Clinical trial NCT02809131
Conditions: Sick Sinus Syndrome Complete Heart Block Syncope Chronic Systolic Heart Failure
Keywords: CIED infection
Sponsor: Vanderbilt University Medical Center
Start date: 2016-04-01; Completion date: 2021-09-30
Enrollment: 1010 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The number of cardiac implantable electronic devices (CIEDs) implanted each year has grown rapidly over the past two decades. CIED infections, defined as infections involving the generator implant site (pocket) and/or intravascular leads, have become increasingly prevalent, with the rate of growth in infections outpacing that of CIED procedures. The odds of both short term and long term mortality are at least doubled in patients who suffer CIED infections, and long term survival is particularly poor in women. Optimal strategies to prevent CIED infections in high-risk patients are largely unproven. However, recent observational studies of an antibiotic-coated envelope implanted at the time of CIED procedure have shown that this strategy is associated with a low incidence of CIED infections. Other interventions to prevent CIED infections, including the use of antibiotic irrigant used to wash the pocket during implantation and postoperative oral antibiotics, are commonly used but not supported by rigorous controlled studies. The Specific Aim of this study is to test the hypothesis that the use of the antibacterial envelope alone is noninferior to a strategy using the antibacterial envelope and intraoperative antibacterial irrigant and postoperative oral antibiotics for the reduction of cardiac implantable device infections in patients with ≥2 risk factors for infection.

Detailed description:
1.0 Background

The number of cardiac implantable electronic devices (CIEDs) implanted each year has grown rapidly over the past two decades, largely due to expanding use of implantable cardioverter-defibrillators (ICDs) and devices capable of delivering cardiac resynchronization therapy (CRT). CIEDs have increasingly been utilized in older patients with multiple medical comorbidities. As a result CIED infections, defined as infections involving the generator implant site (pocket) and/or intravascular leads, have become increasingly prevalent, with the rate of growth in infections outpacing that of CIED procedures. The increase in incidence of CIED infections has outpaced the growth in device implantation, in large part due to the medical complexity of today's CIED patients. These devastating complications are associated with significant cost, morbidity, and mortality. The odds of both short term and long term mortality are at least doubled in patients who suffer CIED infections, and long term survival is particularly poor in women.

Patient-specific risk factors for CIED infections have been examined in multiple registries and case-control studies. For patients with at least two risk factors, the reported incidence of CIED infection is 2-3%. Management of these infections is complex and expensive. The cornerstone of management is the complete removal of all infected hardware whenever possible, which in itself poses significant risks for patients. Therefore prevention of infections is crucial.

Best practices for reducing CIED infections are an active area of research. Since most infections occur as a result of bacterial seeding at the time of device implantation or revision, careful attention to strict sterile technique is mandatory. Optimal skin preparation and perioperative intravenous antibiotics have been associated with a reduced rate of CIED infections in randomized controlled studies. Additionally, several recent retrospective studies have suggested an important role of the minocycline and rifampin impregnated TYRX antibacterial envelope in reducing infections. The device consists of 2 polypropylene mesh sheets joined on 3 sides with a 3mm seam and is available in 2 sizes to accommodate pacemaker and ICD pulse generators. This polypropylene envelope releases minocycline and rifampin from a bioresorbable polyarylate polymer over approximately 7 days, directly into the CIED generator pocket.

Aside from optimal skin preparation and perioperative intravenous antibiotics, other practices to reduce the risk of CIED infections vary widely. Many operators use an antibacterial solution (e.g., polymyxin-B/bacitracin) to irrigate the pocket during device implantation. Additionally, many centers have adopted the routine use of prophylactic postoperative antibiotics to reduce the risk of CIED infections. However, neither of these strategies has been evaluated in randomized clinical studies. Antibacterial irrigation solution is expensive, and oral antibiotics are associated with a small yet clinically important risk of adverse effects, including Clostridium difficile infection. Therefore, prospective randomized studies are needed to evaluate the efficacy, safety, and cost-effectiveness of intraoperative antibacterial rinse and postoperative oral antibiotics.

Summary of significance: CIED infections constitute major complications of device implantations or revisions and are becoming increasingly prevalent. Infections are associated with increased morbidity, mortality, and cost, and are very difficult to treat. Recent studies have explored ways to reduce the incidence of CIED infections, and use of the TYRX antibacterial envelope has emerged as a potential strategy for prevention. Other strategies including intraoperative antibacterial irrigation and postoperative oral antibiotics are commonly used despite the lack of prospective studies documenting efficacy, safety, and cost-effectiveness. We and others have reported a very low incidence (\<1%) of CIED infections in high-risk patients receiving the TYRX antibacterial envelope. One intriguing possibility is that the antibacterial envelope can be used instead of intraoperative antibacterial rinse and postoperative oral antibiotics. Therefore, an important knowledge gap exists about the best practices to prevent CIED infections in high-risk individuals.

2.0 Rationale and Specific Aims

SPECIFIC AIM: to test the hypothesis that the use of the TYRX antibacterial envelope alone is noninferior to a strategy using the antibacterial envelope and intraoperative antibacterial irrigant and postoperative oral antibiotics for the reduction of cardiac implantable device infections in patients with ≥2 risk factors for infection.

