Steroid Administration for Articular Fractures of the Elbow (SAFE Trial): A Randomized, Controlled Trial of Perioperative Glucocorticoids During Treatment of Intraarticular Elbow Fractures
Phase: PHASE4
Conditions: Elbow Fracture
Sponsor: Vanderbilt University Medical Center

 
 
Study Protocol 
 
 Steroid Administration for Articular Fractures of the Elbow (SAFE Trial): A 
Randomized, Controlled Trial of Perioperative Glucocorticoids during Treatment 
of Intraarticular Elbow Fractures 
 
Principal Investigator:   
 
Jed I. Maslow, MD 
 
 
 
 
Assistant Professor, Orthopaedic Surgery 
Protocol Identification Number:  
210125 
Clinicaltrials.gov Identifier: 
 
NCT04738318 
Version Date 
 
 
 
12/06/2022 

Protocol Version #: 6 
 
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Protocol Date: 12/06/2022 
 
  
 
 
 
 
 
 
Steroid Administration for Articular Fractures of the Elbow (SAFE 
Trial): A Randomized, Controlled Trial of Perioperative Glucocorticoids 
during Treatment of Intraarticular Elbow Fractures 
 
 
 
Principal Investigator: 
Jed I. Maslow, MD 
Assistant Professor of Orthopaedic Surgery 
Vanderbilt Department of Orthopaedic Surgery 
MCE, S. Tower, Ste. 3200 
Nashville, TN 37232-8828 
 
Research Locations: 
 
Vanderbilt University Medical Center 
1211 Medical Center Drive, Nashville, TN 
37232 
 
Vanderbilt Health Belle Meade 
6002 Highway 100, Nashville, TN 37205 
 
Vanderbilt Orthopaedics Franklin 
206 Bedford Way, Franklin, TN 37064 
 
Vanderbilt Surgery Center Franklin 
225 Bedford Way, Franklin, TN 37064 
 
Vanderbilt Orthopaedics Lebanon Clinic 
1616 West Main St, Suite. 300 
Lebanon, TN 37087 
 
Vanderbilt Wilson County Surgery Center 
1401 West Baddour Pkwy 
Lebanon, TN 37087 
 
Vanderbilt Wilson County Hospital - 
Operating Suite 
1411 West Baddour Pkwy, Suite 1427 
Lebanon, TN 37087 
 
Vanderbilt Orthopaedics 
Hendersonville 
128 North Anderson Lane 
Hendersonville, TN 37075 
 

Protocol Version #: 6 
 
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Protocol Date: 12/06/2022 
 
Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Previous Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment 
6.0 
Study Procedures 
7.0 
Risks of Investigational Agents/Devices (side effects) 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants 
or Others 
9.0 
Study Withdrawal/Discontinuation 
10.0 
Statistical Considerations 
11.0 
Privacy/Confidentiality Issues 
12.0 
Follow-up and Record Retention 
13.0 
References 
 
 
 
 
 

Protocol Version #: 6 
 
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1.0 
Background 
 
Elbow fractures are complex injuries that often involve the articular surface, are in close 
proximity to critical neurovascular structures, and are prone to post-operative 
complications. Complications following treatment of intra-articular elbow pathology can 
affect over 50% of patients and up to 30% of all patients will require a re-operation. One 
of the most common complications is joint stiffness.1 When a flexion arc of motion is 
diminished to less than 100 degrees, a flexion contracture is present greater than 30 
degrees, or forearm rotation is less than 100 degrees, functional limitations are 
frequently present and further treatment may be recommended.2,3 In fact, contracture 
release may be required in 12-20% of patients after intra-articular elbow fractures and 
carries a relatively high complication rate when performed.  
 
The relationship of post-traumatic elbow contracture to intra-articular fractures is well 
established and can caused by extrinsic factors such as heterotopic ossification (HO), 
fibrosis and capsular thickening, or by intrinsic factors such as failure of nonunion, 
malunion, arthrosis, or loose bodies.2,4 Recent studies analyzing the acute phase 
synovial fluid cytokine profile after an intra-articular elbow fracture have shown 
proinflammatory and catabolic factors in high concentrations that can lead to 
contracture through myofibroblast differentiation and proliferation.4 Furthermore, HO 
can limit range of motion in up to 40% of fractures and may also result from prolonged 
inflammation with elevated IL-1β and TNF-α levels.  
 
