Clinical trial NCT04042233
Conditions: Prosthetic Joint Infection Vancomycin Joint Diseases
Keywords: total hip arthroplasty vancomycin intraosseous vancomycin
Sponsor: The Methodist Hospital Research Institute
Start date: 2019-12-31; Completion date: 2022-09-01
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to evaluate a novel vancomycin intraosseous administration protocol vs a standard IV vancomycin administration protocol for primary total hip arthroplasty patients.

Detailed description:
Patients are randomized to one of two groups.

GROUP A - Will receive IV antibiotics (cefepime \& vancomycin) are started in pre-op approximately 1 hour prior to incision vancomycin dose weight-based at approximately 15mg/kg, generally 1000-1750mg in 500 milliliters (mL) normal saline (NS).

GROUP B - Will have IV cefepime started in pre-op within 1 hour of incision. Intraosseous (IO) administration of vancomycin (500mg in 250 milliliters NS) will be administered in the OR after sterile prep and draping has occurred. Injection will take place into the greater trochanter (within a pre-specified region).

Both Groups will be monitored during surgery and immediately post-operatively for adverse injection reactions (i.e. Red Man Syndrome). Both groups will otherwise follow identical post-operative protocols (including post-operative antibiotic administration).

TISSUE SAMPLES Five (5) tissue samples will be taken from each patient, 2 soft tissue samples and 3 bone samples will be taken throughout the course of the procedure.

One blood sample will be taken in both groups intraoperatively at the time of initiation of closure.

These samples will immediately be sent to a lab for analysis.

Arms: arm 1: Standard IV vancomycin administration protocol. arm 2: Experimental Intraosseous administration protocol.
Interventions: intervention 1: Experimental Intraosseous vancomycin 500mg in 250 mL NS intervention 2: Standard IV administration of vancomycin
Intervention descriptions: intervention 1: 500mg of Vancomycin in 250 mL of normal saline will be injected into a pre-specified region of the greater trochanter during primary total hip arthroplasty. intervention 2: IV antibiotics (cefepime \& vancomycin) are started in pre-op approximately 1 hour prior to incision (vancomycin dose weight-based at approximately 15mg/kg, generally 1000-1750mg in 500 mL NS).

Protocol documents:
Prot_001.pdf: 
Intraosseous Vancomycin in Primary Total Hip Arthroplasty – Designing a Protocol:  
Page 1 of 10 
HMRI Basic Protocol Template v12062019 
 
NCT: 04042233 
 
 
 
PROTOCOL TITLE: 
Intraosseous Vancomycin in Primary Total Hip Arthroplasty – Designing a Protocol 
 
 
Document Date: 4/25/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Intraosseous Vancomycin in Primary Total Hip Arthroplasty – Designing a Protocol:  
Page 2 of 10 
HMRI Basic Protocol Template v12062019 
 
 
INSTRUCTIONS: 
 
 
PROTOCOL TITLE: 
Intraosseous Vancomycin in Primary Total Hip Arthroplasty – Designing a Protocol 
 
PRINCIPAL INVESTIGATOR  
Terry Clyburn 
Houston Methodist Hospital / Orthopedic Surgery 
 
CO-INVESTIGATORS/ COLLABORATORS: 
Francesca Taraballi, PhD / Houston Methodist Research Institute 
Stephen Incavo, MD / Houston Methodist Hospital / Orthopedic Surgery 
Timothy S. Brown, MD  / Houston Methodist Hospital / Orthopedic Surgery 
Kwan Park, MD / Houston Methodist Hospital / Orthopedic Surgery 
 
SPONSOR / FUNDING AGENCY  
N/A 
 
 
VERSION NUMBER/DATE  
 
 
REVISION HISTORY 
   
 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change 
(Yes/No) 
1 
12/3/2021 
Adding doctors Timothy Brown, Kwan Park, and 
Stephen Incavo as sub-investigators. Edited intra-
operative sample collection procedures to include 
glut max at start and end of the case, pulvinar 
tissue sample, and an additional systemic sample 
taken at incision. These samples gathering changes 
were made in order to ensure more consistent 
sample gathering across all participating 
physicians on the study. The additional systemic 
Yes 


