Conditions: Blood Clot Trauma
Keywords: Trauma Blood clot Venous Thromboembolism Pulmonary Embolism Deep Vein Thrombosis Thromboprophylaxis Blood clot prevention trauma patients
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 12424
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare aspirin versus low-molecular weight heparin (LMWH) (Enoxaparin) as a thromboprophylaxis in patients who sustain a fracture.

Detailed description:
Patients who sustain orthopaedic trauma are at an increased risk of venous thromboembolism (VTE), including fatal pulmonary embolism (PE). Current guidelines recommend low-molecular-weight heparin (LMWH) for VTE prophylaxis in orthopaedic trauma patients. However, emerging literature in total joint arthroplasty patients suggests the potential clinical benefits of VTE prophylaxis with aspirin. This trial aims to determine if aspirin is non-inferior to LMWH for thromboprophylaxis in fracture patients.

Arms:
arm 1: Injection of 30 mg enoxaparin, twice a day via injection arm 2: Enteral ingestion or administration of 81 mg ASA, twice a day

Interventions: intervention 1: Acetylsalicylic acid intervention 2: Low Molecular Weight Heparin (LMWH)
Intervention descriptions: intervention 1: The Aspirin intervention will be 81 mg enteral (by mouth, feeding tube or rectal) twice a day with no variation in dosing allowed. intervention 2: The LMWH intervention will be 30 mg enoxaparin subcutaneous (under the skin) twice a day with variations in dosing allowed, per the standard of care at sites, as needed for patients who are very obese or exhibit renal dysfunction.

Protocol document:
Prot_SAP_ICF_000.pdf: 
PREVENT CLOT Protocol and Statistical Analysis Plan 
February 1, 2023 
This document includes the following: 
Document 
Page 
Original protocol (date: March 6, 2017) 
2 
Final protocol (date: June 1, 2021) 
53 
Summary of protocol amendments 
109 
Statistical analysis plan (Note: No revisions were made after the 
SAP approval on January 30, 2021). 
110 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
1 
 Major Extremity Trauma Research Consortium (METRC): 
PREVENTion of Clot in Orthopaedic Trauma (PREVENT CLOT): A Randomized 
Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention 
Medicines Used in Orthopaedic Trauma Patients 
Sponsored by: PCORI 
Contract Number: 
PCS-1511-32745 
IND# 
IDE# N/A 
Principal Investigators/Protocol Chairs: 
Robert O’Toole, MD 
Renan Castillo, PhD 
Deborah Stein, MD 
Medical Monitor: Marc Swiontkowski, MD 
Version # 1.0 
DATE: 03/06/17 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
2 
 
 
 
This template is adapted from the ICH guidance document E6 (Good Clinical Practices), 
Section 6. 
 
 
 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, 
potential investigators, consultants, study staff, and applicable independent ethics 
committees or institutional review boards. The contents of this document shall not be 
disclosed to others without written authorization from METRC (or others, as applicable), 
unless it is necessary to obtain informed consent from potential study participants. 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
3 
 
Table of Contents 
Contents 
Table of Contents .......................................................................................................................... 3 
List of General Abbreviations/Terminology .............................................................................. 6 
PROTOCOL SUMMARY ........................................................................................................... 7 
1. KEY ROLES ............................................................................................................................. 9 
2. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ........................... 10 
2.1 Background Information ..................................................................................................... 10 
2.2 Rationale ................................................................................................................................ 11 
2.3 Potential Risks and Benefits ................................................................................................. 12 
3. STUDY OBJECTIVES & OUTCOMES .............................................................................. 13 
3.1 Primary Objective: ............................................................................................................... 13 
3.2 Secondary Objectives: .......................................................................................................... 13 
3.3 Study Outcomes .................................................................................................................... 14 
4. STUDY OVERVIEW ............................................................................................................. 15 
5. STUDY POPULATION ......................................................................................................... 15 
5.1 Description of the Study Population ................................................................................... 15 
6. STUDY PROCEDURES ........................................................................................................ 16 
6.1 Screening and Enrollment .................................................................................................... 17 
6.2 Baseline Data Collection ....................................................................................................... 19 
6.3 Participant Follow up and Data Collection ........................................................................ 20 
7. STUDY TREATMENTS ........................................................................................................ 20 
7.1 Study Treatments .................................................................................................................. 21 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
4 
 
7.2 Assessment of Participant Adherence with Study Agent(s)/Intervention(s) ................... 22 
7.3 Precautionary and Prohibited Medications and Procedures ............................................ 22 
7.4 Rescue Medications ............................................................................................................... 22 
8. ASSESSMENT OF SAFETY ................................................................................................. 23 
8.1 Definitions .............................................................................................................................. 23 
8.2 Methods and Timing for Assessing, Recording, and Analyzing, Managing Safety 
Parameters ................................................................................................................................... 24 
8.3 Adverse Event Reporting Procedures ................................................................................. 25 
8.4 Reporting Pregnancy (Replace text with “N/A” if not applicable) .................................. 27 
8.5 Type and Duration of the Follow-up of Participants After Adverse Events ................... 27 
8.6 Stopping Rules ....................................................................................................................... 27 
8.7 Premature Withdrawal of a Participant ............................................................................. 28 
8.8 Replacement of a Participant Who Discontinues Study Treatment ................................ 28 
9. MONITORING ....................................................................................................................... 28 
9.1 Site Monitoring Plan ............................................................................................................. 28 
9.2 Safety Monitoring Plan ......................................................................................................... 28 
10. STATISTICAL CONSIDERATIONS ................................................................................ 29 
10.1 Sample Size .......................................................................................................................... 29 
10.2 Randomization .................................................................................................................... 30 
10.3 Missing Data and Measures to Minimize Bias ................................................................. 31 
10.4 Planned Interim Analysis ................................................................................................... 31 
10.5 Analysis Plan ....................................................................................................................... 32 
11. QUALITY CONTROL AND QUALITY ASSURANCE .................................................. 33 
11.1 Data Quality Assurance ...................................................................................................... 33 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
5 
 
11.2 Training and Certification of Centers ............................................................................... 33 
12. ETHICS/PROTECTION OF HUMAN SUBJECTS ......................................................... 33 
12.1 IRB/Ethics Committee ........................................................................................................ 33 
12.2 Exclusion of Women, Minorities, and Children (Special Populations) ......................... 34 
12.3 Participant Confidentiality ................................................................................................ 34 
12.4 Study Discontinuation ........................................................................................................ 34 
13. DATA HANDLING AND RECORD KEEPING ............................................................... 34 
13.1 Data Management Responsibilities ................................................................................... 34 
13.2 Data Capture Methods ....................................................................................................... 35 
13.3 Types of Data ....................................................................................................................... 35 
13.4 Source Documents and Access to Source Data/Documents ............................................ 35 
13.5 Study Records Retention .................................................................................................... 36 
13.6 Protocol Deviations ............................................................................................................. 36 
14. PUBLICATIONS POLICY ................................................................................................. 36 
15. SCIENTIFIC REFERENCES ............................................................................................. 36 
17. APPENDICES ....................................................................................................................... 42 
APPENDIX A: STUDY CONTACT ROSTER ........................................................................ 42 
APPENDIX B: DATA COLLECTION SCHEDULE ............................................................. 43 
ATTACHMENT C: DRAFT CONSENT FORM .................................................................... 47 
 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
6 
 
 
List of General Abbreviations/Terminology 
 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DSMB 
Data and Safety Monitoring Board 
DVT 
Deep Venous Thrombosis 
FDA 
Food and Drug Administration 
FWA 
Federal-Wide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
LMWH 
Low Molecular Weight Heparin 
MedDRA © 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
OHRP 
Office for Human Research Protections 
PE 
Pulmonary Embolism 
PHI 
Protected Health Information 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAB 
Stakeholder Advisory Board 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
VTE 
Venous thromboembolism 
 
  
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
7 
 
PROTOCOL SUMMARY  
Title: Prevention of Clots in Orthopaedic Trauma (PREVENT CLOT): A Randomized 
Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines 
Used in Orthopaedic Trauma Patients 
Sponsor: Patient Centered Outcomes Research Institute (PCORI) 
Type of study: Randomized Pragmatic Trial 
Objective: Is Low Molecular Weight Heparin (LMWH) (Enoxaparin) or Aspirin the better 
medicine to use for preventing death and clinically important blood clots in the lungs in patients 
who sustain trauma?  
We aim to make the following comparisons between aspirin and the LMWH: 
Specific Aim 1: The proportion of patients who sustain death due to PE or VTE prophylaxis 
after orthopaedic trauma treated with injectable LMWH compared to those treated with 
aspirin. (Hypothesis 1: The rate will be non-inferior in the aspirin group.) 
Specific Aim 2: The proportion of patients who sustain clinically important pulmonary 
embolism (PE) after orthopaedic trauma treated with injectable LMWH compared to those 
treated with aspirin. (Hypothesis 2: The rate will be non-inferior in the aspirin group.) 
Specific Aim 3: The proportion of complications (clinically significant bleeding or infection 
events) in orthopaedic trauma patients treated with injectable LMWH compared to those 
treated with aspirin. (Hypothesis 3: The rate of complications will be superior (i.e., lower) in 
the aspirin group) 
We will pursue the following secondary aims: 
Secondary Aim #1: Assess satisfaction with care in orthopaedic trauma patients treated with 
injectable LMWH compared to those treated with aspirin. (Hypothesis 4: Satisfaction will be 
superior in the aspirin group.) 
Secondary Aim #2: Estimate out of pocket patient costs in orthopaedic trauma patients 
treated with injectable LMWH compared to those treated with aspirin. (Hypothesis 5: Out of 
pocket costs will be lower in the aspirin group.) 
Secondary Aim #3: Examine the proportion of minor clot events that are less important to 
patients (clots in the proximal legs, incidental PE) in orthopaedic trauma patients treated with 
injectable LMWH compared to those treated with aspirin. (Hypothesis 6: The rate will be 
non-inferior in the aspirin group.) 
Secondary Aim #4: Estimate adherence with treatment among orthopaedic trauma patients 
treated with injectable LMWH compared to those treated with aspirin. (Hypothesis 7: 
Adherence will be higher in the aspirin group.) 
Study duration: 5 years: 1 year of planning, 3.5 years of recruitment and follow-up, 0.5 years of 
analysis and dissemination of study results 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
8 
 
Sample size: 12,200 (6,100 per arm (2) arms) 
Number of study sites: up to 30 
Study population: Orthopaedic trauma patients, ages 18 and over 
Inclusion criteria: Trauma patients who are at increased risk of blood clots from their traumatic 
orthopaedic injury and are therefore currently treated with blood clot prevention medicine, 
including operatively treated extremity injuries and all pelvis or acetabulum fractures (operative 
and non-operative) 
Exclusion criteria: Patients who do not require prophylactic blood thinners as standard of 
practice; Patients who are already on long term blood thinners (other than low-dose aspirin or 
platelet inhibitors such as Plavix or Aggrenox) or who require therapeutic (as opposed to 
prophylactic) blood thinners for an acute issue such as a blood clot in the last 6 months); Patients 
who cannot receive either of the study medications due to an allergy (history of heparain induced 
thrombocytopenia, allergy to aspirin, or NSAIDs) or other medical contraindication to blood 
thinners; Patients who are on higher dose aspirin (>81 mg once a day or higher) for medical 
reasons or who will be treated with higher dose aspirin; Patients with underlying chronic clotting 
disorders (i.e. Factor V Leiden, hyperhomocystinuria, Protein C and S deficiency) that require 
full dose anticoagulation or are a contraindication to VTE chemoprophylaxis; End stage renal 
disease, impaired creatinine clearance <30 ml/min at time of randomization (note: creatinine 
clearance does not need to be documented if prescribing physician would order medication 
without test as SOC); Pregnant or lactating patients; Patients contraindicated for any reason for 
either medicine; Prisoners; Patients who do not speak either English or Spanish. Patients may be 
excluded for other reasons at the discretion of the treating physician; the reason for exclusion 
must be documented on the screening form. Patients must be enrolled prior to receiving more 
than 2 doses of LMWH or Aspirin for initial prophylaxis.  
Outcome measure: Death, pulmonary embolism, orthopaedic complication requiring surgery, 
satisfaction, out of pocket patient costs, minor clotting events. 
Statistical analysis: Non-inferiority intent to treat analysis for study primary aim. 
Randomization: Block randomization at the center level. 
Safety monitoring: The Medical Monitor is responsible for monitoring serious adverse events 
(SAEs) as the study progresses to ensure patient safety. The DSMB will review all safety data at 
its scheduled meetings. The Medical Monitor may convene a meeting of the DSMB to evaluate 
any SAEs that he/she determines require immediate attention. 
Data Safety and Monitoring Board (DSMB): The DSMB is an independent body responsible 
for evaluating recruitment, safety and outcome data. The DSMB has the authority to stop the 
study based on its findings.  


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
9 
 
1. KEY ROLES  
Protocol Committee- Responsible for developing a detailed study protocol, provides oversight on 
study progress and acts to correct deficiencies in the conduct of the study. This committee also 
drafts the main publications related to the study. 
Steering Committee- The Science Committee of the METRC Consortium will review the 
composition of the protocol committee and provide scientific review of the study protocol, with 
the purpose of presenting the protocol to the Consortium Steering Committee for approval. 
Additionally, the study will have a Steering Committee comprised of the study investigators, an 
orthopaedic and general surgery investigator from each participating center, 2-3 experts on clot 
prevention, and the patient and consumer stakeholders who comprise our Stakeholder Advisory 
Committee. 
METRC Coordinating Center- Responsible for maintaining all study documentation, developing 
and maintaining the master IRB application and consent, circulating any changes to study 
documents including protocols, case report forms, and IRB materials to each participating center, 
providing daily oversight and management of study implementation, providing payment to sites 
for patients enrolled, performing site monitoring, data quality control and analysis of study 
results.  
Clinical Sites- Responsible for the conduct of clinical studies including patient enrollment, 
performing study procedures, data collection and conducting study follow-up visits.  
Clinical Outcome Adjudication Committee (COAC)- This committee will be responsible for 
developing the timely medical review and adjudication of trial-specific endpoints utilizing trial-
specific definitions; engages other reviewers as needed and in accordance with the COAC 
Policy; and reports adjudication results to the trial-specific Protocol Committee. 
Publication Committee- Responsible for reviewing manuscripts prior to journal submission and 
reviewing presentations prior to presentation; for mediating and settling disputes and conflicts 
among study investigators over publication or presentation priorities, authorship, and any other 
issues related to publications or presentations; for preparing and maintaining a list of concepts 
for publications and preparing and maintaining a list of approved METRC publications, which 
shows the status of each manuscript from initiation through publication. 
DSMB- Independent Data and Safety Monitoring Board (DSMB) convened for this project, 
responsible for monitoring the accumulated interim data as the trial progresses to ensure patient 
safety and to review efficacy, evaluate recruitment, and assess overall data quality.  
Medical Monitor- Responsible for providing medical guidance and overseeing patient safety for 
the study. The MM participates in determining the course of action necessary to meet safety 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
10 
 
goals and objectives. This is achieved through the review of safety reports; resolving safety 
issues; and interacting with Principal Investigators.  
2. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
2.1 Background Information 
Importance of Blood Clots and Blood Clot Prevention Medicines. Preventing venous 
thromboembolism (VTE) in the legs or lungs is a major unsolved problem in modern medicine. 
Each year, in the United States alone, blood clots are estimated to affect 300,000 – 600,000 
patients.1 These events may have important consequences for patients. VTE can include both 
deep venous thrombosis (DVT) and pulmonary embolism (PE). Even minor blood clots require a 
minimum of 6 months of medication, often with frequent blood tests, and increased risk of 
medication-related bleeding. At the most severe end, PEs are thought to account for 60,000–
100,000 deaths per year in the United States.2 
Patients who sustain trauma are well known to be at an increased risk for blood clots throughout 
their body, including fatal PE’s.3 There are 6 million fractures treated each year in the United 
States alone and 2.3 million patients are admitted each year after trauma.4-6 Hip and femur 
fractures specifically are among the most common fractures and are associated with a 
particularly high risk of blood clots.7,8 Current guidelines indicate that most orthopaedic trauma 
patients should be given medication to reduce the risk of blood clots.9,10 Despite the common 
nature of these injuries and the potential devastating impact that blood clots can have on patients’ 
lives, we currently do not know the best prophylactic regimen for these patients. 
The ideal clot prevention medication for orthopaedic trauma patients would prevent death from 
PE and other consequences of blood clots while also limiting complications from the medication, 
such as bleeding from surgical wounds and other sources.11 A blood clot resulting in death is 
obviously a devastating outcome for a patient and their family; however, other complications 
from clot prevention medications are not insignificant and may require surgery and have a major 
impact on the lives of patients, including, permanent disability in some cases.12,13 Even under 
ideal conditions the medications used to reduce clots cannot completely eliminate the chance of 
blood clots and in some instances may lead to death themselves.12-14  
Low molecular weight heparins (LMWH) are medications that have been utilized to lower the 
rates of proximal deep venous thrombosis in trauma patients since the 1990’s and are currently 
the preferred agents across many guidelines, including those from the American College of Chest 
Physicians and the Eastern Association for the Surgery of Trauma.9,10 The case for the use of 
LMWH in this trial is relatively straight forward as it is the current treatment recommended by 
these guidelines and is commonly used in most north American trauma centers.  While these 
guidelines are well intentioned, they are based on limited evidence regarding fracture patients, 
and do not incorporate patient preferences. There is good evidence that LMWH’s are effective at 
limiting DVT, particularly asymptomatic DVT found on screening studies as a part of a research 
protocol.3,15,16  However feedback from patients indicates that they are more concerned with PE’s 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
11 
 
that might cause death or clot prevention medication-related complications that require surgical 
treatment, rather than blood clots in the leg that are often asymptomatic or of minimal clinical 
consequence. This was confirmed by our own pilot research (conducted under a separate IRB). 
We interviewed 232 orthopaedic trauma patients and found that patients value the prevention of 
death and avoidance of surgical complications much more than other issues related to clot 
prevention medications.17 
Despite the widespread use of LMWH to reduce PE after orthopaedic trauma, a recent Cochrane 
review actually showed limited evidence that LMWH affects the rate of PE or mortality in 
trauma patients,3 and there is concern that there is potential for higher rates of bleeding into 
critical organs and surgical wounds associated with LMWH compared to other clot prevention 
medications in non-trauma related orthopaedic surgery.18-20 This has led many to wonder if there 
is another alternative to clot prevention than LMWH for trauma patients. 
Aspirin is another commonly used clot prevention medication, which may have a similar efficacy 
at preventing both PE and death in lower extremity injuries.21 For both hip fracture and lower 
extremity arthroplasty surgery, substantial reductions in surgical wound hematomas have been 
noted with aspirin.22 In addition, after lower extremity arthroplasty, LMWH has been associated 
with higher all-cause mortality as compared to the use of aspirin.12 Although there are certainly 
strong advocates for the use of aspirin in orthopaedic trauma patients and some solid studies in 
arthroplasty supporting its use,21,23-25 the efficacy of ASA has not been characterized relative to 
LMWH in this population yet. 
 
No Data for Guidelines: A recent study on this topic by the Orthopaedic Trauma Association 
Evidence Based Quality Value and Safety Committee highlighted a knowledge gap surrounding 
clot prevention in orthopaedic trauma patients and concluded that there is “wide variability in 
practice patterns, poor scientific support for various therapeutic regimens” and guidelines are 
needed to “improve patient care.”26 As demonstrated by this study, there is a clear need for 
guidelines on clot prevention in trauma patients,26 but there are no large high quality trials upon 
which to base these guidelines, as described by the Cochrane review on this topic.3 Most of the 
existing guidelines make recommendations that are based on either arthroplasty patients (who are 
a poor surrogate for trauma patients), or an older subset of hip fracture patients, limiting the 
applicability to the vast majority of patients who fundamentally differ from either of these 
groups. Unfortunately this knowledge gap leaves clinicians and patients to make decisions about 
which VTE prophylaxis to use in this large patient population without adequate data to guide 
them.  
2.2 Rationale 
The best medication to reduce the risk of fatal PE for orthopaedic trauma patients who are 
admitted to a hospital after trauma each year in the United States is still unknown, creating 
decisional uncertainty for both patients and clinicians.26 Recent meta-analysis on medications to 
prevent blood clots after major lower extremity surgery included no studies involving high 
energy trauma and only two small studies on hip fractures, concluding that “the rarity of 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
12 
 
pulmonary embolism made meaningful comparisons between aspirin and anticoagulation 
impossible …”22 The rarity of PE requires a large trial to answer this question and none exist to 
date. Similarly, a recent Cochrane review on this topic in trauma patients did not address the use 
of aspirin for clot prevention presumably due to a complete lack of data on the topic.3 
There is little data on how commonly used medications like LMWH perform in trauma patients 
relative to enteral aspirin, likely because of the large patient sample size needed to address this 
issue. Moreover, the currently limited research in this topic has focused more on clinically 
insignificant DVTs, and have not been powered to address the outcomes most important to 
patients and clinicians, including bleeding complications and fatal PE.3,22 
In addition to the lack of guidelines to support clinical decision making, there is a lack of 
evidence on how the choice of chemoprophylaxis following orthopaedic trauma affects patient 
satisfaction. Factors that are important to patients such as the need for the medicine to be injected 
or the out of pocket costs have been almost totally ignored to date.3,22,26,27  
To address these critical gaps in the evidence we have designed a large, pragmatic, multicenter 
randomized clinical trial. This trial will provide definitive evidence for decision makers on 
whether aspirin is as effective as LMWH at preventing death and symptomatic PE, while 
potentially resulting in significantly fewer medication associated complications. The study fills 
several large and critical knowledge gaps of great interest to patients and clinicians and has great 
potential to improve the quality of evidence available for patients and other stakeholders to make 
informed decisions. 
 
2.3 Potential Risks and Benefits 
2.3.1 Potential Risks The risks associated with participation in this study are primarily the risks 
that are associated with each of the study drugs.  
Patients randomized to the LMWH arm would have no drug-related risk over and above the risk 
they would experience as standard of care. These risks include bruising or infection at the site of 
injection and allergic reaction, ranging from hives and itching to difficulty breathing or throat 
swelling. Some participants may experience Heparin Induced Thrombocytopenia, which results 
in a reduced number of platelets and hypercoagulability. Risks associated with the LMWH arm 
also include bleeding complications, which could require transfusion or operation, and kidney 
damage.  
Patients randomized to the aspirin arm would have no drug-related risk over and above the risk 
they would experience as using aspirin for blood clot prevention. These risks include the 
potential to experience the risks associated with aspirin, including possible risk of inflammation 
or ulceration of the stomach, allergic reaction (ranging from hives and itching to difficulty 
breathing or throat swelling), ringing of the ears, and worsening asthma. Additionally, some 
patients have increased risk of bleeding and of kidney damage.  


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
13 
 
There is potential that patients in the aspirin arm will be at lower or higher risk relative to the 
patients in the LMWH arm just as there is a risk for patients in the LMWH arm to have better or 
worse outcomes than those in the aspirin arm. The trial is designed to assess this potential 
difference in risk.  
A DSMB for the study will closely monitor event reporting, and should differential risks or 
benefits be identified, will consider stopping the study. 
In this study, as with many others, there is a potential risk of breach of confidentiality, although 
the study team will make all reasonable efforts to mitigate this risk. 
 
2.3.2 Potential Benefits It is not clear that one drug treatment will provide any benefit over 
another. Patient participants will receive $20 as compensation for time and effort returning for 
the 3-month study visit.  
 
