Clinical trial NCT04648696
Conditions: Infection
Keywords: infusion therapy continuous infusions nephrotoxicity outpatient parenteral antibiotic therapy vancomycin
Sponsor: Wake Forest University Health Sciences
Start date: 2021-03-03; Completion date: 2022-10-31
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Evaluate the safety and outcomes associated between the two treatment modalities

Detailed description:
Assess the risk of vancomycin-associated nephrotoxicity and outcomes associated with continuous infusions (CI) versus II dosing in the outpatient parenteral antibiotic therapy (OPAT) setting

Arms: arm 1: CI group will have their total daily cumulative dose of vancomycin converted to a 24-hour intravenous infusion upon discharge arm 2: Inpatient study candidates that are randomized to the II group will continue their current intravenous dosing upon discharge
Interventions: intervention 1: Vancomycin CI intervention 2: Vancomycin II
Intervention descriptions: intervention 1: The CI group will have their total daily cumulative dose of vancomycin converted to a 24-hour intravenous infusion upon discharge - the CI will begin with the first scheduled OPAT dose of vancomycin intervention 2: Study candidates that are randomized to the II group will continue their current intravenous dosing upon discharge

Protocol documents:
Prot_SAP_001.pdf: 
 
 
Official Title:   Safety and Outcomes Associated With Continuous Versus Intermittent Infusion 
Vancomycin in Outpatient Parenteral Antibiotic Therapy: a Prospective, Randomized Trial 
NCT04648696  
IRB-Approved Date:  12/22/2020 


 
 
9.30.2020 
 
Study Title: Safety and outcomes associated with continuous versus intermittent infusion vancomycin in 
outpatient parenteral antibiotic therapy: a prospective, randomized trial 
 
Principal Investigator, Co-investigator(s): 
Principal Investigator: 
John Williamson, PharmD, Department of Pharmacy, Wake Forest Baptist Medical Center 
 
Co-investigators: 
Zachary Gruss, PharmD, Department of Pharmacy, Wake Forest Baptist Medical Center 
Erin Barnes, MD, Department of Internal Medicine, Section of Infectious Diseases, Wake Forest Baptist 
Medical Center  
Tyler Stone, PharmD, Department of Pharmacy, Wake Forest Baptist Medical Center 
Lindsey Goldman, PharmD, Department of Pharmacy, Wake Forest Baptist Medical Center 
Sean Lamont, PharmD, Department of Pharmacy, Wake Forest Baptist Medical Center 
 
Sponsor or funding source:  
Wake Forest Baptist Health, Department of Pharmacy  
 
Background, Rationale and Context 
 
The 2020 American Society of Health-System Pharmacists, Infectious Diseases Society of 
America, Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists 
Guidelines for Therapeutic Monitoring of vancomycin for serious methicillin-resistant Staphylococcus 
aureus (MRSA) infections endorse the monitoring of vancomycin by area under the curve (AUC) to 
minimum inhibitory concentration (MIC) ratio per 24 hours (AUC/MIC)1. The AUC/MIC has been 
determined to accurately predict treatment efficacy and decrease the prevalence of adverse drug reactions 
in comparison to trough-based monitoring2-10. In respect to these recommendations, AUC/MIC 
monitoring is the standard of care in the inpatient setting at our institution. However, due to complications 
with home nursing visits and feasibility, this method of monitoring is not well established in the 
outpatient setting. This is secondary to the requirement of appropriately timed vancomycin peak and 
trough concentrations, and the subsequent calculation of the AUC/MIC. One proposed method of 
accurately monitoring AUC/MIC during outpatient therapy is to convert patients to continuous infusions 
(CI) of vancomycin instead of intermittent infusions (II). One random level of vancomycin is sufficient to 
calculate the AUC during a CI of vancomycin. This is performed by multiplying the random level by 24 
hours to obtain an AUC/MIC. In regard to safety, the use of CI vancomycin has been studied in patients 
in intensive care units, and has been associated with lower rates of nephrotoxicity, but no benefit in 
mortality or treatment success11-17. Despite the anticipated benefit of easier AUC monitoring and less 
nephrotoxicity, the comparison of treatment efficacy and safety of CI versus II vancomycin in the 
outpatient setting is limited. 
 
To date, there are only three trials that have evaluated the safety of CI vancomycin in outpatients. 
In 2008, Ingram et al. performed a retrospective cohort study of patients receiving CI vancomycin to 
determine risk factors for vancomycin-associated nephrotoxicity. The authors concluded that the 
following variables were positively associated with new-onset nephrotoxicity: steady state vancomycin 
levels greater-than or equal-to 28, loop diuretics, aminoglycosides, and hypertension18.  
In 2012, Dubee et al. prospectively observed 60 patients receiving high-dose CI vancomycin for 
prosthetic hip infections. The target serum vancomycin level was 30 to 40 mcg/mL, which would 
correlate with an AUC of 720 to 96019. This is above the guideline-recommended range of 400-600, as 
AUCs above 600 have been associated with no difference in treatment outcomes, but an increase in 
nephrotoxicity10. The authors concluded that 19 patients experienced nephrotoxicity, defined as a rise in 
serum creatinine by 50% from baseline, while receiving vancomycin. Of note, 16 of these patients were 
receiving concomitant nephrotoxic medications19. Thus, the outcomes of this trial are limited to higher 
vancomycin dosing and high prevalence of confounding variables, such as concurrent nephrotoxins. 