Intraosseous Vancomycin in Primary Total Hip Arthroplasty – Designing a Protocol:  
Page 3 of 10 
HMRI Basic Protocol Template v12062019 
 
sample taken at incision was added to include a 
baseline systemic vancomycin level present at the 
initiation of the surgical case. 
2 
4/25/2022 
Changed 15 patients per group to 20 to ensure the 
research team is able to recruit 30 patients under 
the current intraoperative sample protocol. Edited 
section 19 of protocol to include additional 
justification for HIPAA waiver. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Study Summary  
N/A  
 
2. Purpose of the Study / Objectives  
 
Purpose of this study is to compare two different antibiotic regimens and techniques during total 
hip arthroplasty.  
 
Primary Objective: Comparable levels of vancomycin will be found in bone, soft tissue, and 
systemic samples between patient groups. 
 
Secondary Objective: Compare 30 day and 90 day post-operative complication rates (infection) 
between the control (standard IV administration of vancomycin) vs the interventional group 
(intraosseous administration of vancomycin). The research team hypothesizes that there will be 
no difference in complication (infection) rates between groups. 
 
3. Background 
 
Vancomycin is commonly used as a prophylactic antibiotic for total joint replacement surgery in 
an attempt to protect against methicillin resistant staph aureus (MRSA). Recent literature has 
suggested that using intraosseus (IO) infusions are capable of providing equivalent systemic 
values to those administered via intravenous (IV) access [1,2]. Because of these findings, some 
began to consider that IO infusions could be a better way to administer prophylactic surgical 
antibiotics. A prospective, randomized study in Australia evaluated the local and systemic 
concentrations of vancomycin after IO vs. IV administration and found that low-dose IO 
vancomycin resulted in tissue concentrations equal or superior to those of systemic 
administration [3]. The researchers concluded that IO optimizes timing of vancomycin 
administration, and the lower dose may reduce the risk of systemic side effects while providing 
equal or enhanced prophylaxis in TKA [3]. Literature has shown that this benefit remains intact, 


Intraosseous Vancomycin in Primary Total Hip Arthroplasty – Designing a Protocol:  
Page 4 of 10 
HMRI Basic Protocol Template v12062019 
 
even for those with a higher BMI [4]. No protocol exists for the use of IO in total hip 
arthroplasty (THA). While literature supports the greater trochanter and anterior superior iliac 
spine as viable intraosseus administration locations [5], the practicality of using such a location 
outside of the pediatric population has not been assessed. We intend to test whether or not IO 
protocols are a feasible option in the administration of vancomycin prior to THA. 
4. Study Design 
 
This study is a prospective, randomized, single-blinded, controlled trial. 20 patients in each 
treatment arm: 20 patients will be given IV vancomycin, 20 patients will be given IO 
vancomycin.  
 
 
Control – Standard IV administration of vancomycin 
• Patients will receive the Houston Methodist Hospital orthopedic surgeon’s standard of 
care pre-operative antibiotic regimen for primary total hip arthroplasty patients. This 
includes IV abx (typically ancef or cefepime and vancomycin) will be started in the pre-
operative period approximately 1 hour prior to incision (vancomycin dose weight-based 
at approximately 15mg/kg [6,7] generally 1000-1750mg in 500mL NS). 
 
 
Intervention – Intraosseous (IO) administration of vancomycin 
• IV antibioitcs (per physician’s standard of care): Typically ancef or cefepime is started 
in pre-op within 1 hour of incision 
• IO vancomycin is administered in the OR after sterile prep and draping has occurred 
(500mg in 150mL NS). 
• Injection will take place into the greater trochanter (within a pre-specified region)  
 
 
All patients in both groups will be monitored during the surgery and immediately post-
operatively for adverse injection reactions (i.e. Red Man Syndrome) as this is the standard of 
care. 
 
