Tissue Plasminogen Activator Dwells to Reduce Catheter-associated Thrombosis and Infection
Phase: PHASE2
Conditions: Central Venous Catheter Thrombosis, Central Venous Catheter Associated Bloodstream Infection
Sponsor: Medical College of Wisconsin

 
t-PA Prophylaxis to Reduce Central Venous Catheter Associated 
Infection and Thrombosis (TOPCAT) 
 
NCT03672006 
 
February 5, 2019 
 

 
 
TOPCAT Protocol 
 
INSTITUTIONAL REVIEW BOARD 
       SUMMARY 
 
 
 
PRINCIPAL INVESTIGATOR:  Sheila Hanson, MD 
 
STUDY TITLE:  t-PA Prophylaxis to reduce Central Venous Catheter Associated Infection and Thrombosis 
(TopCAT) 
 
A. 
PURPOSE OF THE STUDY 
 
The purpose of this pilot study is to test feasibility of concept, consent and enrollment rates, and 
mechanics of study designed to assess if intra-catheter dwells of tissue plasminogen activator (t-PA: 
Alteplase; Activase®, Genentech)is effective in decreasing the rate of clinically diagnosed central line 
associated blood stream infection (CLABSI) or venous thromboembolism (VTE) in central venous 
catheters (CVC) compared to standard of care heparin dwell.  
 
B. 
HYPOTHESIS / SPECIFIC AIMS 
 
We hypothesize there will be a lower rate of CLABSI or VTE in CVCs who receive t-PA as a dwell 
medication. 
 We will test this hypothesis in the following aims:  
Aim 1: It is feasible to enroll patients with CVC and randomize to receive t-PA vs heparin 
dwell. 
-Determine number of eligible patients, consents rates, and adherence to study 
protocol in patients with CVC in the CHW Intensive Care Unit (ICU). 
-Calculate the number of centers needed to adequately power a multi-center trial to 
determine if t-PA is effective in reducing CVC complications from the rates found in 
this pilot study. 
 
Aim 2: Compare the rate of VTE and CLABSI in patients with a CVC in the ICU randomized to 
receive t-PA vs. heparin as a dwell in the CVC. 
-This will be a prospective, blinded, RCT enrolling 20 patients in the ICU with a CVC to 
receive t-PA or heparin to dwell for a minimum of 30 minutes every three days until 
CVC removal, discharge from the ICU or a maximum of 10 doses have been received. 
 
 
C. 
BACKGROUND, SIGNIFICANCE, AND RATIONALE  

 
 
TOPCAT Protocol 
Central line associated blood stream infection (CLABSI) and venous thromboembolism (VTE) 
continue to be a major source of morbidity in patients with central venous catheter (CVC). There 
is physiologic plausibility that by decreasing fibrin development with the use of t-PA in CVCs, the 
rate of CVC-associated VTE and CLABSI would be decreased.  
It is well established that t-PA is safe and effective in restoring CVC patency after occlusion in 
adults (Deitcher 2002, Ponec 2001) and children (Blaney 2006), and is FDA approved for this use 
in both adults and children. Using t-PA for occluded CVC is standard of care in CHW PICU and is 
recommended by clinical practice standards, including Infusion Nurses Society (INS), Association 
for Vascular Access (AVA), American Association of Critical Care Nurses (AACN), Oncology 
Nursing Society (ONS). 
It is not known if t-PA would be effective in preventing fibrin deposition and subsequent 
complications of VTE and CLABSI if administered prophylactically. Analysis of prophylactic t-PA 
used as a dwell solution for dialysis catheters suggests that this may be the case. A meta-analysis  
(Firwana 2011) reviewing randomized controlled trials of t-PA as a preventative locking solution 
for hemodialysis catheters compared to heparin found a decrease adverse events including 
thrombosis with the use of t-PA (Schenk 2000, Hemmelgarn 2011, Gittins 2007).  
Use of t-PA for preventing VTE and CLABSI in the non-dialysis catheter is very limited. Preliminary 
evidence in pediatric patients with long term CVC dependency has shown that prophylactic dwell 
of tissue plasminogen activator (t-PA) has decreased episodes of CVC dysfunction; however, that 
study was underpowered to test the outcomes of CLABSI or VTE( Malec 2017). A multicenter 
study would be needed to provide sufficient sample size. The pilot study proposed here will test 
feasibility of concept, enrollment and consent rates, and mechanics of study design to be used to 
inform a grant application for a future multicenter trial. 
Currently, heparin as a capping or locking solution is the standard of care for functioning CVCs at 
CHW with t-PA reserved for restoration of flow with occluded CVC.   
 