2.0 
Hypothesis and Specific Aims 
 
Primary Study Questions 
a. For adult patients (>18yo) who sustain intra-articular elbow fractures (radial 
head, proximal ulna, distal humerus, or combined) that undergo operative 
fixation, does perioperative glucocorticoid administration (IV intra-operative 
followed by a post-operative oral taper course) improve post-operative range of 
motion (flexion/extension and pronation/supination) compared to a placebo? 
 
Secondary Study Questions 
b. Is perioperative glucocorticoid administration more effective in improving range 
of motion for certain intra-operative elbow fractures or depending on the 
mechanism of injury (subgroup comparison based on fracture type and high-
energy or low-energy injuries)? 
c. Do patients that receive perioperative glucocorticoids have a higher surgical site 
infection rate? 
Hypothesis 

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1. Alternative: In adult patients with intra-articular elbow fractures, peri-operative 
dexamethasone administration will improve post-operative active range of 
motion early (≤6 weeks) and at final follow-up (≥6 months). 
2. Null: In adult patients with intra-articular elbow fractures, peri-operative 
dexamethasone administration will not improve post-operative active range of 
motion early or at 6 month follow-up. 
3.0 
Animal Studies and Previous Human Studies 
 
Prior investigators have sought to improve post-operative range of motion by 
modulating the inflammatory cascade. Desai et al. performed a retrospective review of 
26 patients with a terrible triad injury (radial head fracture, coronoid fracture, and 
elbow dislocation) treated either with or without perioperative dexamethasone. The 
authors noted a significant improvement in the elbow arc of flexion (132.5ᵒ vs 105.5ᵒ) 
and in pronosupination (165.8ᵒ vs 132.2ᵒ) with no difference in infection rate.5 Other 
animal studies have shown improved range of motion and decreased fibrotic reactions 
after joint immobilization in subjects treated with dexamethasone compared to 
controls.6 Studies involving hip and knee arthroplasty have also shown a dose effect of 
dexamethasone in improving range of motion and reducing inflammatory cytokines.7,8 
Currently, no prospective studies of intra-operative or post-operative glucocorticoid use 
in upper extremity intra-articular fractures exist. 
 
4.0 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
• All adults ≥18 years old with an intra-articular traumatic elbow fracture to be 
treated with operative intervention and a standardized post-operative rehab 
protocol 
o Intra-articular elbow fracture defined as: 
▪ Distal humerus 
▪ Proximal ulna 
▪ Radial head fracture 
▪ Combination fracture of two or more of the above 
o Radiographs present confirming intra-articular injury 
Exclusion Criteria 
• Patients with bilateral elbow fractures 
• Patients with an altered mental status 
• Pregnant  
• Allergy or contra-indication to glucocorticoid administration 
• Type 1 or Type 2 diabetes 
• Pre-injury limitation in elbow range or motion (patient reported) 
• Unable to provide consent for themselves 

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5.0 
Enrollment/Randomization 
 
General inclusion/exclusion criteria will be used to determine patient eligibility for this 
study.  Potential study participants will be identified when they present to Vanderbilt 
University Medical Center or Vanderbilt Orthopaedic outpatient clinics for operative 
treatment of their intra-articular traumatic elbow fracture.   
 
In-person Consent Process: 
When a patient is determined to be eligible for the study, study personnel will approach 
the patient about taking part in the study.  If the patient agrees to participate in the 
study, they will be provided with an informed consent document to review. The consent 
process will be conducted using either 1) a paper version of the appropriate consent 
form or 2) a REDCap-based electronic consent form.  The electronic consent form has 
been developed in REDCap, a secure, web-based, HIPAA-compliant, data collection 
platform with a user management system. The REDCap-based electronic consent form 
can be accessed by research personnel using any electronic device.  Eligible patients will 
be given an opportunity to ask questions about the study.  If the patient agrees to 
participate in the study by signing the informed consent document, they will be 
provided with a copy of the signed consent form for their records.    
 