 
 
9.30.2020 
 
 
In 2009, Ingram et al. studied the prevalence of nephrotoxicity between CI and II vancomycin in 
patients seen by an outpatient parenteral antibiotic therapy (OPAT) clinic in Singapore. The authors noted 
that there was an increased prevalence of nephrotoxicity in the II group than the CI (23.6% and 11.6%, 
respectively), but the two groups were not matched in regard to patient characteristics. Overall, the 
patients in the CI arm had a younger mean age by approximately 10 years (46.7 vs 57.3 years) with less 
evidence of hypertension (25.9% vs 47.3%), diabetes mellitus (21.4% vs 50.9%), and ACE-
inhibitor/ARB use (13.4% vs 41.8%), as well as lower mean serum creatinine (0.71 vs 0.84 mg/dL)20.  
 
Similarly, two trials have evaluated the efficacy comparing CI and II. In 2004, Vaugant et al. 
prospectively measured the efficacy of CI versus II in 43 patients with osteomyelitis. Both treatment arms 
targeted serum vancomycin levels/troughs of 20 to 25 mcg/mL21. For those that were receiving trough-
based monitoring, this level is above traditional dosing recommendations of 15 to 20 mcg/mL1,8. 
Secondary to this higher target, four patients in the II group and zero in the CI group experienced 
nephrotoxicity. Treatment failure occurred in two patients in each group21.  
 
In 2012, Verrall et al. expanded upon these findings by retrospectively reviewing patients 
receiving CI or II vancomycin in the OPAT setting for any MRSA infection. This study included patients 
that were treated in accordance with current guideline recommended therapy: vancomycin trough goal of 
15 to 20 mcg/mL in the II group, and vancomycin random level of 15 to 25 mcg/mL in the CI group1. The 
authors concluded that a higher rate of clinical failure occurred in the II group than the CI group (30.4% 
vs 21.3%, respectively). However, there were numerously more patients in the CI group (145 vs 40 
patients), and a higher rate of unplanned re-admissions occurred in the II group, which drove this primary 
endpoint of clinical failure22.  
 
Thus, to supplement the paucity of data of CI versus II vancomycin in the outpatient setting, the 
purpose of this study is to evaluate the safety and outcomes associated between the two treatment 
modalities. 
 
 
 
Objectives 
The objectives of the study are to assess the risk of vancomycin-associated nephrotoxicity and outcomes 
associated with CI versus II dosing in the OPAT setting.  
 
Methods and Measures 
 
Design 
Prospective, randomized, open-label, single-center trial  
 
Setting 
       Wake Forest Baptist Health OPAT service 
 
Subjects selection criteria 
• 
Inclusion Criteria 
- 
Adult patients at least 18 years of age  
- 
Receiving Wake Forest Baptist Health OPAT services   
- 
Will receive vancomycin therapy from Wake Forest Baptist Health Specialty Home 
Infusion Pharmacy   
- 
Planned therapy with vancomycin in the outpatient setting for at least 2 weeks in duration  
- 
Prescribed vancomycin with a frequency of either every 12 hours or every 8 hours dosing 
at the time of enrollment  
• 
Exclusion Criteria 
- 
Presence of diseases or conditions known to affect the pharmacokinetics of vancomycin 
o Pregnancy 
o Ascites 


 
 
9.30.2020 
 
o Burn injury 
o Cystic fibrosis  
o Weight greater-than or equal-to 150 kg 
- 
Pre-existing leukopenia  
o WBC < 4,000 x 103 cells/µL 
• 
Sample Size 
Assuming that II vancomycin therapy will be associated with an increase in nephrotoxicity by 
15% and a level of significance of 0.05 and 80% power, the sample size needed in each group 
is 100 patients. 
 