 
D. 
DESIGN AND METHODS 
 
This pilot study at CHW will be a prospective, blinded, RCT enrolling 20 patients in the PICU with a CVC 
to receive t-PA (study drug) or heparin (current standard of care and defined as control arm for this 
study) to dwell for a minimum of 30 minutes every three days until catheter removal or discharge from 
the PICU. Primary outcomes would be CLABSI or VTE. Secondary outcomes would be episodes of CVC 
dysfunction, off study use of t-PA, and bleeding.   
 
Patients meeting the following criteria will be eligible for study participation 
 
Inclusion criteria:  
• Age >2 weeks( corrected for gestational age)  to ≤ 18 years old 

 
 
TOPCAT Protocol 
• PICU admission  
• CVC placed within 72 hours of enrollment (tunneled such as PICC, Broviac or Hickman, or  
untunneled) and in place during hospitalization 
 
Exclusion criteria:  
• Pregnancy  
• Non-English-speaking subjects and/or parent/guardian 
• Platelet count < 20,000  
• Active CVC infection-defined as positive blood culture from the in -situ CVC at time of 
enrollment 
• Current radiographically confirmed VTE 
• Currently receiving treatment doses of anticoagulation (heparin infusion >15U/kg/hr, 
enoxaparin injections >=2mg/kg/day or >=60mg/day) 
• CVC diameter <1.9 Fr 
• Current or previous diagnosis of Heparin Induced Thrombocytopenia or allergy to heparin 
or t-PA 
• Med-a-port catheters 
• Active internal bleeding 
• Recent intracranial or intraspinal surgery 
• Serious head trauma 
• Intracranial conditions that may increase the risk of bleeding 
• Bleeding diathesis 
• Current severe uncontrolled hypertension 
 
 
Any patient admitted to the ICU and meeting the above inclusion criteria will be approached for consent 
within 72 hours CVC placement. Randomization and administration of t-PA/heparin control treatment 
will be initiated within 24 hours of enrollment.   
 
After 1:1 randomization, t-PA/heparin will be infused in the CVC for a dwell duration of 30 minutes-4 
hours and then withdrawn (lock therapy) every 3 days until discharge from the PICU, CVC removal or a 
maximum of 10 doses received. Additional lumens will be treated on subsequent days. Any lumen 
requiring continuous infusion of vaso-active medication will not receive dwell therapy, evaluated on a 
day-to-day basis. Timing of instillation of study dwell medication will be adjusted so as not to interfere 
with medications for patient care. Other stopping points of t-PA treatment are in Section L.  
 
 
E. 
TOTAL NUMBER OF HUMAN RESEARCH PARTICIPANTS PROPOSED FOR THIS STUDY AT THIS SITE 
AND GLOBALLY.  WHAT ARE THESE NUMBERS BASED ON? 
 
This single center, pilot study will enroll 20 subjects at CHW.  This sample size was chosen for the ability 
to be internally funded and to complete pilot data collection in a timely manner, with anticipated grant 
submission for a multi-center study in 2020. 

 
 
TOPCAT Protocol 
 
F. 
DRUGS OR PROCEDURES  
 
Procedures to be completed for this study are as follows: 
 
After informed consent/assent, the patient will be randomized and assigned to either the treatment arm 
(t-PA lock) or control arm (heparin lock).  Randomization will be stratified by age (<5 or ≥5 years old). 
Pharmacy will blind the study medication t-PA so that it is indistinguishable from the control arm. 
Randomization will be done in the investigational pharmacy prior to the dispensing of the t-PA/heparin.   
During enrollment, the unblinded assignment log will be kept in the locked investigational room in 
central pharmacy. 
 
Study Treatment and Dosing 
In subjects randomized to the t-PA (Alteplase; Activase®, Genentech, 1mg/cc concentration), dosing will 
comply with the CHW Policy and Procedure Protocol t-PA Administration for Central Venous Access 
Devices (CVAD); subjects randomized to the control arm, standard of care heparin group, will receive an 
equivalent volume for weight of heparin 10 units/ml.  The bedside RN will administer the study 
medication/heparin as per the above protocol. The CVC should be flushed with normal saline prior to 
infusion of t-PA/heparin.  After dwelling time of 30 minutes-4 hours, t-PA/heparin control should be 
withdrawn, check for blood return in CVC and flush line with normal saline as per policy.  Each lumen of 
multi-lumen CVC should be treated every 3 days until patient discharge from ICU, removal of CVC, or a 
maximum of 10 doses of t-PA/heparin control are received. 
 