Electronic Consent Process: 
In the event a potential study candidate is missed during a consultation ER or outpatient 
clinic visit, or research personnel are unavailable to consent in-person, study personnel 
will contact the subject by phone to notify them of their study eligibility and ask if they 
would be interested in taking part. If the subject is interested in taking part in the study, 
study personnel will send a link to the REDCap-based electronic consent form by e-mail.  
If the subject agrees to take part in the study after reading the informed consent 
document, there will be an option for them to electronically sign their name and date 
the informed consent document.  Once they electronically sign the electronic informed 
consent document, they will be given an option to save or print the signed electronic 
informed consent documents for their files.  
 
Mail Consent Process: 
If the subject does not wish to provide their email address, they will be sent two copies 
of the informed consent document by mail.  If they agree to take part in the study, they 
will be asked to sign one copy and return it by fax or mail, and they will retain the 
second copy for their files.   
 
Screening Form 
Once the patient has signed the informed consent document, the study team will 
document subject eligibility by completing the REDCap Screening Form. This step will 
ensure only eligible patients are included in the study.  The REDCap screening form will 
be completed prior to randomization activities.    

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Enrollment Goal 
We will seek to enroll 18 patients in each treatment arm per fracture type and 18 
patients in each control arm, for a total of 144 patients.   
 
Fracture Type 
Treatment 
Arm 
Control Arm 
Total 
Distal humerus 
fracture 
18 
18 
36 
Radial head 
18 
18 
36 
Proximal ulna 
18 
18 
36 
Combined 
18 
18 
36 
 
144 
 
Randomization 
Patients will be randomized according to a stratified permuted block randomization with 
a block size of 4.  Randomization will be stratified based on fracture type: radial head, 
distal humerus, proximal ulna, combined.  Treatment A will receive glucocorticoid and 
Treatment B will receive placebo.  There will be 9 total blocks per fracture type, for 36 
patients in each fracture-type strata and an even balance in all 4 strata, for 18 in each 
treatment arm.  
 
Randomization will take place after consent.   A randomization allocation table will be 
uploaded into REDCap.  Randomization will be conducted by an Orthopaedic research 
coordinator. The treating physician, study research coordinator and patient will be 
blinded to the treatment assignment. 
 
6.0 
Study Procedures 
 
Enrollment Visit  
In addition to the enrollment and randomization procedures noted in Study Protocol 
Item 5.0, patient demographics and injury information will be documented as part of 
the patient’s baseline assessment.  Patient demographics will be imported from eStar 
into the REDCap database using the REDCap Clinical Data Interoperability Services (CDIS) 
tools. 
 
Operative Visit 
Preoperative- 
Patients will be counseled regarding the possible adverse effects of the 
methylprednisolone and will be instructed to stop taking the drug immediately if they 
begin to experience the following adverse effects: skin rash, vision problems, muscle 
weakness, swollen face. The total dose up to stoppage will be recorded.  
 

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Intraoperative- 
Patients will receive either a single intraoperative dose of 10mg of intravenous 
dexamethasone (Treatment A) or a single intraoperative dose of 10 mg of saline 
(Treatment B) based on their randomization allocation.  
 
Postoperative  
Discharge or Hospitalization 
Following surgery, the participant will be provided with either a 1) six-day oral  
methylprednisolone taper course (Treatment A) or a six-day placebo course (Treatment 
B).  Both medications will be in identical packaging. If the patient is admitted to the 
hospital following surgery, they will take the taper or placebo course as a home 
medication.  
 
Day 0 (Day of surgery): 24mg oral dose, once daily 
Day 1: 20mg oral dose, once daily 
Day 2: 16mg oral dose, once daily 
Day 3: 12mg oral dose, once daily 
Day 4: 8mg oral dose, once daily 
Day 5: 4mg oral dose, once daily 
Day 6- Patients will be contacted by phone to assess compliance and experience 
(adverse effects).  
 