CIED infections are devastating yet potentially preventable complications. We previously conducted a retrospective study of the TYRX antibacterial envelope and found that use of the device in patients with ≥2 risk factors for CIED infection was associated with a markedly decreased infection rate (0.4% with the device versus 3% without, adjusted odds ratio \[95% confidence interval\]: 0.09 \[0.01 to 0.73\], P =0.02). All patients in our previous study had intraoperative irrigation of the device pocket with polymyxin-B/bacitracin solution and received routine postoperative oral antibiotics consistent with local practices. However, whether use of intraoperative irrigant and postoperative antibiotics reduces the risk of infection has not been evaluated in prospective, randomized trials. Moreover, it is unknown whether these treatments offer any incremental benefit over the use of the TYRX antibacterial envelope alone.

Given the significant cost of polymyxin-B/bacitracin solution and concerns over unnecessary use of oral antibiotics and emerging resistant microorganisms, it is critically important to establish whether these treatments offer any incremental benefit for patients at high risk for a CIED infection who are receiving the TYRX antibacterial envelope. The Specific Aim of this study will be to prospectively test the hypothesis that an infection risk-reduction strategy using the TYRX antibacterial envelope alone is noninferior to a strategy using the envelope with intraoperative antibacterial irrigant and postoperative oral antibiotics in patients undergoing a CIED procedure who have at least 2 CIED infection risk factors.

3.0 Previous Animal and Human Studies

The TYRX antibacterial envelope effectively prevented CIED infections in an animal model. In an animal model of direct bacterial inoculation into the device pocket, the TYRX antibacterial envelope showed excellent activity against Staphylococcus epidermidis, Staphylococcus capitis, Escherichia coli, and Acinetobacter baumannii. Importantly, systemic levels of minocycline and rifampin were undetectable.

Use of the TYRX antibacterial envelope has been associated with a reduced incidence of CIED infections in retrospective studies of high-risk patients. In a multi-center trial, use of the TYRX antibacterial envelope was associated with a low risk of CIED infections (0.5%). However, the relatively short follow-up period (mean: 1.9 months) and lack of a control arm limited the interpretation of the study's results. We conducted a retrospective controlled study of the TYRX antibacterial envelope in patients with at least 2 CIED infection risk factors at our institution. Among 260 TYRX envelope recipients, the incidence of CIED infection after a mean 18.7 month follow-up period was 0.4%, compared with 3% in 639 high-risk controls who did not receive the envelope (adjusted odds ratio: 0.09, 95% confidence interval 0.01 to 0.73, P =0.02). Another retrospective study at a high-volume center found that the prevalence of CIED infections decreased from 1.5% to 0.6% after the TYRX antibacterial envelope was instituted into practice (P =0.03).

Based on these and other studies, the Worldwide Randomized Antibiotic Envelope CIED Infection Prevention Trial (WRAP-IT) was conceived. This landmark trial will prospectively evaluate the efficacy of the TYRX-A antibacterial envelope. However, our proposed study will be complementary to the WRAP-IT trial because we will specifically evaluate whether the TYRX-A antibacterial envelope alone offers ample protection against CIED infections without the use of intraoperative antibacterial solution and postoperative oral antibiotics.

6.0 Study Procedures

Device implantation and follow-up. CIED procedures will be performed in accordance with established practice guidelines. Perioperative procedures to reduce the risk of CIED infection including optimal skin preparation and intravenous antibiotics (cefazolin or vancomycin) will be applied to all patients. All patients will receive the TYRX absorbable antibacterial envelope. Patients randomized to the intraoperative antibacterial irrigant/postoperative oral antibiotic (control) arm will undergo irrigation of the device pocket with up to 1 liter polymyxin-B/bacitracin solution. Patients in the control arm will also receive 3 days of postoperative oral antibiotics (cephalexin 500mg 3 times daily, clindamycin 300mg 3 times daily, or levofloxacin 500mg once daily) as per investigator routine ordering practice with discretion per each individual patient. Patients randomized to the experimental arm will not receive intraoperative antibacterial irrigation (will be allowed up to 1 liter sterile saline irrigation), nor post-operative oral antibiotics.

All patients will be followed after their procedures according to established practice guidelines. At a minimum, patients will be seen 4 weeks after the procedure for a wound check, at 6 months, and then every year or more frequently as dictated by each patient's clinical status. A digital photograph of the device pocket will be captured at the 4-week postoperative visit. In addition, the study nurse will telephone each patient 3 months after implantation to assess for symptoms and signs of infection. For the purposes of the study, patients will continue to be followed for a minimum of 6 months after the procedure, but additional follow-up data after six months may be collected continuously until the study closes.

Ascertainment of the primary endpoint: CIED infection after a minimum 6-month follow-up period. The primary study endpoint will be CIED infection resulting in complete CIED system removal, antibiotic therapy in patients who are not candidates for system removal, or death due to CIED infection. To avoid detection bias we will prospectively apply criteria for definition of the primary endpoint and ask treating physicians to thoroughly document objective findings.

Examples of objective signs of CIED infection.

Objective findings of CIED infection

* Fever or leukocytosis without an alternative explanation (e.g., urinary tract infection or pneumonia)
* Tenderness, erythema, or warmth at the pulse generator site
* Purulent discharge from the pulse generator site (from incision or fistula)
* Positive blood or pulse generator site cultures
* Vegetation adherent to CIED hardware
* Purulent material within pulse generator pocket upon reoperation

A digital photograph of the device pocket will be captured routinely at the postoperative visit and whenever CIED infection is a consideration. In case of a suspected CIED infection, treating physicians will be strongly encouraged to obtain peripheral blood cultures prior to initiation of antibiotic therapy and intraoperative cultures during CIED system removal. A panel of 3 physicians at the coordinating center who are blinded to study assignment (experimental versus control) will independently adjudicate outcomes in "real time" and will vote whether or not the criteria for CIED infection have been met. A minor superficial infection of the incision that does not involve the generator pocket, does not result in any systemic symptoms or signs, and is treated with either observation or a short course of oral antibiotics, will not be counted as a CIED infection but will be considered a secondary endpoint.