Patient weight                  Volume T-PA/Heparin 
0-10kg  
 
 
0.5ml 
10-20kg 
 
 
1 ml 
>20kg  
 
 
2 ml 
 
These doses by body weight have been approved by the FDA for and CHHS Patient Care Protocol (tPA 
Administration for Central Venous Access Devices (CVADs) for use in children with CVC and are not 
associated with significant bleeding. If a 2mg (ml) dose of t-PA is administered by bolus injection directly 
into the systemic circulation, rather than as a dwell within the CVC, the drug concentration would return 
to endogenous levels with 30 minutes. 
 
Ultrasound imaging 
At the end of the study period, a noninvasive ultrasound with doppler will be performed for research 
purposes to assess for asymptomatic thrombosis in the blood vessel of the CVC location. 
 
 
G. 
RISK CATEGORY: 
 
Both arms of the study: Risk Level (2) 45 CFR 46.405  - Research involving greater than minimal risk but 
presenting the prospect of direct benefit to the individual child subjects involved in the research. 
 

 
 
TOPCAT Protocol 
 
H. 
RISKS AND THE PRECAUTIONS WHICH WILL BE TAKEN TO MINIMIZE RISK EXPOSURE 
 
There is a risk of bleeding at higher doses of both the study drug (t-PA) and heparin control, as both 
drugs used in standard clinical practice alter the coagulation system.  However, the doses by body 
weight used in this study have been approved by the FDA for and CHW Policy tPA Administration for 
CVADs for use in children with CVC and are not associated with significant bleeding. If a 2mg (ml) dose of 
t-PA is administered by bolus injection directly into the systemic circulation, rather than as a dwell 
within the CVC, the drug concentration would return to endogenous levels with 30 minutes.  As a 
precaution, we will monitor the dose of drug received and follow the CHW policy and procedure for 
administration.  Both arms of the study are currently used in clinical care, it is the timing of the 
intervention that is under study.  As additional precaution, we will exclude patients at increased risk of 
bleeding (platelet count < 20,000 or receiving therapeutic dosed anticoagulation). 
 
All adverse events experiencing by study subjects will be monitored throughout the active study 
treatment period and for 30 days following the last dose of the t-PA/heparin, or for 7 days after CVC 
removal, whichever occurs first. For patients with CVC in place at time of hospital discharge, chart 
review will be performed to capture events up to 7 days after discharge. 
 
 
Breach of Confidentiality 
Data necessary for the completion of this study will be extracted from the subject electronic medical 
record and maintained in a REDCap database on the CTSI server. Some PHI will be maintained in this 
database but will only be accessible to study team members listed on the registration page.  Any study 
information maintain on paper will be held in a locked file cabinet in the Critical Care offices.  
 
I. 
PROVISION FOR THE PROTECTION OF PRIVACY OF SUBJECTS AND TO MAINTAIN THE 
CONFIDENTIALITY OF DATA 
 
As of October 2017, the NIH has updated their policy on Certificates of Confidentiality and are 
automatically issuing these for eligible studies that are NIH funded.  They no longer issue a paper 
certificate, nor only submit on request.  
 
Does this study qualify for automatic issuance of a Certificate of Confidentiality by the NIH? 
  
No    
Yes 
 
The following encryption products employ cryptographic modules that the National Institute of 
Standards and Technology has certified as meeting FIPS 140-2 requirements.  Children’s Hospital  
and Health System endorsed the use of these products made to encrypt hard drives and removable 
media.  All electronic research data must be encrypted using one or more of these products.   
 
Please indicate which encryption tools you are using to secure your research data. 
 