Follow-up Clinic Visits 
Based on routine care, patients will follow-up in the outpatient clinic at the following 
post-operative intervals: 2-week, 6-week, 3-month, and 6-month follow-up. The 
following data points will be collected at the routine care appointments: 
• Active range of motion measurements by treating surgeon using a universal 
goniometer  
o Flexion/extension arc (degrees) 
o Pronation/supination arc (degrees) 
• Surgical site infection requiring treatment (antibiotics or debridement: Y/N) 
• Revision surgery (Y/N) 
• Numeric pain score (0-10)  
• Patient reported outcome Quick Disabilities of the Arm, Shoulder and Hand 
(QuickDASH) score 
• Radiographic evidence of heterotopic ossification (present Y/N) 
• Other complication not requiring revision surgery (nonunion, malunion, 
hardware failure, neuritis, synostosis) 
 
If a participant misses a routine care postoperative visit or if the research coordinator is 
not available on site the day of the subject’s appointment, the research coordinator will 

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attempt to contact the patient by phone, mail or electronically using REDCap, to obtain 
the outcomes data. 
 
Noncompliance 
All patients will be evaluated based on an intention-to-treat analysis. If there is 
noncompliance to the medicine home taper course indicating cross-over from the 
treatment arm to the control arm, the overall dose of glucocorticoid will be noted, and 
patients will be analyzed in their original randomization arm. 
 
Unmasking 
Unmasking of the treatment arm will occur should emergency medical services be 
required within the first 6 days after surgery and emergency personnel need to access a 
full medicine list for the study patient. 
 
Research Locations 
Research will be conducted at the following locations: 
 
Vanderbilt University Medical Center 
1211 Medical Center Drive, Nashville, TN 
37232 
 
Vanderbilt Health Belle Meade 
6002 Highway 100, Nashville, TN 37205 
 
Vanderbilt Orthopaedics Franklin 
206 Bedford Way, Franklin, TN 37064 
 
Vanderbilt Surgery Center Franklin 
225 Bedford Way, Franklin, TN 37064 
 
Vanderbilt Orthopaedics Lebanon Clinic 
1616 West Main St, Suite. 300 
Lebanon, TN 37087 
 
Vanderbilt Wilson County Surgery Center 
1401 West Baddour Pkwy 
Lebanon, TN 37087 
 
Vanderbilt Wilson County Hospital - 
Operating Suite 
1411 West Baddour Pkwy, Suite 1427 
Lebanon, TN 37087 
 
Vanderbilt Orthopaedics 
Hendersonville 
128 North Anderson Lane 
Hendersonville, TN 37075 
 
 
 
7.0 
Risks 
 
Side effects that can come from taking Dexamethasone or Methylprednisolone:  
• upset stomach 
• stomach irritation 
• vomiting 
• headache 

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• dizziness 
• insomnia 
• restlessness 
• depression 
• anxiety 
• acne 
• increased hair growth 
• easy bruising 
• irregular or absent menstrual periods 
• skin rash 
• swollen face, lower legs, or ankles 
• vision problems 
• cold or infection that lasts a long time 
• muscle weakness 
• black or tarry stool 
 
Breach of Confidentiality Risk: 
Because patient data is being collected there is a slight risk of a breach of 
confidentiality.  During this study every attempt will be made to keep the patient’s 
protected health information (PHI) private. Most study data will be maintained in a 
Vanderbilt REDCap database.  Vanderbilt Redcap is a secure, web-based application for 
building and managing online databases.  The data obtained and stored in Redcap will 
only be accessible by research personnel.  Any data sent to non-key study personnel for 
statistical analysis will be de-identified (dates will be shifted using a Redcap feature).   
Project team members listed as Key Study Personnel with existing electronic health 
record (EHR) system access rights may also be granted use of REDCap Clinical Data 
Interoperability Services (CDIS) tools.  These tools are designed to enable transfer of 
relevant study-related data from the Vanderbilt Research Derivative and/or directly 
from the EHR into REDCap. Any physical study forms (ex. consent documents, surveys) 
will be kept in a locked cabinet in the principal investigator’s office].  All study data will 
be maintained for 6 years following study completion.  Following this 6-year period, the 
Redcap database will be archived, and all physical study forms will be disposed of in 
shred-it confidentiality bins. 
 