Study oversight: The principal investigator at each study sight will be responsible for all aspects of the study at their respective sites. To ensure fidelity with the study protocol, an independent study coordinator at Vanderbilt University who is not directly involved with the study will review upon initiation of the study and first patient enrolled at each site, and then a random selection (10%) of patient records at each site (including Vanderbilt University) on a continuous basis set out by the monitoring agreement throughout the duration of the study, and quarterly prepare a report for the study's principal investigator.

Arms: arm 1: Saline irrigation arm 2: Antibacterial irrigant (polymyxinB/bacitracin) and postoperative oral antibiotics (cephalexin, clindamycin, or levofloxacin)
Interventions: intervention 1: polymixin/bacitracin intervention 2: cephalexin, or levofloxacin, or clindamycin intervention 3: Saline
Intervention descriptions: intervention 1: Antibacterial irrigation intervention 2: Post operative oral antibiotics intervention 3: Saline irrigation

Protocol documents:
Prot_SAP_000.pdf: 
Antibacterial Envelope Noninferiority Study 
December 6, 2019 
1 
 
A Randomized Noninferiority Study of the TYRX-A Antibacterial 
Envelope Alone Versus Envelope Plus Intraoperative Antibacterial 
Irrigant and Postoperative Oral Antibiotics to Prevent Cardiac 
Implantable Electronic Device Infections in High-Risk Patients 
 
NCT02809131 
Current Protocol Version date:    December 6, 2019 
 
Christopher R. Ellis, M.D. – Principal Investigator 
 
 
Previous Version date: March 6, 2015 
Previous Version date: November 1, 2015 
Previous Version date: May 14, 2016 
Previous Version date:  November 16, 2017 
Previous Version date:  November 12, 2019 (contained a 
clerical error and not distributed to sites) 
 
 
 
 
 


Antibacterial Envelope Noninferiority Study 
December 6, 2019 
 
2 
 
Table of Contents: 
 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Previous Animal and Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
7.0 
Risks of Investigational Agents/Devices (side effects) 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
9.0 
Study Withdrawal/Discontinuation 
10.0 Statistical Considerations 
11.0 Privacy/Confidentiality Issues 
12.0 Follow-up and Record Retention 
 
 


Antibacterial Envelope Noninferiority Study 
December 6, 2019 
 
3 
1.0 
Background  
 
 
 
 
 
The number of cardiac implantable electronic devices (CIEDs) implanted each 
year has grown rapidly over the past two decades, largely due to expanding use of 
implantable cardioverter-defibrillators (ICDs) and devices capable of delivering cardiac 
resynchronization therapy (CRT).8 CIEDs have increasingly been utilized in older 
patients with multiple medical comorbidities. As a result CIED infections, defined as 
infections involving the generator implant site (pocket) and/or intravascular leads, have 
become increasingly prevalent, with the rate of growth in infections outpacing that of 
CIED procedures.9 The increase in 
incidence of CIED infections has outpaced 
the growth in device implantation, in large 
part due to the medical complexity of 
today’s CIED patients.9-11 These 
devastating complications are associated 
with significant cost, morbidity, and 
mortality.4,9,12-14 The odds of both short 
term and long term mortality are at least 
doubled in patients who suffer CIED 
infections, and long term survival is 
particularly poor in women.4,11,12 
 
 
 
Patient-specific risk factors for 
CIED infections have been examined in multiple registries and case-control studies 
and are presented in Table 1. For patients with at least two risk factors, the reported 
incidence of CIED infection is 2-3%.1,14,15 Management of these infections is complex 
and expensive. The cornerstone of management is the complete removal of all infected 
hardware whenever possible, which in itself poses significant risks for patients.16,17 
Therefore prevention of infections is crucial. 
 
Best practices for reducing CIED infections are an active area of research.  
Since most infections occur as a result of 
bacterial seeding at the time of device 
implantation or revision, careful attention to strict 
sterile technique is mandatory. Optimal skin 
preparation and perioperative intravenous 
antibiotics have been associated with a reduced 
rate of CIED infections in randomized controlled 
studies.7,18 Additionally, several recent 
retrospective studies have suggested an 
important role of the minocycline and rifampin 
impregnated TYRX antibacterial envelope in 
reducing infections. The device consists of 2 
polypropylene mesh sheets joined on 3 sides 
with a 3mm seam and is available in 2 sizes to 
accommodate pacemaker and ICD pulse 
CIED infection risk factor 
References 
Diabetes mellitus 
1,2 
Chronic kidney disease 
1-4 
Therapeutic anticoagulation 
1,2,4 
Chronic heart failure 
4 
Chronic corticosteroid use 
5 
Fever or leukocytosis 
6 
Device revision* 
1,2,7 
Three or more leads 
5 
Early re-operation 
6,7 
Prior device infection 
5 
Table 1: Established CIED infection risk 
factors. *Includes generator change, pocket 
revision, and lead revision. 
Figure 1: ICD generator within an antibacterial 
envelope just prior to implantation. 