3. STUDY OBJECTIVES & OUTCOMES 
3.1 Primary Objective:  
We aim to make the following comparisons between aspirin and the LMWH: 
Specific Aim 1: The proportion of patients who sustain death due to PE or VTE prophylaxis 
after orthopaedic trauma treated with injectable LMWH compared to those treated with 
aspirin. (Hypothesis 1: The rate will be non-inferior in the aspirin group.) 
Specific Aim 2: The proportion of patients who sustain clinically important pulmonary 
embolism (PE) after orthopaedic trauma treated with injectable LMWH compared to those 
treated with aspirin. (Hypothesis 2: The rate will be non-inferior in the aspirin group.) 
Specific Aim 3: The proportion of complications (clinically significant bleeding or infection 
events) in orthopaedic trauma patients treated with injectable LMWH compared to those 
treated with aspirin. (Hypothesis 3: The rate of complications will be superior (i.e., lower) in 
the aspirin group) 
3.2 Secondary Objectives:  
We will pursue the following secondary aims: 
Secondary Aim #1: Assess satisfaction with care in orthopaedic trauma patients treated with 
injectable LMWH compared to those treated with aspirin. (Hypothesis 4: Satisfaction will be 
superior in the aspirin group.) 
Secondary Aim #2: Estimate out of pocket patient costs in orthopaedic trauma patients 
treated with injectable LMWH compared to those treated with aspirin. (Hypothesis 5: Out of 
pocket costs will be lower in the aspirin group.) 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
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Secondary Aim #3: Examine the proportion of minor clot events that are less important to 
patients (clots in the proximal legs, incidental PE) in orthopaedic trauma patients treated with 
injectable LMWH compared to those treated with aspirin. (Hypothesis 6: The rate will be 
non-inferior in the aspirin group.) 
Secondary Aim #4: Estimate adherence with treatment among orthopaedic trauma patients 
treated with injectable LMWH compared to those treated with aspirin. (Hypothesis 7: 
Adherence will be higher in the aspirin group.) 
3.3 Study Outcomes 
To meet study objectives, the following clinical outcomes will be assessed: 
• Death: The primary outcome for this study is death due to pulmonary embolism or VTE 
prophylaxis. Cause of death will be recorded in addition to an assignment of certainty of 
the attribution. Cause of death will be categorized as “Certain” (e.g. there is an autopsy or 
operative note indicating cause of death), “Highly Likely” (e.g. clinical information 
available indicating likely cause of death, but no autopsy or corroborating data available), 
or “Uncertain” (e.g. participant did not die in a clinical setting and only data available to 
support assignment of causality is based on the report on non-clinical family or friends). 
From this information, we will be able to analyze data on all cause mortality in addition 
to deaths attributable to pulmonary embolism or VTE prophylaxis. 
• Clinically important pulmonary embolism (massive, submassive, or other symptomatic 
events (found by test for PE)28 ) 
• Complications, including the following: 
o Wound drainage, hematoma or seroma of an orthopaedic injury requiring 
reoperation  
o Diagnosis of deep surgical site infection of an orthopaedic injury requiring 
operation. 
o Diagnosis of a deep surgical site infection of an orthopaedic injury, not requiring 
operation 
o Clinically overt bleed with a > 2g/dL drop in Hb or requiring > 2U transfusion29,30 
o GI bleed 
o Other bleeding complications following study enrollment and receipt of first dose 
of study medication requiring procedure  
o Lower extremity DVT distal to knee 
o Lower extremity or pelvic DVT proximal to knee 
o Other DVT 
o Studies ordered related to concerns for bleeding or VTE event 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
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§ Negative VTE study (type and date) 
§ Negative study for bleeding concern (type and date) 
The following outcomes will be assessed to address the study’s secondary aims: 
• Patient satisfaction will be measured using a validated questionnaire called the Short 
Form Patient Satisfaction Questionnaire (PSQ-18).31,32 The PSQ was originally 
developed by Ware and colleagues,33 included 80 items, and was successfully used as 
part of the RAND Health Insurance Experiment and Medical Outcomes Study.34 The 
PSQ-18 measures all 6 sub-domains (technical quality, interpersonal manner, 
communication, financial aspects of care, time spent with doctor, and accessibility) as the 
longer form, as well as a single global satisfaction domain.35 The domains measured by 
the PSQ-18 correlate at 0.8 or better with domains measured using the long form PSQ.32 
The PSQ will be revised to be made specific to the treatments under study. Two questions 
specific to orthopaedic trauma care using the same format and structure as the rest of the 
instrument will be added to measure satisfaction with treatment for this study. 
• Direct out of pocket medication cost to the patients related to the blood clot medicines as 
reported at the final follow up visit  
• Blood clots in the legs or lungs that are not associated with a PE and discovered through 
routine, standard of care procedures. No additional tests (venography) will be performed 
to screen for these events, as blood clots that are causing no symptoms are likely of no 
clinical consequence and are not important to patients. Furthermore, additional tests 
could potentially decrease the willingness of patients to participate in the trial. The 
outcome will be driven only those blood clots that are discovered as part of the normal 
clinical care at each trauma center.  
• Adherence to treatment will be defined as percent of doses taken compared to those 
prescribed, assessed while in-patient and at the final follow up visit. 
4. STUDY OVERVIEW 
The proposed study is a pragmatic multi-center, prospective, randomized trial of 30 mg of 
subcutaneous low molecular weight heparin/enoxaparin (LMWH) administered twice daily 
versus 81 mg of enteral aspirin (ASA) taken twice daily in orthopaedic trauma patients. 
Treatment will be initiated during the initial hospitalization for injury, and will continue for the 
duration of time the patient is prescribed prophylactic clot prevention medication, per the 
standard of care at the treating facility. Patients will be followed for 3 months (plus or minus 1 
month) following date of admission to the trauma center to assess for death, rehospitalization, or 
complication which occurred between discharge and follow up. At this time, satisfaction, 
adherence and out of pocket costs will also be reported.  
 
5. STUDY POPULATION 
5.1 Description of the Study Population  


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
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Approximately 12,200 participants (6,100 per treatment arm) will be enrolled from participating 
METRC centers over a 42 month period. Participants will be recruited as soon as the decision to 
place them on prophylactic clot prevention medication is made at the initial hospitalization for 
their injuries. Consenting procedures are described in detail in Section 6 of this protocol. 
 
5.1.1 Participant Inclusion Criteria 
We will include patients ages 18 years and over and anticipate that participants’ demographics 
will be representative of the US trauma population in terms of gender, race, and ethnicity due to 
our multicenter design. The study will include trauma patients who are at increased risk of blood 
clots from their orthopaedic traumatic injury (operatively treated extremity injuries and all pelvis 
or acetabulum fractures that are treated either operatively or non operatively) and for whom a 
prophylactic blood thinner regimen would be standard of care at their institution. To ensure that 
our population is representative of typical trauma patients and to enhance the generalizability of 
our findings, the participants may have other orthopaedic and non-orthopaedic injuries and still 
be included.  
5.1.2 Participant Exclusion criteria  
Patients who do not require prophylactic blood thinners as standard of practice; Patients who are 
already on long term blood thinners (other than low-dose aspirin or platelet inhibitors such as 
Plavix or Aggrenox) or who require therapeutic (as opposed to prophylactic) blood thinners for 
an acute issue such as a blood clot in the last 6 months); Patients who cannot receive either of the 
study medications due to an allergy (history of heparain induced thrombocytopenia, allergy to 
aspirin, or NSAIDs) or other medical contraindication to blood thinners; Patients who are on 
higher dose aspirin (>81 mg once a day or higher) for medical reasons or who will be treated 
with higher dose aspirin; Patients with underlying chronic clotting disorders (i.e. Factor V 
Leiden, hyperhomocystinuria, Protein C and S deficiency) that require full dose anticoagulation 
or are a contraindication to VTE chemoprophylaxis; End stage renal disease, impaired creatinine 
clearance <30 ml/min at time of randomization (note: creatinine clearance does not need to be 
documented if prescribing physician would order medication without test as SOC); Pregnant or 
lactating patients; Patients contraindicated for any reason for either medicine; Prisoners; Patients 
who do not speak either English or Spanish. Patients may be excluded for other reasons at the 
discretion of the treating physician; the reason for exclusion must be documented on the 
screening form. Patients must be enrolled prior to receiving more than 2 doses of LMWH or 
Aspirin for initial prophylaxis.  
5.1.3 Co-Enrollment Guidelines 
Patients may be co-enrolled into this and other studies, depending on the practices of the local 
IRB. Co-enrollment must be documented, and event reporting for either study must be reported 
for both projects. 
 
6. STUDY PROCEDURES 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
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in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
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6.1 Screening and Enrollment 
6.1.1 Screening 
All patients 18 years of age and older with an orthopaedic injury and for whom prophylactic clot 
prevention medication is indicated will be screened for eligibility at each site by the local 
Research Coordinator in close collaboration with the surgeon investigators. In this study, it will 
be important to enroll patients soon after admission to ensure study medication can commence in 
a timely manner.  
A partial HIPAA Waiver will be requested for the purposes of screening for enrollment. The 
study team will discuss all participants meeting inclusion criteria, and complete and submit a 
screening case report form (CRF) on every potentially eligible participant. The medical record 
will be reviewed to assess for exclusion criteria, and the results will be entered into REDCap, the 
METRC electronic data capture system, in order to document screen failures. The study PI will 
be available via text or email to answer questions regarding study eligibility. This service will be 
active during regular east and west coast business hours. When the study PI is not available, this 
coverage will be provided by a designated co-investigator. Contact information for the PI and 
alternate contact is available in Appendix A.  
 
6.1.2 Consent and Enrollment 
Once eligibility has been confirmed, the informed consent process will be completed by the 
Research Coordinator and/or a clinician certified to participate in this study. Eligible study 
participants or their legally authorized representative (LAR) will be approached as soon as they 
are able to give consent, and may be enrolled in the study through the time that the first two 
doses of anticoagulation therapy are administered; i.e. they may receive 2 doses of SOC (as 
defined by the center) therapy prior to randomization and initiation of the study-directed 
medication. Individual sites will develop local procedures that will ensure these requirements can 
be met. Patients and their families will be provided with a pamphlet describing the study, the 
risks and benefits of participation and what will be expected of them if they choose to 
participate. If a patient is unable to consent before 2 doses of SOC anticoagulation therapy are 
administered and there is no LAR available, the patient will not be eligible for study participation 
and will be recorded as such. Consent will be obtained in accordance with principles of GCP and 
ICH guidelines. 
  
A prototype consent has been prepared for this study and is attached in Appendix C. Individual 
sites may add material but may not delete material thought to be necessary for informed consent. 
Clinical sites may reformat and reword information to conform to their local requirements. The 
consent form describes the purpose of the study, the procedures to be followed, and the risks and 
benefits of participation. Copies of the signed consent forms will be given to the patient, and this 
fact will be documented in the patient’s record.  
 
All study materials will be provided in English and/or Spanish as appropriate. 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
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Following completion of informed consent, the participant information will be entered into 
REDCap where a study number will be assigned, final eligibility criteria confirmed, and the 
participant will be randomized to a treatment group. 
 
6.1.3 Assessing Capacity to Consent and Consenting a Proxy Respondent 
The research staff will endeavor to answer all questions posed by the patient and his/her family 
to ensure their understanding of the protocol. After introducing the study and reviewing the 
consent form, the research coordinator will pose several questions assessing the participant’s 
comprehension of the study and what it means to participate, their appreciation of the 
consequences of participation, and their ability to consider alternatives to participation. The 
Research Coordinator will ask the questions and determine the appropriateness of the responses. 
If the Research Coordinator is at all unsure about the patient’s ability to consent s/he will consult 
with the study site PI.  
 
By virtue of the types of injuries studied (resulting from high energy mechanisms such as high 
speed motor vehicle crashes, high falls, and blast injuries) it is expected that we will have 
patients with an associated traumatic brain injury which may render them unable to provide 
consent for the study. Other patients may remain intubated for some time due to lung issues or 
other reasons related to their trauma. It will be important not to exclude these patients from the 
study, as it would significantly reduce our ability to produce generalizable knowledge. These 
patients are at no greater risk of adverse consequences by virtue of their participation in the 
study, and should be given the same opportunity to participate.  
 
A legally authorized representative (LAR) with reasonable knowledge of the potential participant 
will be approached to consent on the patient’s behalf if one of the following is true: 
• The patient is unresponsive or intubated (and likely to remain unresponsive or intubated 
during the enrollment window for the study).  
• The patient cannot adequately answer at least 2 questions regarding study participation or 
it is determined that the patient’s level of cognition is not likely to change before study 
medication can be initiated.  
 
The choice of LAR will follow standard procedures and be any of the following: Legal guardian,  
Proxy (health care agent) named in an advance directive or durable power of attorney for health 
care; or Family member or other surrogate identified by the state law on health care decisions.  
 
Guidance will be provided to assist the LAR in making the consent decision. They will be 
advised to base the decision on the participant’s expressed wishes, or, if these are not known, 
what they believe the participant would have desired under the circumstances of the injury, their 
beliefs and values and a willingness to administer the study medication, if the patient is still 
unable to consent at the time of discharge. If the LAR does not know what the participant would 
have wanted, the LAR will advised to base the decision with the participant’s best interest in 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
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mind. They will be asked to carefully consider how much leeway the participant would likely 
give the LAR in making the choice about participation in the study. 
 
Recognizing that consent is an ongoing process, the study team will continue to assess the 
participant for their ability to provide consent, and at the earliest possible time, will obtain 
informed consent from the patient him or herself. Similarly, any participant may withdraw 
consent at any time during participation in this study. 
 
6.1.4 Informed Consent Process or Assent (for a minor) 
N/A 
 
6.2 Baseline Data Collection 
Once consent is obtained, baseline data regarding participant characteristics, injury 
characteristics, fracture classification and medical history/co-morbidities will be collected and 
entered into the METRC custom version of the REDCap data collection system. Characteristics 
about hospital course and treatment received will also be collected. A brief interview will be 
conducted with the participant or his/her surrogate. 
 
6.2.1 Medical Record Review 
For all enrolled participants, data related to the index hospitalization will be collected. This will 
include a daily check of the medication administration record to ensure that the patient is 
receiving the study drug to which he/she was assigned and to document adherence. If treatment 
is stopped, held or changed the research team member will either identify the reason for change 
from the chart or by asking the primary team if the reason is not documented. Other data to be 
collected includes orthopaedic and other injury characteristics, admission labs, and 
complications, including a fatal bleed, >= 2 g/dL drop in hemoglobin, reoperation for hematoma 
evacuation or surgical site infection, other clinically significant bleeding or infectious 
complication, VTE, PE, and any imaging studies (and results) conducted for bleeding or VTE 
concerns. Information on the administration of a limited number of concomitant medications 
with known potential for bleeding side effects will also be collected, including Plavix, or other 
platelet inhibitors, aspirin, NSAIDs (e.g. toradol, ibuprofen), and any administration of a full 
dose of anticoagulation medication, as well as the reason, will be recorded. 
 
6.2.2 Clinical Assessment 
No additional clinical assessments will be conducted as part of this study.  
 
6.3.3 Participant Interview 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
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in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
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Participants, or their proxies, will complete a brief baseline data, including age, race, history of 
tobacco, medical history, including history of VTE, peptic ulcer, DM, or cancer, or if they are 
immunosuppressed, in addition to use of home OCP/estrogen, Plavix, or daily aspirin. 
6.3 Participant Follow up and Data Collection 
6.3.1  Follow-up Visit Schedule 
Participants will return for a regularly scheduled standard of care follow-up visit at 3 months 
post admission. Each visit will have an interval of time surrounding the ideal date for the visit 
during which the visit may be completed and the data included in the trial database. This interval 
is approximately 4 weeks before or after the ideal date for the visit, which is the exact 
anniversary from the time of the admission. 
 
At the time of the follow up visit, participants will be interviewed by the Research Coordinator 
to assess for the occurrence of any clinical outcomes, including VTE events or complications 
secondary to treatment since their hospitalization. For each event identified, the participant will 
fill out a release of information form that will allow the research staff to obtain records related to 
the event, if they occurred outside the index facility. Additionally, the medical record will be 
carefully reviewed to assess for any complications treated at the index facility, including in the 
clinic, ED, or resulting in a rehospitalization.  
Participants who do not return to the study site will complete the same questions either by phone 
or an email link to the survey.  
Attempts will be made to obtain medical records or autopsy reports for all participants who are 
discovered to be deceased at the time of the follow up visit. If the participant died at home, 
family members will be asked to provide a cause of death, if known. A search of the National 
Death Index will be conducted annually for all participants who cannot be found. This search 
will take place at the local site level. No attempts will be made to follow up with family, and the 
deaths will be recorded as “unknown” cause. 
6.3.2 Retention  
Every effort will be made to retain participants in the study. The study participants will receive 
an honorarium in recognition of their time and effort. $20 will be given for completing the 3 
month visit in appreciation for their time and effort. Participants who complete follow-up 
activities by phone or email will be given $20 for competing the interview. We will also keep 
participants engaged through use of study updates on the study webpage and distribution of 
follow-up reminders, which can include mailings and e-mails. 
 
7. STUDY TREATMENTS 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
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Patients meeting inclusion/exclusion criteria will be prospectively randomized to one of two 
treatment arms using the REDCap Database randomization tool embedded. Block randomization 
with variable block sizes will be used.  
 
7.1 Study Treatments  
7.1.1 Description of treatment  
Study Treatment 1: LMWH is currently an accepted medication used to prevent blood clots after 
trauma, and and its is supported by existing guidelines so it is already in widespread use through 
the United States.9,10 Enoxaparin is available from multiple manufacturers; local site purchasing 
will determine the product received by the patient. Clear guidelines already exist regarding 
dosing in very obese patients as well as in patients with renal disease.36,37 The LMWH 
intervention is expected to be 30 mg enoxaparin SC twice a day which is already standard in 
many trauma hospitals. The protocol for this pragmatic trial will allow for variations in dosing, 
per the standard of care at sites, as needed for patients who are very obese or exhibit renal 
dysfunction. These variances will be recorded to allow them to be identified in the data.  
 
Study Treatment 2: Aspirin is currently regarded as an accepted medication to prevent blood 
clots after orthopaedic surgery, is supported by existing guidelines38 and is already in widespread 
use in the United States.  Aspirin is less commonly used in trauma although it has gained 
significant popularity in the orthopaedic arthroplasty (joint replacement) domain.22,23,27 Aspirin 
was chosen as the comparative intervention because it is thought to have an excellent 
complication profile (low rates of bleeding and chronic wound drainage) and still to be effective 
in preventing blood clots in the lung, although these data are in joint replacement 
patients.22,23,27,38 Aspirin works by effecting platelets irreversibly and this effect typically lasts 7 
days, which is a potentially important difference from the shorter acting LMWH. The advantage 
of a shorter acting medication is that the effect can be turned off easily when the patient needs 
additional surgery or if a contraindication for bleeding develops. A down side is that missed 
doses with LMWH quickly place the patient with no blood clot prevention. Aspirin is typically 
continued even when surgeries are performed so the fact that aspirin cannot be “reversed” is 
likely not important in this domain, but the importance of this effect in trauma patients is 
unknown.  
 
The dose of aspirin for this study is not obvious as several reported doses have been used 
successfully. Options include 81 mg once a day, 81 mg twice a day, 180 mg once a day, 325 mg 
once a day, and 325 mg twice a day. The desired effect of reducing the risk of clots is thought to 
occur at the 81 mg dose once a day and many joint replacement surgeons use this dose to prevent 
blood clots.39 Anti-inflammatory effects are thought to become more pronounced as the dose 
increases and some of the original joint replacement studies used 325 mg twice a day. We 
believe that lower doses may be desirable in trauma as it likely reduces the chance of bleeding 
from other traumatic injuries and it is not necessarily desirable to have the anti-inflammatory 
effects of higher doses, as anti-inflammatory medicines have been linked to delayed bone healing 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
22 
 
in animal models.40 We therefore have chosen 81 mg twice a day as it represents a dose towards 
the lower end of the dosing spectrum and gives twice a day dosing, similar to LMWH, 
decreasing the chance of patients missing a dose for the whole day. Further, a study of geriatric 
hip fractures,21 which is as close to our population as has been studied for this question, 
successfully used 160 mg once a day. 
 
7.1.2 Investigational Drug Status  
Both study treatments are FDA approved medications that are commonly used for the indication 
proposed in this application; however only LMWH has this listed as an approved indication in its 
product labelling. ASA for this indication is “off label” for use as DVT prophylaxis.  In 
accordance with 21 CFR 312.2, this study meets IND Exemption requirements. An application 
for an IND exemption was approved by the FDA for the proposed indications outlined in this 
protocol. The intention of the protocol is not to support a new indication for use or significant 
change in labeling of the drugs; is not intended to support a change in advertising for the drugs; 
will not test a new route of administration or dosage of the drug, nor is it being used in a new 
clinical population; and the study will be conducted with informed consent and in compliance 
with 21 CFR 312.7 regarding promotion and sale of drugs. Patients in the study will be actively 
monitored for any adverse reactions. 
7.2 Assessment of Participant Adherence with Study Agent(s)/Intervention(s)  
Adherence to study medications and out of pocket costs will be assessed at the 3 month follow 
up visit, including assessing for any potential occurrence of treatment crossover. 
 
If participants do not return for the 3 month study visit, they will be contacted by the study 
research coordinator by phone, mail and/or email. The participant will be asked to return to the 
clinic for a follow-up appointment. If the participant is unwilling to return, follow up information 
will be collected by phone or via an email survey assessing for adherence and study outcomes. 
 
7.3 Precautionary and Prohibited Medications and Procedures  
In this trial, participants will be randomized to receive either LMWH or aspirin. Participants in 
this study may not receive any other full dose medication as prophylaxis for anticoagulation or as 
treatment for a VTE even, nor may they receive additional dosages of aspirin above 81 mg daily. 
There are no other prohibitions regarding medications management, and participants will be 
treated according to the local standard of care. Data on specific concomitant medications will be 
collected (See Section 6.2.1). Should it be determined that the medication the participant was 
randomized to is no longer clinically appropriate, the study medication will be stopped, the 
research team will record the reason for medication discontinuation, and the participant will 
continue to be followed through the 3 month follow up.  
 
7.4 Rescue Medications  


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
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in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
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Any need for rescue medication resulting from a drug overdose or sensitivity will be handled per 
the standard of care at the treating institution or where the patient seeks care. 
 
8. ASSESSMENT OF SAFETY 
The study will monitor and report adverse events to ensure patient safety. Definitions and 
procedures for reporting adverse events are designed to satisfy 45 CFR Part 46, Subpart A; the 
“Common Rule”, shared by 17 Departments and Agencies as well as 21 CFR 312, the FDA 
regulation for adverse events. The Common Rule requires written procedures and policies for 
ensuring reporting of “unanticipated problems” involving risks to participants to IRBs, 
appropriate institutional officials, and the Department or Agency Head. The approach to defining 
and reporting events is based on the 2009 FDA Guidance for Clinical Investigators, Sponsors, 
and IRBs on adverse event reporting to IRBs 
(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126572.pdf) 
 
The medical monitor (MM) is responsible for providing medical guidance and overseeing patient 
safety for the study. The MM participates in determining the course of action necessary to meet 
safety goals and objectives. This is achieved through the review of Serious Adverse Event 
reports; resolving safety issues; and interacting with Principal Investigators. 
Each participating site is responsible for ensuring that all local IRB requirements for reporting 
adverse events (both internal and external) are met.  
 
8.1 Definitions 
8.1.1 Adverse event 
Any untoward or unfavorable medical occurrence in a human subject, including abnormal sign 
(e.g., abnormal physical exam or laboratory finding), symptom or disease temporally associated 
with the subject’s participation in the study, whether or not considered related to the subject’s 
participation. Several adverse events, or complications, will be collected as primary and 
secondary outcomes of the study. The most severe of these events include: (1) Death, (2) Fatal 
bleeding into a critical organ (retroperitoneal, intracranial, intraocular, intraspinal); (3) 
Significant/massive PE central pulmonary embolism with resulting heart strain (PE); (4) Wound 
drainage or hematoma requiring reoperation; (5) Wound drainage, bleeding or hematoma that 
does not require reoperation; (6) Bleeding event that requires intervention (e.g. chest tube, 
interventional radiology embolization); (7) Surgical Site Infection requiring reoperation; (7/8) 
Surgical site infection that does no lead to reoperation but requiring antibiotic treatment; (9) 
Greater that 2 mg/dL drop in hemoglobin within 24 hrs; and (10) GI Bleed. These and other 
complications common in the trauma population will be reviewed in aggregate twice annually by 
the DSMB to assess for differences between treatment groups. They will be reported to the IRB 
on an annual basis, unless they meet the criteria for Serious Adverse Event (see below). 
 
8.1.2 Unanticipated problem 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
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in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
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Any incident, experience, or outcome that meets all of the following criteria: 
(1) 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 study. 
 
(2) is related or possibly related to treatment/procedures under study; possibly related 
means there is a reasonable possibility that the incident, experience, or outcome may 
have been caused by the study procedures or treatments. 
 
(3) suggests that the participation in the study may place subjects or others at a greater 
risk of harm (including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
Please note that not all adverse events are unanticipated problems and only some unanticipated 
problems are in fact adverse events. For instance, if a laptop containing study data is stolen, this 
is an unanticipated problem but it is not an adverse event since it is not an untoward or 
unfavorable medical occurrence in a human subject 
 
8.1.3 Serious Adverse Event 
A serious adverse event is defined as: 
1. Unanticipated events possibly related to exposure to study 
medications such as angioedema, agranulocytosis, hepatic injury, 
or Stevens Johnson syndrome 
2. Other events that are serious AND either related or possibly related 
to the study which occur at a higher rate than expected in this 
population 
3. Other events that are unexpected AND serious AND either related 
or possibly related to the study beyond the complications expected 
in this population 
Note that deaths are an expected outcome in this population, and will not be reported as serious 
adverse events, unless they are determined to be related to study treatment and occur at higher 
than expected rates in the study population. 
 
8.2 Methods and Timing for Assessing, Recording, and Analyzing, Managing Safety 
Parameters 
8.2.1 Methods and Timing of Assessment  
Adverse events (complications) may be discovered during regularly scheduled visits or through 
unscheduled patient contacts between visits. Adverse events will be assessed for during the index 
hospitalization and at the 3 month study visit. They will be recorded on study data forms with an 
indication of whether or not they are thought to be associated with participation in the study. 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
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8.2.2 AE/SAE Grading and Relationship Assignment 
Adverse event grading: Adverse events will be graded using standard criteria. Relationship of 
event to the study procedure will be determined by the study physician.  
GRADE 1 (Mild) Transient or mild discomfort (< 48 hours); no medical intervention/therapy 
required 
 
 
 
GRADE 2 (Moderate) Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required 
 
 
 
GRADE 3 (Severe) Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations possible 
 
GRADE 4 (Life-threatening) Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable. 
 
Relationship Assignment The relationship of the adverse event to participation in the study will 
be assessed as either:  
 
 
Definitely related  
Probably related 
Possibly related 
Unlikely related 
Unrelated  
 
8.2.2.1 Adverse Events related to study medications. 
The study will capture safety information on LMWH and aspirin, both of which are licensed by 
the FDA. Complications will be classified as study outcomes (8.1.1), and their relatedness to 
medication exposure will be assessed by the treating physician. 
 
8.2.3 Recording and Documentation  
Sites will maintain source documents including but not limited to laboratory and radiology 
reports, clinical notes and discharge summaries. After review of initial and final reports by the 
medical monitor, the events may be reclassified at their discretion. 
 
8.2.4. Management of Adverse Events 
Adverse Events and Serious Adverse Events will be managed according the medical judgment of 
the treating physician. 
 
8.3 Adverse Event Reporting Procedures 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
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8.3.1 Local Reporting Requirements.  
 
Study sites must always follow and comply with their own local institution’s adverse event 
reporting requirements. Depending on the local requirements, a site may report events locally 
and not report those events to the METRC Coordinating Center. Each participating site is 
responsible for ensuring that all local IRB requirements for reporting adverse events (both 
internal and external) are met.  
 
8.3.2 SAE and Unanticipated Problem Reporting Requirements 
All Serious Adverse Events that are unexpected AND related or possibly related to the study 
must be reported to the Medical Monitor and METRC Coordinating Center within 72 hours of 
being made aware of the event. The MM will review the event within 48 hours of receiving 
notice of the event, and will make a determination of relatedness as well as the required action 
(stopping medication, informing other sites, etc). When necessary, the MM may convene the 
DSMB to discuss an event. 
 
In addition, Unanticipated Problems (UPs) that are not adverse events must also be reported to 
the METRC Coordinating Center within 14 calendar days after the event has been discovered.  
SAEs/UPs will be reported to the METRC Coordinating Center by entering the SAE/UP form 
into REDCAP. REDCap is programmed to automatically send an email to the Coordinating 
Center for both SAEs and UPs, and to the Medical Monitor in the case of an SAE.  
 
