External Beam Radiotherapy as Prophylaxis for Heterotopic Ossification After Surgical Fixation of Acetabular Fractures: a Prospective, Randomized Feasibility Study
Phase: NA
Conditions: Acetabular Fracture, Heterotopic Ossification
Sponsor: University of Maryland, Baltimore

HO Prophylaxis - Protocol v1 (2021.01.22)  
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
University of Maryland, Shock Trauma Center 
Department of Orthopaedics 
 
 
 
External Beam Radiotherapy as Prophylaxis for Heterotopic Ossification After Surgical Fixation of 
Acetabular Fractures: a Prospective, Randomized Feasibility Study 
 
 
NCT04867278 
 
Principal Investigator: Robert O’Toole, MD 
 
Version 1 
 
January 22, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

HO Prophylaxis - Protocol v1 (2021.01.22)  
 
 
 
 
 
 
 
 
2 
 
TABLE OF CONTENTS  
 
 
List of General Abbreviations/Terminology………………………………...…………….. 3 
Protocol Summary ………………………………………………………………………… 4 
Introduction ……………….……………………………………………………………….. 5 
Study Objectives ……………….…………………………………………………………...5 
Study Design ……………….……………………………………………………………….5 
Methods ……………….…………………………………………………………………….5 
Sample Size ……………….………………………………………………………………...7 
Statistical Analysis ……………….…………………………………………………….…...7 
Data Management ……………….…………………………………………………………..7 
Ethics ……………….………………………………………………………………………..7 
Safety Reporting and Monitoring……………….……………………………………………7 
 
 

HO Prophylaxis - Protocol v1 (2021.01.22)  
 
 
 
 
 
 
 
 
3 
 
 
List of General Abbreviations/Terminology 
 
HO 
 
 
Heterotopic Ossification 
CRF 
 
 
Case Review Form 
IRB 
 
 
Institutional Review Board 
LAR 
 
 
Legally Authorized Representative 
PI 
 
 
Principal Investigator 
XRT 
 
 
External Beam Radiation 
STC  
 
 
University of Maryland R Adams Cowley Shock Trauma Center 
RCT 
 
 
Randomized Controlled Trial 

HO Prophylaxis - Protocol v1 (2021.01.22)  
 
 
 
 
 
 
 
 
4 
 
PROTOCOL SUMMARY 
 
Title 
External Beam Radiotherapy as Prophylaxis for Heterotopic Ossification 
After Surgical Fixation of Acetabular Fractures: a Prospective, 
Randomized Feasibility Study 
Short Title 
HO Prophylaxis  
Type of Study 
Pilot RCT study  
Primary Objective 
To determine severe HO formation (Brooker class III-IV) between XRT 
versus no XRT. 
Sample Size 
100  
Diagnosis and Main 
Inclusion Criteria 
Patients 18+ with an acetabular fracture requiring surgical intervention 
amenable to XRT. 
Length of Follow-up  3 months post-operative 
 
 

HO Prophylaxis - Protocol v1 (2021.01.22)  
 
 
 
 
 
 
 
 
5 
 
 
Introduction 
 
Heterotopic ossification (HO) is a common complication after surgical fixation of acetabular fractures, with 
incidence reported as high as 90%. HO can be a debilitating complication and surgical excision for more severe 
cases carries a high complication rate.  Numerous strategies have been employed to prevent HO formation, but 
results are often conflicting, and the optimal treatment strategy remains controversial. 
 
The most common interventions used to prevent HO formation are oral administration of indomethacin or 
single-dose external beam irradiation therapy (XRT). Despite the common use of indomethacin and 
observational data to support its use, more recent randomized controlled trials (RCTs) have failed to 
demonstrate any significant reduction in the incidence of severe HO when patients were administered 6 weeks 
of indomethacin versus placebo. In contrast, XRT has been shown to be effective against HO formation but 
there remain concerns surrounding the cost and potential long-term effects of XRT. Other authors have 
described debridement of the gluteus minimus muscle as a primary form of prevention, but the severe HO rate 
in the largest series of this approach (12%) is higher than that of numerous series that administered XRT as 
prophylaxis (1-5%).  
 
Given the high incidence of HO, the impact of severe HO on outcomes, and the controversy regarding 
prophylaxis methods, there remains a need for randomized controlled trials (RCT) to determine optimal 
strategies for HO prophylaxis. The primary aim of this study is to assess the effect of XRT in preventing severe 
HO after acetabular surgery. 
 
Study Objectives 
This pilot RCT will determine the effect of external beam radiation (XRT) on preventing severe heterotopic 
ossification (HO) after acetabular surgery. 
 
Study Design 
This prospective pilot RCT will enroll 100 patients 18 years and older with an acetabular fracture requiring 
surgical intervention. Patients will be randomized to receive XRT or no XRT post-operatively.  
 