Antibacterial Envelope Noninferiority Study 
December 6, 2019 
 
4 
generators. This polypropylene envelope releases minocycline and rifampin from a 
bioresorbable polyarylate polymer over approximately 7 days, directly into the CIED 
generator pocket (Figure 1). 
 
 
Aside from optimal skin preparation and perioperative intravenous antibiotics, 
other practices to reduce the risk of CIED infections vary widely. Many operators use an 
antibacterial solution (e.g., polymyxin-B/bacitracin) to irrigate the pocket during device 
implantation. Additionally, many centers have adopted the routine use of prophylactic 
postoperative antibiotics to reduce the risk of CIED infections. However, neither of these 
strategies has been evaluated in randomized clinical studies. Antibacterial irrigation 
solution is expensive, and oral antibiotics are associated with a small yet clinically 
important risk of adverse effects, including Clostridium difficile infection. Therefore, 
prospective randomized studies are needed to evaluate the efficacy, safety, and cost-
effectiveness of intraoperative antibacterial rinse and postoperative oral antibiotics.  
 
 
Summary of significance: CIED infections constitute major complications of 
device implantations or revisions and are becoming increasingly prevalent. Infections 
are associated with increased morbidity, mortality, and cost, and are very difficult to 
treat. Recent studies have explored ways to reduce the incidence of CIED infections, 
and use of the TYRX antibacterial envelope has emerged as a potential strategy for 
prevention. Other strategies including intraoperative antibacterial irrigation and 
postoperative oral antibiotics are commonly used despite the lack of prospective studies 
documenting efficacy, safety, and cost-effectiveness. We and others have reported a 
very low incidence (<1%) of CIED infections in high-risk patients receiving the TYRX 
antibacterial envelope. One intriguing possibility is that the antibacterial envelope can 
be used instead of intraoperative antibacterial rinse and postoperative oral antibiotics. 
Therefore, an important knowledge gap exists about the best practices to prevent 
CIED infections in high-risk individuals. 
 
 
2.0 
Rationale and Specific Aims 
 
SPECIFIC AIM: to test the hypothesis that the use of the TYRX antibacterial 
envelope alone is noninferior to a strategy using the antibacterial envelope and 
intraoperative antibacterial irrigant and postoperative oral antibiotics for the 
reduction of cardiac implantable device infections in patients with ≥2 risk factors 
for infection. 
 
CIED infections are devastating yet potentially preventable complications. We 
previously conducted a retrospective study of the TYRX antibacterial envelope and 
found that use of the device in patients with ≥2 risk factors for CIED infection was 
associated with a markedly decreased infection rate (0.4% with the device versus 3% 
without, adjusted odds ratio [95% confidence interval]: 0.09 [0.01 to 0.73], P =0.02). All 
patients in our previous study had intraoperative irrigation of the device pocket with 
polymyxin-B/bacitracin solution and received routine postoperative oral antibiotics 
consistent with local practices. However, whether use of intraoperative irrigant and 


Antibacterial Envelope Noninferiority Study 
December 6, 2019 
 
5 
postoperative antibiotics reduces the risk of infection has not been evaluated in 
prospective, randomized trials. Moreover, it is unknown whether these treatments offer 
any incremental benefit over the use of the TYRX antibacterial envelope alone.  
 
Given the significant cost of polymyxin-B/bacitracin solution and concerns over 
unnecessary use of oral antibiotics and emerging resistant microorganisms, it is 
critically important to establish whether these treatments offer any incremental benefit 
for patients at high risk for a CIED infection who are receiving the TYRX antibacterial 
envelope. The Specific Aim of this study will be to prospectively test the hypothesis 
that an infection risk-reduction strategy using the TYRX antibacterial envelope 
alone is noninferior to a strategy using the envelope with intraoperative 
antibacterial irrigant and postoperative oral antibiotics in patients undergoing a 
CIED procedure who have at least 2 CIED infection risk factors.  
 
 
3.0 
Previous Animal and Human Studies 
 
The TYRX antibacterial envelope effectively prevented CIED infections in 
an animal model. In an animal model of direct bacterial inoculation into the device 
pocket, the TYRX antibacterial envelope showed excellent activity against 
Staphylococcus epidermidis, Staphylococcus capitis, Escherichia coli, and 
Acinetobacter baumannii.19 Importantly, systemic levels of minocycline and rifampin 
were undetectable. 
 
Use of the TYRX antibacterial envelope has been associated with a reduced 
incidence of CIED infections in retrospective studies of high-risk patients. In a 
multi-center trial, use of the TYRX antibacterial envelope was associated with a low risk 
of CIED infections (0.5%).20 However, the relatively short follow-up period (mean: 1.9 
months) and lack of a control arm limited the interpretation of the study’s results. We 
conducted a retrospective controlled study of the TYRX antibacterial envelope in 
patients with at least 2 CIED infection risk factors at our institution. Among 260 TYRX 
envelope recipients, the incidence of CIED infection after a mean 18.7 month follow-up 
period was 0.4%, compared with 3% in 639 high-risk controls who did not receive the 
envelope (adjusted odds ratio: 0.09, 95% confidence interval 0.01 to 0.73, P =0.02).15 
Another retrospective study at a high-volume center found that the prevalence of CIED 
infections decreased from 1.5% to 0.6% after the TYRX antibacterial envelope was 
instituted into practice (P =0.03).21 
 
 
Based on these and other studies, the Worldwide Randomized Antibiotic 
Envelope CIED Infection Prevention Trial (WRAP-IT) was conceived. This landmark trial 
prospectively evaluated the efficacy of the TYRX-A antibacterial envelope. However, 
our study is complementary to the WRAP-IT trial because we will specifically evaluate 
whether the TYRX-A antibacterial envelope alone offers ample protection against CIED 
infections without the use of intraoperative antibacterial solution and postoperative oral 
antibiotics.  
 