The Medical Monitor for this study is: 
Mark Swiontkowski, MD, FACS 
Department of Orthopedic Surgery 
2450 Riverside Ave., R200 
Minneapolis, MN 55454 
Telephone: (612) 273-7951  
Fax: (612) 273-7959 
E-mail: swion001@umn.edu  
 
LMWH and aspirin are available from multiple sources and have generic versions available so 
consequently there will be variability in manufacturer.  
 
8.3.3 METRC Coordinating Center Reporting Responsibilities  
When an event is determined to be unexpected and related to study medication exposure, the 
Coordinating Center will send a copy of each report received about the event to all clinical sites, 
with instructions for each to forward the report to their IRB.  
 
Copies of the report will also be sent to the Study PI, and to the DSMB. The MCC will maintain 
a list of such events for reporting and review at DSMB and Steering Committee meetings. 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
27 
 
 
8.4 Reporting Pregnancy (Replace text with “N/A” if not applicable) 
Pregnancy will always be captured on case report forms as a medical event. LMWH is 
considered a category “B” medication – to be used only if clearly needed. Aspirin is considered a 
category “D” medication – adverse reactions have been found in humans – but only in the third 
trimester, and no participant who is not pregnant at the time of enrollment will still be on study 
drugs by the final trimester of the pregnancy. If a woman becomes pregnant while on the study 
medication, the decision to continue study medication will be made by the local treating 
physician, and the event will be reported in an Unexpected Event Form. Regardless of whether 
the medication is discontinued or not, the patient will remain in follow-up until the follow-up 
period is completed and a report on the outcome will be submitted. 
 
8.5 Type and Duration of the Follow-up of Participants After Adverse Events 
Study patients who experience an SAE will be followed until resolution of the event, and a final 
report will be submitted to the medical monitor, the coordinating center and the pharmaceutical 
company (if applicable). 
8.6 Stopping Rules  
The DSMB will review the overall progress of the trial in terms of recruitment, data quality, and 
event frequency and makes a formal recommendation to the DOD at the end of each scheduled 
meeting as to whether the trial should continue unmodified, continue with protocol modifications 
or be stopped. 
There are two formal interim analyses and one final analysis planned to assess the harm of 
aspirin with respect to death (due to PE or VTE prophylaxis). The first will occur after one-third 
of enrolled patients are followed for 3 months. The second will occur after two-thirds of enrolled 
patients are followed for 3 months. At each interim analysis, the DSMB will evaluate whether 
there is an increased risk of death/PE of aspirin relative to LMWH. Specifically, they will assess 
whether the absolute difference in the risk of death between aspirin and LMWH is greater than 
0.36% and whether the absolute difference in the risk of PE between aspirin and LMWH is 
greater than 3.9%. At each interim analysis, one-sided lower confidence intervals for the 
difference in risk for death and for PE will be computed. Harm with respect to death or PE will 
be declared if the lower bound is greater than 0.36% or 3.9%, respectively. For each endpoint, 
the overall type I error of the interim monitoring procedure will be controlled by using an 
O’Brien-Fleming spending function to compute the level of the confidence intervals at the 
interim and final analyses (99.99% at first interim analysis, 99.40% at the second interim 
analysis and 98.00% at the final analysis). For both the death and PE endpoints, these stopping 
boundaries will ensure that if the difference between aspirin and LMWH are equal or less than 
0.36% and 3.9%, respectively, the probability of declaring harm is less than 2.5%. 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
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8.7 Premature Withdrawal of a Participant 
A participant may be withdrawn from the study without consent if the sponsor decides to end the 
study. Other reasons for removing a participant without consent may include but are not limited 
to non-adherence with the protocol and/or therapy, inappropriate behavior towards study 
personnel, and incarceration.  
8.8 Replacement of a Participant Who Discontinues Study Treatment  
Participants who are withdrawn from the study will not count towards the total sample size 
accrual and will be replaced. Participants who are lost to follow up and have unknown treatment 
or outcome status will be counted as lost and will not be replaced. 
9. MONITORING  
 
9.1 Site Monitoring Plan 
 
The METRC Coordinating Center will be responsible for site monitoring consistent with 
ICH/FDA guidelines. Monitoring will include a combination of remote and on-site visits of 
participating clinical research sites to review the individual subject records, including consent 
forms, case report forms, supporting data, laboratory specimen records, and medical records 
(physicians’ progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection of 
study subjects, compliance with the protocol, and accuracy and completeness of records. During 
the site certification process, the monitors also use remote methods to inspect sites’ regulatory 
files to ensure that regulatory requirements are being followed.  
The site PI will make study documents (e.g., consent forms, case report forms) and pertinent 
hospital or clinic records readily available for inspection by the local IRB, the site monitors, or 
other regulatory authorities for confirmation of the study data. 
9.2 Safety Monitoring Plan 
 
9.2.1 Safety Review Plan by the DSMB 
An independent Data and Safety Monitoring Board (DSMB) is responsible for monitoring the 
accumulated interim data as the trial progresses to ensure patient safety and to review efficacy, 
evaluate recruitment, and assess overall data quality. Two interim analyses will occur, the first 
after 1/3 patients are at 3 months from enrollment and the second after 2/3 of the patients are at 3 
months from enrollment 
The DSMB is a multidisciplinary group with a written charge provided by METRC. The DSMB 
will meet in person to review the protocol. After the trial commences, the DSMB meets twice a 
year to review data or other issues. The DSMB may request more frequent meetings if necessary 
to fulfill it charge. It may also request additional safety reports on a more frequent basis. For 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
29 
 
example, all serious adverse events (SAE) are reported to the DSMB for their consideration and 
recommendations as they occur. 
At its first meeting the DSMB will review definition of all outcomes, adverse events and serious 
adverse events and revisions to the protocol made as appropriate. Summary data on adverse 
events (together with study outcomes) will be monitored by the DSMB at its semiannual 
meetings or more frequently, as needed. These summaries will include analyses comparing rates 
of adverse events (complications) by blinded treatment group, by clinic, or in other subgroups 
requested by the DSMB. 
After each meeting, the DSMB will issue a written summary of its review of the study data, 
including adverse events (complications) and serious adverse events, for transmission to the 
IRBs at each of the study centers. Analyses or listings of adverse events will not be provided to 
the IRBs; however, adverse events involving unanticipated problems involving risks to 
participants, or breaches of protocol which might entail risk to participants must be reported to 
local IRBs as soon as possible after they are discovered. Each participating center is responsible 
for ensuring that all local IRB requirements for reporting adverse events are met. 
The DSMB will review semi-annual reports by masked treatment groups of the primary and 
secondary outcomes as well as all adverse events that are not identified as outcomes per se.  
Interim data on safety measures requested by the DSMB are reviewed at each of the scheduled 
semi-annual full meetings. Analyses will be prepared comparing rates of adverse events by 
treatment group, by clinical center or by other subgroups as requested by the DSMB. Serious 
adverse events will be reviewed by the medical monitor as they occur with the option of a 
teleconference if any DSMB member requests 
 
10. STATISTICAL CONSIDERATIONS 
 
10.1 Sample Size  
The study is well powered to address all of the specific aims. The primary driver of size is 
specific aim 1, which involves non-inferiority for death (due to PE or VTE prophylaxis). We 
plan for a sample size of 12,200.   
For specific aim 1, we assume a non-inferiority margin of 0.36%. This margin is derived from a 
discrete choice experiment in which patients indicated a willingness to accept a 0.08% increased 
risk of death (due to clots or clot prevention medicine) in exchange for each of a specific set of 
benefits of taking aspirin over LMWH.  These benefits include their preference for (1) oral vs. 
injectable medicine, (2) decreased risk of bruising, (3) lower out of pockets costs and (4) 1% 
reduction in complication rates.  Given that we expect a 1.5% reduction in the complication rate, 
we value the fourth benefit as 1.5 times the value of each of the other three benefits.  Thus, we 
set the non-inferiority margin at 0.36% (0.08% + 0.08% + 0.08% + 1.5*0.08%), as the maximum 
increased risk of death (due to clots or clot prevention medicine) to which the patients would be 
indifferent given the hypothesized benefits of aspirin over LMHW use.    


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
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We anticipate the rate of clot- and clot prevention medicine-related death to be around 0.25%. 
However, we also anticipate that a proportion of deaths will be adjudicated as being potentially 
due to clots or clot prevention medicine.  If the probability of death (attributable or potentially 
attributable to either clots or clot prevention) in the LMWH arm is 0.445%, we determined 
(using simulation) that the proposed sample size will provide (1) an 80% chance of declaring 
non-inferiority if the probability of death for aspirin is 0.445% (that is, if the probability of death 
is truly the same in both arms) (2) an 80% chance of declaring harm if the probability of death 
for aspirin is 1.28%. 
If the probability of death (attributable to either clots or clot prevention) in the LMWH arm is 
0.25%, we determined (using simulation) that the proposed sample size will provide (1) greater 
than a 95% chance of declaring non-inferiority if the probability of death for aspirin is 0.25% 
(that is, if the probability of death is truly the same in both arms) (2) an 80% chance of declaring 
harm if the probability of death for aspirin is 1.00%. 
For specific aim 2, which involves non-inferiority for PE, we considered power associated with a 
non-inferiority margin of 0.87%. This non-inferiority margin is highly conservative as patients 
have expressed a willingness to accept this 0.87% increase in clot complications just for the 
advantage of oral versus injection medication. Based upon the discrete choice experiment, a non-
inferiority of 3.9% (0.87% + 0.87% + 0.87% + 1.5*0.87%) is justifiable. Assuming a probability 
of PE for LMWH of 1.5% and a loss to follow-up rate of 7.5%, we determined (using 
simulation) that the proposed sample size will provide (1) greater than a 95% chance of declaring 
non-inferiority if the probability of PE for aspirin is 1.5% (that is, if the probability of PE is truly 
the same in both arms) (2) an 80% chance of declaring harm if the probability of PE for aspirin is 
3.19%. 
With regards to specific aim 3, the planned sample size will provide 80% power to detect risk of 
infection/bleeding from 10% in the LMWH arm to 8.47% in the aspirin, assuming a 7.5% loss to 
follow-up rate. 
The study is overpowered for all secondary aims. 
10.2 Randomization 
 
Patients who provide consent to be enrolled in the study will be randomized electronically by the 
online Data Management System maintained at the Coordinating Center at the Johns Hopkins 
School of Public Health. Following consent, a randomization code is provided assigning 
treatment group and whether or not the participant was selected to be prospectively surveyed 
regarding out of pocket costs and treatment adherance. Randomization tables are encrypted and 
will not be shared with study investigators. While this study is not blinded, provision of linkages 
between randomization codes and treatment assignment will follow existing METRC unblinding 
SOP. Patients will be randomly assigned (within center) using block randomization with variable 
block sizes to either LMWH or aspirin. Compliance regarding the proper treatment protocols will 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
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be monitored by local Research Coordinators in cooperation with the attending surgeon. Any 
deviation from the assigned treatment group and the actual treatment received will be recorded.  
 
10.3 Missing Data and Measures to Minimize Bias 
 
Missing data is a serious concern that complicates the interpretation of the study results. For 
missing baseline data, we will use multiple imputation. We do not expect any missing outcome 
data for death or clinically significant PE. As with most prospective studies, missing data will be 
unavoidable, even with excellent follow-up. We will employ the following strategies to address 
missing data in the design, conduct, analysis and reporting of study results: (1) limit participant 
burden and inconvenience in data collection, (2) provide compensation for participation and 
completion in the study; (3) provide pre-study training of investigators and research staff to 
emphasize the importance of full participation in the study during the consent process (even if 
the patient is “feeling better”); (3) reimburse study sites based on follow-ups completed rather 
than on per-patient basis; (4) monitor and report missing data rates during the study and provide 
on-study reinforcement and support to ensure high follow-up rates; (5) collect information on the 
reasons for missing data; (6) actively engage participants in the study and educate them about the 
importance of their participation; and (7) collect surrogate information on participants who miss 
clinic visits; (8) require sites to go back and fill in missing data using medical record information 
when applicable; (9) carefully track and collect data on any discontinuations, to include the 
reasons for discontinuation, who decided that the participant would discontinue; and whether the 
discontinuation involves some or all types of participation; (10) avoid using single imputation 
methods and will employ multiple imputation strategies for handling missing information when 
necessary; (11) analyze data under a variety of modeling assumptions regarding how strongly the 
missingness mechanism is related to outcomes; (12) conduct sensitivity analyses to evaluate the 
robustness of the study results to various untestable assumptions about the missing data 
mechanism; (13) estimate treatment effects (utilizing relevant auxiliary information) under the 
missing at random assumption; (14) explore the effect of departures from the missing at random 
assumption using pattern-mixture and selection modeling techniques; and (14) we will account 
for all participants who enter the study in the reporting or our results whether or not they are 
included in the analysis.  
10.4 Planned Interim Analysis 
 
As described above, an independent Data and Safety Monitoring Board (DSMB) will monitor 
interim data as the trial progresses to ensure patient safety, review efficacy, evaluate recruitment, 
and assess overall data quality. O’Brien-Fleming stopping guidelines for efficacy will apply. The 
interim analysis will occur twice, once when the first third of patients are enrolled, and then 
again when two thirds of patients are enrolled, and will look specifically at the risk of death/PE 
among patients receiving aspirin relative to those receiving LMWH. After reviewing the results, 
the DSMB will then a formal recommendation as to whether the trial should continue 
unmodified, continue with protocol modifications, or to be stopped. 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
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10.5 Analysis Plan 
 
Patients will be followed for 3 months post-injury. The primary statistical analysis will follow 
the intent-to-treat paradigm, which means all patients will be analyzed according to the treatment 
group to which they were randomized. For the five distinct endpoints under evaluation, no 
multiple comparison adjustments are planned. 
Crossover: We will monitor and calculate crossover rates. Due to insurance issues, we expect 
greater crossover in the LMWH arm. This will introduce a validity threat by attenuating any 
effects towards the null. As this is a pragmatic trial and crossover can be expected in the real 
world, our primary analysis will be based on the intent-to-treat paradigm. However, as a 
secondary analysis, we will use causal inference techniques (e.g., inverse-probability of 
treatment weighting, propensity scores) to draw inferences in a counterfactual world without 
crossover. 
Binary Endpoints. Treatment effects for binary endpoints (e.g., death, PE, bleeding/infection) 
will be estimated using a two-group comparison of proportions; confidence intervals for the 
absolute risk difference will be reported. 
Continuous Endpoints. Treatment effects for continuous endpoints (e.g., satisfaction with care) 
will be estimated using a two-group comparison of means; confidence intervals for the difference 
in means will be reported. 
Superiority Analyses. Primary Aim 3 will be addressed by computing, at the final analysis, a 
two-sided 95% confidence interval for the difference in probability of bleeding/infection 
complications between aspirin and LMWH. Superiority of aspirin will be declared if the upper 
bound of the confidence interval is less than zero. Alternatively, superiority of LMWH will be 
declared if the lower bound of the confidence interval is greater than zero. Similarly, Secondary 
Aims 2 and 3 will be addressed by computing, at the final analysis, a two-sided 95% confidence 
interval for the difference in mean PSQ-18 and out of pocket costs, between aspirin and LMWH, 
respectively. Superiority of aspirin will be declared if the lower bound of the confidence interval 
is greater than zero, with the converse indicating superiority of LMWH. 
Non-inferiority Analyses. Primary Aim 1 will be addressed by computing, at the final analysis, a 
one-sided 98% upper confidence interval for the difference in probability of death between 
aspirin and LMWH. Non-inferiority of aspirin with respect to death (due to PE or VTE 
prophylaxis) will be declared if the bound of the confidence interval is less than 0.36%. A 98% 
upper confidence interval is used to ensure that if the difference between aspirin and LMWH is 
equal or greater than 0.36%, the probability of declaring non-inferiority is less than 2.5%. 
Similarly, Primary Aim 2 will be addressed by computing, at the final analysis, a one-sided 98% 
upper confidence interval for the difference in probability of clinically important PE between 
aspirin and LMWH. Non-inferiority of aspirin with respect to death will be declared if the bound 
of the confidence interval is less than 3.9%. A 98% upper confidence interval is used to ensure 
that if the difference between aspirin and LMWH is equal or greater than 3.9% the probability of 
declaring non-inferiority is less than 2.5%. For these endpoints, there are two ways of making an 
error when the difference between aspirin and LMWH is equal to the indifference threshold: 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
33 
 
declaring harm or declaring non-inferiority. The statistical procedure we have described controls 
the overall error rate to less than the 5% level. Secondary Aim 3 will be addressed by computing, 
at the final analysis, a one-sided 95% upper confidence interval for the difference in probability 
of minor clotting between aspirin and LMWH. The non-inferiority of aspirin will be declared if 
the upper bound of the confidence interval is less than 3.9% (conservative). 
 
11. QUALITY CONTROL AND QUALITY ASSURANCE  
 
11.1 Data Quality Assurance 
 
Quality Control (Q/C) and Quality Assurance (Q/A) procedures that apply to all studies are 
outlined in the METRC Manual of Operations (MOP). A certification process will be used as a 
basis for training and certification of the study personnel involved in data collection. In addition 
to consortium wide training and certification procedures, additional requirements may be added 
based on the nature of the study. Ongoing data edits and audits will be performed to ensure 
collection of quality data. The continuous and timely flow of data from the centers to the MCC is 
an essential prerequisite for maintaining data quality.  
Monthly enrollment reports will be distributed to each center that will summarize recruitment, 
data completion and timeliness of data entry. These reports will also include a set of queries 
generated by REDCap and sites will be asked to address these queries within 10 business days. 
 
11.2 Training and Certification of Centers 
 
All participating centers together with their respective study personnel will undergo certification 
that included training, local site IRB, and a knowledge assessment on the study design and 
procedures. This training will include a training for research coordinators in the submission of 
regulatory documents, data collection procedures, and study follow-up, as well as meetings 
between the PI, study project director, and the study team at each site to ensure that the 
procedures are well understood prior to engaging with research subjects. 
 
12. ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
12.1 IRB/Ethics Committee 
 
IRB approval will be obtained from the MCC at Johns Hopkins Bloomberg School of Public 
Health, the University of Maryland School of Medicine, and each participating clinical site 
according to METRC policies and procedures. Sites that recruit patients will submit METRC 
study recruitment materials to their organization’s IRB prior to use at that facility. 
Sites must provide the Coordinating Center with a copy of the initial IRB approval notice and 
subsequent renewals as well as copies of the IRB approved consent statements. 
No site can begin work related to this study until the site has been certified by the MCC in 
accordance with METRC policies and procedures. 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
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12.2 Exclusion of Women, Minorities, and Children (Special Populations) 
 
The proposed study anticipates recruiting a significant proportion of racial/ethnic minorities 
(African-Americans, Asian-Americans and Hispanics) as well as non-Hispanic white subjects. 
The study will not include children or prisoners. 
 
12.3 Participant Confidentiality 
 
It is the investigator’s responsibility to conduct the protocol under the current version of 
Declaration of Helsinki, ICH Guidelines, Good Clinical Practice, and rules of local IRBs. The 
investigator must ensure that the patient’s anonymity be maintained in their data submission to 
the Data Coordinating Center.  
 
Patients will be identified in the central data collection system, REDCap only by an 
identification code but not by their name, SSN, or hospital medical record number. Study Site 
Investigators will maintain a separate confidential enrollment log which matches identifying 
codes with the patients’ names and addresses available only to local clinic staff certified by the 
MCC to participate in the study.  
 
The subset of the participants who agree to participate in the adherence study will sign a HIPAA 
authorization form allowing their contact information to be shared with the coordinating center 
so that follow up calls can be made.  
 
All study forms, reports, and other records that are part of the study data collection materials will 
be identified by coded number to maintain patient confidentiality. All paper records will be kept 
in locked file cabinets. All electronic records of study data will be identified by coded number. 
Clinical information will not be released without written permission of the patient, except as 
necessary for monitoring by the sponsor (MCC), IRB, DOD, or DSMB. Consent procedures and 
forms, and the communication, transmission and storage of patient data will comply with 
individual site IRB and DOD requirements for compliance with The Health Insurance Portability 
and Accountability Act (HIPAA). 
 
12.4 Study Discontinuation  
 
Participants will be informed that they may discontinue the study at any time, for any reason. 
They will be assured that the medical care which they receive at the participating facility will not 
be affected should they elect to discontinue participation in the study.  
13. DATA HANDLING AND RECORD KEEPING 
 
13.1 Data Management Responsibilities 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
35 
 
 
Each study site is responsible for collecting and uploading study data in a timely fashion. 
The research coordinators at each site will obtain the information necessary to complete the 
electronic case report forms (eCRFs) from several sources including but not limited to, the 
patient's medical record, clinical evaluations and patient interviews. The Site Research 
Coordinator will enter non-personally identifiable information into a central /and secured web-
based data management system being implemented for all Consortium studies, known as 
REDCap. This data management system has incorporated state-of-the-art features for electronic 
data collection and is configured in accordance with best practices for information technology 
and research data management.  
 
The PI will certify completeness and accuracy of the study data at two time points: once 
following completion of all baseline data and treatment information, and then again following 
completion of the 3 month visit. This will take place through review of a summary of data in 
REDCap and a certification that data collected for the study are true and accurate. 
  
All research data, in hard copy or electronic form, will be stored and managed in a secure 
manner following applicable federal regulations and ICH guidelines and according to 
institutional policies and practices. Hard copy documents generated by the sites which contain 
subject data, patient identifiers and contact information will be stored in secure, locked 
containers (file cabinets, drawers, etc.) in accordance with standard document management 
practices.  
 
At all times only MCC-certified key personnel specifically designated and authorized by the 
Principal Investigator shall have access to any research related documents, including electronic 
data and medical records. All such personnel will be properly trained and supervised regarding 
the management and handling of confidential materials. The Principal Investigator assumes full 
responsibility for such training, supervision, and conduct. This information will be available for 
audit by study monitors and representatives of the local IRB and the MCC. 
 
13.2 Data Capture Methods 
 
Data will be collected in real time by the investigator or study coordinator directly on electronic 
Case Report Forms (CRFs).  
 
13.3 Types of Data 
 
Data will include: medical and surgical histories, laboratory reports, radiology reports, clinical 
evaluations, medication administration records, adverse events and patient interviews.  
 
13.4 Source Documents and Access to Source Data/Documents 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
36 
 
 
Source documents laboratory results, patient surveys, medical records, etc. will be maintained at 
the site and will be made available to study monitors, and representatives of regulatory agencies 
including the MCC and IRB.  
 
13.5 Study Records Retention 
 
Study records will be maintained in accordance with current ICH guidelines. Data will be 
maintained for five years following the end of research-related activities, including data cleaning 
and analysis. At the end of this period, each site will provide the Coordinating Center a signed 
verification that these data have been destroyed. 
 
13.6 Protocol Deviations 
 
Records of protocol deviations will be noted on the Protocol Deviation CRF (AF05) with the 
reason for the deviation recorded, as well as any action taken to mitigate the deviation. This 
information will be entered into REDCap. These records will be provided to the site’s IRB in 
accordance with local reporting requirements and be made available to study monitors. 
 
14. PUBLICATIONS POLICY 
Publications will be written in accordance with the METRC publication policy (available on the 
METRC website: www.metrc.org). 
 