Interventions and Interactions 
Patients will be identified during routine care by members of the Infectious Diseases (ID) Consult 
service C team (ID-C), Specialty Home Infusion Pharmacy, or Wake Forest Baptist Infectious Diseases 
clinic. Members of the study team will review the electronic medical record (EMR) to apply study criteria 
for inclusion. Written informed consent will be secured by in-person, non-biased explanation of the study. 
Study candidates that are currently admitted to the hospital will receive education about the study in his or 
her hospital room. Study participants that provide written, informed consent will be randomized into 
either the CI or II group by a random number generator. All patients will receive their first dose of 
vancomycin as an intermittent infusion. 
Inpatient study candidates that are randomized to the CI group will have their total daily cumulative 
dose of vancomycin converted to a 24-hour intravenous infusion upon discharge. The CI will begin with 
the first scheduled OPAT dose of vancomycin. Inpatient study candidates that are randomized to the II 
group will continue their current intravenous dosing upon discharge. Members of the Specialty Home 
Infusion Pharmacy will ensure vancomycin is dispensed as single or multiple elastomeric balloon pumps 
depending assigned group. Prior to discharge, the study candidate or caretaker will receive education on 
how to administer doses of vancomycin per standard of care. 
Study candidates that are receiving their first dose of vancomycin in the day hospital after being 
transferred from the OPAT Clinic, will receive education about the study in his or her Day Hospital room. 
Outpatient or Day Hospital study candidates randomized to the CI or II group will receive vancomycin 
dosed according to OPAT team recommendations. Members of the Specialty Home Infusion Pharmacy 
will ensure vancomycin is dispensed as single or multiple elastomeric balloon pumps depending on 
assigned group. Prior to discharge, the study candidate or caretaker will receive education on how to 
administer doses of vancomycin per standard of care.  
After enrollment, data will be collected from the EMR, including: demographic information, 
laboratory data, anthropometry measurements, comorbid or chronic diseases or conditions, concurrent 
medications, information about the infection, planned duration of therapy, planned dose of vancomycin, 
results of vancomycin concentrations, and previous and concurrent antibiotic therapy. Data will be 
recorded using a pre-defined data collection form (RedCap). 
After discharge, vancomycin will be monitored as established by the standard procedures of the 
Specialty Home Infusion Pharmacy and OPAT service. The standard monitoring frequency for 
vancomycin concentrations is at least weekly for all OPAT patients. If randomized to the CI group, 
vancomycin random concentrations will be used to guide dosing based on AUC determinations. The CI 
goal AUC is 400-600 mg x hr/L. If randomized to the II group, vancomycin monitoring will be performed 
one of two ways, depending on whether the inpatient (pre-discharge) dose of vancomycin was determined 
by AUC monitoring. If it was, the target vancomycin trough concentration will approximate the trough 
that corresponded to the dose that resulted in an AUC of 400-600 mg x hr/L. If the discharge dose of 
vancomycin was not determined by inpatient AUC monitoring, a pre-determined target range will be 
established based on the indication for vancomycin, typically 15 – 20 mcg/mL for difficult to treat 
infections. Adjustments of vancomycin doses will be made by pharmacists of the Specialty Home 
Infusion Pharmacy or providers working on the OPAT service. Other monitoring labs that will be 


 
 
9.30.2020 
 
performed weekly per standard of care include basic metabolic panel and complete blood cell count with 
differential. 
Study participants will follow-up at regularly scheduled OPAT Clinic visits in accordance with 
routine care. The treating clinician will monitor for signs and symptoms of infection to determine 
resolution or persistence of disease during these visits per usual care. Data collection for study purposes 
will occur for the entire duration of vancomycin therapy.  
 
A table illustrating the schedule of events in the study is attached as Appendix 3.    
 
Outcome Measure(s) 
- 
Safety:  
o Nephrotoxicity: Any increase in Scr by 50% from baseline, an increase in Scr by 
0.5 mg/dL, or an increase in Scr by 0.3 mg/dL on two consecutive measurements 
▪ 
Baseline SCr is defined as the most recent SCr measurement prior to 
randomization 
o Leukopenia 
▪ 
WBC < 4,000 x 103 cells/µL 
o Infusion-related reactions 
▪ 
Flushing 
▪ 
Erythema  
▪ 
Rash 
▪ 
Red Man Syndrome 
o Serious adverse events  
▪ 
FDA, Common Terminology Criteria for Adverse Events (CTCAE), 
Grade 3 events – severe or medically significant, but not immediately 
life-threatening events leading to hospitalization or disability  
• 
Disability means to limit the ability to conduct self-care 
activities of daily living (bathing, dressing, feeding self, using 
the toilet, taking medications, and not bedridden) 
▪ 
FDA, CTCAE, Grade 4 events – life-threatening adverse events 
requiring urgent intervention  
- 
Total number of serum vancomycin concentrations during treatment period 
- 
Number of serum vancomycin measurements within therapeutic range 
o CI goal  
▪ 
AUC/MIC 400 – 600 mg x hr/L (a vancomycin random within 16.7 and 
25.0 mcg/mL will correlate with this range) 
o II goal 
• 
If inpatient dose was determined by AUC monitoring: A 
vancomycin trough that is within 3.0 mcg/mL of the trough that 
correlated with a therapeutic AUC based on inpatient 
monitoring.  
▪ 
If inpatient dose was not determined by AUC monitoring or vancomycin 
was initiated as outpatient: A vancomycin trough of 10.0 – 20.0 mcg/mL  
- 
Treatment Success 
o Resolution of signs and symptoms associated with the infection 
▪ 
Systemic signs and symptoms of infection  
• 
Fever (100.4 degrees Fahrenheit sustained over 1 hour or a 
single measurement of 101 degrees Fahrenheit or more) 
• 
Elevated WBC greater than 12.0 cells x 103 cells/µL 
• 
Chills 