Antibacterial Envelope Noninferiority Study 
December 6, 2019 
 
6 
4.0 
Inclusion/Exclusion Criteria 
 
 
 
 
5.0 
Enrollment/Randomization 
 
General approach and study design: In a multicenter randomized controlled 
trial, we will recruit up to 1492 patients scheduled to undergo an elective CIED 
procedure with use of the TYRX-A antibacterial envelope. Using a parallel group design, 
patients will be randomized 1:1 to either: 
1. intraoperative irrigation solution using bacitracin, that may also include neomycin, 
polymixin-B or amikacin, plus post-operative oral antibiotics (cephalexin, 
clindamycin, or levofloxacin; control arm)  
 
OR 
 
Inclusion criteria 
Exclusion criteria 
Age ≥18 years old 
Medical condition that is likely to be fatal 
in less than one year 
Able to give informed consent 
Emergent CIED procedure 
At least 2 of the following risk factors for 
infection: 
• Diabetes mellitus 
• Chronic kidney disease (estimated 
creatinine clearance <30 ml/min 
• Therapeutic anticoagulation 
• Chronic heart failure 
• Chronic use of corticosteroids 
• Fever ≥38° C or leukocytosis 
(≥11,000 cells/mm3) within 24 hrs 
of implant 
• Device revision (including 
generator change, or extraction) 
• ≥3 leads  (receiving a new CRT 
system, current leads, or 
previously abandoned leads) 
• Early reoperation (pocket re-entry 
<2 weeks) 
• Previous CIED infection 
 
Allergy to rifampin or minocycline 
Allergy to polymyxin-B, bacitracin, 
neomycin or amikacin 
Subject is pregnant 
 
Current CIED pocket infection 


Antibacterial Envelope Noninferiority Study 
December 6, 2019 
 
7 
2. no intraoperative antibiotic irrigant/post-operative oral antibiotics (experimental 
arm).  
 
Patients will be followed for CIED infections for a minimum of 180 days. The primary 
analysis will test whether the antibacterial envelope alone is noninferior to a strategy 
using the envelope and antibacterial irrigant and oral antibiotics. 
 
Recruitment and retention: Patients will be enrolled at 4 high-volume centers: 
Vanderbilt University Medical Center in Nashville, Tennessee (the coordinating center), 
Thomas Jefferson University Hospital in Philadelphia, Pennsylvania, The Valley 
Hospital in Ridgewood, New Jersey, and Cooper Health System in Camden, New 
Jersey. Additional sites may be added as needed. Patients will be screened from 
cardiology clinic schedules, electrophysiology lab schedules, and inpatient censuses. A 
research coordinator at each site will be responsible for screening, enrollment, and data 
collection. The principal investigator for each site will be responsible for the conduct of 
all study procedures with appropriate oversight from the institutional review board at 
each site. 
 
Patients who are scheduled to undergo a de novo pacemaker or ICD implant, 
generator exchange, device, lead, or pocket revision, or re-implantation after a recent 
CIED infection will be screened for entry into the study. After careful consideration of 
inclusion and exclusion criteria, prospective participants will receive written and verbal 
information about the study from study personnel. Willing participants will be provided a 
written informed consent form, and after all questions have been answered, will be 
asked to sign the form.  
 
Patients scheduled for CIED implantation with a device not manufactured by 
Medtronic Inc. will be considered for our study. In addition, de novo Medtronic Inc. non-
CRT pacemaker and ICD implantations will be considered.  
 
Patients with a current CIED pocket infection will be excluded since the TYRX 
antibacterial envelope is not indicated for the treatment of an active infection. However, 
patients with a recent infection, who have had successful CIED system explantation and 
are scheduled for implantation of a new CIED system (usually on the contralateral side 
of the chest) will be considered for inclusion in our study. 
 
Randomization: Randomization will be performed at the coordinating center 
using a permuted block design with random block sizes of 2, 4, or 6 patients. 
Randomization will be stratified by center and by history of previous CIED infection. 
 
 
6.0 
Study Procedures 
 
Device implantation and follow-up. CIED procedures will be performed in 
accordance with established practice guidelines. Perioperative procedures to reduce the 
risk of CIED infection including optimal skin preparation and intravenous antibiotics 


Antibacterial Envelope Noninferiority Study 
December 6, 2019 
 
8 
(cefazolin or vancomycin) will be applied to all patients. All patients will receive the 
TYRX absorbable antibacterial envelope per routine care.  
 
Patients randomized to the intraoperative antibacterial irrigant/postoperative oral 
antibiotic (control) arm will undergo irrigation of the device pocket with up to 1 liter of an 
antibiotic solution using bacitracin, that may also include neomycin, polymixin-B or 
amikacin, in accordance with the local hospital standard. Patients in the control arm will 
also receive 3 days of postoperative oral antibiotics (cephalexin 500mg 3 times daily, 
clindamycin 300mg 3 times daily, or levofloxacin 500mg once daily) as per investigator 
routine ordering practice with discretion per each individual patient. Patients randomized 
to the experimental arm will not receive intraoperative antibacterial irrigation (will be 
allowed up to 1 liter sterile saline irrigation), nor post-operative oral antibiotics.  
 