Benefits 
We hope to determine if post-operative range of motion can be improved by peri-
operative use of Dexamethasone.   
 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants 
or Others 
 

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All adverse events related to this study (breach of confidentiality or drug adverse event) 
should be reported to the principal investigator immediately.  The principal investigator 
will then ensure prompt reporting to the IRB based on policy number III.L.   
 
9.0 
Study Withdrawal/Discontinuation 
 
Participant Withdrawal 
Participation in this study is voluntary.  If at any time a study participant wishes to be 
withdrawn from the study, they may do so by contacting their treating physician, the 
principal investigator or the research coordinator and letting them know they withdraw 
their consent.  The date in which the participant withdraws their consent will be noted 
in their study file.  
 
Safety Monitor 
The Principal Investigator will designate a Safety Monitor for this study. The Safety 
Monitor will not be involved in the study work and will work independently of the 
Principal Investigator.   The Safety Monitor will be provided reports by the statistician 
every 6 months, from first subject enrollment, and make a determination on the 
continuance of the study based on reports of adverse events and protocol deviations.  
 
10.0 
Statistical Considerations 
 
Sample Size Justification 
Prior studies suggest Flexion/extension arc after intra-articular fracture ~105ᵒ. 
Difference suggested by prior retrospective study with dexamethasone shows potential 
improvement (δ) of 27ᵒ (avg post-operative AROM 132.5ᵒ). Conservatively, will attempt 
to see an improvement of 25ᵒ (δ). Average standard deviation from literature of post-
operative intra-articular elbow fractures range of motion is 17ᵒ (σ).  A total of 22 
patients are needed (11 treatment and 11 control) to be able to reject the null 
hypothesis with 90% power and α = 0.05. Assuming a 20% loss to follow-up based on 
prior studies9 (~10%) + non-compliance of six-day home taper course. As we are 
stratifying our treatment and control groups based on fracture type, we will need 18 
patients in each treatment arm for each fracture and 18 patients in each control arm.  
 
Statistical Analysis 
a. Primary analysis 
i. Intention-to-treat 
ii. Baseline characteristics between treatment arms will be compared using 
univariate descriptive statistics.  
iii. Primary end-point (range of motion: continuous variable) → Univariate 
analysis of unmatched, interval variable with two groups assuming non-
normal distribution: Mann-Whitney U Test will be performed. 

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iv. Secondary end-points that are dichotomous (infection, revision surgery, 
heterotopic ossification, and other complication) will be analyzed with a 
chi-square or Fisher’s exact test where the assumptions for a chi-square 
test are not met. 
v. Secondary end-points that are nominal or ordinal (Pain score, DASH 
score) will be analyzed using a Mann-Whitney U Test. 
b. Subgroup analysis 
i. Analysis will be performed based on fracture type and stratification will 
make comparison possible.  
ii. Multivariate analysis using linear regression for the interval variable 
(range of motion) will be performed based on: 
1. Age <65 vs Age >65 
2. Mechanism of injury (High-energy vs. Low-energy) 
3. Treatment type 
4. Time from injury to surgery 
11.0 
Privacy/Confidentiality Issues 
 
During this study every attempt will be made to keep the patient’s protected health 
information (PHI) private. Most study data will be maintained in a Vanderbilt REDCap 
database.  Vanderbilt Redcap is a secure, web-based application for building and 
managing online databases.  The data obtained and stored in Redcap will only be 
accessible by research personnel.  Any data sent to non-key study personnel for 
statistical analysis will be de-identified (dates will be shifted using a Redcap feature).   
Project team members listed as Key Study Personnel with existing electronic health 
record (EHR) system access rights may also be granted use of REDCap Clinical Data 
Interoperability Services (CDIS) tools.  These tools are designed to enable transfer of 
relevant study-related data from the Vanderbilt Research Derivative and/or directly 
from the EHR into REDCap. The Research Derivative is a database of clinical and related 
data derived from the Vanderbilt University Medical Center’s (VUMC) clinical systems 
and restructured for research. Data is repurposed from VUMC’s enterprise data 
warehouse, which includes data from StarPanel, VPIMS, and ORMIS (Operating Room 
Management Information System), EPIC, Medipac, and HEO among others. The medical 
record number and other person identifiers are preserved within the database. Data 
types include reimbursement codes, clinical notes and documentation, nursing records, 
medication data, laboratory data, encounter and visit data, among others. Output may 
include structured data points, such as ICD 9 or 10 codes and encounter dates, semi-
structured data such as laboratory tests and results, or unstructured data such as 
physician progress reports. The database is maintained by the Office of Research 
Informatics under the direction of Paul Harris, Ph.D. Any physical study forms (ex. 
consent documents, surveys) will be kept in a locked cabinet in the principal 
investigator’s office].  All study data will be maintained for 6 years following study 