 
15. SCIENTIFIC REFERENCES 
1. Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous thromboembolism: A public 
health concern. Am J Prev Med. 2010;38(4 Suppl):S495-501. 
2. Center for Disease Control and Prevention. Venous throboembolism (blood clots). 
http://www.cdc.gov/ncbddd/dvt/data.html. Updated 2015. Accessed 02/11, 2016. 
3. Barrera LM, Perel P, Ker K, Cirocchi R, Farinella E, Morales Uribe CH. Thromboprophylaxis 
for trauma patients. Cochrane Database Syst Rev. 2013;(3):CD008303. doi(3):CD008303. 
4. National Center for Health Statistics. Public use microdata file documentation, national 
hospital ambulatory medical care survey, 2011. Hyattsville, MD: National Technical 
Information Service; 2011. 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
37 
 
5. American Academy of Orthopaedic Surgeons. Ortho info. 
http://orthoinfo.aaos.org/menus/injury.cfm. Updated 2016. Accessed 02/11/2016. 
6. MacKenzie EJ, Bosse MJ. Factors influencing outcome following limb-threatening lower limb 
trauma: Lessons learned from the lower extremity assessment project (LEAP). J Am Acad 
Orthop Surg. 2006;14(10 Spec No.):S205-10. 
7. Geerts WH, Code KI, Jay RM, Chen E, Szalai JP. A prospective study of venous 
thromboembolism after major trauma. N Engl J Med. 1994;331(24):1601-1606. 
8. Haut ER, Chang DC, Pierce CA, et al. Predictors of posttraumatic deep vein thrombosis 
(DVT): Hospital practice versus patient factors-an analysis of the national trauma data bank 
(NTDB). J Trauma. 2009;66(4):994-9; discussion 999-1001. 
9. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery 
patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of 
chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e278S-
325S. 
10. Rogers FB, Cipolle MD, Velmahos G, Rozycki G, Luchette FA. Practice management 
guidelines for the prevention of venous thromboembolism in trauma patients: The EAST practice 
management guidelines work group. J Trauma. 2002;53(1):142-164. 
11. Streiff MB, Haut ER. The CMS ruling on venous thromboembolism after total knee or hip 
arthroplasty: Weighing risks and benefits. JAMA. 2009;301(10):1063-1065. 
12. Sharrock NE, Gonzalez Della Valle A, Go G, Lyman S, Salvati EA. Potent anticoagulants 
are associated with a higher all-cause mortality rate after hip and knee arthroplasty. Clin Orthop 
Relat Res. 2008;466(3):714-721. 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
38 
 
13. Jameson SS, Baker PN, Charman SC, et al. The effect of aspirin and low-molecular-weight 
heparin on venous thromboembolism after knee replacement: A non-randomised comparison 
using national joint registry data. J Bone Joint Surg Br. 2012;94(7):914-918. 
14. Haut ER, Lau BD, Streiff MB. New oral anticoagulants for preventing venous 
thromboembolism. BMJ. 2012;344:e3820. 
15. Geerts WH, Jay RM, Code KI, et al. A comparison of low-dose heparin with low-molecular-
weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J 
Med. 1996;335(10):701-707. 
16. Adams RC, Hamrick M, Berenguer C, Senkowski C, Ochsner MG. Four years of an 
aggressive prophylaxis and screening protocol for venous thromboembolism in a large trauma 
population. J Trauma. 2008;65(2):300-6; discussion 306-8. 
17. Haac B, O’Hara N, Stein D, et al. What do orthopaedic trauma patients value in venous 
thromboembolism prevention? results of a prospective discrete choice experiment. Under 
Review.  
18. Burnett RS, Clohisy JC, Wright RW, et al. Failure of the american college of chest 
physicians-1A protocol for lovenox in clinical outcomes for thromboembolic prophylaxis. J 
Arthroplasty. 2007;22(3):317-324. 
19. Mortazavi SM, Hansen P, Zmistowski B, Kane PW, Restrepo C, Parvizi J. Hematoma 
following primary total hip arthroplasty: A grave complication. J Arthroplasty. 2013;28(3):498-
503. 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
39 
 
20. Novicoff WM, Brown TE, Cui Q, Mihalko WM, Slone HS, Saleh KJ. Mandated venous 
thromboembolism prophylaxis: Possible adverse outcomes. J Arthroplasty. 2008;23(6 Suppl 
1):15-19. 
21. Group PEPPTC. Prevention of pulmonary embolism and deep vein thrombosis with low dose 
aspirin: Pulmonary embolism prevention (PEP) trial. Lancet (London, England). 
2000;355(9512):1295. 
22. Drescher FS, Sirovich BE, Lee A, Morrison DH, Chiang WH, Larson RJ. Aspirin versus 
anticoagulation for prevention of venous thromboembolism major lower extremity orthopedic 
surgery: A systematic review and meta-analysis. J Hosp Med. 2014;9(9):579-585. 
23. Raphael IJ, Tischler EH, Huang R, Rothman RH, Hozack WJ, Parvizi J. Aspirin: An 
alternative for pulmonary embolism prophylaxis after arthroplasty? Clin Orthop Relat Res. 
2014;472(2):482-488. 
24. An VV, Phan K, Levy YD, Bruce WJ. Aspirin as thromboprophylaxis in hip and knee 
arthroplasty: A systematic review and meta-analysis. J Arthroplasty. 2016;31(11):2608-2616. 
25. Ogonda L, Hill J, Doran E, Dennison J, Stevenson M, Beverland D. Aspirin for 
thromboprophylaxis after primary lower limb arthroplasty: Early thromboembolic events and 90 
day mortality in 11,459 patients. Bone Joint J. 2016;98-B(3):341-348. 
26. Sagi HC, Ahn J, Ciesla D, et al. Venous thromboembolism prophylaxis in orthopaedic 
trauma patients: A survey of OTA member practice patterns and OTA expert panel 
recommendations. J Orthop Trauma. 2015;29(10):e355-62. 
27. Wong A, Kraus PS, Lau BD, et al. Patient preferences regarding pharmacologic venous 
thromboembolism prophylaxis. J Hosp Med. 2015;10(2):108-111. 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
40 
 
28. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive 
pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary 
hypertension. Circulation. 2011;123:1788-1830. 
29. Dahl OE, Quinlan DJ, Bergqvist D, Eikelboom JW. A critical appraisal of bleeding events 
reported in venous thromboembolism prevention trials of patients undergoing hip and knee 
arthroplasty. J Thromb Haemost. 2010;8(9):1966-1975. 
30. European Agency for the Evaluation of Medicinal Products. The european agency for the 
evaluation of medicinal products, committee for medicinal products for human use 
(CHMP). Guideline on clinical investigation of medicinal products for prophylaxis of high intra- 
and post-operative venous thromboembolic risk. . 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500
003301.pdf. Updated 2007. Accessed 11/8/2016. 
31. Knutsen EJ, Paryavi E, Castillo RC, O'Toole RV. Is satisfaction among orthopaedic trauma 
patients predicted by depression and activation levels? J Orthop Trauma. 2015;29(5):e183-7. 
32. Castillo RC, Mackenzie EJ, Bosse MJ, METRC Investigators. Measurement of functional 
outcomes in the major extremity trauma research consortium (METRC). J Am Acad Orthop 
Surg. 2012;20 Suppl 1:S59-63. 
33. Ware J, Snyder M, Wright W, Davies A. Defining and measuring patient satisfaction with 
medical care. Eval Program Plann. 1983;6:247-263. 
34. Stewart AL, Ware JE, eds. Measuring functioning and well-being. the medical outcomes 
study approach. Durham: Duke University Press; 1992. 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
41 
 
35. Marshall GN, Hays RD. The patient questionnaire short-form (PSQ-18). Santa Monica: 
Rand; 1994. 
36. Bartlett MA, Mauck KF, Daniels PR. Prevention of venous thromboembolism in patients 
undergoing bariatric surgery. Vasc Health Risk Manag. 2015;11:461-477. 
37. Muntz JE, Michota FA. Prevention and management of venous thromboembolism in the 
surgical patient: Options by surgery type and individual patient risk factors. Am J Surg. 
2010;199(1 Suppl):S11-20. 
38. Stewart DW, Freshour JE. Aspirin for the prophylaxis of venous thromboembolic events in 
orthopedic surgery patients: A comparison of the AAOS and ACCP guidelines with review of 
the evidence. Ann Pharmacother. 2013;47(1):63-74. 
39. Anderson DR, Dunbar MJ, Bohm ER, et al. Aspirin versus low-molecular-weight heparin for 
extended venous thromboembolism prophylaxis after total hip arthroplasty: A randomized trial. 
Ann Intern Med. 2013;158(11):800-806. 
40. Abdul-Hadi O, Parvizi J, Austin MS, Viscusi ER, Einhorn TA. Nonsteroidal anti-
inflammatory drugs in orthopaedics. Instr Course Lect. 2010;59:607-617. 
  


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
42 
 
17. APPENDICES 
APPENDIX A: STUDY CONTACT ROSTER 
Principal Investigator (Protocol Chair) 
Robert V.O’Toole, MD 
Professor of Orthopaedic Trauma 
University of Maryland School of Medicine 
22 S Greene St 
Baltimore, MD 21201 
Phone: 410-328-2391 
E mail: ROtoole@umoa.umm.edu 
 
 
METRC Coordinating Center Study Principal 
Investigator 
Renan Castillo, PhD 
Associate Professor 
Johns Hopkins Bloomberg School of Public Health 
624 N Broadway, 5th Floor 
Baltimore, MD 21205 
Phone: 410-614-4025 
Email: rcastil1@jhu.edu 
 
 
 
 
Medical Monitor 
 
Marc Swiontkowski, MD  
Professor of Orthopaedic Surgery 
University of Minnesota  
2512 South 7th Street 
Suite R200 
Minneapolis, MN 55454 
Phone: (612) 273-8000 
Email: swion001@umn.edu 
 
 
METRC Coordinating Center  
 Clinical Research Manager 
Katherine Frey, RN, MPH 
Assistant Scientist 
Johns Hopkins Bloomberg School of Public Health415 
N Washington St, 3rd Floor 
Baltimore, MD 21205 
Phone: 410-502-9109 
Email: kparris1@jhu.edu 
 
METRC Coordinating Center Study Manager 
Tara Taylor, MPH 
Johns Hopkins Bloomberg School of Public Health415 
N Washington St, 3rd Floor 
Baltimore, MD 21205 
Phone: 410-614-6081 
Email: ttaylo56@jhu.edu 
 
METRC Coordinating Center  
Director of Data Management 
 
Anthony Carlini, MS 
Johns Hopkins Bloomberg School of Public Health 
Dept of Health Policy and Management 
624 N. Broadway Room 501 
Baltimore MD, 21205 
Phone: 410-502-8455 
Email: acarlini@jhsph.edu 
 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
43 
 
 APPENDIX B: DATA COLLECTION SCHEDULE 
Assessment 
Baseline 
Baseline 
– 3 
months 
3 month 
CRF00: Inclusion/Exclusion  
X 
 
 
CRF01: Patient Contact Information 
X 
 
 
CRF02: Patient Characteristics 
X 
 
 
Demographics  
• DOB 
• Age 
• Sex 
• Race 
• Height  
• Weight 
• Tobacco use 
• Health Insurance  
• Education 
 
 
 
CRF03: Medical History 
X 
 
 
• Medications taken Prior to Injury 
o OCP or Estrogen use 
o Antiplatelet agent 
o ASA daily use 
o Blood thinners 
o NSAIDs (daily use or prescription) 
• Co-morbidities  
o Charlson Comorbidity Index 
o History of VTE, peptic ulcer, DM 
o Cancer 
o Immunosuppression 
 
 
 
CRF04: Injury Characteristics 
X 
 
 
• Injury date/time 
• Circumstances  
• Type of Injuries (orthopaedic/non-orthopaedic) 
• Side of Injuries  
• AO/OTA Fracture classification  
• Gustilo Classification 
• Tscherne Classification of Soft Tissue Injuries 
• Injury Severity Score, TRISS, ICU days, ventilator 
days 
 
 
 
CRF05: Index Hospitalization 
X 
 
 
• Admission date/time 
 
 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
44 
 
Assessment 
Baseline 
Baseline 
– 3 
months 
3 month 
• Discharge date/time 
• Discharge outcome (discharged/death) 
• Admission labs (if tested) 
o INR 
o PTT 
o Platelets 
o Max serum lactate (first 24 hours) 
o Creatinine  
o TEG parameters (if ordered) 
• Surgical data 
o Surgery info (ortho/non-ortho surgeries)  
§ Dates 
§ Total number of surgeries  
§ Weight bearing status on discharge  
o Total number of surgeries (ortho/non-ortho) 
• Imaging studies (and results) conducted for 
bleeding or VTE  
o Angiogram 
o Ventilation perfusion (VQ) scan 
o Duplex scan/ultrasound 
o CT angiogram (CTA) 
o MRI 
o Other 
• Complications 
o fatal bleed 
o ≥2g/dL drop in hemoglobin 
o reoperation for hematoma evacuation 
o other clinical significant bleeding  
o infectious complication 
o VTE 
o PE 
• Concomitant meds 
o LMWH 
o Aspirin 
o Plavix 
o platelet inhibitors 
o NSAIDs 
o Anticoagulation medications outside 
treatment assignment 
CRF06: VTE Prophylaxis (Inpatient) 
X 
 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
45 
 
Assessment 
Baseline 
Baseline 
– 3 
months 
3 month 
• Pre & Post Randomization Prophylaxis Use 
• Treatment Arm: Aspirin Dosage (Dose, Dose Unit, 
Route, Date/Time of Start/Stop of Administration) 
• Treatment Arm: LMWH Dosage (Dose, Dose Unit, 
Route, Date/Time of Start/Stop of Administration) 
• Reasons prophylaxis held or discontinued (if 
applicable)  
• Doses ordered vs doses received or missed & 
reason missed 
• Treatment crossover information: number of doses 
& therapeutic anticoagulation therapy status (date, 
dose, reason) 
 
 
 
CRF07: Clinical Follow-up  
 
 
X 
• Documented prescribed prophylaxis and duration 
• Out of pocket costs 
• Satisfaction 
• Prescribed medications 
• Any other treatment for PE/VTE event  
• Re-hospitalizations related to PE/VTE event– 
review medical records 
• Imaging studies 
• Post discharge surgeries 
o Planned elective surgeries 
• Complications (type, severity, treatment)  
o Fatal bleed 
o GI bleed 
o ≥2g/dL drop in hemoglobin 
o reoperation for hematoma evacuation 
o other clinical significant bleeding  
o infectious complication 
o VTE 
o DVT (blood clot in arms/legs) 
o Pulmonary Embolism 
o Imaging studies for bleeding or VTE 
o Surgical wound infection 
o Surgical wound hematoma 
o Abnormal postoperative bleeding 
o Any complications secondary to treatment 
since hospitalization 
 
 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
46 
 
Assessment 
Baseline 
Baseline 
– 3 
months 
3 month 
CRF08: Patient Follow-up 
 
 
X 
• Hospitalizations r/t PE/VTE outside the study 
center 
• PSQ-18 Patient Satisfaction Questionnaire  
 
 
 
CRF09: Diagnosis of Infection 
X 
X 
X 
• CDC Criteria 
• Culture Data 
• Lab Data 
• Imaging Studies 
• Wound Characteristics  
• Time to Wound Closure 
• Type of Soft Tissue Coverage 
• Limb Complications (type, severity, treatment) 
 
 
 
CRF10: SAE 
X 
X 
X 
Unanticipated events possible related to exposure to study 
medications (angioedema, agranulocytosis, hepatic injury, 
Stevens Johnson syndrome), other events that are serious 
and either related or possibly related to the study, other 
events that are unexpected and serous and either related or 
possibly related to the study beyond the expected 
complications.  
 
 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
47 
 
ATTACHMENT C: CONSENT FORM 
JOHNS HOPKINS BLOOMBERG SCHOOL OF PUBLIC HEALTH 
INFORMED CONSENT DOCUMENT 
Patient Consent Form 
Study Title: PREVENTion of Clot in Orthopaedic Trauma (PREVENT CLOT): A 
Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot 
Prevention Medicines Used in Orthopaedic Trauma Patients 
 
Principal Investigator: Robert O’Toole, MD (Clinical PI) and Renan Castillo, PhD 
(Research PI) 
IRB No.:  
PI Version Date: Version 1; 03/06/17 
 
You are being asked to volunteer to be a part of a research study. Please read this form carefully 
before you sign it. This consent form explains the research study and your part in the study. If 
you decide not to participate in this study there will be no impact on your medical care. You can 
choose not to take part and if you join, you may quit at any time. Ask the study doctor or the 
study staff to explain any words or procedures that you do not clearly understand. Ask as many 
questions as needed. All of your questions should be answered to your satisfaction before you 
sign this form.  
1. WHAT IS THE PURPOSE OF THIS RESEARCH STUDY? 
The purpose of this research study is to help determine the best treatment for preventing blood 
clots that are formed following trauma like yours that could potentially lead to death. At the 
moment researchers do not know if using medications called low molecular weight heparin or 
aspirin is better in preventing life threatening blot clots in trauma patients. In this study, we are 
trying to answer this question. Usually either low molecular weight heparin is given by 
subcutaneous (under the skin) injections (liquid) medicine or aspirin (pill) medicine is given by 
mouth while in the hospital and after you go home to prevent blood clots. There has not been a 
study to compare these two types of medicines for preventing blood clots in trauma patients and 
order to find out which medicine is best this study will compare these two forms of treatment. 
The PREVENT CLOT Study is funded by the Patient-Centered Outcomes Research Institute 
(PCORI) and is being carried out in more than 20 major trauma centers across the United States 
and Canada, including military centers that are taking care of service members who were injured 
in the line of duty.  


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
48 
 
2. WHY AM I BEING ASKED TO PARTICIPATE? 
You are being asked to join this study because you are at least 18 years old and have experienced 
a traumatic orthopaedic injury(ies) which puts you at increased risk of blood clots and also you 
are currently being treated with blood clot prevention medicine. People like you who are being 
treated at major trauma centers from around the county are being asked to participate. You are 
one of over 12,000 patients expected to join the PREVENT CLOT study. 
3. HOW LONG WILL THE STUDY LAST? 
If you agree to participate in this study, you will be followed for up to three months after 
admission to the hospital for your traumatic injury.   
4. HOW DOES THE STUDY WORK? 
If you agree to participate in the PREVENT CLOT Study you will be assigned by chance (like 
flipping a coin) to one of the two treatments being studied: 
• Treatment A: Low molecular weight heparin (Lovenox/Enoxaparin) medicine given two 
times a day subcutaneously (under the skin) by injections. 
• Treatment B: Aspirin medicine given two times a day in pill form by mouth. 
You have an equal chance of getting any of the treatments.  We are using this method for 
deciding which treatment you will get because it is not clear at the present time which treatment 
is better at preventing blood clots for you and for people like you with similar injuries. 
You will begin receiving medicine immediately after you are enrolled. When you are discharged 
from the hospital you will continue taking the medicine you were assigned for the same period of 
time as if you were not in the study. Your doctors will prescribe the correct length of time for 
you to take this medicine based on the types of injuries you have and any other medical 
conditions you may have. Some people do not take any more medicine when they leave the 
hospital, and others can take the medicine for several months.  
A group of randomly selected participants will be contacted and asked to report on how many 
times they take their medication daily at home. If you are one of the selected individuals you will 
receive a phone call or email from the research team and will be asked a few questions on how 
many medicine doses you have taken so far.  
When you come back for normal clinical follow up visit to see your surgeon at 3 months after 
your hospital admission you will be asked to complete a 15-30 minute interview where you will 
be asked questions about how your recovery is going and your overall satisfaction with your 
care. If you are not able to come back, we may contact you by telephone or email to do these 
interviews. 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
49 
 
5. WHAT ARE THE POTENTIAL RISKS OR DISCOMFORTS? 
There are some risks related to taking either medication in this study. If you experience any of 
the risks listed below please immediately proceed to the nearest emergency room and let then let 
the study team know as soon as possible: signs of bleeding (vomiting blood or vomit that looks 
like coffee grounds; coughing up blood; blood in the urine, black, red or tarry stools, bleeding 
from the gums, abnormal vaginal bleeding; bruising without a reason or that get bigger; or any 
severe or persistent bleeding), severe dizziness, fainting, fall or head injury, confusion, severe 
headache, burning or numbness feeling or loss of strength. Signs of significant allergic reaction – 
wheezing, chest tightness, fever, itching, tight cough; change in skin color; seizures or swelling 
of face, lips, tongue or throat. The risks of taking either medication are as follows: 
• Treatment A (Low molecular weight heparin (enoxaparin)): nausea; diarrhea, injection 
site irritation, bruising, pain or possible infection; allergic reaction ranging from hives 
and itching to difficulty breathing or throat swelling; Heparin Induced Thrombocytopenia 
which results in a reduced number of platelets and impaired ability to form clots; 
bleeding complications which could require transfusion or operation and kidney damage.  
• Treatment B (Aspirin): Risk of inflammation or ulceration of the stomach, allergic 
reaction (ranging from hives and itching to difficulty breathing or throat swelling), 
ringing of the ears, and worsening asthma. Increased risk of bleeding and of kidney 
damage. Potential risk of risk of Reyes syndrome in younger partitipants during influenza 
season. Symptom of Reyes syndrome include: fever, lack of energy or interest in things, 
sleepiness, changes in personality, vomiting or diarrhea. 
6. WHAT ARE THE POTENTIAL BENEFITS? 
You will not benefit directly from your participation in this study. Your participation in the study 
could help us determine the best treatment to prevent life threating blot clots resulting from 
injuries like yours. This information could be very helpful to other people who have this same 
injury in the future.  
7. DO I GET ANY PAYMENT FOR BEING IN THE STUDY? 
You will receive an honorarium in recognition of your time and effort. $20 will be given to you 
for completing the 3 month visit in appreciation for your time and effort. If you complete follow-
up activities by phone or email will also be given $20 for competing the interview.  
8. ARE THERE ANY COSTS INVOLVED IN BEING IN THE STUDY? 
There are no additional costs for taking part in this research study above the reasonable and 
customary costs of caring for patients with injuries like yours who are not in the study.    
9. WILL MY INFORMATION BE KEPT PRIVATE? 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
50 
 
The information we collect from you will be kept private to the best of our ability. Your name, 
birth date, medical record number and any other information that could identify you as an 
individual will be removed from all study forms. Instead, we will label your forms with a unique 
study number. The link between your name and your study number will be kept confidential to 
the greatest extent provided by law. The information collected for the study will be stored in a 
password protected, HIPAA compliant computer database that only authorized members of our 
research team can use. When we report the results of the study, we will combine the information 
about you with similar information about hundreds of other people so your individual 
information will not be identifiable.  
All study records will be considered confidential, and your name will not be used in reports or 
publications.  
10. WILL YOU SHARE MY INFORMATION WITH OTHERS? 
We will use your information only for the purposes of this study. The data from the study may be 
published. However, you will not be identified by name. People designated from the institutions 
where the study is being conducted will be allowed to inspect sections of your medical and 
research records related to the study. This includes people designated by The Johns Hopkins 
Bloomberg School of Public Health who are overseeing this study. Everyone using study 
information will work to keep your personal information confidential. Your personal information 
will not be given out unless required by law. 
 
The Patient-Centered Outcomes Research Institute (PCORI) is providing funding to sponsor this 
study. PCORI representatives and your local IRB may have access to research records in their 
role to protect human subjects engaged in research.  
  
11. WHAT ARE MY ALTERNATIVES TO PARTICIPATION? 
Your alternative is to not take part. If you choose not to take part, your healthcare will not be 
affected. 
12. WHAT HAPPENS IF I LEAVE THE STUDY EARLY? 
Your participation in this study is completely voluntary. You have the right to withdraw from the 
research study at any time without penalty. Your decision will not affect the medical care you 
receive. If you decide to stop participating, you should notify the study doctor or the research 
coordinator at your center.  
Your participation in this research study could be ended without your consent. Possible reasons 
could include our decision to end the study early or other reasons.  


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
51 
 
13. WHAT HAPPENS IF I AM INJURED OR BECOME ILL BECAUSE I TOOK PART 
IN THIS STUDY? 
If you are injured or become ill because of your participation in this study, you will receive 
emergency medical care if needed and you will receive assistance in getting other medical care 
as needed. You or your insurance carrier will be billed for the cost of care, just as you would be 
billed for any other medical care. If you have any costs that are not covered by insurance, they 
are your responsibility.  
You do not give up any of your legal rights by signing this form. You can seek legal 
compensation for any injury that may occur to you during the study as a result of an error by a 
member of the research staff or others.  
14. WHO DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
• <<insert name>>, the study coordinator at your hospital has discussed this information 
with you and offered to answer any questions you may have. If you have further 
questions or get sick or injured as a result of being in this study, you can contact << insert 
him/her>> at <<telephone number>>. You may also call the Director of the Study at your 
hospital, <<insert name>>, at <<telephone number>>.  
• If you have further questions about your rights as a study participant you can call or 
contact the Johns Hopkins Bloomberg School of Public Health IRB Office. The Johns 
Hopkins Bloomberg School of Public Health is serving as the overall coordinating center 
for this study that is being conducted in hospitals around the country. Contact the Johns 
Hopkins IRB if you feel you have not been treated fairly or if you have other concerns. 
The IRB contact information is:  
 
Address: 
Johns Hopkins Bloomberg School of Public Health 
 
 
 
615 N. Wolfe Street, Suite E1100 
 
 
 
Baltimore, MD 21205 
 
Telephone: 
410-955-3193 
 
 Toll Free: 
1-888-262-3242 
 
   Fax: 410-502-0584 
 
  E-mail: 
irboffice@jhsph.edu 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 1.0 03/06/17 
 
52 
 
What does your signature (or thumbprint/mark) on this consent form mean? 
Your signature (or thumbprint/mark) on this form means: 
• You have been informed about this study’s purpose, procedures, possible benefits and 
risks. 
• You have been given the chance to ask questions before you sign. 
• You have voluntarily agreed to be in this study.  
________________________ _____________________________ __________ 
Print name of Adult Participant    Signature of Adult Participant       Date               
        
________________________ _____________________________ __________ 
Print name of Legally Authorized   Signature of LAR            Date                
Representative (LAR) 
 
___________________________________________________________________ 
Relationship of LAR to Participant  
 
Ask the participant to mark a “left thumb impression” in this box if the participant (or 
participant’s parent) is unable to provide a signature above.  
 
________________________ _____________________________ __________ 
Print name of Person Obtaining   Signature of Person Obtaining Consent   Date   
Consent              
Give one copy to the participant and keep one copy in study records 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 1 
 
 Major Extremity Trauma Research Consortium (METRC): 
PREVENTion of Clot in Orthopaedic Trauma (PREVENT CLOT): A Randomized 
Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention 
Medicines Used in Orthopaedic Trauma Patients 
 
Sponsored by: PCORI 
 
Contract Number: 
PCS-1511-32745 
 
 
IND#        
IDE# N/A 
 
Principal Investigators/Protocol Chairs:  
Robert O’Toole, MD 
Renan Castillo, PhD 
Deborah Stein, MD 
 
Medical Monitor: Gregory Vercellotti, MD 
 
Version # 11.0 
 
DATE: 6/1/2021 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 2 
 
 
 
 
 
This template is adapted from the ICH guidance document E6 (Good Clinical Practices), 
Section 6. 
 