All patients will be followed after their procedures according to established 
practice guidelines. At a minimum, patients will be seen 2-4 weeks after the procedure 
for a wound check, at 6 months, and then every year or more frequently as dictated by 
each patient’s clinical status. For patients who are referred to a study center for their 
CIED procedure and follow-up with a local electrophysiologist a study coordinator will 
call the patient at 6 months to ascertain study endpoints and request a copy of the 
follow-up clinic visit note. We anticipate that this will apply to only a small minority 
(<10%) of study subjects. A digital photograph of the device pocket will be captured at 
the 2-4-week postoperative visit. In addition, the study nurse will telephone each patient 
3 months after implantation to assess for symptoms and signs of infection. For the 
purposes of the study, patients will continue to be followed for a minimum of 6 months 
after the procedure, but additional follow-up data after six months may be collected 
continuously until the study closes. 
 
Ascertainment of the primary endpoint: CIED infection after a minimum 6-
month follow-up period. The primary study endpoint will be CIED infection resulting in 
complete CIED system removal, antibiotic therapy in patients who are not candidates 
for system removal, or death due to CIED infection. To avoid detection bias we will 
prospectively apply criteria for definition of the primary endpoint and ask treating 
physicians to thoroughly document objective findings (Table 2). 
 
Table 2: Examples of objective signs of CIED infection. 
 
 
 
Objective findings of CIED infection 
*Fever or leukocytosis without an alternative explanation (e.g., urinary 
  tract infection or pneumonia) 
*Tenderness, erythema, or warmth at the pulse generator site 
*Purulent discharge from the pulse generator site (from incision or fistula) 
*Positive blood or pulse generator site cultures 
*Vegetation adherent to CIED hardware 
*Purulent material within pulse generator pocket upon reoperation 


Antibacterial Envelope Noninferiority Study 
December 6, 2019 
 
9 
 A digital photograph of the device pocket will be captured routinely at the 2-4 
week postoperative visit and whenever CIED infection is a consideration. In case of a 
suspected CIED infection, treating physicians will be strongly encouraged to obtain 
peripheral blood cultures prior to initiation of antibiotic therapy and intraoperative 
cultures during CIED system removal per standard guidelines. A panel of 3 physicians 
at the coordinating center who are blinded to study assignment (experimental versus 
control) will independently adjudicate outcomes in “real time” and will vote whether or 
not the criteria for CIED infection have been met. A minor superficial infection of the 
incision that does not involve the generator pocket, does not result in any systemic 
symptoms or signs, and is treated with either observation or a short course of oral 
antibiotics, will not be counted as a CIED infection but will be considered a secondary 
endpoint. 
 
Study oversight: The principal investigator at each study sight will be 
responsible for all aspects of the study at their respective sites. To ensure fidelity with 
the study protocol, an independent study coordinator at Vanderbilt University who is not 
directly involved with the study will review upon initiation of the study and first patient 
enrolled at each site, and then a random selection (10%) of patient records at each site 
(including Vanderbilt University) on a continuous basis set out by the monitoring 
agreement throughout the duration of the study, and quarterly prepare a report for the 
study’s principal investigator. 
 
 
7.0 
Risks 
 
Risks associated with the TYRX-A antibacterial envelope: The TYRX-A 
antibacterial envelope has been used extensively at each study site since 2009, and all 
implanting electrophysiologists are familiar with its use. The volume of the device 
generator pocket has to be expanded by approximately 10-20% to accommodate the 
envelope. This creates the potential for an increased risk of bleeding and hematoma, 
although these have not been quantified. Other potential risks of envelope use include 
allergic reaction and pain or discomfort at the generator site. Importantly, systemic 
levels of rifampin and minocycline were undetectable in animals that received the 
antibacterial envelope in a previous study.19 The previous generation, non-absorbable 
envelope was associated with increased scarring within the generator pocket that posed 
difficulty with explantation in a minority of cases. The absorbable envelope to be used in 
the current study was developed with this limitation in mind and should reduce scarring, 
although this requires further study. In summary, the antibacterial envelope has been 
implanted in thousands of patients to date and has been associated with a very low 
incidence of adverse events. 
 
Risks associated with polymyxin-B: Although parenteral use of polymyxin-B is 
associated with significant adverse effects, the risks associated with intraoperative 
irrigation are largely undefined but believed to be minimal. 
 


Antibacterial Envelope Noninferiority Study 
December 6, 2019 
 
10
Risks associated with neomycin:  The most common adverse reactions to 
oral neomycin are nausea, vomiting and diarrhea.  However, the risks associated 
with intraoperative irrigation are thought to be minimal. 
 
Risks associated with amikacin:  Approximately 1-10% experience 
neurotoxicity, nephrotoxicity and ototoxicity.  Less than 1% experience 
hypotension, headache, rash, nausea, vomiting, tremors, arthralgia, weakness 
and allergic reacting.  However, the risks associated with intraoperative irrigation 
are believed to be minimal. 
 
Risks associated with bacitracin: The topical use of bacitracin is generally safe 
but has been associated with rare incidents of allergic reactions and anaphylaxis. 
Systemic use of bacitracin is associated with rash, albuminuria, nausea, vomiting, 
azotemia, nephrotoxicity, pain at injection site, renal failure, and anaphylaxis. The risks 
associated with intraoperative irrigation with bacitracin solution are largely undefined but 
thought to be minimal due to little, if any, systemic absorption. 
 