 
 
9.30.2020 
 
▪ 
Localized signs and symptoms of infection 
• 
Erythema at the site of infection 
• 
Drainage at the site of infection 
• 
Fluctuance 
• 
Heat or localized warmth 
• 
Tenderness on palpation  
• 
Swelling or induration  
▪ 
No need for additional induction therapy beyond the planned end date 
• 
Induction therapy is defined as the initial antibiotic regimen 
prescribed to treat the patient’s infection, typically 6-8 weeks of 
intravenous therapy  
- 
Treatment Failure 
o Persistence, new onset, or worsening local or systemic signs and symptoms of 
infection  
o Amputation due to progression of disease within 90 days after the end of 
induction or consolidation antibiotics  
o Breakthrough positive cultures with the same causative pathogen while receiving 
or at the conclusion therapy with vancomycin. This includes those undergoing 
two-stage joint replacements that have repeat culture of the same causative 
pathogen prior to the placement of new prosthetic material.  
o The need for additional antibiotic use for no response or worsening after 
improvement  
o Patients will not be considered as treatment failure if they require oral 
consolidation or long-term suppressive antibiotic therapy after the completion of 
vancomycin. 
 
Analytical Plan 
Results will be analyzed initially using descriptive statistics.  Comparison between groups will be done 
using Chi square test for categorical data, and Student t-tests or ANOVA for continuous variables. Safety 
outcomes will be evaluated using an intention to treat (ITT) population and clinical outcomes will be 
evaluated using a modified intention to treat (mITT) population. The ITT population will be all patients 
that receive at least one dose after randomization. The mITT group will consist of those that completed 
the planned treatment course. Other inferential statistical analyses will be conducted as appropriate. 
 
Human Subjects Protection 
The primary investigators will be responsible for maintaining the integrity of all data. Only study 
investigators will have access to secured data for the study. 
 
Subject Recruitment Methods 
Study candidates will primarily be identified by members of the ID-C, Specialty Home Infusion 
Pharmacy, and Infectious Diseases Clinic staff during routine care. Key members of the ID-C, Specialty 
Home Infusion Pharmacy, and Infectious Diseases Clinic staff are study investigators. Study candidates 
may be identified during Infectious Diseases Clinic visits if the initiation of therapy with vancomycin is 
warranted in the outpatient setting.  
 
As all patients with osteomyelitis, prosthetic joint infections, endocarditis, epidural abscesses, and 
complicated MRSA bacteremia have an equal opportunity to require therapy with vancomycin, women 
and minorities have equal access to participation in this study.  
 


 
 
9.30.2020 
 
The privacy of potential subjects during recruitment will be protected by HIPAA requirements, as the 
members of the study team are the members of the treatment teams. Collection and documentation of 
study enrollment or decline will be saved on a password-protected file and will be deleted after data 
analysis is finalized.  
 
Informed Consent 
Signed informed consent will be obtained from each subject. A study investigator will obtain informed 
consent from each patient while they are receiving care at WFBMC. This includes, but is not limited to, 
the patient’s hospital room, Day Hospital room, or Infectious Diseases Clinic location.  
 
Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly identify 
subjects, and maintaining all study information in a secure manner. To help ensure subject privacy 
and confidentiality, only a unique study identifier will appear on the data collection form. Any 
collected patient identifying information corresponding to the unique study identifier will be 
maintained on a linkage file, store separately from the data. The linkage file will be kept secure, with 
access limited to designated study personnel. Following data collection and analysis subject 
identifying information will be destroyed, consistent with data validation and study design, producing 
an anonymous analytical data set. Data access will be limited to study staff. Data and records will be 
kept locked and secured, with any computer data password protected.  No reference to any individual 
participant will appear in reports, presentations, or publications that may arise from the study. 
 
Data and Safety Monitoring 
The principal investigator will be responsible for the overall monitoring of the data and safety of 
study participants.  The principal investigator will be assisted by other members of the study staff. 
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol changes 
will be promptly reported by the principal investigator or designated member of the research team to 
the IRB and sponsor or appropriate government agency if appropriate. 
 