All patients (IV and IO) will otherwise follow identical post-operative protocols (including post-
operative antibiotic administration) 
 
Intra-Op Sample Collection 
Samples will be taken from the following locations at the following times: 
o Systemic Sample – Start of Case 
▪ A vancomycin blood level will be drawn by the anesthesiologist staff 
(CRNA, MD) at the start of incision and should occur simultaneously with 
the final soft tissue sample collection above  
o Soft tissue sample – Glut Max Start 
▪ A small soft tissue sample will be taken from the glut max upon entering 
the hip joint. This sample will only be taken if it is readily available for the 
surgeon to gather. 


Intraosseous Vancomycin in Primary Total Hip Arthroplasty – Designing a Protocol:  
Page 5 of 10 
HMRI Basic Protocol Template v12062019 
 
o Bone Sample – Bone from Femoral Head 
▪ After the femoral neck is cut with the “cookie cutter” instrument a portion 
of femoral head/neck will be removed and placed in a separate specimen 
jar (remainder of head will be sent to pathology as usual). 
o Soft Tissue sample - Pulvinar 
▪ A sample will be taken from Pulvinar tissue located between the 
acetabulum and femoral head. 
o Bone Sample – Acetabulum Reamings 
▪ The reamings from the first acetabulum reamer will be placed in a 
specimen jar for testing. 
o Bone Sample – Intramedullary Bone 
▪ Just prior to insertion of final femoral implant (after removal of trial 
implants) a small portion of intramedullary bone will be taken for sample 
and placed in a specimen cup 
o Soft Tissue Sample – Glut Max End 
▪ A small soft tissue sample will be taken from the glut max prior to 
initiation of wound closure. This sample will only be taken if it is readily 
available for the surgeon to gather. 
o Systemic Sample 
▪ A vancomycin blood level will be drawn by the anesthesiologist staff 
(CRNA, MD) at the time of initiation of closure and should occur 
simultaneously with the final soft tissue sample collection above  
 
 
Inclusion Criteria 
• Patient is undergoing a primary total hip arthroplasty. 
• Patient gives informed consent to participate in the study. 
• Age Range >18 
 
Exclusion Criteria 
• Previous surgery on the hip (including hip scopes) 
• BMI above 35 
• Contraindication to receiving vancomycin, cefepime, ancef, or other standard of care 
pre-operative antibiotic (allergy, medical issue, etc). 
• Inability to locate the greater trochanter or administer the IO infusion 
• Refusal to participate 
• Diabetes 
• Immunocompromised or immunosuppressed patients (HIV, Hep C, ESRD, dialysis, 
transplant, chemo/radiation treatment in last 6 months, medications) 
 
Data Variables to be Recorded 
• Age (calculated from DOB), date of surgery, discharge date, sex, laterality, study group, 
pre-op creatinine, post-op creatinine, systemic vancomycin level at incision, soft tissue 
vancomycin level (glut max start, pulvinar tissue, glut max end), femoral head bone 
sample vanc level, acetabulum reamings vanc level, intramedullary bone vanc level, and 


Intraosseous Vancomycin in Primary Total Hip Arthroplasty – Designing a Protocol:  
Page 6 of 10 
HMRI Basic Protocol Template v12062019 
 
systemic vancomycin level at initiation of wound closure. Additionally, adverse 
local/systemic reactions as determined from patient’s chart, 30-day complications, 90-day 
complications, cost, time from antibiotic administration to incision, operative time, and 
incision time. 
5. Study Intervention  
 
All research procedures include the intra-operative sample collections (tissue, bone, and systemic 
blood sample). If the patient is randomized into the interventional group (IO injection of 
vancomycin) then instead of receiving pre-operative IV vancomycin they will receive it 
intraoperatively through IO injection. These are the only changes to the patient’s care during 
their hospital stay. All other pre-operative and post-operative care will be standard of care 
including pre-operative, peri-operative, and post-operative monitoring. There will be no 
additional study visits and the anticipated time the subject will be in the study is 90 days. The 
research anticipates it will take 1 years to enroll all study subjects and for investigators to 
complete primary analyses. 
  