Risks associated with cephalexin: Risks include agitation, confusion, 
dizziness, fatigue, hallucination, headache, erythema multiforme (rare), genital pruritus, 
skin rash, Stevens-Johnson syndrome (rare), toxic epidermal necrolysis (rare), urticaria, 
abdominal pain, diarrhea, dyspepsia, gastritis, nausea (rare), pseudomembranous 
colitis, vomiting (rare), genital candidiasis, vaginal discharge, vaginitis, eosinophilia, 
hemolytic anemia, neutropenia, thrombocytopenia, cholestatic jaundice (rare), hepatitis 
(transient, rare), increased serum aminotransferase levels, anaphylaxis, angioedema, 
hypersensitivity reaction, arthralgia, arthritis, arthropathy, and interstitial nephritis (rare). 
 
Risks associated with clindamycin: Risks include cardiac arrest (rare; IV 
administration), hypotension (rare; IV administration), thrombophlebitis (IV), metallic 
taste (IV), acute generalized exanthematous pustulosis, erythema multiforme (rare), 
exfoliative dermatitis (rare), maculopapular rash, pruritus, skin rash, Stevens-Johnson 
syndrome (rare), toxic epidermal necrolysis, urticaria, vesiculobullous dermatitis,  
abdominal pain, antibiotic-associated colitis, Clostridium difficile associated diarrhea, 
diarrhea, esophageal ulcer, esophagitis, nausea, pseudomembranous colitis, 
unpleasant taste (IV), vomiting, azotemia, oliguria, proteinuria, vaginitis, 
agranulocytosis, eosinophilia (transient), neutropenia (transient), thrombocytopenia, 
abnormal hepatic function tests, jaundice, anaphylactoid reaction (rare), DRESS 
syndrome, abscess at injection site (IM), induration at injection site (IM), irritation at 
injection site (IM), pain at injection site (IM), polyarthritis (rare), and renal insufficiency 
(rare). 
 
Risks associated with levofloxacin: Risks include chest pain (1%), edema 
(1%), headache (6%), insomnia (4%), dizziness (3%), skin rash (2%), pruritus (1%), 
nausea (7%), diarrhea (5%), constipation (3%), abdominal pain (2%), dyspepsia (2%), 
vomiting (2%), vaginitis (1%), candidiasis (1%), injection site reaction (1%), and 
dyspnea (1%). The following adverse reactions have been noted in less than 1% of 
cases: abnormal electroencephalogram, abnormal gait, acute renal failure, ageusia, 


Antibacterial Envelope Noninferiority Study 
December 6, 2019 
 
11
agranulocytosis, anaphylactoid reaction, anemia (including aplastic and hemolytic), 
anorexia, anosmia, brain disease (rare), cardiac arrest, cardiac arrhythmia (including 
ventricular tachycardia/fibrillation and torsades de pointes), Clostridium difficile-
associated diarrhea, confusion, convulsions, crystalluria, cylindruria, depression, 
elevation in serum levels of skeletal-muscle enzymes, eosinophilia, epistaxis, erythema 
multiforme, esophagitis, exacerbation of myasthenia gravis, gastritis (including 
gastroenteritis), glossitis, granulocytopenia, hallucination, hepatic failure (some fatal), 
hepatic insufficiency, hepatitis, hyperglycemia, hyperkalemia, hyperkinesias, 
hypersensitivity reaction (including anaphylaxis, angioedema, rash, pneumonitis, and 
serum sickness), hypertension, hypertonia, hypoacusis, hypoglycemia, hypotension, 
increased INR, increased intracranial pressure, increased serum alkaline phosphatase, 
increased serum transaminases, interstitial nephritis, intestinal obstruction, jaundice, 
leukocytosis, leukopenia, leukorrhea, lymphadenopathy, multiorgan failure, muscle 
injury, muscle spasm, pancreatitis, pancytopenia, paralysis, paranoia, peripheral 
neuropathy (may be irreversible), phlebitis, phototoxicity, prolonged prothrombin time, 
prolonged QT interval on ECG, pseudotumor cerebri, psychosis, renal function 
abnormality, rhabdomyolysis, rupture of tendon, scotoma, seizure, skeletal pain, skin 
photosensitivity, sleep disorder (including abnormal dreams and nightmares), Stevens-
Johnson syndrome, stomatitis, suicidal ideation, syncope, tachycardia, tendonitis, toxic 
epidermal necrolysis, toxic psychosis, thrombocytopenia (including thrombotic 
thrombocytopenic purpura), uveitis, vasculitis (leukocytoclastic), vasodilatation, visual 
disturbances(including diplopia), and voice disorder. 
  
 
8.0 
Reporting of Adverse Events or Unanticipated Problems Involving Risk to 
Participants or Others 
 
All serious related adverse events and incidents of noncompliance with the 
protocol will be reported to the institutional review board and coordinating center. For 
the purposes of the study, serious adverse events will only be documented if there is a 
reasonable suspicion that they are related to the envelope, procedure, infection, or 
death.  A serious adverse event will be defined as an untoward medical occurrence that 
results in death, is life-threatening, requires hospitalization, results in persistent or 
significant disability, or requires intervention to prevent permanent disability or death. 
Other untoward medical occurrences that do not meet the above criteria will be 
classified as adverse events. Study personnel will monitor for adverse events. All 
suspected or confirmed adverse events will promptly be reported to the principal 
investigator, who will collect data on these occurrences. The principal investigator will 
report unexpected and related serious adverse events to the institutional review board, 
coordinating center, and any other applicable authority, within 10 days of knowledge of 
the occurrence or sooner depending on local IRB policy. If a death occurs, it will be 
reported within 24 hours of knowledge of the death. The principal investigator will report 
unrelated serious and non-serious adverse events to the institutional review board on 
an annual basis per local IRB policy. Non-serious adverse events will be reported at the 
time of continuing review per local IRB policy. 
 