References 
1. Rybak MJ, Le J, Lodise TP, et al. Therapeutic monitoring of vancomycin for serious methicillin-
resistant Staphylococcus aureus infections: A revised consensus guideline and review by the 
American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the 
Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J 
Health-Syst Pharm. 2020 Mar 19;77(11):835-63. 
2. Moise-Broder PA, Forrest A, Birmingham MC, Schentag JJ. Pharmacodynamics of vancomycin 
and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. 
Clin Pharmacokinet. 2004; 43(13):925-942. 
3. Kullar R, Davis SL, Levine DP, Rybak MJ. Impact of vancomycin exposure on outcomes in 
patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus 
guidelines suggested targets. Clin Infect Dis. 2011;52(8):975-981. 
4. Brown J, Brown K, Forrest A. Vancomycin AUC24/MIC ratio in patients with complicated 
bacteremia and infective endocarditis due to methicillin-resistant Staphylococcus aureus and its 
association with attributable mortality during hospitalization. Antimicrob Agents Chemother. 
2012;56(2):634-638. 
5. Holmes NE, Turnidge JD, Munckhof WJ et al. Vancomycin AUC/MIC ratio and 30-day mortality 
in patients with Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 
2013;57(4):1654-1663. 


 
 
9.30.2020 
 
6. Gawronski KM, Goff DA, Brown J,Khadem TM, Bauer KA. A stewardship program’s 
retrospective evaluation of vancomycin AUC24/MIC and time to microbiological clearance in 
patients with methicillin-resistant Staphylococcus aureus bacteremia and osteomyelitis. Clin 
Ther. 2013;35(6):772-779. 
7. Jung Y, Song KH, Cho Je et al. Area under the concentration-time curve to minimum inhibitory 
concentration ratio as a predictor of vancomycin treatment outcome in methicillin-resistant 
Staphylococcus aureus bacteraemia. Int J Antimicrob Agents. 2014;43(2):179-183. 
8. van Hal SJ, Paterson DL, Lodise TP. Systematic review and meta-analysis of vancomycin-
induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 
milligrams per liter. Antimicrob Agents Chemother. 2013; 57(2):734-744. 
9. Neely MN, Youn G, Jones B et al. Are vancomycin trough concentrations adequate for optimal 
dosing? Antimicrob Agents Chemother. 2014;58(1):309-316. 
10. Aljefri DM, Avedissian SN, Rhodes NJ, Postelnick MJ, Nguyen K, Scheetz MH. Vancomycin 
area under the curve and acute kidney injury: a meta-analysis. Clin Infect Dis. 2019; 69(11):1881-
1887. 
11. Wysocki M, Delatour F, Faurisson F et al. Continuous versus intermittent infusion of vancomycin 
in severe staphylococcal infections: prospective multicenter randomized study. Antimicrob 
Agents Chemother. 2001;45(9):2460-2467. 
12. Schmelzer TM, Christmas AB, Norton HJ, Heniford BT, Sing RF. Vancomycin intermittent 
dosing versus continuous infusion for treatment of ventilator-associated pneumonia in trauma 
patients. Am Surg. 2013;79(11):1185-1190. 
13. Tafelski S, Nachtigall I, Troeger U, et al. Observational clinical study on the effects of different 
dosing regimens on vancomycin target levels in critically ill patients: continuous versus 
intermittent application. J Infect Public Health. 2015;8(4):355-363. 
14. Hutschala D, Kinstner C, Skhirdladze K, Thalhammer F, Muller M, Tschernko E. Influence of 
vancomycin on renal function in critically ill patients after cardiac surgery: continuous versus 
intermittent infusion. Anesthesiology. 2009;111(2):356-365. 
15. Akers KS, Cota JM, Chung KK, Renz EM, Mende K, Murray CK. Serum vancomycin levels 
resulting from continuous or intermittent infusion in critically ill burn patients with or without 
continuous renal replacement therapy. J Burn Care Res. 2012; 33(6):e254-e262. 
16. Saugel B, Nowack MC, Hapfelmeier A et al. Continuous intravenous administration of 
vancomycin in medical intensive care unit patients. J Crit Care. 2013; 28(1):9-13. 
17. Hanrahan TP, Harlow G, Hutchinson J et al. Vancomycin-associated nephrotoxicity in the 
critically ill: a retrospective multivariate regression analysis*. Crit Care Med. 2014;42(12):2527-
2536. 
18. Ingram PR, Lye DC, Tambyah PA, Goh WP, Tam VH, Fisher DA. Risk factors for 
nephrotoxicity associated with continuous vancomycin infusion in outpatient parenteral antibiotic 
therapy. J Antimicrob Chemother. 2008;62(1):168-171. 
19. Dubée V, Zeller V, Lhotellier L et al. Continuous high-dose vancomycin combination therapy for 
methicillin-resistant staphylococcal prosthetic hip infection: a prospective cohort study. Clin 
Microbiol Infect. 2013;19(2):E98-E105. 
20. Ingram PR, Lye DC, Fisher DA, Goh WP, Tam VH. Nephrotoxicity of continuous versus 
intermittent infusion of vancomycin in outpatient parenteral antimicrobial therapy. Int J 
Antimicrob Agents. 2009; 34(6):570-574. 
21. Vuagnat A, Stern R, Lotthe A et al. High dose vancomycin for osteomyelitis: continuous vs. 
intermittent infusion. J Clin Pharm Ther. 2004;29(4):351-357. 
22. Verrall AJ, Llorin R, Tam VH et al. Efficacy of continuous infusion of vancomycin for the 
outpatient treatment of methicillin-resistant Staphylococcus aureus infections. J Antimicrob 
Chemother. 2012; 67(12):2970-2973. 
 
