study.  If you decide not to sign 
this authorization, that will not harm your relations with your doctors or with Carolinas HealthCare 
System.   
 
You have the right to inspect your medical record at any time.  Your research record may be 
unavailable until the conclusion of the study.  At that point, it will be available.  Please speak with 
the study doctor if you desire to access your record. 
 
You have been told whenever your personal information is processed; it will be kept confidential 
and secure, to the best of our ability.  It will be used only for the purpose for which it was collected. 
 
This Authorization does not have an expiration date.  You have been told that according to the 
guidelines for good clinical practice, the study investigator and sponsor will keep your personal 
information for at least 6 years. If you do not withdraw this Authorization in writing, it will remain 


Botox Use in Pilon Fractures 
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Revised: 4/15/2013 
Expiration: June 19, 2013  
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in effect indefinitely.  If you wish to revoke authorization to use your personal information, you will 
notify the study doctor, Dr. Karunakar (contact information listed below) in writing.  Some of the 
data obtained from your record prior to your revocation may still be used if considered necessary for 
the study.    
 
FINANCIAL INTEREST OF INVESTIGATOR  
None of the doctors asking you to participate in this study have received or will receive money or 
other benefits for personal use from the study sponsor.  However, the sponsor will give money or 
other benefits to a research fund, foundation, educational institution, or other organization with 
which the doctor or study staff is associated. 
 
 
QUESTIONS  
The researchers doing the study at Carolinas HealthCare System are Drs. Karunakar, Cohen, 
Ellington, Seymour, Hsu, and Ruffolo.  You may ask them any questions you have now.  If you have 
questions later, you may contact Dr. Karunakar at: 
 
 
Department of Orthopaedic Surgery              
 
Carolinas Medical Center 
 
1025 Morehead Medical Dr. 
 
Charlotte, NC 28203 
 
Telephone 704-355-4638         
 
The Institutional Review Board is a group of people who review the research to protect your rights.  
If you have questions about the conduct of this study or about your rights as a research subject, you 
may call the chairperson of the Institutional Review Board of Carolinas HealthCare System for 
information regarding patients' rights in a research study.  You can obtain the name and number of 
this person by calling (704) 355-3158. 
 
 
 
 
 


Botox Use in Pilon Fractures 
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Revised: 4/15/2013 
Expiration: June 19, 2013  
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CONSENT   
I have read the above information.  I have asked any questions I had, and those questions 
have been answered.  I agree to be in this study and authorize the use of my personal health 
information. Dr. Karunakar will give me a copy of this form.  
 
 
_________________________________       ___________________ 
_________________ 
   Patient [guardian] Print Name 
 
 
Date  
 
Time 
 
 
   ________________________________       ___________________ 
 _________________ 
   Patient [guardian] Signature 
 
 
Date  
              Time  
 
 
__________________________________       __________________ 
__________________ 
   Signature of Person Obtaining Consent  
Date  
 
   Time 
 
 
__________________________________       ___________________ 
__________________ 
   Investigator Signature 
 
 
 
Date  
Time 
 
 
Identity of representative: 
 
___Next of Kin 
 
 
 
 
___Parent/Guardian  
___Healthcare Power of Attorney