 
6. Drugs, Biologics, Devices  
 
N/A 
7. Collaborative / Multi-site Research 
 
N/A 
8. Data Privacy / Confidentiality  
 
 
Houston Methodist policies for Protected Health Information will be followed, including all 
requirements for physical and electronic data security, use of encrypted devices and HM 
password protected servers. All data for this study will be complete, accurate, original, and 
legible. All physical study data such as data recorded in the intra-operative sample collection 
sheet will be stored in a locked office cabinet of a qualified member of the research team. All 
electronic data will be password protected and only accessible by members of the research team. 
The data for this study will be maintained indefinitely. Any data that is published as a result of 
this study will be completely de-identified including the removal of any PHI. 
 
The only PHI being used by the research team for this study are dates including discharge dates 
and birth date (to determine age at time of surgery) as well as MRNs. The use of identifiable data 
is necessary for the research team to confirm past medical history (example: Diabetes) for the 
inclusion/exclusion criteria. No PHI will ever be disclosed beyond Houston Methodist. This data 
will be stored along with other data recorded from Epic on password protected servers accessible 
only to qualified members of the research team. 


Intraosseous Vancomycin in Primary Total Hip Arthroplasty – Designing a Protocol:  
Page 7 of 10 
HMRI Basic Protocol Template v12062019 
 
 
 
Identifier (or parts of)  
Recorded  Disclosed  Comment 
Names 
Yes 
No 
Recorded prior to any 
recruitment method. Needed 
so that qualified members of 
the research team can 
properly address the patient 
to inform them about the 
study. 
All elements of dates (except year) for dates 
directly related to an individual, including 
birth date, admission date, discharge date, 
date of death; and all ages over 89 and 
elements of dates (including year) 
indicative of such age 
Yes 
No 
Recording birth date to 
determine age at time of 
surgery. Recording surgery 
date of surgery as well. 
Phone numbers; Fax numbers 
Yes 
No 
For recruitment purposes. 
However, the informed 
consent for this study will 
only take place in person 
with a qualified member of 
the research team. 
Medical record numbers 
Yes 
No 
Necessary to confirm past 
medical history during the 
screening process. 
 
9. Data and Specimen Banking  
 
N/A 
10. 
Study Population  
 
Described in Section 4 “Study Design” 
11. 
Screening and Recruitment S R 
 
Potential study patients will be identified by the research team prior to their surgery date by 
looking at Dr. Incavo’s, Dr. Clyburn’s, Dr. Park’s, and Dr. Brown’s surgery schedules searching 
for primary total hip arthroplasty surgeries. The potential study patient’s medical records will 
then be viewed in Epic to identify and confirm inclusion and exclusion criteria including age 
>18, past surgical history on the operative hip, BMI level, any contraindication to receiving 
vancomycin, cefepime, or ancef such as allergy, diabetes, and immunocompromised or 
immunosuppressed status. If the patient meets the initial criteria to participate in the study then a 
qualified member of the research team will email or call the patient to inform them about the 


Intraosseous Vancomycin in Primary Total Hip Arthroplasty – Designing a Protocol:  
Page 8 of 10 
HMRI Basic Protocol Template v12062019 
 
study and determine if they are interested in possibly participating. Alternatively, the recruitment 
process may also take place at in clinic (6445 Main Street Houston, Texas 77030) after the 
patient’s visit with their physician. In either scenario, meaning phone/email/or in person 
recruitment, potential study patients will be screened for inclusion and exclusion criteria prior to 
the informed consent. The informed consent will take place in person with a qualified member of 
the research team where the patient will be informed about all aspects of the research study to 
determine if they wish to participate. 
 