Appendix 


 
 
9.30.2020 
 
1. Data collection form 
2. Informed consent form 
3. Schedule of events tables 
4. Copies of each questionnaires or surveys that will be used  

ICF_002.pdf: 
Official Title:   Safety and Outcomes Associated With Continuous Versus Intermittent 
Infusion Vancomycin in Outpatient Parenteral Antibiotic Therapy: a Prospective, 
Randomized Trial
NCT04648696 
IRB-Approved Date:  12/20/2021


Page 1 of 8
Adult Consent Form
12/14/2021
Department of Pharmacy; Department of Internal Medicine, Section of Infectious Diseases
SAFETY AND OUTCOMES ASSOCIATED WITH CONTINUOUS VERSUS 
INTERMITTENT INFUSION VANCOMYCIN IN OUTPATIENT PARENTERAL 
ANTIBIOTIC THERAPY: A PROSPECTIVE, RANDOMIZED TRIAL
Informed Consent Form to Participate in Research
John Williamson, PharmD, Principal Investigator
SUMMARY
You are invited to participate in a research study. The purpose of this research is to test the safety 
and outcomes of continuous infusion vancomycin compared to intermittent infusion vancomycin.  
You are invited to be in this study because your doctor has determined that you need treatment 
with vancomycin in the outpatient setting for at least two weeks. Your participation in this 
research will last for the duration of vancomycin therapy, which is expected to be approximately 
2 to 8 weeks. Participation in this study will involve outpatient therapy with vancomycin, regular 
laboratory monitoring, and follow-up visits in the Infectious Diseases Clinic.
All research studies involve some risks.  A risk of therapy with vancomycin is acute kidney 
injury. The risk of acute kidney injury is not expected to increase if you choose to participate in 
this study. There is the possibility that you may benefit from participation in this study.  
Your participation in this study is voluntary.  You do not have to participate in this study if you 
do not want to.  If you choose not to participate in this study, you will receive intermittent 
infusion vancomycin, as prescribed by your doctor.  You will not lose any services, benefits, or 
rights you would normally have if you choose not to participate. 
The remainder of this form contains a more complete description of this study. Please read this 
description carefully. You can ask any questions if you need help deciding whether to join the 
study. The person in charge of this study is John Williamson, PharmD (Principal Investigator). 
If you have questions, suggestions, or concerns regarding this study or you want to withdraw 
from the study his contact information is: 
. 
If you have any questions, suggestions or concerns about your rights as a volunteer in this 
research, contact the Institutional Review Board at
 or the Research Subject 
Advocate at Wake Forest at 
.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00069815
Meeting Date Approved 12/20/2021          
Version Valid Until: 12/19/2022


Page 2 of 8
Adult Consent Form
12/14/2021
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you have an infection that requires long-term outpatient treatment with 
vancomycin. Your participation is voluntary. Please take your time in making your decision as to 
whether or not you wish to participate. Ask your study doctor or the study staff to explain any 
words or information contained in this informed consent document that you do not understand. 
You may also discuss the study with your friends and family.
WHY IS THIS STUDY BEING DONE?
The purpose of this research study is to compare the safety and effectiveness of continuous 
infusion vancomycin with intermittent infusion vancomycin.  The primary objective of this study 
is to evaluate if continuous infusion vancomycin is safer for kidneys. 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
Two-hundred people will take part in this study at Wake Forest Baptist Health.
WHAT IS INVOLVED IN THE STUDY?
You will be randomized into one of the study groups described below. Randomization means 
that you are put into a group by chance. It is like flipping a coin. You will have an equal chance 
of being placed in either group.
You will receive vancomycin in the outpatient setting as treatment for your condition for at least 
2 weeks. This has already been determined by your doctor. You will be randomized to receive 
vancomycin as a continuous infusion (24-hour infusion) or intermittent infusions (shorter 
infusions scheduled 2-3 times per day). You will be trained on how to self-administer doses of 
vancomycin irrespective of which infusion type you receive. Regardless of the group you are 
assigned, you will receive the same amount of vancomycin. 
There are many facets of standard care provided in the Infectious Diseases Clinic for patients 
receiving vancomycin, regardless of your participation in this study. The following describes 
parts of this care you will receive regardless of which group you are assigned: follow-up visits at 
the Infectious Diseases Clinic, home health visits, telephone calls, laboratory tests, and x-rays or 
other scans. Your doctor or pharmacist will determine what visits are needed, and what tests 
need to be performed. Continuous infusion is not expected to result in more or less laboratory 
tests than receiving multiple shorter infusions. No extra laboratory tests will be performed 
because of your participation in this study. Treatment with vancomycin will be continued until 
your doctor tells you to stop taking it. 
HOW LONG WILL I BE IN THE STUDY?
You will be in the study until your doctor decides to stop vancomycin, either approximately 2 – 8 
weeks or if a safety event occurs. You can stop participating at any time. If you decide to stop 
participating in the study we encourage you to talk to the investigators or study staff first to learn 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00069815
Meeting Date Approved 12/20/2021          
Version Valid Until: 12/19/2022