 
 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, 
potential investigators, consultants, study staff, and applicable independent ethics 
committees or institutional review boards. The contents of this document shall not be 
disclosed to others without written authorization from METRC (or others, as applicable), 
unless it is necessary to obtain informed consent from potential study participants. 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 3 
 
Table of Contents 
Contents 
Table of Contents .......................................................................................................................... 3 
List of General Abbreviations/Terminology .............................................................................. 6 
PROTOCOL SUMMARY ........................................................................................................... 7 
1. KEY ROLES ........................................................................................................................... 10 
2. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ........................... 11 
2.1 Background Information ..................................................................................................... 11 
2.2 Rationale ................................................................................................................................ 12 
2.3 Potential Risks and Benefits ................................................................................................. 13 
3. STUDY OBJECTIVES & OUTCOMES .............................................................................. 14 
3.1 Primary Objective: ............................................................................................................... 14 
3.2 Secondary Objectives: .......................................................................................................... 14 
3.3 Study Outcomes .................................................................................................................... 14 
4. STUDY OVERVIEW ............................................................................................................. 17 
5. STUDY POPULATION ......................................................................................................... 17 
5.1 Description of the Study Population ................................................................................... 17 
6. STUDY PROCEDURES ........................................................................................................ 19 
6.1 Screening and Enrollment .................................................................................................... 19 
6.2 Baseline Data Collection ....................................................................................................... 22 
6.3 Participant Follow up and Data Collection ........................................................................ 23 
7. STUDY TREATMENTS ........................................................................................................ 27 
7.1 Study Treatments .................................................................................................................. 27 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 4 
 
7.2 Assessment of Participant Adherence with Study Agent(s)/Intervention(s) ................... 29 
7.3 Precautionary and Prohibited Medications and Procedures ............................................ 29 
7.4 Rescue Medications ............................................................................................................... 30 
8. ASSESSMENT OF SAFETY ................................................................................................. 30 
8.1 Definitions .............................................................................................................................. 30 
8.2 Methods and Timing for Assessing, Recording, and Analyzing, Managing Safety 
Parameters ................................................................................................................................... 31 
8.3 Adverse Event Reporting Procedures ................................................................................. 33 
8.4 Reporting Pregnancy (Replace text with “N/A” if not applicable) .................................. 34 
8.5 Type and Duration of the Follow-up of Participants After Adverse Events ................... 34 
8.6 Stopping Rules ....................................................................................................................... 34 
8.7 Premature Withdrawal of a Participant ............................................................................. 35 
8.8 Replacement of a Participant Who Discontinues Study Treatment ................................ 35 
9. MONITORING ....................................................................................................................... 35 
9.1 Site Monitoring Plan ............................................................................................................. 35 
9.2 Safety Monitoring Plan ......................................................................................................... 35 
10. STATISTICAL CONSIDERATIONS ................................................................................ 36 
10.1 Sample Size .......................................................................................................................... 36 
10.2 Randomization .................................................................................................................... 37 
10.3 Missing Data and Measures to Minimize Bias ................................................................. 37 
10.4 Planned Interim Analysis ................................................................................................... 38 
10.5 Analysis Plan ....................................................................................................................... 38 
11. QUALITY CONTROL AND QUALITY ASSURANCE .................................................. 39 
11.1 Data Quality Assurance ...................................................................................................... 39 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 5 
 
11.2 Training and Certification of Centers ............................................................................... 39 
12. ETHICS/PROTECTION OF HUMAN SUBJECTS ......................................................... 40 
12.1 IRB/Ethics Committee ........................................................................................................ 40 
12.2 Exclusion of Women, Minorities, and Children (Special Populations) ......................... 40 
12.3 Participant Confidentiality ................................................................................................ 40 
12.4 Study Discontinuation ........................................................................................................ 41 
13. DATA HANDLING AND RECORD KEEPING ............................................................... 41 
13.1 Data Management Responsibilities ................................................................................... 41 
13.2 Data Capture Methods ....................................................................................................... 42 
13.3 Types of Data ....................................................................................................................... 42 
13.4 Source Documents and Access to Source Data/Documents ............................................ 42 
13.5 Study Records Retention .................................................................................................... 42 
13.6 Protocol Deviations ............................................................................................................. 42 
14. PUBLICATIONS POLICY ................................................................................................. 42 
15. SCIENTIFIC REFERENCES ............................................................................................. 43 
17. APPENDICES ....................................................................................................................... 50 
APPENDIX A: STUDY CONTACT ROSTER ........................................................................ 50 
APPENDIX B: DATA COLLECTION SCHEDULE ............................................................. 51 
ATTACHMENT C: DRAFT CONSENT FORM ......................... Error! Bookmark not defined. 
 
 
 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 6 
 
List of General Abbreviations/Terminology 
 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DSMB 
Data and Safety Monitoring Board 
DVT 
Deep Venous Thrombosis 
FDA 
Food and Drug Administration 
FWA 
Federal-Wide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
LMWH 
Low Molecular Weight Heparin 
MedDRA © 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
OHRP 
Office for Human Research Protections 
PE 
Pulmonary Embolism 
PHI 
Protected Health Information 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAB 
Stakeholder Advisory Board 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
VTE 
Venous thromboembolism 
 
  
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 7 
 
PROTOCOL SUMMARY  
Title: Prevention of Clots in Orthopaedic Trauma (PREVENT CLOT): A Randomized 
Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines 
Used in Orthopaedic Trauma Patients 
Sponsor: Patient Centered Outcomes Research Institute (PCORI) 
Type of study: Randomized Pragmatic Trial 
Objective: To compare aspirin versus low-molecular weight heparin (LMWH) (Enoxaparin) as 
a thromboprophylaxis in patients who sustain a fracture.  
We aim to make the following comparisons between aspirin and the LMWH: 
Specific Aim 1: Compare the proportion of patients who die after orthopaedic trauma treated 
with LMWH compared to those treated with aspirin. (Hypothesis 1: Aspirin will be non-
inferior to LMWH.) 
Specific Aim 2: Compare the proportion of patients who sustain non-fatal PE or deep vein 
thrombosis (DVT) after orthopaedic trauma treated with LMWH compared to those treated 
with aspirin. (Hypothesis 2: Aspirin will be non-inferior to LMWH.) 
Specific Aim 3: Compare the proportion of patients who sustain a bleeding event, a wound 
complication, or deep surgical site infection (SSI) after orthopaedic trauma patients treated 
with LMWH compared to those treated with aspirin. (Hypothesis 3: The rate of 
complications will be superior (i.e., lower) in the aspirin group compared to LMWH.) 
We will pursue the following secondary aims: 
Secondary Aim #1: Assess satisfaction with care in orthopaedic trauma patients treated with 
injectable LMWH compared to those treated with aspirin. (Hypothesis 4: Satisfaction will be 
superior in the aspirin group.) 
Secondary Aim #2: Estimate out of pocket patient costs in orthopaedic trauma patients 
treated with injectable LMWH compared to those treated with aspirin. (Hypothesis 5: Out of 
pocket costs will be lower in the aspirin group.) 
 
Study duration: 5 years: 1 year of planning, 3.5 years of recruitment and follow-up, 0.5 years of 
analysis and dissemination of study results 
Sample size: 12,200 (6,100 per arm (2) arms) 
Number of study sites: up to 30 
Study population: Orthopaedic trauma patients, ages 18 and over 
Inclusion criteria:  


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 8 
 
1. Does the patient have a planned operative or non-operative pelvis or acetabular fracture, or 
any operative extremity fracture proximal to the metatarsals/carpals? 
2. Is the patient at increased risk of blood clot(s) from their orthopaedic injury(ies) and will 
receive a prophylactic blood thinner regimen per standard of care? 
3. Is the patient 18 years or older? 
 
Exclusion criteria:  
1. Did the patient present to the hospital more than 48 hours post injury?  
2. Has the patient received more than 2 doses of LMWH or Aspirin for initial prophylaxis? 
3. Is the patient on long term blood thinners (other than low-dose aspirin or platelet inhibitors 
such as Plavix or Aggrenox)? 
4. Did the patient have a VTE within the last 6 months? 
5. Is the patient on therapeutic (as opposed to prophylactic) blood thinners for an acute issue at 
the time of admission? 
6. Does the patient have a newly diagnosed indication for therapeutic blood thinners (for 
example vascular injury) that will require therapeutic anticoagulation for more than one 
week?  
7. Does the patient have an allergy to aspirin, or NSAIDs, or a history of heparin induced 
thrombocytopenia, or other medical contraindication to blood thinners (e.g. peptic ulceration, 
gastrointestinal bleeding, etc.)?  
8. Is the patient on higher dose aspirin (>81 mg once a day or higher) for medical reasons or 
will be treated with higher dose aspirin? 
9. Does the patient have underlying chronic clotting disorders (i.e. Factor V Leiden, 
hemophilia, Protein C and S deficiency) that require full dose anticoagulation or are a 
contraindication to VTE chemoprophylaxis? 
10. Does the patient have end stage renal disease, or impaired creatinine clearance <30 ml/min at 
time of randomization? 
11. Is the patient pregnant or lactating? 
12. Does the patient speak neither English nor Spanish? 
13. Is the patient a prisoner? 
14. Is the patient likely to have severe problems maintaining follow-up? 
15. Is the patient, based upon the clinical judgment of the treating clinician, NOT equally suited 
for treatment with either Aspirin or Lovenox? 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 9 
 
16. Should the patient be excluded for other reasons at the discretion of the treating physician? 
17. Does the patient have a known COVID-19 diagnosis prior to fracture treatment or within 3 
months of the index fracture? 
 
Outcome measures: All-cause mortality, cause-specific mortality, non-fatal pulmonary 
embolism, deep vein thrombosis, bleeding event, wound complication, deep surgical site 
infection, satisfaction, out of pocket patient costs 
Statistical analysis: Non-inferiority intention to treat analysis for study primary aim. 
Randomization: Block randomization at the center level. 
Safety monitoring: The Medical Monitor is responsible for monitoring serious adverse events 
(SAEs) as the study progresses to ensure patient safety. The DSMB will review all safety data at 
its scheduled meetings. The Medical Monitor may convene a meeting of the DSMB to evaluate 
any SAEs that he/she determines require immediate attention. 
Data Safety and Monitoring Board (DSMB): The DSMB is an independent body responsible 
for evaluating recruitment, safety and outcome data. The DSMB has the authority to stop the 
study based on its findings.  


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 10 
 
1. KEY ROLES  
Protocol Committee- Responsible for developing a detailed study protocol, provides oversight on 
study progress and acts to correct deficiencies in the conduct of the study. This committee also 
drafts the main publications related to the study. 
Steering Committee- The Science Committee of the METRC Consortium will review the 
composition of the protocol committee and provide scientific review of the study protocol, with 
the purpose of presenting the protocol to the Consortium Steering Committee for approval. 
Additionally, the study will have a Steering Committee comprised of the study investigators, an 
orthopaedic and general surgery investigator from each participating center, 2-3 experts on clot 
prevention, and the patient and consumer stakeholders who comprise our Stakeholder Advisory 
Committee. 
METRC Coordinating Center- Responsible for maintaining all study documentation, developing 
and maintaining the master IRB application and consent, circulating any changes to study 
documents including protocols, case report forms, and IRB materials to each participating center, 
providing daily oversight and management of study implementation, providing payment to sites 
for patients enrolled, performing site monitoring, data quality control and analysis of study 
results.  
Clinical Sites- Responsible for the conduct of clinical studies including patient enrollment, 
performing study procedures, data collection and conducting study follow-up visits.  
Clinical Outcome Adjudication Committee (COAC)- This committee will be responsible for 
developing the timely medical review and adjudication of trial-specific endpoints utilizing trial-
specific definitions; engages other reviewers as needed and in accordance with the COAC 
Policy; and reports adjudication results to the trial-specific Protocol Committee. 
Publication Committee- Responsible for reviewing manuscripts prior to journal submission and 
reviewing presentations prior to presentation; for mediating and settling disputes and conflicts 
among study investigators over publication or presentation priorities, authorship, and any other 
issues related to publications or presentations; for preparing and maintaining a list of concepts 
for publications and preparing and maintaining a list of approved METRC publications, which 
shows the status of each manuscript from initiation through publication. 
DSMB- Independent Data and Safety Monitoring Board (DSMB) convened for this project, 
responsible for monitoring the accumulated interim data as the trial progresses to ensure patient 
safety and to review efficacy, evaluate recruitment, and assess overall data quality.  
Medical Monitor- Responsible for providing medical guidance and overseeing patient safety for 
the study. The MM participates in determining the course of action necessary to meet safety 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 11 
 
goals and objectives. This is achieved through the review of safety reports; resolving safety 
issues; and interacting with Principal Investigators.  
2. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
2.1 Background Information 
Importance of Blood Clots and Blood Clot Prevention Medicines. Preventing venous 
thromboembolism (VTE) in the legs or lungs is a major unsolved problem in modern medicine. 
Each year, in the United States alone, blood clots are estimated to affect 300,000 – 600,000 
patients.1 These events may have important consequences for patients. VTE can include both 
deep venous thrombosis (DVT) and pulmonary embolism (PE). Even minor blood clots require a 
minimum of 6 months of medication, often with frequent blood tests, and increased risk of 
medication-related bleeding. At the most severe end, PEs are thought to account for 60,000–
100,000 deaths per year in the United States.2 
Patients who sustain trauma are well known to be at an increased risk for blood clots throughout 
their body, including fatal PE’s.3 There are 6 million fractures treated each year in the United 
States alone and 2.3 million patients are admitted each year after trauma.4-6 Hip and femur 
fractures specifically are among the most common fractures and are associated with a 
particularly high risk of blood clots.7,8 Current guidelines indicate that most orthopaedic trauma 
patients should be given medication to reduce the risk of blood clots.9,10 Despite the common 
nature of these injuries and the potential devastating impact that blood clots can have on patients’ 
lives, we currently do not know the best prophylactic regimen for these patients. 
The ideal clot prevention medication for orthopaedic trauma patients would prevent death from 
PE and other consequences of blood clots while also limiting complications from the medication, 
such as bleeding from surgical wounds and other sources.11 A blood clot resulting in death is 
obviously a devastating outcome for a patient and their family; however, other complications 
from clot prevention medications are not insignificant and may require surgery and have a major 
impact on the lives of patients, including, permanent disability in some cases.12,13 Even under 
ideal conditions the medications used to reduce clots cannot completely eliminate the chance of 
blood clots and in some instances may lead to death themselves.12-14  
Low molecular weight heparins (LMWH) are medications that have been utilized to lower the 
rates of proximal deep venous thrombosis in trauma patients since the 1990’s and are currently 
the preferred agents across many guidelines, including those from the American College of Chest 
Physicians and the Eastern Association for the Surgery of Trauma.9,10 The case for the use of 
LMWH in this trial is relatively straight forward as it is the current treatment recommended by 
these guidelines and is commonly used in most north American trauma centers.  While these 
guidelines are well intentioned, they are based on limited evidence regarding fracture patients, 
and do not incorporate patient preferences. There is good evidence that LMWH’s are effective at 
limiting DVT, particularly asymptomatic DVT found on screening studies as a part of a research 
protocol.3,15,16  However feedback from patients indicates that they are more concerned with PE’s 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 12 
 
that might cause death or clot prevention medication-related complications that require surgical 
treatment, rather than blood clots in the leg that are often asymptomatic or of minimal clinical 
consequence. This was confirmed by our own pilot research (conducted under a separate IRB). 
We interviewed 232 orthopaedic trauma patients and found that patients value the prevention of 
death and avoidance of surgical complications much more than other issues related to clot 
prevention medications.17 
Despite the widespread use of LMWH to reduce PE after orthopaedic trauma, a recent Cochrane 
review actually showed limited evidence that LMWH affects the rate of PE or mortality in 
trauma patients,3 and there is concern that there is potential for higher rates of bleeding into 
critical organs and surgical wounds associated with LMWH compared to other clot prevention 
medications in non-trauma related orthopaedic surgery.18-20 This has led many to wonder if there 
is another alternative to clot prevention than LMWH for trauma patients. 
Aspirin is another commonly used clot prevention medication, which may have a similar efficacy 
at preventing both PE and death in lower extremity injuries.21 For both hip fracture and lower 
extremity arthroplasty surgery, substantial reductions in surgical wound hematomas have been 
noted with aspirin.22 In addition, after lower extremity arthroplasty, LMWH has been associated 
with higher all-cause mortality as compared to the use of aspirin.12 Although there are certainly 
strong advocates for the use of aspirin in orthopaedic trauma patients and some solid studies in 
arthroplasty supporting its use,21,23-25 the efficacy of ASA has not been characterized relative to 
LMWH in this population yet. 
 
No Data for Guidelines: A recent study on this topic by the Orthopaedic Trauma Association 
Evidence Based Quality Value and Safety Committee highlighted a knowledge gap surrounding 
clot prevention in orthopaedic trauma patients and concluded that there is “wide variability in 
practice patterns, poor scientific support for various therapeutic regimens” and guidelines are 
needed to “improve patient care.”26 As demonstrated by this study, there is a clear need for 
guidelines on clot prevention in trauma patients,26 but there are no large high quality trials upon 
which to base these guidelines, as described by the Cochrane review on this topic.3 Most of the 
existing guidelines make recommendations that are based on either arthroplasty patients (who are 
a poor surrogate for trauma patients), or an older subset of hip fracture patients, limiting the 
applicability to the vast majority of patients who fundamentally differ from either of these 
groups. Unfortunately, this knowledge gap leaves clinicians and patients to make decisions about 
which VTE prophylaxis to use in this large patient population without adequate data to guide 
them.  
2.2 Rationale 
The best medication to reduce the risk of fatal PE for orthopaedic trauma patients who are 
admitted to a hospital after trauma each year in the United States is still unknown, creating 
decisional uncertainty for both patients and clinicians.26 Recent meta-analysis on medications to 
prevent blood clots after major lower extremity surgery included no studies involving high 
energy trauma and only two small studies on hip fractures, concluding that “the rarity of 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 13 
 
pulmonary embolism made meaningful comparisons between aspirin and anticoagulation 
impossible …”22 The rarity of PE requires a large trial to answer this question and none exist to 
date. Similarly, a recent Cochrane review on this topic in trauma patients did not address the use 
of aspirin for clot prevention presumably due to a complete lack of data on the topic.3 
There is little data on how commonly used medications like LMWH perform in trauma patients 
relative to enteral aspirin, likely because of the large patient sample size needed to address this 
issue. Moreover, the currently limited research in this topic has focused more on clinically 
insignificant DVTs, and have not been powered to address the outcomes most important to 
patients and clinicians, including bleeding complications and fatal PE.3,22 
In addition to the lack of guidelines to support clinical decision making, there is a lack of 
evidence on how the choice of chemoprophylaxis following orthopaedic trauma affects patient 
satisfaction. Factors that are important to patients such as the need for the medicine to be injected 
or the out of pocket costs have been almost totally ignored to date.3,22,26,27  
To address these critical gaps in the evidence we have designed a large, pragmatic, multicenter 
randomized clinical trial. This trial will provide definitive evidence for decision makers on 
whether aspirin is as effective as LMWH at preventing death and symptomatic PE, while 
potentially resulting in significantly fewer medication associated complications. The study fills 
several large and critical knowledge gaps of great interest to patients and clinicians and has great 
potential to improve the quality of evidence available for patients and other stakeholders to make 
informed decisions. 
 
2.3 Potential Risks and Benefits 
2.3.1 Potential Risks The risks associated with participation in this study are primarily the risks 
that are associated with each of the study drugs.  
Patients randomized to the LMWH arm would have no drug-related risk over and above the risk 
they would experience as standard of care. These risks include bruising or infection at the site of 
injection and allergic reaction, ranging from hives and itching to difficulty breathing or throat 
swelling. Some participants may experience Heparin Induced Thrombocytopenia, which results 
in a reduced number of platelets and hypercoagulability. Risks associated with the LMWH arm 
also include bleeding complications, which could require transfusion or operation, and kidney 
damage.  
Patients randomized to the aspirin arm would have no drug-related risk over and above the risk 
they would experience as using aspirin for blood clot prevention. These risks include the 
potential to experience the risks associated with aspirin, including possible risk of inflammation 
or ulceration of the stomach, allergic reaction (ranging from hives and itching to difficulty 
breathing or throat swelling), ringing of the ears, and worsening asthma. Additionally, some 
patients have increased risk of bleeding and of kidney damage.  


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 14 
 
There is potential that patients in the aspirin arm will be at lower or higher risk relative to the 
patients in the LMWH arm just as there is a risk for patients in the LMWH arm to have better or 
worse outcomes than those in the aspirin arm. The trial is designed to assess this potential 
difference in risk.  
A DSMB for the study will closely monitor event reporting, and should differential risks or 
benefits be identified, will consider stopping the study. 
In this study, as with many others, there is a potential risk of breach of confidentiality, although 
the study team will make all reasonable efforts to mitigate this risk. 
 
2.3.2 Potential Benefits It is not clear that one drug treatment will provide any benefit over 
another. Patient participants will receive $20 as compensation for time and effort returning for 
the 3-month study visit.  
 
3. STUDY OBJECTIVES & OUTCOMES 
3.1 Primary Objective:  
We aim to make the following comparisons between aspirin and the LMWH: 
Specific Aim 1: Compare the proportion of patients who die after orthopaedic trauma treated 
with LMWH compared to those treated with aspirin. (Hypothesis 1: Aspirin will be non-
inferior to LMWH.) 
Specific Aim 2: Compare the proportion of patients who sustain non-fatal PE or deep vein 
thrombosis (DVT) after orthopaedic trauma treated with LMWH compared to those treated 
with aspirin. (Hypothesis 2: Aspirin will be non-inferior to LMWH.) 
Specific Aim 3: Compare the proportion of patients who sustain a bleeding event, a wound 
complication, or deep surgical site infection (SSI) after orthopaedic trauma patients treated 
with LMWH compared to those treated with aspirin. (Hypothesis 3: The rate of 
complications will be superior (i.e., lower) in the aspirin group compared to LMWH.) 
3.2 Secondary Objectives:  
We will pursue the following secondary aims: 
Secondary Aim #1: Assess satisfaction with care in orthopaedic trauma patients treated with 
injectable LMWH compared to those treated with aspirin. (Hypothesis 4: Satisfaction will be 
superior in the aspirin group.) 
Secondary Aim #2: Estimate out of pocket patient costs in orthopaedic trauma patients 
treated with injectable LMWH compared to those treated with aspirin. (Hypothesis 5: Out of 
pocket costs will be lower in the aspirin group.) 
3.3 Study Outcomes 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 15 
 
To meet study objectives, the following clinical outcomes will be assessed: 
 
3.3.1 Primary Outcome  
All-Cause Mortality 
The primary outcome for this study is all-cause mortality by 90 days post-randomization. The 
primary study outcome was changed from PE-related death to all-cause mortality during the 
course of the trial. At the recommendation of an external peer reviewer for the protocol 
manuscript, the trial’s steering committee determined that it was unfeasible to adjudicate death 
due to pulmonary embolism (PE) with reasonable certainty. Misclassification of the primary 
outcome of PE-related death would bias the results to non-inferiority. As such, the trial’s steering 
committee decided to change the primary outcome from PE-related death to all-cause mortality. 
All-cause mortality was viewed as more important than PE-related death by our patient 
stakeholder and protocol committees and had greater scientific reliability. The DSMB was not 
involved in these decisions due to their knowledge of treatment effect from interim analyses. The 
decision of the trial’s steering committee to change the primary outcome and non-inferiority 
margin was supported by the protocol committee, patient stakeholder committee, and sponsor.  
 
3.3.2 Secondary Efficacy Outcomes  
Cause-Specific Death 
Cause-specific death will remain as a secondary outcome. Cause of death will be recorded in 
addition to an assignment of certainty of the attribution. The study’s 3-person Clinical Outcome 
Adjudication Committee (COAC) is composed of experts not otherwise involved in any other 
aspect of the study. The committee is blinded to treatment arm and receives these data with the 
goal of classifying the death into 1 of 5 categories: a) Certainly PE (e.g., an autopsy or operative 
note indicates cause of death), b) More likely to be caused by PE than something else (e.g., 
clinical information available indicating likely cause of death, but no autopsy or corroborating 
data available), c) Equally likely to be caused by PE or something else (e.g., patient did not die in 
a clinical setting, and only data available to support assignment of causality is based on the 
report on non-clinical family or friends), d) More likely to be a cause other than PE (e.g., the 
clinical course was highly suggestive that the cause of death was not PE), and e) Certainly not 
due to PE (e.g., the cause of death was not related to a PE). There must be agreement among at 
least 2 of the 3 committee members, with no more than 1 level of disagreement among members, 
for the cause of death category determination to be finalized.  We will report cause-specific death 
as: i) category a or b; ii) category a, b, or c; iii) category d or e. 
 
Non-Fatal Pulmonary Embolism 
Non-fatal PE is a key secondary outcome. The local site investigators categorize PE events, 
which are adjudicated centrally as one of four levels: Massive and submassive PE events are 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 16 
 
defined based on the American Heart Association recommendations24; Other clinically 
significant PE events are determined when a diagnostic test was performed due to symptoms or 
signs concerning for PE, but the symptoms or signs do not meet the massive or submassive 
criteria; Other clinically insignificant PE events include PEs found incidentally, or as part of a 
test performed for screening, or for another reason that does not meet the definition of “clinically 
significant.” Additionally, PE events are sub-classified as being segmental or non-segmental. 
Similar to the adjudication of the cause of death, the categorization of PE requires two-thirds 
consensus from the COAC. We report non-fatal PE as: i) any level; ii) sub-classified as massive, 
sub-massive, clinically significant, clinically non-significant; and iii) sub-classified as segmental, 
non-segmental. 
 
Deep Vein Thrombosis (DVT) 
DVT can be either symptomatic or asymptomatic and require a confirmed imaging diagnosis. 
We will report all confirmed symptomatic DVT events, and subclassified by proximal DVT and 
distal DVT.  
 
3.3.3 Secondary Safety Outcomes  
Bleeding Complications 
Bleeding complications are a composite endpoint previously defined in the literature that 
includes, 1) symptomatic bleeding into a critical area or organ, 2) bleeding causing a drop in 
hemoglobin level of 2 g/dL or more over a 24-hour period, or leading to transfusion of two or 
more units of whole blood or red cells or; 3) bleeding requiring reoperation. 
 
Wound Complications 
Wound complications include wound drainage, hematoma, or seroma of an orthopaedic injury 
that requires a subsequent surgery. 
 
Deep Surgical Site Infection 
Deep surgical site infection is defined based on the Centers for Disease Control and Prevention’s 
National Healthcare Safety Network criteria for deep or organ space infections at the fracture site 
and requires surgical treatment. 
 
3.3.4 Tertiary Outcomes  
The following outcomes will be assessed to address the study’s secondary aims: 
• Patient medication satisfaction will be measured using the Treatment Satisfaction 
Questionnaire for Medication (TSQM).31 The 14 item TSQM was developed and 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 17 
 
validated by Akinson and colleagues and effectively measures patient satisfaction with 
various medications. TSQM domains include side effects, effectiveness, and 
convenience, which sum to a single measure of the patient’s medication-related 
experience satisfaction.   
• Direct out of pocket medication cost to the patients related to the blood clot medicines as 
reported at the final follow up visit  
 
4. STUDY OVERVIEW 
The proposed study is a pragmatic multi-center, prospective, randomized trial of 30 mg of 
subcutaneous low molecular weight heparin/enoxaparin (LMWH) administered twice daily 
versus 81 mg of enteral aspirin (ASA) taken twice daily in orthopaedic trauma patients. 
Treatment will be initiated during the initial hospitalization for injury, and will continue for the 
duration of time the patient is prescribed prophylactic clot prevention medication, per the 
standard of care at the treating facility. Patients will be followed for 3 months following date of 
randomization to the trauma center to assess for death, rehospitalization, or complication which 
occurred between discharge and follow up. At this time, satisfaction, adherence and out of 
pocket costs will also be reported.  
 
5. STUDY POPULATION 
5.1 Description of the Study Population  
Approximately 12,200 participants (6,100 per treatment arm) will be enrolled from participating 
METRC centers over a 42-month period. Participants will be recruited as soon as the decision to 
place them on prophylactic clot prevention medication is made at the initial hospitalization for 
their injuries. Consenting procedures are described in detail in Section 6 of this protocol. 
 