Methods 
Setting 
Patients will be enrolled at the University of Maryland STC and Emery University. Each clinical site will 
require local IRB approval. The PI at STC will provide oversight and guidance for the trial and regulatory 
requirements.  
 
Eligibility Criteria 
The inclusion criteria are:  
1. Ages 18+ 
2. Acute acetabular fracture  
3. Indicated for surgical fixation via a posterior or combined anterior and posterior approach 
 
The exclusion criteria are: 
1. Contraindication to radiotherapy, such as history of cancer/RT 
2. Patient is getting an acute total hip arthroplasty at the time of fixation of the acetabular fracture. 
3. Patient is currently pregnant or breastfeeding. 
4. Patient is likely to have difficulty returning for post-operative follow-ups (i.e. homeless, incarceration) 
5. Patient does not speak English. 

HO Prophylaxis - Protocol v1 (2021.01.22)  
 
 
 
 
 
 
 
 
6 
 
 
Recruitment Strategy, Patient Screening, and Consent 
All patients 18 years or older presenting to the hospital with an acute acetabular fracture indicated for surgical 
fixation will be screened for eligibility by local research staff in close coordination with surgeons and relevant 
medical staff. Research staff will review the daily orthopaedic trauma census and confirm eligibility by 
reviewing patient medical records. The PI will be available to answer questions regarding study eligibility. 
When the PI is not available, any questions will be forwarded to available medical personnel or designated 
research team member. Surgeons must be willing to participate and have their patients enrolled. Once eligibility 
has been confirmed, the informed consent process will be completed by research staff with surgeon assistance if 
possible. Patients will be approached in person by study staff prior to surgery or immediately after about 
potential participation in the study, whichever is most feasible following determination of eligibility. 
 
Legally Authorized Representative Consent: This study will include vulnerable patients incapable to give 
informed consent. For these individuals we will obtain consent from a legal authorized representative (LAR). 
The choice of LAR will follow standard procedures. The following with be approached in this order of priority: 
• Legal guardian 
• Proxy (health care agent) named in an advance directive or durable power of attorney for health care; 
• Family member or other surrogate identified by the state law on health care decisions. 
 
Patients, family members, and/or authorized representatives will be included in all study-related discussions and 
at the time of consent, they will be reminded that all participation is voluntary and the alternative is not to 
participate. During this consent process, we will review the study and consent forms, and use an Evaluation to 
Sign Consent Form asking questions based on the study to assess their full understanding and comprehension of 
what we are asking. 
 
If/when the patient recovers and is able to provide consent for him or herself, we will repeat the consent process 
with the patient to ensure he or she is still willing to participate. 
 
Randomization: Once consented, eligible patients will be randomized by study staff to XRT versus control. 
Randomization will be a 50/50 chance, like the flip of a coin. Randomization will occur in REDCap.  
 
Trial Interventions: Both arms will receive gluteus minimus debridement in the OR, which is considered the 
standard of care. If randomized to the treatment group, patients that undergo surgical fixation of an acetabular 
fracture via a posterior or combined anterior and posterior approach will undergo a single fraction of external 
beam radiotherapy to the surgical site within 72 hours of surgery. This treatment is currently the standard 
procedure performed for all patients who undergo a posterior or combined approach. The control treatment arm 
will only include gluteus minimus debridement in the OR and will not receive XRT.  
 
Data Collection  
After obtaining informed consent, research personnel will record the baseline data on the study CRFs. They will 
obtain this information directly from the participant or proxy, from the participant’s medical chart, and the 
participant’s treating surgeon. Data collected will include patient demographics and injury characteristics, 
operative details, imaging, medical history, and complications (i.e. reoperation). 3 month post operative x-rays 
will be reviewed to assess HO formation. Additionally, any serious adverse events will be recorded. All data 
will be de-identified and recorded in REDCap. 
 
 
 
 

HO Prophylaxis - Protocol v1 (2021.01.22)  
 
 
 
 
 
 
 
 
7 
 
Sample Size 
We will enroll 100 patients across all sites. Enrolling 100 patients will give the study 80% power to detect an 
88% reduction in the odds of severe HO using a two-sided alpha level of 0.05. The calculation assumes the rate 
of severe HO in the control group would be 20%. 
 
Statistical Analysis 
The primary analysis will follow the intention to treat principle, evaluating patients according to the group to 
which they were randomly assigned. To guard against any imbalances in randomization, the effect of XRT on 
our study outcomes using logistic regression models will be assessed, which will include a treatment indicator 
and adjusted for head injury, mechanical ventilation, acetabular hip dislocation, and associated fracture pattern. 
An as-treated sensitivity analysis will also be performed, in which patients will be evaluated according to the 
HO prophylaxis they received regardless of the treatment assignment. All analyses will be completed using R 
Version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria). 
 