Page 3 of 8
Adult Consent Form
12/14/2021
about any potential health or safety consequences. If you stop participating in the study, your 
doctor may continue therapy with vancomycin, but possibly with different infusion. 
WHAT ARE THE RISKS OF THE STUDY?
Your doctor has decided to treat you with vancomycin. It is uncertain whether the type of 
infusion effects your chance of having a side effect. Small studies have not identified an 
increased chance in experiencing a side effect if given continuous infusion. You should discuss 
the risk of being in this study with the study staff. Risks and side effects related to vancomycin 
(given by continuous infusion or intermittent infusion) include:
-
Kidney injury
o
~5% of patients
o
This is usually reversible
o
The risk is increased with age and in combination with other medications known 
to harm the kidney.
-
Allergic reactions: 
o
This is reversible
o
Flushing, hives, rash
-
“Red Man Syndrome”: flushing, swelling, or rash on the face, neck, chest or upper 
extremities. Low blood pressure may occur, as well. 
o
Uncommon
o
When it does occur, this will typically happen during the beginning or end of the 
infusion. 
o
This is reversible and prevented by slowing down the rate of the infusion.
-
Nausea
o
Uncommon
-
Low white blood cell count 
o
Uncommon
o
This is reversible upon discontinuation of therapy
-
Low platelet count
o
Uncommon
o
This is reversible upon discontinuation of therapy.
-
Hearing toxicity
o
Rare and may be temporary or permanent. 
o
This is associated with high peak levels that are not seen in modern dosing of 
vancomycin.
In addition, there is a slight risk of a breach of confidentiality.  We will do our best to protect 
your confidential information.  There also may be other risks that we cannot predict. You should 
tell the research staff about all the medications, vitamins and supplements you take and any 
medical conditions you have. This may help avoid side effects, interactions and other risks.
Taking part in this research study may involve providing information that you consider 
confidential or private.  Efforts, such as coding research records, keeping research records secure 
and allowing only authorized people to have access to research records, will be made to keep 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00069815
Meeting Date Approved 12/20/2021          
Version Valid Until: 12/19/2022


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your information safe. 
During blood draws for vancomycin monitoring:
No matter which infusion of vancomycin you receive, blood draws for vancomycin levels will be 
performed. The amount of blood required to monitor vancomycin will be determined by the 
number of lab tests ordered by your doctor. No extra blood draws will be performed because of 
your participation in this research. You may experience discomfort, bruising and/or bleeding 
where the needle is inserted. Occasionally some people become dizzy lightheaded or feel faint. 
Infection may occur on rare occasions. Frequent donation of blood can result in low iron in your 
blood (iron deficient anemia).  
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may or may not be direct benefit to you. We hope the 
information learned from this study will benefit other people in the future. A possible benefit of 
participating in this study is reduced risk of kidney injury as a side effect of vancomycin. 
Because individuals respond differently to therapy, no one can know in advance if it will be 
helpful in your particular case.
Based on what is known about continuous infusion vancomycin, the chance of success in treating 
your infection is not expected to be any different than intermittent infusion vancomycin.
WHAT OTHER CHOICES ARE THERE?
You do not have to be in this study to receive treatment. If you choose not to participate in this 
study, you will receive intermittent infusions of vancomycin. You should talk to your doctor 
about all the choices you have. 
WHAT ARE THE COSTS?
As your doctor has determined that treatment with vancomycin is necessary, there is no 
additional cost for participating in this study. Costs for your regular medical care, which are not 
related to this study, will be your own responsibility.
You or your insurance company will be billed for home infusion services including medications 
and devices related to vancomycin administration. The cost of continuous infusion vancomycin 
will be equal to the cost of intermittent infusion vancomycin, because the amount and duration of 
vancomycin treatment will be the same regardless of the type of infusion. If your insurance 
company is billed, they will determine your out of pocket cost for therapy. 
WILL YOUR RESEARCH RECORDS BE CONFIDENTIAL?
The results of this research study may be presented at scientific or medical meetings or published 
in scientific journals.  Your identity and/or your personal health information will not be disclosed 
unless it is authorized by you, required by law, or necessary to protect the safety of yourself or 
others. There is always some risk that even de-identified information might be re-identified. 
Participant information may be provided to Federal and other regulatory agencies as required.  
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00069815
Meeting Date Approved 12/20/2021          
Version Valid Until: 12/19/2022


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The Food and Drug Administration (FDA), for example, may inspect research records and learn 
your identity if this study falls within its jurisdiction.
 