5.1.1 Participant Inclusion Criteria 
1. Does the patient have a planned operative or non-operative pelvis or acetabular fracture, or 
any operative extremity fracture proximal to the metatarsals/carpals? 
2. Is the patient at increased risk of blood clot(s) from their orthopaedic injury(ies) and will 
receive a prophylactic blood thinner regimen per standard of care? 
3. Is the patient 18 years or older? 
5.1.2 Participant Exclusion criteria  
1. Did the patient present to the hospital more than 48 hours post injury?  
2. Has the patient received more than 2 doses of LMWH or Aspirin for initial prophylaxis? 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 18 
 
3. Is the patient on long term blood thinners (other than low-dose aspirin or platelet inhibitors 
such as Plavix or Aggrenox)? 
4. Did the patient have a VTE within the last 6 months? 
5. Is the patient on therapeutic (as opposed to prophylactic) blood thinners for an acute issue at 
the time of admission? 
6. Does the patient have a newly diagnosed indication for therapeutic blood thinners (for 
example vascular injury) that will require therapeutic anticoagulation for more than one 
week?  
7. Does the patient have an allergy to aspirin, or NSAIDs, or a history of heparin induced 
thrombocytopenia, or other medical contraindication to blood thinners (e.g. peptic ulceration, 
gastrointestinal bleeding, etc)?  
8. Is the patient on higher dose aspirin (>81 mg once a day or higher) for medical reasons or 
will be treated with higher dose aspirin? 
9. Does the patient have underlying chronic clotting disorders (i.e. Factor V Leiden, 
hemophilia, Protein C and S deficiency) that require full dose anticoagulation or are a 
contraindication to VTE chemoprophylaxis? 
10. Does the patient have end stage renal disease, or impaired creatinine clearance <30 ml/min at 
time of randomization? 
11. Is the patient pregnant or lactating? 
12. Does the patient speak neither English nor Spanish? 
13. Is the patient is a prisoner? 
14. Is the patient is likely to have severe problems maintaining follow-up? 
15. Is the patient, based upon the clinical judgment of the treating clinician, NOT equally suited 
for treatment with either Aspirin or Lovenox? 
16. Should the patient be excluded for other reasons at the discretion of the treating physician? 
17. Does the patient have a known COVID-19 diagnosis prior to fracture treatment or within 3 
months of the index fracture? 
Due to the acute nature of injuries experienced by the trauma patient population, some patients 
may have conditions or treatment plans that are unknown at the time of enrollment that, but 
when discovered later causes them to become ineligible. Patients who are enrolled and later meet 
an exclusion criterion that was present but undiagnosed at the time of enrollment will be 
withdrawn and considered a late ineligible participant.  
 
5.1.3 Co-Enrollment Guidelines 


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Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 19 
 
Patients may be co-enrolled into this and other studies, depending on the practices of the local 
IRB. Co-enrollment must be documented, and event reporting for either study must be reported 
for both projects. 
 
6. STUDY PROCEDURES 
6.1 Screening and Enrollment 
6.1.1 Screening  
All patients 18 years of age and older with an orthopaedic injury and for whom prophylactic clot 
prevention medication is indicated will be screened for eligibility at each site by the local 
Research Coordinator in close collaboration with the surgeon investigators. In this study, it will 
be important to enroll patients soon after admission to ensure study medication can commence in 
a timely manner.  
Screening will take place either in the hospital or remotely by a Research Coordinator depending 
on access available to hospital facilities. Remote screening will involve communication between 
Advanced Practice Providers and a member of the study team in order to document all eligible 
patients even when the Research Coordinator is not physically at the site. Patients screening 
status will be logged using REDCap website and either randomized, when eligible, or excluded 
as an ineligible patient. 
A partial HIPAA Waiver will be requested for the purposes of screening for enrollment. The 
study team will discuss all participants meeting inclusion criteria, and complete and submit a 
screening case report form (CRF) on every potentially eligible participant. The medical record 
will be reviewed to assess for exclusion criteria, and the results will be entered into REDCap, the 
METRC electronic data capture system, in order to document screen failures. The study PI will 
be available via text or email to answer questions regarding study eligibility. This service will be 
active during regular east and west coast business hours. When the study PI is not available, this 
coverage will be provided by a designated co-investigator. Contact information for the PI and 
alternate contact is available in Appendix A.  
 
6.1.2 Consent and Enrollment 
In-person consent: 
Once eligibility has been confirmed, the informed consent process will be completed by the 
Research Coordinator and/or a clinician certified to participate in this study. Eligible study 
participants or their legally authorized representative (LAR) will be approached as soon as they 
are able to give consent, and may be enrolled in the study through the time that the first two 
doses of anticoagulation therapy are administered; i.e. they may receive 2 doses of SOC (as 
defined by the center) therapy prior to randomization and initiation of the study-directed 
medication. Individual sites will develop local procedures that will ensure these requirements can 
be met. Patients and their families may be provided with a pamphlet (Attachment C) describing 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 20 
 
the study, the risks and benefits of participation and what will be expected of them if they choose 
to participate. A video (Attachment D) describing the study treatment and procedures may be 
provided to assist with the recruitment process. If a patient is unable to consent before 2 doses of 
SOC anticoagulation therapy are administered and there is no LAR available, the patient will not 
be eligible for study participation and will be recorded as such. Consent will be obtained in 
accordance with principles of GCP and ICH guidelines. 
 
Tele or remote consent: 
When the Research Coordinator is unable to access the site tele or remote consenting process 
will be completed by the Research Coordinator in collaboration with an Advanced Practice 
Provider.  Once eligibility is confirmed, the Advance Practice Provider will approach the 
participant or LAR to provide information on the study, a physical copy of the consent form and 
an opportunity to be contacted by phone or video call from the Research Coordinator. Once 
notified, Research Coordinator will contact all willing participants or their LAR and provide 
additional information about the study and also offer to send a link to the patient recruitment 
video (Attachment D) for the participant/LAR to view on a personal device. The Research 
Coordinator will offer to answer questions or put the participant in contact with the treating 
Physician when necessary. The participant will be offered the opportunity to consult with any 
family members or friends prior to making a decision on consenting into the study. Consent will 
be obtained over the phone or video call and documented by the Research Coordinator.     
 
Remote review of consent will not change the requirement for written consent to be documented, 
unless local regulations relax those requirements for the duration of the COVID-19 pandemic 
response. 
   
A prototype consent has been prepared for this study (Attachment A) and individual sites may 
add material but may not delete material thought to be necessary for informed consent. Clinical 
sites may reformat and reword information to conform to their local requirements. The consent 
form describes the purpose of the study, the procedures to be followed, and the risks and benefits 
of participation. Copies of the signed consent forms will be given to the patient, and this fact will 
be documented in the patient’s record. Once the patient is enrolled into the study they may 
receive a card/key chain (Attachment E) for study identification and to prompt adherence to the 
study assigned treatment.  
 
All study materials will be provided in English and/or Spanish as appropriate. 
 
Following completion of informed consent, the participant information will be entered into 
REDCap where a study number will be assigned, final eligibility criteria confirmed, and the 
participant will be randomized to a treatment group. 
 
6.1.3 Assessing Capacity to Consent and Consenting a Proxy Respondent 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 21 
 
The research staff will endeavor to answer all questions posed by the patient and his/her family 
to ensure their understanding of the protocol. After introducing the study and reviewing the 
consent form, the research coordinator will pose several questions assessing the participant’s 
comprehension of the study and what it means to participate, their appreciation of the 
consequences of participation, and their ability to consider alternatives to participation. The 
Research Coordinator will ask the questions and determine the appropriateness of the responses. 
If the Research Coordinator is at all unsure about the patient’s ability to consent s/he will consult 
with the study site PI.  
 
By virtue of the types of injuries studied (resulting from high energy mechanisms such as high 
speed motor vehicle crashes, high falls, and blast injuries) it is expected that we will have 
patients with an associated traumatic brain injury which may render them unable to provide 
consent for the study. Other patients may remain intubated for some time due to lung issues or 
other reasons related to their trauma. It will be important not to exclude these patients from the 
study, as it would significantly reduce our ability to produce generalizable knowledge. These 
patients are at no greater risk of adverse consequences by virtue of their participation in the 
study, and should be given the same opportunity to participate.  
 
A legally authorized representative (LAR) with reasonable knowledge of the potential participant 
will be approached to consent on the patient’s behalf if one of the following is true: 
• The patient is unresponsive or intubated (and likely to remain unresponsive or intubated 
during the enrollment window for the study).  
• The patient cannot adequately answer at least 2 questions regarding study participation or 
it is determined that the patient’s level of cognition is not likely to change before study 
medication can be initiated.  
 
The choice of LAR will follow standard procedures and be any of the following: Legal guardian,  
Proxy (health care agent) named in an advance directive or durable power of attorney for health 
care; or Family member or other surrogate identified by the state law on health care decisions.  
 
Guidance will be provided to assist the LAR in making the consent decision. They will be 
advised to base the decision on the participant’s expressed wishes, or, if these are not known, 
what they believe the participant would have desired under the circumstances of the injury, their 
beliefs and values and a willingness to administer the study medication, if the patient is still 
unable to consent at the time of discharge. If the LAR does not know what the participant would 
have wanted, the LAR will advised to base the decision with the participant’s best interest in 
mind. They will be asked to carefully consider how much leeway the participant would likely 
give the LAR in making the choice about participation in the study. 
 
Recognizing that consent is an ongoing process, the study team will continue to assess the 
participant for their ability to provide consent, and at the earliest possible time, will obtain 
informed consent from the patient him or herself. Similarly, any participant may withdraw 
consent at any time during participation in this study. 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 22 
 
 
6.1.4 Informed Consent Process or Assent (for a minor) 
N/A 
 
6.2 Baseline Data Collection 
Once consent is obtained, baseline data regarding participant characteristics, injury 
characteristics, fracture classification, medical history/co-morbidities and The Adherence 
Estimator,33,34 a brief questionnaire assessing the patient’s view of prescription medication use 
will be collected and entered into the METRC custom version of the REDCap data collection 
system. Characteristics about hospital course and treatment received will also be collected. A 
brief interview will be conducted with the participant or his/her surrogate. 
 
6.2.1 Medical Record Review 
For all enrolled participants, data related to the index hospitalization will be collected. This will 
include a daily check of the medication administration record to ensure that the patient is 
receiving the study drug to which he/she was assigned and to document adherence. If treatment 
is stopped, held or changed the research team member will either identify the reason for change 
from the chart or by asking the primary team if the reason is not documented. Other data to be 
collected includes orthopaedic and other injury characteristics, admission labs, and 
complications, including a fatal bleed, >= 2 g/dL drop in hemoglobin, reoperation for hematoma 
evacuation or surgical site infection, other clinically significant bleeding or infectious 
complication, VTE, PE, and any imaging studies (and results) conducted for bleeding or VTE 
concerns. Information on the administration of a limited number of concomitant medications 
with known potential for bleeding side effects will also be collected, including Plavix, or other 
platelet inhibitors, aspirin, NSAIDs (e.g. toradol, ibuprofen), and any administration of a full 
dose of anticoagulation medication, as well as the reason, will be recorded. 
 
Due to the potential affects that COVID-19 has on patients, ie increased risk of clotting, COVID-
19 status will be recorded if available via medical record review during the index hospitalization 
and at follow up. Research team member will record whether the patient is experiencing any 
symptoms related to COVID-19 or has tested positive. Patients who have tested positive during 
the index hospitalization will be excluded from the study. Patients who test positive between 
discharge from the index hospitalization and follow up will remain in the study with data 
collection of COVID-19 status in the case report form. These data will also be retrospectively 
collected on all patients who have enrolled into the study since January 2020. 
 
6.2.2 Clinical Assessment 
No additional clinical assessments will be conducted as part of this study.  
 
6.3.3 Participant Interview 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 23 
 
Participants, or their proxies, will complete a brief baseline data, including age, race, history of 
tobacco, medical history, including history of VTE, peptic ulcer, DM, or cancer, or if they are 
immunosuppressed, in addition to use of home OCP/estrogen, Plavix, or daily aspirin. The 
patient will also be asked to assess their views on prescription medication via The Adherence 
Estimator questionnaire.33,34  
6.3 Participant Follow up and Data Collection 
6.3.1  Follow-up Visit Schedule 
Each participant will receive a weekly check in via phone call, text message, mobile application 
or email by an automated computerized system, Twilio, which will be administered centrally 
from the data coordinating center at Johns Hopkins.  Each participant will also have the option of 
mailing in a pre-addressed, pre-stamped post card documenting adherence using provided by the 
study team (Attachment F). Each week, participants will respond to a series of questions, that 
contain questions from The Brief Medication Quesitonnaire,32 with automated responses 
designed to assess adherence to study assigned medication, potential medication crossover and 
use of other blood clot prophylaxis. At the time of this contact, if a participant is found to no 
longer be taking prophylaxis for any reason other than discontinuation by the treating physician, 
the participant will receive a message that he/she is at increased risk of blood clot due to his/her 
injury experience, and should contact his/her surgeon to determine whether or not continued 
prophylaxis is still indicated (Attachment B).  If the patient does not respond to two subsequent 
surveys they will be contacted by a representative from the coordinating center. The automated 
contact will stop when the participant responds that prophylaxis is no longer indicated or at the 
time of the 3 month follow-up visit, whichever comes first.  
Participants may opt out of this contact at the time of enrollment or any time during the follow 
up period. 
 
All outcomes in this study will be assessed at 90 days (3 months) post randomization, and all 
efforts will be made to ascertain outcomes at this point in time. Because this is a pragmatic study 
and there are no study visits, participants will also complete a visit which will coincide with a 
regularly scheduled standard of care follow-up visit approximately 3 months post randomization 
at which point study outcomes will be assessed. If participants are unable to return to the clinic 
they may be contacted to complete the 3 month follow up visit via phone call, email, or mail. If a 
patient completes the follow up visit prior to the 3 month anniversary, a medical record review 
will be conducted in order to assess for potential outcomes that were not recorded at the 
premature follow up visit. To fully assess for any missed outcomes, the research coordinator may 
assess for potential events in the patient’s medical record..  
 
At the time of the 3 month follow up visit (in-person or virtual), participants will be interviewed 
by the Research Coordinator to assess for the occurrence of any clinical outcomes, including 
VTE events or complications secondary to treatment since their hospitalization. For each event 
identified, the participant will fill out a release of information form that will allow the research 
staff to obtain records related to the event, if they occurred outside the index facility. Participants 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 24 
 
will be asked about study medication satisfaction using the Treatment Satisfaction Questionnaire 
for Medication (TSQM)31 and about their total out of pockets costs related to obtaining the study 
assigned medication. Additionally, the medical record will be carefully reviewed to assess for 
any complications treated at the index facility, including in the clinic, ED, or resulting in a 
rehospitalization.  
As stated above, due to the potential affects that COVID-19 has on patients, ie increased risk of 
clotting, COVID-19 status will be recorded if available via medical record review also at follow 
up. Research team member will record whether the patient is experiencing any symptoms related 
to COVID-19 or has tested positive. This data will be collected on all patients who have enrolled 
into the study since January 2020. 
Lost to follow up participants 
A percentage of participants will fall in the category where they cannot be contacted,  do not 
return to clinic, or return to clinic but do not have 90 days of follow-up. Additional contact 
methods will be used to verify these participants’ death status which is critical for determining 
the primary outcome, all-cause mortality. The following methods, which are also described in 
more detail below, will be used to assess outcomes on these individuals: (1) medical record 
review, (2) postcard questionnaire, (3) phone call or text follow up from coordinator (4) search 
via LexisNexis Accurint system, (5) phone call and text message follow up from MCC, (6) 
search via Limited Access Death Master File (LADMF)  
Medical Record Review  
If the participant cannot be contacted and does not return for a final research visit, medical 
records will be abstracted through the last orthopaedic encounter occurring between anytime 
from the last clinical encounter to the time of medical record review. The visit occurring closest 
to the 3 month follow-up target should be recorded(e.g. for a participant seen at 60 days, 185 
days and 400 days, the 60 day visit should be recorded to demonstrate use of services in the 
follow-up interval, and the 185 day visit should be recorded to demonstrate that the participant 
was alive and free of any orthopaedic events at 185 days and therefore also alive and event-free 
at 90 days, the date of interest. No other visit data should be recorded. Attempts will be made to 
obtain medical records or autopsy reports for all participants who are discovered to be deceased 
at the time of the follow up visit. If the participant died at home, family members will be asked 
to provide a cause of death, if known.  No attempts will be made to follow up with family, and 
the deaths will be recorded as “unknown” cause. 
If a patient cannot be contacted AND has no evidence of returning for any orthopaedic clinical 
visit, the medical record will be searched for any evidence of an encounter with the medical 
system documenting that the patient survived through at least 3 months post randomization. If 
the encounter occurred before 3 month post randomization information, information related to 
study outcomes available at the encounter. If the encounter occurs anytime following the 3 
month post randomization date the date and visit type will be recorded. The resulting information 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 25 
 
will provide evidence that the patient was alive during the window of interest, allowing 
ascertainment of information on the primary outcome. 
Postcard questionnaire 
Each lost to follow up participant will receive a one-time pre-stamped postcard questionnaire 
requesting information on the participant’s death status. The postcard will be addressed to the 
participant however may be returned by a family member, friend, or resident of the participant’s 
home. Sample of this postcard is in Attachment H. 
To facilitate centralized distribution and retrieval of these cards, clinical sites will send the 
patient’s full name and mailing address, along with the study ID number, to the MCC using a 
secure, encrypted, password-protected File Transfer Protocol. The MCC will centrally send out 
postcards using an automated postcard development and mailing electronic service. 
Phone call/text message follow up (Research Coordinator) 
Research coordinators will call the participant or emergency contact listed in the participant’s 
medical record or social work/case management file to determine the participant’s death status. 
This phone call will be in addition to any attempts made during the follow up period. If the 
Research Coordinator gets in contact with the patient a full follow up visit and questionnaire will 
be conducted. If the Research Coordinator can only determine the participant’s death status 
based on conversations with the family and/or emergency contact the death status will be 
recorded. Sample of the text message/call script is in Attachment I. 
Search via LexisNexis Accurint Services 
The MCC will obtain identifiers such as but not limited to the patient’s name, date of birth, 
social security number, and last known address using a secure, encrypted, password-protected 
File Transfer Protocol. The identifier will be used to conduct probabilistic mapping through 
public and proprietary database search. Any identifiers will aid in specialized mapping of this 
database will be used in the search, and the database will return up to date mailing and phone 
contact information for the participant, as well as any publicly reported deaths.  
Phone call/text message follow up (Centralized through MCC) 
The MCC will centrally contact each participant and emergency contact, when necessary to 
evaluate the death status of the participant using the contact phone numbers previously provided 
by participating centers for weekly follow up as well as information obtained from the Accurint 
search. Clinical sites may also obtain any additional phone numbers associated with the 
participant’s medical record and transfer it, along with the study ID number, to the MCC using a 
secure, encrypted, password-protected File Transfer Protocol. All statues will be saved in 
REDCap. Sample of the text message/call script is in Attachment I. 
Search via Limited Access Death Master File (LADMF) 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 26 
 
There will be a subset of patients who cannot be contacted AND have no evidence of any further 
encounters with the clinical system. For these cases, ascertaining final death status is critical to 
the validity of the study, and the study team has developed a plan to allow sites to obtain this 
information while conforming to local policies regarding the sharing of PHI and accessing 
available data. Because this study is being executed in 21 trauma centers, including 2 centers in 
Canada, the method for determining if a patient passed away during the study interval will vary. 
Local IRBs will review the protocol and make a determination regarding if and how this 
information will be obtained, according to the following options: 
A. Sites have the option to send a secure, encrypted password-protected LOOK-UP File 
to the MCC for a centralized database search of the Limited Access Death Master File 
(LADMF). 
B. Sites have the option to locally and independently access the LADMF or local death 
record database, including Canadian sites, to conduct a search of patients.  
C. Sites are unable to access the LADMF either locally or send data for a centralized 
search and therefore opt out of obtaining this information for their patients.  
Option A: Established by the National Center for Health Statistics of the Centers for Disease 
Control and Prevention (CDC) the LADMF is a centralized database of death record information 
of all state vital statistics offices. The LADMF requires at least one of the following identifiers: 
name, date of birth, and social security number to obtain accurate information. Consequently, for 
each patient completely lost to follow up, clinical sites may obtain the patient’s social security 
number from the hospital billing record and transfer it, along with the study ID number, patient 
name, and date of birth to the MCC using a secure, encrypted, password-protected File Transfer 
Protocol. The MCC will link these data with the Social Security Administration Death Master 
File to determine if a death has been registered for the study patient. Only the study ID and death 
status for the patient will then be linked to the study database.  
A HIPAA waiver will be sought to cover the exchange of PHI between institutions for patients 
whose death status is unknown to determine the primary outcome on patients who are lost to 
follow up. The data obtained for this purpose will saved in a separate LOOK-UP file and will not 
be linked to contact data or identifiable data of the study dataset. 
The MCC may access the patient’s SSN and develop a LOOK-UP File for all those individuals 
identified as loss to follow up with unknown death status. This LOOK-UP File contain 
information needed to conduct a search on the LADMF (may include: name, date of birth, SSN). 
A HIPAA waiver will be sought to share this information for the purposes of obtaining death 
status on every patient who is lost to follow up with no indication of the status of this outcome. 
Waiver of Consent. We are requesting a waiver of consent for accessing identifiable data. We 
believe that we meet the Code of Federal Regulations criteria for a waiver of consent as follows:  
Can informed consent be waived or consent elements be altered under 45 CFR 46.116(d) 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 27 
 
a. The research involves minimum risk to subjects: Yes, the research will involve 
existing data 
b. The waiver or alteration will not adversely affect the rights and welfare of the 
participants: Yes, the data currently exist and will only be used for the search and 
determination of status. The analysis will be conducted using de-identified data with 
additional data will be collected, nor will any procedures be performed as part of the 
proposed analysis.  
c. The research could not practicably be carried out without the alteration or waiver: 
Yes. The cases where the patient is lost to follow up would not allow for an opportunity 
to obtain consent. 
d. Whenever appropriate, the subject will be given additional information about the 
research after it is completed: Yes. Study results will be posted on a study website.  
Option B: For sites that will conduct a search locally will obtain an account to and search the 
LADMF or a different local death record database independent of the MCC. The results of each 
patient’s primary outcome status will be recorded in the patient case report form. Sites are 
permitted to use a local death record centralized databased in addition to or instead of the 
LADMF to obtain final death status on lost to follow up patients.  
Option C: For sites that will not conduct a search either locally or centrally through the MCC 
will not obtain the primary outcome on these patients and those data will be considered missing. 
6.3.2 Retention  
Every effort will be made to retain participants in the study. The study participants will receive 
an honorarium in recognition of their time and effort. $20 will be given for completing the 3 
month visit in appreciation for their time and effort. Participants who complete follow-up 
activities by phone or email will be given $20 for competing the interview. We will also keep 
participants engaged through use of study updates on the study webpage and distribution of 
follow-up reminders, which can include mailings and e-mails. 
 
7. STUDY TREATMENTS 
Patients meeting inclusion/exclusion criteria will be prospectively randomized to one of two 
treatment arms using the REDCap Database randomization tool embedded. Block randomization 
with variable block sizes will be used.  
 
7.1 Study Treatments  
7.1.1 Description of treatment  


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 28 
 
Study Treatment 1: LMWH is currently an accepted medication used to prevent blood clots after 
trauma, and it is supported by existing guidelines so it is already in widespread use through the 
United States.9,10 Enoxaparin is available from multiple manufacturers; local site purchasing will 
determine the product received by the patient. Clear guidelines already exist regarding dosing in 
very obese patients as well as in patients with renal disease.35,36 The LMWH intervention is 
expected to be 30 mg enoxaparin SC twice a day which is already standard in many trauma 
hospitals. The protocol for this pragmatic trial will allow for variations in dosing, per the 
standard of care at sites, as needed for patients who are very obese or exhibit renal dysfunction. 
These variances will be recorded to allow them to be identified in the data.  
 
Study Treatment 2: Aspirin is currently regarded as an accepted medication to prevent blood 
clots after orthopaedic surgery, is supported by existing guidelines37 and is already in widespread 
use in the United States.  Aspirin is less commonly used in trauma although it has gained 
significant popularity in the orthopaedic arthroplasty (joint replacement) domain.22,23,27 Aspirin 
was chosen as the comparative intervention because it is thought to have an excellent 
complication profile (low rates of bleeding and chronic wound drainage) and still to be effective 
in preventing blood clots in the lung, although these data are in joint replacement 
patients.22,23,27,37 Aspirin works by effecting platelets irreversibly and this effect typically lasts 7 
days, which is a potentially important difference from the shorter acting LMWH. The advantage 
of a shorter acting medication is that the effect can be turned off easily when the patient needs 
additional surgery or if a contraindication for bleeding develops. A down side is that missed 
doses with LMWH quickly place the patient with no blood clot prevention. Aspirin is typically 
continued even when surgeries are performed so the fact that aspirin cannot be “reversed” is 
likely not important in this domain, but the importance of this effect in trauma patients is 
unknown.  
 
The dose of aspirin for this study is not obvious as several reported doses have been used 
successfully. Options include 81 mg once a day, 81 mg twice a day, 180 mg once a day, 325 mg 
once a day, and 325 mg twice a day. The desired effect of reducing the risk of clots is thought to 
occur at the 81 mg dose once a day and many joint replacement surgeons use this dose to prevent 
blood clots.38 Anti-inflammatory effects are thought to become more pronounced as the dose 
increases and some of the original joint replacement studies used 325 mg twice a day. We 
believe that lower doses may be desirable in trauma as it likely reduces the chance of bleeding 
from other traumatic injuries and it is not necessarily desirable to have the anti-inflammatory 
effects of higher doses, as anti-inflammatory medicines have been linked to delayed bone healing 
in animal models.39 We therefore have chosen 81 mg twice a day as it represents a dose towards 
the lower end of the dosing spectrum and gives twice a day dosing, similar to LMWH, 
decreasing the chance of patients missing a dose for the whole day. Further, a study of geriatric 
hip fractures,21 which is as close to our population as has been studied for this question, 
successfully used 160 mg once a day. 
 