Sensitive information such as history of HIV will be asked during the screening process. Should 
a patient admit to that history and consequently be excluded from the study the screening 
document will immediately be disposed of in a HIPAA bin to later be shredded. Any data from 
that patient prior to inclusion in the study will be deleted except for their name and 
“EXCLUDED FROM PARTICIPATION” in the dataset. It is important to note that screening 
data will not be collected from email and will only be done either in person or over the phone. 
 
12. 
Withdrawal of Subjects 
 
Patients may be withdrawn from the study if it is discovered that they have any of the 
exclusion criteria that was not previously identified during the recruitment and screening 
process. If this is the case the patient will be informed of their removal from the study 
and the reason why they were removed from the study 
 
13. 
Provisions to Protect the Privacy Interests of Subjects  
 
If a patient has indicated on their electronic medical record in Epic that they do not want to 
participate in research or share any of their personal information that request will be honored and 
they will not be included in this research study. 
14. 
Risks to Subjects 
 
Local tissue reaction to injection 
Damage to the greater trochanter (i.e. fracture) – minimal as the IO injection will occur in the 
same location as medical standard of care for IO injections in pediatric patients.  
Hardware damage (i.e. needle breakage, etc). 
 
No patients develop a therapeutic level of vancomycin after a single dose (1g dose) so the risk 
for overdosing despite infusion times is minimal if not non-existent [12] 
 
Research has also shown that patients receiving rapid infusions of vancomycin in critically ill 
patients showed that even those who developed RedMan syndrome did not develop vital organ 
hypoperfusion and maintained hemodynamic pressure. RedMan was resolved with anti-
histamine medications [13]. 
 


Intraosseous Vancomycin in Primary Total Hip Arthroplasty – Designing a Protocol:  
Page 9 of 10 
HMRI Basic Protocol Template v12062019 
 
15. 
Potential Benefits  
 
Red Man Syndrome is generally quoted to occur in 5–13% of patients, especially when the 
infusion is given over less than 1 hour [8]. However, there are varied incidence reports, ranging 
between 3.7 and 47% in infected patients [9] to between 30 and 90% of healthy volunteers 
receiving vancomycin [10]. Additionally, the rate of nephrotoxicity with use of modern 
preparations of vancomycin varies in the literature, with the incidence ranging from as low as 0% 
in the absence of concurrent nephrotoxins to over 40% [11]. The dose of vancomycin in IO 
administration is lower than that of IV administration (500mg in IO vs. 1000-1750mg in IV). 
This may reduce the risk of systemic side effects such as Red Man Syndrome while providing 
equal or enhanced prophylaxis in THA. 
 
16. 
Financial and Economic Issues  
 
N/A 
17. 
Data Safety Plan  
 
The study will be monitored by clinicians involved in the study. Interim analysis will be 
performed yearly.  
 
18. 
Informed Consent Documentation and Process  
 
The initial identification and screening process are described in section 11 of this protocol. 
Following screening, patients will meet with a qualified member of the research team to explain 
all aspects of the study and answer any questions that the patient may have. Then, should the 
patient agree to participate in the study, both the patient and the member of the research team 
will sign the informed consent. The patient will be encouraged to take a copy of the informed 
consent for their records should they have any additional questions at a later time. 
 
19. 
Waiver of Informed Consent and /or Authorization  
 
There will be no waiver of informed consent for this study.  
 
The research team requests a waiver of authorization for preparatory for research. The use of PHI 
involves no more than a minimal risk to the privacy of individuals. Only qualified members of 
the research team will have access to this information and it will be stored on password protected 
Houston Methodist servers. Identifiers will be destroyed at the earliest opportunity consistent 
with conduct of the research study. This will include removing PHI at the end of every month. It 
would not be practical to conduct this research study without preliminary screening of potential 
study patients. Without the waiver the research team would have to request fan authorization to 
view PHI from every patient of Dr. Clyburn, Dr. Kwan Park, Dr. Stephen Incavo, and Dr. 