WILL YOU BE PAID FOR PARTICIPATING?
You will receive no payment or other compensation for taking part in this study.
WHO IS SPONSORING THIS STUDY?
This study is being conducted by the Wake Forest Baptist Health and there is no external sponsor 
involved. 
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY?
Wake Forest Baptist Health will not reimburse for medical expenses incurred by research 
subjects for medical care, including hospitalization, in the treatment of adverse reactions arising 
from study drugs, devices, intervention, procedures and tests following their administration or 
use in accordance with the protocol, which expenses were not caused by negligence or 
misconduct of any person in the employment of Wake Forest University Health Sciences or to 
your own failure to follow instructions. Wake Forest Baptist Health is not responsible for 
expenses that are due to pre-existing medical conditions or underlying disease. 
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call John Williamson, PharmD at 
WHAT ABOUT MY HEALTH INFORMATION?
In this research study, any new information we collect from you and/or information we get from 
your medical records or other facilities about your health or behaviors is considered Protected 
Health Information. The information we will collect for this research study includes: age, weight, 
list of medical problems/diagnoses, progress notes, home medications, laboratory values 
(complete blood cell count, basic metabolic panels, etc.), vancomycin dose, vancomycin levels, 
and interpretation of imaging studies (x-ray, CT scan, MRI, etc.).
We will make every effort to keep your Protected Health Information private. We will store 
records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer. 
Your personal health information and information that identifies you (“your health information”) 
may be given to others during and after the study. This is for reasons such as to carry out the 
study, to determine the results of the study, to make sure the study is being done correctly, and to 
provide required reports.  
Some of the people that may receive and use your health information are the research personnel, 
the Institutional Review Board, representatives from government agencies such as the Food and 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00069815
Meeting Date Approved 12/20/2021          
Version Valid Until: 12/19/2022


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Drug Administration (FDA) or the Office of Human Research Protections (OHRP), and the 
Department of Health and Human Services (DHHS).  
Some of these people, agencies and businesses may further disclose your health information. If 
disclosed by them, your health information may no longer be covered by federal or state privacy 
regulations.  Your health information may be disclosed if required by law. Your health 
information may be used to create information that does not directly identify you. This 
information may be used by other researchers. You will not be directly identified in any 
publication or presentation that may result from this study unless there are photographs or 
recorded media which are identifiable.
Monitors, auditors, IRB or other regulatory agencies will be granted direct access to the 
participant’s original medical record for verification of clinical trial procedures or data, without 
violating confidentiality of the participant and to the extent permitted by other applicable laws.
If required by law or court order, we might also have to share your Protected Health Information 
with a judge, law enforcement officer, government agencies, or others. If your Protected Health 
Information is shared with any of these groups it may no longer be protected by federal or state 
privacy rules.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for at least one year after the study is finished. At that time any 
research information not already in your medical record will either be destroyed or it will be de-
identified. You will not be able to obtain a copy of your Protected Health Information in the 
research records until all activities in the study are completely finished. 
You can tell John Williamson, PharmD that you want to take away your permission to use and 
share your Protected Health Information at any time by sending a letter to this address:
John Williamson, PharmD
However, if you take away permission to use your Protected Health Information you will not be 
able to be in the study any longer. We will stop collecting any more information about you, but 
any information we have already collected can still be used for the purposes of the research 
study.
By signing this form you give us permission to use your Protected Health Information for this 
study.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00069815
Meeting Date Approved 12/20/2021          
Version Valid Until: 12/19/2022


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who have authorized access to your medical record. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this Web site at any time.
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. The investigators also have the right to stop your participation in the study 
at any time. This could be because of one of the following: it is in your best medical interest, 
your condition worsened, new information becomes available, you had an unexpected reaction, 
you failed to follow instructions, or because the entire study has been stopped.  Information that 
identifies you may be removed from the data and could be used for future research or shared 
with others without additional consent. 
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study. 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, John Williamson at 
. If calling after business hours, please leave a 
message and a call will be returned during the next business day.
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB at 
 or the 
Research Subject Advocate at 
.
You will be given a copy of this signed consent form. 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00069815
Meeting Date Approved 12/20/2021          
Version Valid Until: 12/19/2022


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SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.   By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
Subject Name (Printed):_____________________________
Subject Signature: _________________________________ Date: ________Time:_______ am pm 
Person Obtaining Consent (Printed):_____________________________
Person Obtaining Consent:___________________________ Date:_________ Time:________ am pm
Legally Authorized Representative Name (Print):____________________________________
 
The above named Legally Authorized Representative has legal authority to act for the research 
subject based upon (specify health care power of attorney, spouse, parent, etc.)
Relationship to the Subject:_____________________________                                                
Legal Representative Signature: _________________________ Date:_________ Time:________ am pm
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00069815
Meeting Date Approved 12/20/2021          
Version Valid Until: 12/19/2022