Antibacterial Envelope Noninferiority Study 
December 6, 2019 
 
12
Each site will be required to have a local study coordinator who will be 
responsible for entering the study information into the web-based database and 
uploading the identifiable source documents/medical records associated with the study 
information. 
 
In addition, identifiable source documentation verifying all collected study data 
points will be securely uploaded into the web-based database. 
 
 
9.0 
Study Withdrawal/Discontinuation 
 
Participation in the study is strictly voluntary, and patients will be able to withdraw 
at any time. Following the subject’s withdrawal, no further data will be collected, 
although any analyzed data will be maintained.  
 
 
10.0 Statistical Considerations 
 
We conducted a sample size/power calculation based on both frequentist and 
Bayesian methods. These calculations were performed by Ms. Hui Bian and Ms. Yanna 
Song and overseen by Dr. Chang Yu, Ph.D. in the Vanderbilt University Department of 
Biostatistics. Based on our previous clinical experience, we estimate the infection rate in 
the control group to be 1%. Using frequentist methods and a noninferiority limit of 1%, 
we will need to recruit 1492 subjects to have 80% power to show noninferiority at an 
alpha level of 0.05. We also conducted a simulation using a Bayesian flexible design 
analysis. We again assumed a 1% event rate among controls and a noninferiority limit 
of 1%. In the simulation the odds of being able to claim noninferiority were 0.88 with an 
average sample size of 1492 subjects. This approach offers the distinct advantage of 
being able to stop enrollment early once the threshold for noninferiority is reached. We 
plan to conduct regular interim analyses, beginning after 600 patients are enrolled and 
complete the minimum follow-up period. Therefore, it will be feasible to conduct our 
proposed trial in 3-3.5 years.  
 
11.0 Privacy/Confidentiality Issues 
 
All research hard copy records will be stored in a locked cabinet within a locked 
office with access only to the research personnel. Study data will be stored in the 
secure Research Data Capture (REDCap) database. Only the investigators, staff and 
study monitors will have access to the study data.  
 
12.0 Follow-up and Record Retention 
 
We expect enrollments for 30 months with additional 6 months for follow up on 
last enrolled subject. Then there will be additional 6 months of record retention after the 
last patient enrolled reaches 6 months post op. All data will be archived and stored 
indefinitely. 


Antibacterial Envelope Noninferiority Study 
December 6, 2019 
13 
 
Schedule of Events 
Study Procedure Schedule 
Baseline 
CIED 
Procedure 
Day  
For 3 
days 
Post-op 
Wound check-
approximately 
4 weeks post-
procedure 
(+/1-2 weeks) 
3 month 
Phone 
Call f/u 
6 month 
Visit / or 
Phone 
Call 
Unscheduled/Suspected 
CIED Infection 
Yearly/end 
of study 
Office Visit/History/Physical Exam a 
x 
  
  
x 
  
xᵃ 
x 
x 
Informed Consent 
x 
  
  
  
  
  
  
  
Data collection of routine pre-op 
labs (ie. CBC/CMP) 
x 
 
 
 
 
 
 
 
CIED Device Implant with TYRX 
absorbable antibacterial envelope 
  
x 
  
  
  
  
  
  
Randomization 
  
x 
  
  
  
  
  
  
Irrigation of device pocket b 
  
x 
  
  
  
  
  
  
Prescription for 3 days of 
postoperative oral antibiotics c 
  
x 
x 
  
  
  
  
  
Digital Photograph of device 
pocket 
  
  
  
x 
  
x 
  
Signs and symptoms of infection 
check 
  
  
  
  
x 
  
x 
x 
Adjudicate Criteria for CIED 
infectiond 
  
  
  
  
  
  
x 
  
peripheral blood cultures  
  
  
  
  
  
  
x 
  
Intraoperative cultures during CIED 
system removal 
  
  
  
  
  
  
x 
  
Antibiotic Medication 
Documentation 
  
  
  
  
  
  
x 
  
All patients will be followed after their procedures according to established practice guidelines. At a minimum, patients will be seen 4 weeks after the 
procedure for a wound check, at 6 months, and then every year or more frequently as dictated by each patient’s clinical status 
    
ᵃ   ONLY at the 6 month time point, if the patient cannot be reached after 2 phone calls and a letter, a chart review can be done to retrieve the data needed for the visit 


Antibacterial Envelope Noninferiority Study 
December 6, 2019 
 
14
b   ONLY patients randomized to Control Arm will receive irrigation of the device pocket with up to 1 liter of antibiotic wash 
c    ONLY patients randomized to Control Arm will receive 3 days of postoperative oral antibiotics (cephalexin 500mg 3 times daily, clindamycin 300mg 3 times 
daily, or levofloxacin 500mg once daily) 
d   A panel of 3 physicians at the coordinating center who are blinded to study assignment (experimental versus control) will independently adjudicate 
outcomes in “real time” and will vote whether or not the criteria for CIED infection have been met. 


Antibacterial Envelope Noninferiority Study 
December 6, 2019 
15 
 
 
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