Intraosseous Vancomycin in Primary Total Hip Arthroplasty – Designing a Protocol:  
Page 10 of 10 
HMRI Basic Protocol Template v12062019 
 
Timothy S. Brown. The research could not be practicably conducted without access to and use of 
PHI. 
 
 
20. 
References 
 
1. Strandberg G, Larsson A, Lipcsey M, Michalek J, Eriksson M. Intraosseous and 
intravenous administration of antibiotics yields comparable plasma concentrations during 
experimental septic shock. Acta Anaesthesiol Scand. 2015 Mar; 59(3): 346–353.  
2. Jaimovich DG, Kumar A, Francom S. Evaluation of intraosseous vs intravenous 
antibiotic levels in a porcine model. Am J Dis Child. 1991 Aug;145(8):946-9. 
3. Young SW, Zhang M, Freeman JT, Mutu-Grigg J, Pavlou P, Moore GA. Higher tissue 
concentrations of vancomycin with low-dose intraosseous regional versus systemic 
prophylaxis in TKA: a randomized trial. Clin Orthop Relat Res. 2014 Jan;472(1):57-65. 
4. Chin SJ, Moore GA, Zhang M, Clarke HD, Spangehl MJ, Young SW. Intraosseous 
Regional Prophylaxis Provides Higher Tissue Concentrations in High BMI Patients in 
Total Knee Arthroplasty: A Randomized Trial. J Arthroplasty. 2018 Jul;33(7S):S13-S18. 
5. Friery J et al. Star an IV in that bone. Emergency. November 1987: 28 – 33. 
6. Astagneau P, Rioux C, Golliot F. Brücker G; INCISO Network Study Group. Morbidity 
and mortality associated with surgical site infections: results from the 1997-1999 INCISO 
surveillance. J Hosp Infect. 2001;48:267–274. doi: 10.1053/jhin.2001.1003. 
7. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, Kaplan SL, Karchmer 
AW, Levine DP, Murray BE. J Rybak M, Talan DA, Chambers HF; Infectious Diseases 
Society of America. Clinical practice guidelines by the Infectious Diseases Society of 
America for the treatment of methicillin-resistant Staphylococcus aureus infections in 
adults and children. Clin Infect Dis. 2011;52:e18–55. doi: 10.1093/cid/ciq146. 
8. Wallace M, Mascola J, Oldfiels E., Ill Red-man syndrome: Incidence, etiology, and 
prophylaxis. J Infect Dis. 1991;164:1180–1185.  
9. Lori WaznyD, Behnam D. Desensitization protocols for vancomycin hypersensitivity. 
Ann Pharmacother. 2001;35:1458–1464. 
10.  Ross M. Red-man syndrome: a preventable adverse drug reaction 
11.  Jeffres M.N., Isakow W., Doherty J.A., Micek S.T. & Kollef M.H. A retrospective 
analysis of possible renal toxicity associated with vancomycin in patients with health 
care‐associated methicillin‐resistant staphylococcus aureus pneumonia. Clin. Ther. 29, 
1107–1115 (2007). 
12. Nunn, M. O., Corallo, C. E., Aubron, C., Poole, S., Dooley, M. J., & Cheng, A. C. 
(2011). Vancomycin Dosing: Assessment of Time to Therapeutic Concentration and 
Predictive Accuracy of Pharmacokinetic Modeling Software. Annals of 
Pharmacotherapy, 45(6), 757–763. https://doi.org/10.1345/aph.1P634 
13. STIER GR, McGORY RW, SPOTNITZ WD, SCHWENZER KJ. Hemodynamic effects 
of rapid vancomycin infusion incritically ill patients. Anesth Analg 1990;71:394-9.