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completion.  Following this 6-year period, the Redcap database will be archived, and all 
physical study forms will be disposed of in shred-it confidentiality bins. 
 
12.0 
Follow-up and Record Retention 
 
The duration of this study will last until we have enrolled and completed follow-up on 
144 participants.  Based on historical frequency, expected study period to accrue the 
expected sample size will be 2-3 years. All study data will be maintained for 6 years 
following study completion.  Following this 6-year period, the Redcap database will be 
archived, and all physical study forms will be disposed of in shred-it confidentiality bins. 
 
13.0 
References 
 
1.  
Chen H, Liu G, Wu L. Complications of Treating Terrible Triad Injury of the Elbow: 
A Systematic Review. PLoS ONE. 2014;9(5). doi:10.1371/journal.pone.0097476 
2.  
Kodde IF, van Rijn J, van den Bekerom MPJ, Eygendaal D. Surgical treatment of 
post-traumatic elbow stiffness: a systematic review. J Shoulder Elbow Surg. 
2013;22(4):574-580. doi:10.1016/j.jse.2012.11.010 
3.  
Morrey BF, Askew LJ, Chao EY. A biomechanical study of normal functional elbow 
motion. J Bone Joint Surg Am. 1981;63(6):872-877. 
4.  
Wahl EP, Lampley AJ, Chen A, Adams SB, Nettles DL, Richard MJ. Inflammatory 
cytokines and matrix metalloproteinases in the synovial fluid after intra-articular 
elbow fracture. J Shoulder Elbow Surg. 2020;29(4):736-742. 
doi:10.1016/j.jse.2019.09.024 
5.  
Desai MJ, Matson AP, Ruch DS, Leversedge FJ, Aldridge JM, Richard MJ. 
Perioperative Glucocorticoid Administration Improves Elbow Motion in Terrible 
Triad Injuries. J Hand Surg. 2017;42(1):41-46. doi:10.1016/j.jhsa.2016.11.011 
6.  
Kaneguchi A, Ozawa J, Yamaoka K. Anti-inflammatory Drug Dexamethasone 
Treatment During the Remobilization Period Improves Range of Motion in a Rat 
Knee Model of Joint Contracture. Inflammation. 2018;41(4):1409-1423. 
doi:10.1007/s10753-018-0788-5 
7.  
Wu Y, Lu X, Ma Y, et al. Perioperative multiple low-dose Dexamethasones 
improves postoperative clinical outcomes after Total knee arthroplasty. BMC 
Musculoskelet Disord. 2018;19(1):428. doi:10.1186/s12891-018-2359-1 
8.  
Xu H, Zhang S, Xie J, Lei Y, Cao G, Pei F. Multiple Doses of Perioperative 
Dexamethasone Further Improve Clinical Outcomes After Total Knee 
Arthroplasty: A Prospective, Randomized, Controlled Study. J Arthroplasty. 
2018;33(11):3448-3454. doi:10.1016/j.arth.2018.06.031 
9.  
Pugh DMW, Wild LM, Schemitsch EH, King GJW, McKee MD. Standard surgical 
protocol to treat elbow dislocations with radial head and coronoid fractures. J 
Bone Joint Surg Am. 2004;86(6):1122-1130. doi:10.2106/00004623-200406000-
00002