Data Management 
All eCRFs will be completed by designated, trained site personnel. Research personnel will enter data as 
detailed on the CRFs into the secure University of Maryland, Baltimore REDCap system. Clinical site 
personnel will have a unique login and password for the system and will be able to view and modify data for 
participants recruited at their local site. The University of Maryland, Baltimore staff will monitor and oversee 
all data as it is collected across both sites, ensuring there is no missing, implausible, or inconsistent data. The 
trial will be conducted following GCP guidelines.  
 
Ethics 
The University of Maryland, Baltimore, and Emory University will obtain ethics/IRB approval prior to 
commencement of participant enrollment.  
 
Confidentiality 
Information about trial participants will be kept confidential and will be managed in accordance with the below 
rules: 
1) All trial-related information will be stored securely. 
2) All trial participant information will be stored in locked file cabinets and accessible only 
to site research personnel. 
3) All paper and electronic CRFs will be identified only by a coded participant number. 
4) All databases will be password protected. 
 
If a participant revokes authorization to collect or use personal health information, the clinical site retains the 
ability to use all information collected prior to the revocation of participant authorization.  
 
Protocol Amendments 
Any amendments to the study protocol which may affect the conduct of the study, the potential safety of, or 
benefits to participants (e.g., changes to the objectives, design, sample size, or procedures) will require a formal 
amendment to the protocol. Any protocol amendments will be approved by the Principal Investigator and may 
require approval by all applicable ethics committees and regulatory agencies. Clinical sites will also be required 
to submit amendment requests to their ethics committee to obtain approval for the amendment. Administrative 
changes (e.g., minor corrections or clarifications that have no effect on the way the trial is conducted) will not 
need to undergo a formal amendment process. 
 
Safety Reporting and Monitoring 
Safety Plan 

HO Prophylaxis - Protocol v1 (2021.01.22)  
 
 
 
 
 
 
 
 
8 
 
The safety plan for participants in this study is based on clinical experience with the trial interventions in 
completed and ongoing studies. The trial period during which AEs must be reported begins after the patient has 
consented and enrolled in the study and continues until the end of the participant follow-up period at their first 
post-operative visit. AEs recorded during this period will be followed through to resolution, or until the event is 
deemed chronic or stable. 
 
The anticipated important safety risks are outlined below. Several measures will be taken to ensure the safety of 
participants, including the use of inclusion and exclusion criteria and close monitoring of participants. 
Administration of the study procedures will be performed in a setting in which participants are closely 
monitored for potential adverse events, and there is immediate access to trained personnel and adequate 
equipment and medicine to manage potentially serious reactions. 
 
Definitions 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a participant administered medicinal product and which does not 
necessarily have a causal relationship with this treatment. It can therefore include any unfavorable and 
unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product 
or other protocol-imposed intervention. 
 
Serious Adverse Event (SAE) 
An AE should be classified as a SAE if any of the following criteria are met: 
• It results in death (e.g., the AE causes or leads to death). 
• It is life-threatening (e.g., the AE, in the view of the investigator, places the participant at immediate risk of 
death. It does not include an AE that, had it occurred in a more severe form, might have caused death.). 
• It requires or prolongs inpatient hospitalization. 
• It results in persistent or significant disability/incapacity (e.g., the AE results in substantial disruption of the 
participant’s ability to conduct normal life functions). 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the 
investigational medical product. 
• It is considered a significant medical event by the investigator based on medical judgment (e.g., may 
jeopardize the participant or may require medical/surgical intervention to prevent one of the outcomes listed 
above). 
 
Unexpected Serious Adverse Event 
Any SAE that meets all the following criteria: 
• Is unexpected, in terms of nature, severity, or frequency, given the research procedures that are described in 
the protocol and informed consent document and the characteristics of the patients eligible for the trial. 
• Is related or possibly related to treatment/procedures under trial; possibly related means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the trial procedures or treatments. 
• Suggests that participation in the trial may place participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
Some unanticipated problems may not classify as adverse events. To be considered an adverse event, the 
unanticipated problem must be an untoward or unfavorable medical occurrence in a trial participant. 
 
Reporting AEs and Unanticipated Events 
Local Investigator Reporting 

HO Prophylaxis - Protocol v1 (2021.01.22)  
 
 
 
 
 
 
 
 
9 
 
The local investigator is responsible for ensuring that all AEs including SAEs that are observed or collected 
during the study are reported to the appropriate local IRBs and the Methods Center, in accordance with 
applicable regulatory requirements. 
 
Event Reporting Timelines 
Local site investigators will report SAEs within the following timelines: 
• All deaths and immediately life-threatening events, whether related or unrelated, will be recorded and reported 
to the sponsor within 24 hours of awareness. 
• SAEs, other than deaths and immediately life-threatening events, will be reported within 72 hours of site 
awareness. 
 
SAE information must be submitted no later than 30 calendar days from the time the local investigator becomes 
aware of the event. 
 
Clinical sites will follow local procedures for submitting safety reports and follow-up information to their local 
ethics committee.