7.1.2 Investigational Drug Status  


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 29 
 
Both study treatments are FDA approved medications that are commonly used for the indication 
proposed in this application; however only LMWH has this listed as an approved indication in its 
product labelling. ASA for this indication is “off label” for use as DVT prophylaxis.  In 
accordance with 21 CFR 312.2, this study meets IND Exemption requirements. An application 
for an IND exemption was approved by the FDA for the proposed indications outlined in this 
protocol. The intention of the protocol is not to support a new indication for use or significant 
change in labeling of the drugs; is not intended to support a change in advertising for the drugs; 
will not test a new route of administration or dosage of the drug, nor is it being used in a new 
clinical population; and the study will be conducted with informed consent and in compliance 
with 21 CFR 312.7 regarding promotion and sale of drugs. Patients in the study will be actively 
monitored for any adverse reactions. 
For patients enrolled at Canadian sites, the in-patient administration of ASA and the ASA 
prescribed to the study participant at their discharge will be dispensed by the treating hospital’s 
pharmacy. As per the labelling standards of the Food and Drug Regulations (C.05.011) labels for 
the ASA, in both English and French, will be included with each administered dose. The label 
will state that the ASA is for clinical trial use only, the name and identifying mark of the drug, 
the expiration date of the drug, the recommended storage conditions for the drug, the lot number 
for the drug, the protocol code “PREVENT CLOT”, and the name of the sponsor (R Adams 
Cowley Shock Trauma Center, University of Maryland, 22 Greene St., 3rd Floor, Baltimore, MD, 
21201).  
7.2 Assessment of Participant Adherence with Study Agent(s)/Intervention(s)  
Adherence to study medications and out of pocket costs will be assessed at the 3 month follow 
up visit, including assessing for any potential occurrence of treatment crossover. 
 
If participants do not return for the 3 month study visit, they will be contacted by the study 
research coordinator by phone, mail and/or email. The participant will be asked to return to the 
clinic for a follow-up appointment. If the participant is unwilling to return, follow up information 
will be collected by phone or via an email survey assessing for adherence and study outcomes. 
 
7.3 Precautionary and Prohibited Medications and Procedures  
In this trial, participants will be randomized to receive either LMWH or aspirin. Participants in 
this study may not receive any other full dose medication as prophylaxis for anticoagulation or as 
treatment for a VTE even, nor may they receive additional dosages of aspirin above 81 mg daily. 
There are no other prohibitions regarding medications management, and participants will be 
treated according to the local standard of care. Data on specific concomitant medications will be 
collected (See Section 6.2.1). Should it be determined that the medication the participant was 
randomized to is no longer clinically appropriate, the study medication will be stopped, the 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 30 
 
research team will record the reason for medication discontinuation, and the participant will 
continue to be followed through the 3 month follow up.  
 
7.4 Rescue Medications  
Any need for rescue medication resulting from a drug overdose or sensitivity will be handled per 
the standard of care at the treating institution or where the patient seeks care. 
 
8. ASSESSMENT OF SAFETY 
The study will monitor and report adverse events to ensure patient safety. Definitions and 
procedures for reporting adverse events are designed to satisfy 45 CFR Part 46, Subpart A; the 
“Common Rule”, shared by 17 Departments and Agencies as well as 21 CFR 312, the FDA 
regulation for adverse events. The Common Rule requires written procedures and policies for 
ensuring reporting of “unanticipated problems” involving risks to participants to IRBs, 
appropriate institutional officials, and the Department or Agency Head. The approach to defining 
and reporting events is based on the 2009 FDA Guidance for Clinical Investigators, Sponsors, 
and IRBs on adverse event reporting to IRBs 
(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126572.pdf) 
 
The medical monitor (MM) is responsible for providing medical guidance and overseeing patient 
safety for the study. The MM participates in determining the course of action necessary to meet 
safety goals and objectives. This is achieved through the review of Serious Adverse Event 
reports; resolving safety issues; and interacting with Principal Investigators. 
Each participating site is responsible for ensuring that all local IRB requirements for reporting 
adverse events (both internal and external) are met.  
 
8.1 Definitions 
8.1.1 Adverse event 
Any untoward or unfavorable medical occurrence in a human subject, including abnormal sign 
(e.g., abnormal physical exam or laboratory finding), symptom or disease temporally associated 
with the subject’s participation in the study, whether or not considered related to the subject’s 
participation. Several adverse events, or complications, will be collected as primary and 
secondary outcomes of the study. The most severe of these events include: (1) Death, (2) Fatal 
bleeding into a critical organ (retroperitoneal, intracranial, intraocular, intraspinal); (3) 
Significant/massive PE central pulmonary embolism with resulting heart strain (PE); (4) Wound 
drainage or hematoma requiring reoperation; (5) Wound drainage, bleeding or hematoma that 
does not require reoperation; (6) Bleeding event that requires intervention (e.g. chest tube, 
interventional radiology embolization); (7) Surgical Site Infection requiring reoperation; (7/8) 
Surgical site infection that does no lead to reoperation but requiring antibiotic treatment; (9) 
Greater that 2 mg/dL drop in hemoglobin within 24 hrs; and (10) GI Bleed. These and other 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 31 
 
complications common in the trauma population will be reviewed in aggregate twice annually by 
the DSMB to assess for differences between treatment groups. They will be reported to the IRB 
on an annual basis, unless they meet the criteria for Serious Adverse Event (see below). 
 
8.1.2 Unanticipated problem 
Any incident, experience, or outcome that meets all of the following criteria: 
(1) 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 study. 
 
(2) is related or possibly related to treatment/procedures under study; possibly related 
means there is a reasonable possibility that the incident, experience, or outcome may 
have been caused by the study procedures or treatments. 
 
(3) suggests that the participation in the study may place subjects or others at a greater 
risk of harm (including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
Please note that not all adverse events are unanticipated problems and only some unanticipated 
problems are in fact adverse events. For instance, if a laptop containing study data is stolen, this 
is an unanticipated problem but it is not an adverse event since it is not an untoward or 
unfavorable medical occurrence in a human subject 
 
8.1.3 Serious Adverse Event 
A serious adverse event is defined as: 
1. Unanticipated events possibly related to exposure to study 
medications such as angioedema, agranulocytosis, hepatic injury, 
or Stevens Johnson syndrome 
2. Other events that are serious AND either related or possibly related 
to the study which occur at a higher rate than expected in this 
population 
3. Other events that are unexpected AND serious AND either related 
or possibly related to the study beyond the complications expected 
in this population 
Note that deaths are an expected outcome in this population, and will not be reported as serious 
adverse events, unless they are determined to be related to study treatment and occur at higher 
than expected rates in the study population. 
 
8.2 Methods and Timing for Assessing, Recording, and Analyzing, Managing Safety 
Parameters 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 32 
 
8.2.1 Methods and Timing of Assessment  
Adverse events (complications) may be discovered during regularly scheduled visits or through 
unscheduled patient contacts between visits. Adverse events will be assessed for during the index 
hospitalization and at the 3 month study visit. They will be recorded on study data forms with an 
indication of whether or not they are thought to be associated with participation in the study. 
 
8.2.2 AE/SAE Grading and Relationship Assignment 
Adverse event grading: Adverse events will be graded using standard criteria. Relationship of 
event to the study procedure will be determined by the study physician.  
GRADE 1 (Mild) Transient or mild discomfort (< 48 hours); no medical intervention/therapy 
required 
 
 
 
GRADE 2 (Moderate) Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required 
 
 
 
GRADE 3 (Severe) Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations possible 
 
GRADE 4 (Life-threatening) Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable. 
 
Relationship Assignment The relationship of the adverse event to participation in the study will 
be assessed as either:  
 
 
Definitely related  
Probably related 
Possibly related 
Unlikely related 
Unrelated  
 
8.2.2.1 Adverse Events related to study medications. 
The study will capture safety information on LMWH and aspirin, both of which are licensed by 
the FDA. Complications will be classified as study outcomes (8.1.1), and their relatedness to 
medication exposure will be assessed by the treating physician. 
 
8.2.3 Recording and Documentation  
Sites will maintain source documents including but not limited to laboratory and radiology 
reports, clinical notes and discharge summaries. After review of initial and final reports by the 
medical monitor, the events may be reclassified at their discretion. 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 33 
 
 
8.2.4. Management of Adverse Events 
Adverse Events and Serious Adverse Events will be managed according the medical judgment of 
the treating physician. 
 
8.3 Adverse Event Reporting Procedures 
8.3.1 Local Reporting Requirements.  
 
Study sites must always follow and comply with their own local institution’s adverse event 
reporting requirements. Depending on the local requirements, a site may report events locally 
and not report those events to the METRC Coordinating Center. Each participating site is 
responsible for ensuring that all local IRB requirements for reporting adverse events (both 
internal and external) are met.  
 
8.3.2 SAE and Unanticipated Problem Reporting Requirements 
All Serious Adverse Events that are unexpected AND related or possibly related to the study 
must be reported to the Medical Monitor and METRC Coordinating Center within 72 hours of 
being made aware of the event. The MM will review the event within 48 hours of receiving 
notice of the event, and will make a determination of relatedness as well as the required action 
(stopping medication, informing other sites, etc). When necessary, the MM may convene the 
DSMB to discuss an event. 
 
In addition, Unanticipated Problems (UPs) that are not adverse events must also be reported to 
the METRC Coordinating Center within 14 calendar days after the event has been discovered.  
SAEs/UPs will be reported to the METRC Coordinating Center by entering the SAE/UP form 
into REDCAP. REDCap is programmed to automatically send an email to the Coordinating 
Center for both SAEs and UPs, and to the Medical Monitor in the case of an SAE.  
 
The Medical Monitor for this study is: 
Gregory Vercellotti, MD, FACP 
University of Minnesota 
Division of Hematology, Oncology and Transplantation 
420 Delaware Street SE 
Minneapolis, MN 55455 
Telephone: 612-624-5620 Fax: 612-625-6919 
Email: verce001@umn.edu  
 
LMWH and aspirin are available from multiple sources and have generic versions available so 
consequently there will be variability in manufacturer.  
 
8.3.3 METRC Coordinating Center Reporting Responsibilities  


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 34 
 
When an event is determined to be unexpected and related to study medication exposure, the 
Coordinating Center will send a copy of each report received about the event to all clinical sites, 
with instructions for each to forward the report to their IRB.  
 
Copies of the report will also be sent to the Study PI, and to the DSMB. The MCC will maintain 
a list of such events for reporting and review at DSMB and Steering Committee meetings. 
 
8.4 Reporting Pregnancy (Replace text with “N/A” if not applicable) 
Pregnancy will always be captured on case report forms as a medical event. LMWH is 
considered a category “B” medication – to be used only if clearly needed. Aspirin is considered a 
category “D” medication – adverse reactions have been found in humans – but only in the third 
trimester, and no participant who is not pregnant at the time of enrollment will still be on study 
drugs by the final trimester of the pregnancy. If a woman becomes pregnant while on the study 
medication, the decision to continue study medication will be made by the local treating 
physician, and the event will be reported in an Unexpected Event Form. Regardless of whether 
the medication is discontinued or not, the patient will remain in follow-up until the follow-up 
period is completed and a report on the outcome will be submitted. 
 
8.5 Type and Duration of the Follow-up of Participants After Adverse Events 
Study patients who experience an SAE will be followed until resolution of the event, and a final 
report will be submitted to the medical monitor, the coordinating center and the pharmaceutical 
company (if applicable). 
8.6 Stopping Rules  
The DSMB will review the overall progress of the trial in terms of recruitment, data quality, and 
event frequency and makes a formal recommendation to PCORI at the end of each scheduled 
meeting as to whether the trial should continue unmodified, continue with protocol modifications 
or be stopped. 
There are two formal interim analyses and one final analysis planned to assess differences 
between group with respect to death within 90 days of randomization. The first will occur after 
one-third of enrolled patients are followed for 3 months. The second will occur after two-thirds 
of enrolled patients are followed for 3 months. At each interim analysis, the DSMB will evaluate 
whether there is a difference in mortality rates between groups. Specifically, they will assess 
whether the absolute difference in the risk of death between aspirin and LMWH is different than 
zero. At each interim analysis, two-sided confidence intervals for the difference in risk for death 
will be computed. The overall type I error of the interim monitoring procedure will be controlled 
by using a 99.6% confidence interval at the first interim analysis, 98.8% confidence interval at 
the second interim analysis and a 96.2% at the final analysis. If probability of dying is 1% in 
both arms, the probability of falsely declaring harm using this procedure is less than 5%.  


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 35 
 
8.7 Premature Withdrawal of a Participant 
A participant may be withdrawn from the study without consent if the sponsor decides to end the 
study. Other reasons for removing a participant without consent may include but are not limited 
to non-adherence with the protocol and/or therapy, inappropriate behavior towards study 
personnel, and incarceration.  
8.8 Replacement of a Participant Who Discontinues Study Treatment  
Participants who are withdrawn from the study will not count towards the total sample size 
accrual and will be replaced. Participants who are lost to follow up and have unknown treatment 
or outcome status will be counted as lost and will not be replaced. 
9. MONITORING  
 
9.1 Site Monitoring Plan 
 
The METRC Coordinating Center will be responsible for site monitoring consistent with 
ICH/FDA guidelines. Monitoring will include a combination of remote and on-site visits of 
participating clinical research sites to review the individual subject records, including consent 
forms, case report forms, supporting data, laboratory specimen records, and medical records 
(physicians’ progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection of 
study subjects, compliance with the protocol, and accuracy and completeness of records. During 
the site certification process, the monitors also use remote methods to inspect sites’ regulatory 
files to ensure that regulatory requirements are being followed.  
The site PI will make study documents (e.g., consent forms, case report forms) and pertinent 
hospital or clinic records readily available for inspection by the local IRB, the site monitors, or 
other regulatory authorities for confirmation of the study data. 
9.2 Safety Monitoring Plan 
 
9.2.1 Safety Review Plan by the DSMB 
An independent Data and Safety Monitoring Board (DSMB) is responsible for monitoring the 
accumulated interim data as the trial progresses to ensure patient safety and to review efficacy, 
evaluate recruitment, and assess overall data quality. Two interim analyses will occur, the first 
after 1/3 patients are at 3 months from enrollment and the second after 2/3 of the patients are at 3 
months from enrollment 
The DSMB is a multidisciplinary group with a written charge provided by METRC. The DSMB 
will meet in person to review the protocol. After the trial commences, the DSMB meets twice a 
year to review data or other issues. The DSMB may request more frequent meetings if necessary, 
to fulfill it charge. It may also request additional safety reports on a more frequent basis. For 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 36 
 
example, all serious adverse events (SAE) are reported to the DSMB for their consideration and 
recommendations as they occur. 
At its first meeting the DSMB will review definition of all outcomes, adverse events and serious 
adverse events and revisions to the protocol made as appropriate. Summary data on adverse 
events (together with study outcomes) will be monitored by the DSMB at its semiannual 
meetings or more frequently, as needed. These summaries will include analyses comparing rates 
of adverse events (complications) by masked treatment group, by clinic, or in other subgroups 
requested by the DSMB. 
After each meeting, the DSMB will issue a written summary of its review of the study data, 
including adverse events (complications) and serious adverse events, for transmission to the 
IRBs at each of the study centers. Analyses or listings of adverse events will not be provided to 
the IRBs; however, adverse events involving unanticipated problems involving risks to 
participants, or breaches of protocol which might entail risk to participants must be reported to 
local IRBs as soon as possible after they are discovered. Each participating center is responsible 
for ensuring that all local IRB requirements for reporting adverse events are met. 
The DSMB will review semi-annual reports by masked treatment groups of the primary and 
secondary outcomes as well as all adverse events that are not identified as outcomes per se.  
Interim data on safety measures requested by the DSMB are reviewed at each of the scheduled 
semi-annual full meetings. Analyses will be prepared comparing rates of adverse events by 
treatment group, by clinical center or by other subgroups as requested by the DSMB. Serious 
adverse events will be reviewed by the medical monitor as they occur with the option of a 
teleconference if any DSMB member requests 
 
10. STATISTICAL CONSIDERATIONS 
 
10.1 Sample Size  
The study is well powered to address all of the specific aims. The primary driver of size is 
specific aim 1, which involves non-inferiority for death. We plan for a sample size of 12,200.  
Enrollment will continue up to 12,400 to account for the potential removal of post-randomization 
inappropriate enrollment and late ineligible patients for a total of up to 12,400 to be randomized, 
but 12,200 included in the final analytic sample. 
Our original sample size estimated the baseline rate of PE-related death was 0.25%. A non-
inferiority margin of 0.36% was based on the costs and administration benefits of aspirin as 
calculated from a discrete choice experiment of 232 orthopaedic trauma patients (Haac 2017). 
Using a noninferiority design, we calculated that a sample size of 12,200 patients would 
provide more than 95% to show that aspirin was noninferior to LMWH for the prevention of PE-
related death. The calculation used an alpha of 2.5% and accounted for two interim analyses and 
7.5% attrition. 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 37 
 
After changing the primary outcome from PE-related death to all-cause mortality, the estimated 
baseline rate increased from 0.25% to 1.0%. A non-inferiority margin of 0.75% was based on the 
patient-important benefits and a survey of experts and orthopaedic surgeons (Haac 2017). Using 
a noninferiority design, we calculate that a sample size of 12,200 patients would provide more 
than 95% to show aspirin was noninferior to LMWH in the preventing death.  If the probability 
of death is 1% in the LMWH arm and 1.75% in the aspirin, the study has less than 2.5% chance 
of declaring non-inferiority. 
 
10.2 Randomization 
 
Patients who provide consent to be enrolled in the study will be randomized electronically by the 
online Data Management System maintained at the Coordinating Center at the Johns Hopkins 
School of Public Health. Following consent, a randomization code is provided assigning 
treatment group and whether or not the participant was selected to be prospectively surveyed 
regarding out of pocket costs and treatment adherence. Randomization tables are encrypted and 
will not be shared with study investigators. While this study is not blinded, provision of linkages 
between randomization codes and treatment assignment will follow existing METRC unblinding 
SOP. Patients will be randomly assigned (within center) using block randomization with variable 
block sizes to either LMWH or aspirin. Compliance regarding the proper treatment protocols will 
be monitored by local Research Coordinators in cooperation with the attending surgeon. Any 
deviation from the assigned treatment group and the actual treatment received will be recorded.  
 
10.3 Missing Data and Measures to Minimize Bias 
 
Missing data is a serious concern that complicates the interpretation of the study results. For 
missing baseline data, we will use multiple imputation. We do not expect any missing outcome 
data for death or clinically significant PE. As with most prospective studies, missing data will be 
unavoidable, even with excellent follow-up. We will employ the following strategies to address 
missing data in the design, conduct, analysis and reporting of study results: (1) limit participant 
burden and inconvenience in data collection, (2) provide compensation for participation and 
completion in the study; (3) provide pre-study training of investigators and research staff to 
emphasize the importance of full participation in the study during the consent process (even if 
the patient is “feeling better”); (3) reimburse study sites based on follow-ups completed rather 
than on per-patient basis; (4) monitor and report missing data rates during the study and provide 
on-study reinforcement and support to ensure high follow-up rates; (5) collect information on the 
reasons for missing data; (6) actively engage participants in the study and educate them about the 
importance of their participation; and (7) collect surrogate information on participants who miss 
clinic visits; (8) require sites to go back and fill in missing data using medical record information 
when applicable; (9) carefully track and collect data on any discontinuations, to include the 
reasons for discontinuation, who decided that the participant would discontinue; and whether the 
discontinuation involves some or all types of participation; (10) avoid using single imputation 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 38 
 
methods and will employ multiple imputation strategies for handling missing information when 
necessary; (11) analyze data under a variety of modeling assumptions regarding how strongly the 
missingness mechanism is related to outcomes; (12) conduct sensitivity analyses to evaluate the 
robustness of the study results to various untestable assumptions about the missing data 
mechanism; (13) estimate treatment effects (utilizing relevant auxiliary information) under the 
missing at random assumption; (14) explore the effect of departures from the missing at random 
assumption using pattern-mixture and selection modeling techniques; and (14) we will account 
for all participants who enter the study in the reporting or our results whether or not they are 
included in the analysis.  
10.4 Planned Interim Analysis 
 
As described above, an independent Data and Safety Monitoring Board (DSMB) will monitor 
interim data as the trial progresses to ensure patient safety, review efficacy, evaluate recruitment, 
and assess overall data quality. O’Brien-Fleming stopping guidelines for efficacy will apply. The 
interim analysis will occur twice, once when the first third of patients are enrolled, and then 
again when two thirds of patients are enrolled, and will look specifically at the risk of death/PE 
among patients receiving aspirin relative to those receiving LMWH. After reviewing the results, 
the DSMB will then a formal recommendation as to whether the trial should continue 
unmodified, continue with protocol modifications, or to be stopped. 
 
10.5 Analysis Plan 
 
10.5.1 Intention to Treat Analysis 
Patients will be followed for 3 months post-randomization. The primary statistical analysis will 
follow the intention-to-treat paradigm, which means all patients will be analyzed according to the 
treatment group to which they were randomized. The primary estimand (difference in all-cause 
mortality between treatment groups) will be estimated using treatment-specific Kaplan-Meier 
estimators. The other intention-to-treat estimands will be estimated using treatment-specific 
cumulative incidence function estimators. Formal definitions of the estimands are provided in the 
Statistical Analysis Plan. 
 
We will test the primary outcome for non-inferiority using the upper bound of a two-sided 96.2% 
confidence interval compared to the pre-specified non-inferiority margin of 0.75%. If non-
inferiority is established at our pre-specific non-inferiority margin, we will test for superiority.  
 
Two-sided 95% confidence intervals will also be presented for all other outcomes, but null-
hypothesis significance tests will not be performed.  
 
10.5.2 Per-Protocol Analysis 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 39 
 
To understand treatment differences in the presence of non-adherence, we will perform a 
secondary per protocol analysis for the nine estimands. The per protocol estimands will only 
include the subset of patients classified as protocol adherent, based on the following definition. 
1. If the patient is prescribed thromboprophylaxis at discharge, the patient must be 
discharged on the allocated study medication. 
2. The patient must have been adherent for at least 80% of their in-hospital study 
medication doses.  
 
Dosage changes due to non-medical reasons, protocol crossovers due to non-medical reasons, 
and patient refusal to continue medication will be considered non-adherence. 
 
 
To the extent possible, we will adjust for key baseline covariates. Missing baseline covariates 
will be imputed using multiple imputation. 
 
 
10.5.3 Subgroup Analysis 
We will perform one subgroup analysis to assess the variation in treatment effect for our primary 
outcome based on patient age, specifically >60 years or age vs. ≤60 years of age. Interaction tests 
will be performed to assess heterogeneity of treatment effects. 
 
Further analysis details are provided in the Statistical Analysis Plan. 
 
11. QUALITY CONTROL AND QUALITY ASSURANCE  
 
11.1 Data Quality Assurance 
 
Quality Control (Q/C) and Quality Assurance (Q/A) procedures that apply to all studies are 
outlined in the METRC Manual of Operations (MOP). A certification process will be used as a 
basis for training and certification of the study personnel involved in data collection. In addition 
to consortium wide training and certification procedures, additional requirements may be added 
based on the nature of the study. Ongoing data edits and audits will be performed to ensure 
collection of quality data. The continuous and timely flow of data from the centers to the MCC is 
an essential prerequisite for maintaining data quality.  
Monthly enrollment reports will be distributed to each center that will summarize recruitment, 
data completion and timeliness of data entry. These reports will also include a set of queries 
generated by REDCap and sites will be asked to address these queries within 10 business days. 
 
11.2 Training and Certification of Centers 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 40 
 
All participating centers together with their respective study personnel will undergo certification 
that included training, local site IRB, and a knowledge assessment on the study design and 
procedures. This training will include a training for research coordinators in the submission of 
regulatory documents, data collection procedures, and study follow-up, as well as meetings 
between the PI, study project director, and the study team at each site to ensure that the 
procedures are well understood prior to engaging with research subjects. 
 
12. ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
12.1 IRB/Ethics Committee 
 
IRB approval will be obtained from the MCC at Johns Hopkins Bloomberg School of Public 
Health, the University of Maryland School of Medicine, and each participating clinical site 
according to METRC policies and procedures. Sites that recruit patients will submit METRC 
study recruitment materials to their organization’s IRB prior to use at that facility. 
Sites must provide the Coordinating Center with a copy of the initial IRB approval notice and 
subsequent renewals as well as copies of the IRB approved consent statements. 
No site can begin work related to this study until the site has been certified by the MCC in 
accordance with METRC policies and procedures. 
 
12.2 Exclusion of Women, Minorities, and Children (Special Populations) 
 
The proposed study anticipates recruiting a significant proportion of racial/ethnic minorities 
(African-Americans, Asian-Americans and Hispanics) as well as non-Hispanic white subjects. 
The study will not include children or prisoners. 
 
12.3 Participant Confidentiality 
 
It is the investigator’s responsibility to conduct the protocol under the current version of 
Declaration of Helsinki, ICH Guidelines, Good Clinical Practice, and rules of local IRBs. The 
investigator must ensure that the patient’s anonymity be maintained in their data submission to 
the Data Coordinating Center.  
 
Patients will be identified in the central data collection system, REDCap only by an 
identification code but not by their name, SSN, or hospital medical record number. Study Site 
Investigators will maintain a separate confidential enrollment log which matches identifying 
codes with the patients’ names and addresses available only to local clinic staff certified by the 
MCC to participate in the study.  
 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 41 
 
The participants who agree to participate in the adherence study will sign a local site-specific 
HIPAA authorization form allowing their contact information to be shared with the coordinating 
center so that follow up calls can be made.  
 
All study forms, reports, and other records that are part of the study data collection materials will 
be identified by coded number to maintain patient confidentiality. All paper records will be kept 
in locked file cabinets. All electronic records of study data will be identified by coded number. 
Clinical information will not be released without written permission of the patient, except as 
necessary for monitoring by the sponsor (MCC), IRB, or DSMB. Consent procedures and forms, 
and the communication, transmission and storage of patient data will comply with individual site 
IRB requirements for compliance with The Health Insurance Portability and Accountability Act 
(HIPAA). 
 
12.4 Study Discontinuation  
 
Participants will be informed that they may discontinue the study at any time, for any reason. 
They will be assured that the medical care which they receive at the participating facility will not 
be affected should they elect to discontinue participation in the study.  
13. DATA HANDLING AND RECORD KEEPING 
 
13.1 Data Management Responsibilities 
 
Each study site is responsible for collecting and uploading study data in a timely fashion. 
The research coordinators at each site will obtain the information necessary to complete the 
electronic case report forms (eCRFs) from several sources including but not limited to, the 
patient's medical record, clinical evaluations and patient interviews. The Site Research 
Coordinator will enter non-personally identifiable information into a central /and secured web-
based data management system being implemented for all Consortium studies, known as 
REDCap. This data management system has incorporated state-of-the-art features for electronic 
data collection and is configured in accordance with best practices for information technology 
and research data management.  
 
Data related to patient clinical course, as well as baseline characteristics and medication 
adherence will be collected prospectively by local research teams. Data related to the primary 
endpoints, pulmonary embolism and death, must be collected and certified by the local study 
investigators.    
 
All research data, in hard copy or electronic form, will be stored and managed in a secure 
manner following applicable federal regulations and ICH guidelines and according to 
institutional policies and practices. Hard copy documents generated by the sites which contain 
subject data, patient identifiers and contact information will be stored in secure, locked 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 42 
 
containers (file cabinets, drawers, etc.) in accordance with standard document management 
practices.  
 
At all times only MCC-certified key personnel specifically designated and authorized by the 
Principal Investigator shall have access to any research related documents, including electronic 
data and medical records. All such personnel will be properly trained and supervised regarding 
the management and handling of confidential materials. The Principal Investigator assumes full 
responsibility for such training, supervision, and conduct. This information will be available for 
audit by study monitors and representatives of the local IRB and the MCC. 
 
13.2 Data Capture Methods 
 
Data will be collected in real time by the investigator or study coordinator directly on electronic 
Case Report Forms (CRFs).  
 
13.3 Types of Data 
 
Data will include: medical and surgical histories, laboratory reports, radiology reports, clinical 
evaluations, medication administration records, adverse events and patient interviews.  
 
13.4 Source Documents and Access to Source Data/Documents 
 
Source documents laboratory results, patient surveys, medical records, etc. will be maintained at 
the site and will be made available to study monitors, and representatives of regulatory agencies 
including the MCC and IRB.  
 
13.5 Study Records Retention 
 
Study records will be maintained in accordance with current ICH guidelines. Data will be 
maintained for five years following the end of research-related activities, including data cleaning 
and analysis. At the end of this period, each site will provide the Coordinating Center a signed 
verification that these data have been destroyed. 
 
13.6 Protocol Deviations 
 
Records of protocol deviations will be noted on the Protocol Deviation CRF (AF05) with the 
reason for the deviation recorded, as well as any action taken to mitigate the deviation. This 
information will be entered into REDCap. These records will be provided to the site’s IRB in 
accordance with local reporting requirements and be made available to study monitors. 
 
14. PUBLICATIONS POLICY 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 43 
 
Publications will be written in accordance with the METRC publication policy (available on the 
METRC website: www.metrc.org). 
 
 
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Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
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in Orthopaedic Trauma Patients Version 11.0 6/1/2021 44 
 
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The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
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in Orthopaedic Trauma Patients Version 11.0 6/1/2021 45 
 
14. Haut ER, Lau BD, Streiff MB. New oral anticoagulants for preventing venous 
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thromboembolism prevention? results of a prospective discrete choice experiment. Under 
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physicians-1A protocol for lovenox in clinical outcomes for thromboembolic prophylaxis. J 
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anticoagulation for prevention of venous thromboembolism major lower extremity orthopedic 
surgery: A systematic review and meta-analysis. J Hosp Med. 2014;9(9):579-585. 
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alternative for pulmonary embolism prophylaxis after arthroplasty? Clin Orthop Relat Res. 
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24. An VV, Phan K, Levy YD, Bruce WJ. Aspirin as thromboprophylaxis in hip and knee 
arthroplasty: A systematic review and meta-analysis. J Arthroplasty. 2016;31(11):2608-2616. 
25. Ogonda L, Hill J, Doran E, Dennison J, Stevenson M, Beverland D. Aspirin for 
thromboprophylaxis after primary lower limb arthroplasty: Early thromboembolic events and 90 
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Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
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in Orthopaedic Trauma Patients Version 11.0 6/1/2021 47 
 
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trauma patients: A survey of OTA member practice patterns and OTA expert panel 
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27. Wong A, Kraus PS, Lau BD, et al. Patient preferences regarding pharmacologic venous 
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pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary 
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The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 48 
 
31. Atkinson MJ, Sinha A, Hass SL, et al. Validation of a general measure of treatment 
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undergoing bariatric surgery. Vasc Health Risk Manag. 2015;11:461-477. 
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Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 49 
 
37. Stewart DW, Freshour JE. Aspirin for the prophylaxis of venous thromboembolic events in 
orthopedic surgery patients: A comparison of the AAOS and ACCP guidelines with review of 
the evidence. Ann Pharmacother. 2013;47(1):63-74. 
38. Anderson DR, Dunbar MJ, Bohm ER, et al. Aspirin versus low-molecular-weight heparin for 
extended venous thromboembolism prophylaxis after total hip arthroplasty: A randomized trial. 
Ann Intern Med. 2013;158(11):800-806. 
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The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
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in Orthopaedic Trauma Patients Version 11.0 6/1/2021 50 
 
17. APPENDICES 
APPENDIX A: STUDY CONTACT ROSTER 
Principal Investigator (Protocol Chair) 
Robert V.O’Toole, MD 
Professor of Orthopaedic Trauma 
University of Maryland School of Medicine 
22 S Greene St 
Baltimore, MD 21201 
Phone: 410-328-2391 
E mail: ROtoole@umoa.umm.edu 
 
 
METRC Coordinating Center Study Principal 
Investigator 
Renan Castillo, PhD 
Associate Professor 
Johns Hopkins Bloomberg School of Public Health 
624 N Broadway, 5th Floor 
Baltimore, MD 21205 
Phone: 410-614-4025 
Email: rcastil1@jhu.edu 
 
 
 
 
Medical Monitor 
 
Marc Swiontkowski, MD  
Professor of Orthopaedic Surgery 
University of Minnesota  
2512 South 7th Street 
Suite R200 
Minneapolis, MN 55454 
Phone: (612) 273-8000 
Email: swion001@umn.edu 
 
 
METRC Coordinating Center  
 Clinical Research Manager 
Katherine Frey, RN, MPH 
Assistant Scientist 
Johns Hopkins Bloomberg School of Public Health415 
N Washington St, 3rd Floor 
Baltimore, MD 21205 
Phone: 410-502-9109 
Email: kparris1@jhu.edu 
 
METRC Coordinating Center Project Director  
Tara Taylor, MPH 
Johns Hopkins Bloomberg School of Public Health415 
N Washington St, 3rd Floor 
Baltimore, MD 21205 
Phone: 410-614-6081 
Email: ttaylo56@jhu.edu 
 
METRC Coordinating Center  
Director of Data Management 
 
Anthony Carlini, MS 
Johns Hopkins Bloomberg School of Public Health 
Dept of Health Policy and Management 
624 N. Broadway Room 501 
Baltimore MD, 21205 
Phone: 410-502-8455 
Email: acarlini@jhsph.edu 
 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 51 
 
 APPENDIX B: DATA COLLECTION SCHEDULE 
Assessment 
Baseline 
Baseline 
– 3 
months 
3 month 
CRF00: Inclusion/Exclusion  
X 
 
 
CRF01: Patient Contact Information 
X 
 
 
CRF02: Patient Characteristics 
X 
 
 
Demographics  
• DOB 
• Age 
• Sex 
• Race 
• Height  
• Weight 
• Tobacco use 
• Health Insurance  
• Education 
• Adherence Estimator  
 
 
 
CRF03: Medical History 
X 
 
 
• Medications taken Prior to Injury 
o OCP or Estrogen use 
o Antiplatelet agent 
o ASA daily use 
o Blood thinners 
o NSAIDs (daily use or prescription) 
• Co-morbidities  
o Charlson Comorbidity Index 
o History of VTE, peptic ulcer, DM 
o Cancer 
o Immunosuppression 
 
 
 
CRF04: Injury Characteristics 
X 
 
 
• Injury date/time 
• Circumstances  
• Type of Injuries (orthopaedic/non-orthopaedic) 
• Side of Injuries  
• AO/OTA Fracture classification  
• Gustilo Classification 
• Tscherne Classification of Soft Tissue Injuries 
• Injury Severity Score, TRISS, ICU days, 
ventilator days, and ICD-9 codes 
 
 
 
CRF05: Index Hospitalization 
X 
 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 52 
 
Assessment 
Baseline 
Baseline 
– 3 
months 
3 month 
• Admission date/time 
• Discharge date/time 
• Discharge outcome (discharged/death) 
• Admission labs (if tested) 
o INR 
o PTT 
o Platelets 
o Max serum lactate (first 24 hours) 
o Creatinine  
o TEG parameters (if ordered) 
• Surgical data 
o Surgery info (ortho/non-ortho surgeries)  
§ Dates 
§ Total number of surgeries  
§ Weight bearing status on discharge  
o Total number of surgeries (ortho/non-
ortho) 
• Imaging studies (and results) conducted for 
bleeding or VTE  
o Angiogram 
o Ventilation perfusion (VQ) scan 
o Duplex scan/ultrasound 
o CT angiogram (CTA) 
o MRI 
o Other 
• Complications 
o fatal bleed 
o ≥2g/dL drop in hemoglobin 
o reoperation for hematoma evacuation 
o other clinical significant bleeding  
o infectious complication 
o VTE 
o PE 
• Concomitant meds 
o LMWH 
o Aspirin 
o Plavix 
o platelet inhibitors 
o NSAIDs 
 
 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 53 
 
Assessment 
Baseline 
Baseline 
– 3 
months 
3 month 
o Anticoagulation medications outside 
treatment assignment 
CRF06: VTE Prophylaxis (Inpatient) 
X 
 
 
• Pre & Post Randomization Prophylaxis Use 
• Treatment Arm: Aspirin Dosage (Dose, Dose 
Unit, Route, Date/Time of Start/Stop of 
Administration) 
• Treatment Arm: LMWH Dosage (Dose, Dose 
Unit, Route, Date/Time of Start/Stop of 
Administration) 
• Reasons prophylaxis held or discontinued (if 
applicable)  
• Doses ordered vs doses received or missed & 
reason missed 
• Treatment crossover information: number of 
doses & therapeutic anticoagulation therapy status 
(date, dose, reason) 
 
 
 
CRF07: Clinical Follow-up  
 
 
X 
• Documented prescribed prophylaxis and duration 
• Out of pocket costs 
• Satisfaction 
• Prescribed medications 
• Any other treatment for PE/VTE event  
• Re-hospitalizations related to PE/VTE event– 
review medical records 
• Imaging studies 
• Post discharge surgeries 
o Planned elective surgeries 
• Complications (type, severity, treatment)  
o Fatal bleed 
o GI bleed 
o ≥2g/dL drop in hemoglobin 
o reoperation for hematoma evacuation 
o other clinical significant bleeding  
o infectious complication 
o VTE 
o DVT (blood clot in arms/legs) 
o Pulmonary Embolism 
o Imaging studies for bleeding or VTE 
 
 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 54 
 
Assessment 
Baseline 
Baseline 
– 3 
months 
3 month 
o Surgical wound infection 
o Surgical wound hematoma 
o Abnormal postoperative bleeding 
o Any complications secondary to treatment 
since hospitalization 
CRF08: Patient Follow-up 
 
 
X 
• Hospitalizations r/t PE/VTE outside the study 
center 
• TSQM: Treatment Satisfaction Questionnaire for 
Medication  
 
 
 
CRF09: Diagnosis of Infection 
X 
X 
X 
• CDC Criteria 
• Culture Data 
• Lab Data 
• Imaging Studies 
• Wound Characteristics  
• Time to Wound Closure 
• Type of Soft Tissue Coverage 
• Limb Complications (type, severity, treatment) 
 
 
 
CRF10: SAE 
X 
X 
X 
Unanticipated events possible related to exposure to study 
medications (angioedema, agranulocytosis, hepatic 
injury, Stevens Johnson syndrome), other events that are 
serious and either related or possibly related to the study, 
other events that are unexpected and serous and either 
related or possibly related to the study beyond the 
expected complications.  
 
 
 
 
 
 


The PREVENT CLOT study protocol is the confidential intellectual property of the PREVENT CLOT 
Principal Investigators, Steering Committee, and the University of Maryland Baltimore and METRC and 
cannot be used in any form without the expressed permission of the Principal Investigators. 
A Randomized Pragmatic Trial Comparing the Complications and Safety of Blood Clot Prevention Medicines Used 
in Orthopaedic Trauma Patients Version 11.0 6/1/2021 55 
 
 
 
 


Summary of Protocol Amendments 
The following summarizes the major actions taken regarding the master protocol.  
 
Date  
Action  
3/1/2017  
Johns Hopkins Bloomberg School of Public Health IRB (JHBSPH) granted initial 
approval. 
4/11/2017 
Initial protocol distributed to sites for submission. 
5/26/2017  
 
Amendment for V2 of the protocol approved by JHBSPH IRB. Amendment adds 
procedures for monitoring adherence and updates consent and recruitment materials. 
7/27/2017 
V2 of the protocol distributed to sites for submission. 
8/16/2017  
 
Amendment for V3 of the protocol approved by JHBSPH IRB. Amendment corrects an 
omission error in the exclusion criteria when updates were made from V1 to V2 of the 
protocol. 
8/18/2017 
V3 of the protocol distributed to sites for submission. 
10/18/2017  
Administrative amendment updating brochure language approved by JHBSPH IRB. 
11/27/2017 
Updated brochure distributed to sites for submission. 
1/3/2018  
Amendment updating text of patient satisfaction questionnaire approved by JHBSPH 
IRB. 
1/12/2018 
Updated questionnaire distributed to sites for submission. 
9/27/2018  
Amendment updating recruitment material to add a weekly adherence survey postcard 
approved by JHBSPH IRB. 
11/6/2018  
Amendment making changes to the weekly adherence follow-up instrument questions 
and change of medical monitor approved by JHBSPH IRB. 
12/17/2018 
Amendment updating patient follow up questionnaire approved by JHBSPH IRB. 
Weekly adherence postcard, updated patient follow up questionnaire and change in 
medical monitor distributed to sites for submission. 
6/19/2019  
 
Amendment to modify follow-up procedures to allow for abstraction of medical records 
for participants who do not return for a research visit approved by JHBSPH IRB. 
6/26/2020  
 
Amendment to update protocol with add the capability of screening and enrollment to 
be conducted remotely by research coordinators in collaboration with on-site advanced 
practice providers in response to the COVID-19 pandemic. 
8/14/2020 
Amendment to update protocol to obtain COVID-19 status of all patients enrolled since 
March 2020 and moving forward. 
9/25/2020  
 
Amendment to update protocol to exclude patients with COVID-19 and collect COVID-
19 status on all patients enrolled since January 2020. Expanded lost to follow up search 
options using Limited Access Death Master File (LADMF) of protocol and consent 
form. 
1/22/2021  
 
Amendment to update protocol to change the primary outcome to all-cause mortality, 
update non-inferiority margin to 0.70%, remove specific aims 3 & 4, remove 1 month 
window-based follow up, add data collection of ICD-9 codes. 
6/1/2021  
Amendment to add postcard, text message, and calls for additional follow up.  
8/6/2021  
Amendment to update total recruitment to 12,400 patients, add phone call/text 
centralized follow up by coordinating center for lost to follow up patients, remove 6-
month limit on medical record review on lost to follow up patients, add use of 
LexisNexis Accurint System for lost to follow up patients, add follow up post card. 
Approved by JHSPH IRB. 


PREVENT CLOT:
Statistical Analysis Plan for Main Outcome Paper
January 21, 2021
The statistical analysis plan was ﬁnalized prior to database lock. Prior
to database lock, the only analyses that were performed were (1) those
masked to treatment group for purposes of DSMB reporting, (2) a formal
DSMB interim analyses of the primary outcome after approximately 4,000
and 8,000 patients completed follow-up.
Per DSMB approval, the study team had access to the following infor-
mation (masked to treatment arm, site-stratiﬁed) during the course of the
trial:
• Crossovers: in-patient, at discharge and overall
• Equipoise: discharge without prophylaxis, DVT imaging and PE imag-
ing
1
Randomization, Treatment Initiation, Time Zero
Prophylaxis medication is typically administered in 12 hour increments. Pa-
tients may receive up to two doses of prophylaxis prior to enrollment/randomization
into the study. After randomization, their next dose of prophylaxis is to
be according to their randomized treatment. There will typically be a lag
between randomization and initiation of randomized treatment. Lags can
occur for a multitude of reasons, as depicted by these examples:
1. Patient is enrolled/randomized at 8 am after 7 am medication. Next
dose is 7pm. Lag is 11 hours.
2. Patient is enrolled/randomized at 8 am after 7 am medication, but she
is sent to the operating room at 6 pm and all medications are held.
Next dose is 7 am next day. Lag is 24 hours.
1


3. Patient is planned for prophylaxis, but due to another injury and risk
of bleeding (e.g., head injury), they will be delayed by several days. Pa-
tient enrolled/randomized but medication is not started until cleared
for prophylaxis 3 days later. Lag is 96 hours.
There could possibly be di↵erences between medication initiation between
treatment arms, particularly in a small subgroup of patients. To address
this issue, we will set time zero to be time of randomization.
2
CONSORT Diagram
The CONSORT Diagram will report the following items in sequential order:
1. the number screened patients
2. number of eligible patients
3. the number of patients not enrolled and associated reasons
4. the number of enrolled and randomized patients
5. number randomized to aspirin group, number randomized to low-
molecular-weight heparin (LMWH) group
6. within treatment group, the number of late ineligibles, late refusals,
and inappropriate enrollments
7. within treatment group, the number initiating treatment protocol
8. within treatment group, information on 90 day follow-up (including
separate metrics for key endpoints)
9. within treatment group, the number included in the per-protocol anal-
ysis
The independent adjudication committee will make the ﬁnal determination
on late ineligibles and inappropriate enrollments while masked to the treat-
ment arm. Late ineligibles and inappropriate enrollments will be removed
from all analyses. The outcomes, complications, adverse events of late in-
eligibles and inappropriate enrollments who received treatment will be re-
ported, to the extent possible.
2


3
Follow-up Time
Patients were expected to return for a study follow-up visit at 90 days post
admission. If participants are unable to return to the clinic, they may be
contacted to complete the 90 days follow up visit via phone or email. In
addition, medical record reviews will be conducted to determine whether
there was documented clinical/research contact beyond the last study follow-
up visit. If that visit occurred less than 90 days following randomization,
the end of follow up will be deﬁned as the last study follow-up visit or the
last clinical/research contact if applicable, and follow-up time will be the
duration between randomization and the end of follow up. A ﬁgure showing
the distribution of follow-up time through 90 days by treatment group will
be produced. Di↵erences between treatment groups based on follow-up time
through 90 days will be evaluated. Details of reasons for premature study
discontinuation will be presented.
4
Baseline Characteristics
A table will report summary statistics of baseline characteristics of partici-
pants by treatment groups. Characteristics will include age, sex, body mass
index, tobacco use, history of venous thromboembolism, co-morbidities, ad-
ditional medications, health insurance status, injury severity score, and in-
jury region.
5
Adherence to Treatment Protocol
As a pragmatic trial, it is up to the treating surgeon to determine the du-
ration of medication of the assigned treatment based on the risk proﬁle of
the patient. As such, duration of medication will vary from person to per-
son. To be classiﬁed as adherent to treatment, the patient must meet the
following criteria:
1. If the patient is prescribed thromboprophylaxis at discharge, the pa-
tient must be discharged on the allocated study medication.
2. The patient must have been adherent for at least 80% of their in-
hospital study medication doses.
Dosage changes due to non-medical reasons, protocol crossovers due to non-
medical reasons, and patient refusal to continue medication will be consid-
3


ered non-adherence. Summary statistics related to in-hospital and discharge
protocol non-adherence will be presented by treatment arm.
6
Serious Adverse Events
By deﬁnition, serious adverse events (SAEs) are severe, undesirable, unex-
pected events that are potentially related to study participation. All SAEs
are reported to the Medical Monitor, who makes a determination of related-
ness and required action (e.g., stopping medication, informing other sites).
A table will report SAEs and relatedness, stratiﬁed by treatment group.
7
Outcome Analyses
7.1
Ascertainment
The primary way in which clinical outcome events are ascertained is through
standard of care clinical interactions, medical record review, review of the
Limited Access Death Master File records, other available death registries,
and, in some cases, phone calls.
7.2
Adjudication
For our secondary outcome of cause-speciﬁc death, all deaths will be adju-
dicated into one of the following ﬁve categories in terms of certainty of a
pulmonary embolism (PE): (a) Certainly PE, (b) More likely PE than some-
thing else, (c) Equally likely to be PE than something else, (d) More likely
something else than PE and (e) Deﬁnitely not PE. For patients in categories
(d) or (e), adjudicators will indicate the most likely cause of death.
7.3
Estimands
Throughout this section, death is considered as an event that preempts the
observation of any future events. In contrast, we consider those individuals
lost-to-followup as being at-risk for future events.
7.3.1
Intention to Treat Analysis
Our primary analysis will use an intention to treat approach. The primary
estimand (1) will be estimated using treatment-speciﬁc Kaplan-Meier es-
timators. The other intention-to-treat estimands will be estimated using
4


treatment-speciﬁc cumulative incidence function estimators.The study has
more than 90% power to address Estimand (1).
7.3.2
Primary Estimand
All-Cause Mortality
1. Di↵erence (aspirin minus LMWH) in the probability of dying due to
any cause by 90 days for eligible patients under assigned treatment, in
a world without loss-to-followup.
7.3.3
Secondary Eﬃcacy Estimands
Cause-Speciﬁc Mortality
2. Di↵erence (aspirin minus LMWH) in the probability of being observed
to die due to PE (using categories a and b from Section 7.2) by 90
days for eligible patients under assigned treatment, in a world without
loss-to-followup;
3. Di↵erence (aspirin minus LMWH) in the probability of being observed
to die due to PE (using categories a, b and c from Section 7.2) by 90
days for eligible patients under assigned treatment, in a world without
loss-to-followup;
4. Di↵erence (aspirin minus LMWH) in the probability of being observed
to die due to non-PE (must be in category d or e from Section 7.2)
causes of death (e.g., myocardial infarction, stroke, bleeding) by 90
days for eligible patients under assigned treatment, in a world without
loss-to-followup;
Non-Fatal Pulmonary Embolism
5. Di↵erence (aspirin minus LMWH) in the probability of being observed
to have a non-fatal PE by 90 days for eligible patients under assigned
treatment, in a world without loss-to-followup, where non-fatal PE
will be categorized in (i) aggregated, (ii) sub-classiﬁed as massive,
sub-massive, clinically signiﬁcant, clinically non-signiﬁcant and (iii)
sub-classiﬁed as segmental, non-segmental;
Deep Vein Thrombosis
6. Di↵erence (aspirin minus LMWH) in the probability of being observed
to have a DVT by 90 days for eligible patients under assigned treat-
ment, in a world without loss-to-followup; where DVT will be catego-
rized as (i) any, (ii) proximal, and (iii) distal.
5


7.3.4
Secondary Safety Estimands
Major Bleeding Event
7. Di↵erence (aspirin minus LMWH) in the probability of being observed
to have a bleeding event by 90 days for eligible patients under assigned
treatment, in a world without loss-to-followup;
Wound Complication
8. Di↵erence (aspirin minus LMWH) in the probability of being observed
to have a wound complication by 90 days for eligible patients under
assigned treatment, in a world without loss-to-followup.
Deep Surgical Site Infection
9. Di↵erence (aspirin minus LMWH) in the probability of being observed
to have a deep surgical site infection by 90 days for eligible patients
under assigned treatment, in a world without loss-to-followup;
7.3.5
Per Protocol Analysis
To understand treatment di↵erences in the presence of non-adherence, we
will perform a secondary per protocol analysis for the nine estimands. The
per protocol estimands will only include the subset of patients classiﬁed as
protocol adherent, as deﬁned in Section 5. To the extent possible, we will
adjust for a limited set of key baseline covariates. Missing baseline covariates
will be imputed using multiple imputation.
7.4
Analytic Strategy
• We will test Estimand 1 for non-inferiority using the upper bound of
a two-sided 96.2% conﬁdence interval compared to the pre-speciﬁed
non-inferiority margin of 0.75%.
• If non-inferiority is established at our pre-speciﬁed non-inferiority mar-
gin, we will test for superiority.
• Two-sided 95% conﬁdence intervals will also be presented for Esti-
mands 2-9 but null-hypothesis signiﬁcance tests will not be performed.
6


7.5
Subgroup Analyses
We will perform one subgroup analysis to assess the variation in treatment
e↵ect for our primary outcome based on patient age:
1. Age > 60 vs. Age 60
Interaction tests will be performed to assess heterogeneity of treatment ef-
fects.
7.6
Comments
• Due to low event rates, it may be impossible to compute reliable con-
ﬁdence intervals.
• We recognize that precision can be increased by leveraging baseline
covariates. To the extent possible, we will leverage age, injury severity,
and other key characteristics.
8
Change in Primary Outcome
The primary study outcome was changed from PE-related death to all-cause
mortality during the course of the trial.
At the recommendation of an external peer reviewer for the protocol
manuscript, the trial’s steering committee determined that it was infeasible
to adjudicate death due to pulmonary embolism (PE) with reasonable cer-
tainty. Misclassiﬁcation of the primary outcome of PE-related death would
bias the results to non-inferiority. As such, the trial’s steering committee
decided to change the primary outcome from PE-related death to all-cause
mortality.
All-cause mortality was viewed as more important than PE-
related death by our patient stakeholder and protocol committees and had
greater scientiﬁc reliability. The change in the primary outcome increased
the anticipated base rate from 0.25% to 1.00% leading to an increase in the
non-inferiority margin from 0.36% to 0.75% to maintain the target sample
size of 12,200 and over 90% power. The DSMB was not involved in these
decisions due to their masked knowledge of treatment e↵ect from interim
analyses. The decision of the trial’s steering committee to change the pri-
mary outcome and non-inferiority margin was supported by the protocol
committee, patient stakeholder committee, and sponsor.
7


Prepared by:
Daniel O. Scharfstein (ScD), Principal Biostatistician
Approved by:
Robert V. O’Toole (MD), Principal Investigator
Renan Castillo (PhD), Co-Principal Investigator.
Deborah M. Stein (MD, MPH), Co-Principal Investigator
Nathan O’Hara (MHA), Co-Investigator
8
SIGN