___Credent Mobile Guardian (RS, PD) 

 
 
TOPCAT Protocol 
___GuardianEdge Hard Disk and GuardianEdge Removable Storage Encryption (HD, RS, PD) 
___IronKey encrypted flash drives (RS) 
___McAfee Endpoint Encryption (HD, RS) 
___Microsoft Bitlocker (HD, RS when used with Windows 7 and FIPS compliant algorithms are enabled) 
___PGP Whole Disk Encryption and PGP Portable (HD, RS) 
___SafeNet Protect Disk and SafeNet Protect File (HD, RS) 
___Seagate Secure Self-Encrypting Drives (HD when encryption option is enabled) 
___Symantec Endpoint Encryption (HD, RS, PD) 
___WinMagic SecureDoc encryption (HD) (for MCW owned computers) 
___Other (add description) 
 
Does not apply because: 
___ Data is de-identified – no PHI collected (please provide detailed information on data elements in 
your protocol application) 
___ Data is stored on paper only 
___ Data is stored on CHW secured shared drives. 
   Data is stored on MCW secured shared drives.  
 
J. 
PROVISIONS FOR MONITORING DATA TO ENSURE THE SAFETY OF SUBJECTS; AND ADDITIONAL 
SAFEGUARDS TO PROTECT THE RIGHTS AND WELFARE OF SUBJECTS WHO ARE LIKELY TO BE 
VULNERABLE 
 
Adverse Event Monitoring 
Any patient receiving a minimum of 1 dose of the t-PA/heparin control will be followed for adverse 
events by the study investigators and research coordinators for 30 days following the last dose of the t-
PA/heparin, or for 7 days after CVC removal, whichever occurs first. For patients with CVC in place at 
time of hospital discharge, chart review will be performed to capture events up to 7 days after 
discharge. 
Adverse events will be considered any change from baseline.  Expected adverse events are listed in 
section H; this section also includes those events considered serious but expected within this protocol. 
Expected SAEs will be reported in aggregate at the study’s annual review.  Any SUSAR experienced 
during the study will be reported per IRB’s Reportable Events guidelines. At completion of the study 
adverse event rates between the study group and heparin control group will be compared and included 
in any final study reports.  
Serious Adverse Events 
If any subject enrolled in the study experiences any serious adverse event, the study team and care 
team will discuss the likely cause of the events.  If it is determined that the event is probably or 
definitely related to the t-PA/heparin control the study treatment can be discontinued at the discretion 
of the care team and study team.  Subjects whose treatment is discontinued will be followed for 30 days 
after the last t-PA/heparin control dose or until hospital discharge, whichever occurs first.  
 
 
K. 
ANTICIPATED BENEFITS ASSOCIATED WITH THE PROTOCOL TO HUMAN RESEARCH PARTICIPANTS 
AND SOCIETY  

 
 
TOPCAT Protocol 
 
Benefit to the individual patient may include a decreased risk of CVC infection or VTE. 
Benefit to society at large will be knowledge gained to optimally design multicenter interventional study 
to develop therapy to reduce the risk of central line infection and/or thrombosis. There is evidence that 
these complications result in unfavorable outcomes such as increased length of mechanical ventilation, 
increased length of stay, increased healthcare cost, and increased mortality.  
 
L. 
STOPPING POINTS THAT WOULD NOT ALLOW THE STUDY TO CONTINUE AS PROPOSED  
 
Withdrawal from study  
The PI or subject’s primary care team can withdrawal the subject from this study due to 
• Consent is withdrawn by subject’s family 
• Treating physician wishes to withdrawal subject for any reason 
 
 
 
M. 
IS THERE A DATA SAFETY MONITORING BOARD IN PLACE?  WHO ARE IT'S MEMBERS?  HOW 
OFTEN DO THEY MEET?   
 
There is no DSMB planned for this study.  
N. 
DESCRIBE HOW THE CONSENT AND ASSENT PROCESS WILL TAKE PLACE.  INCLUDE A LIST OF 
APPROPRIATELY TRAINED PERSONNEL WHO WILL BE INVOLVED.   
 
After an eligible subject is identified, written informed consent will be obtained in person by an 
investigator or coordinator listed on the registration page for this study.  Study investigators who are 
also the eligible subject’s attending physician at the time of consent will not participate in the consent 
conversation to remove any undue influence posed by the duel role. Following consent, a copy of the 
completed documents will be placed in the subject’s medical record, and a second copy will be given to 
the subject’s family. A consenting and enrollment log will be maintained by the research team for all the 
patients who are screened for study, approached meeting eligibility criteria of the study and who 
consented/ or denied participation in the study. 
 
We are requesting a waiver of assent for patients intubated, pharmacologically sedated, cognitively 
delayed that they would not fully comprehend what they are consenting to, and patients too critically ill 
defined as reduced consciousness or impaired decision-making capacity. The decision of an individual’s 
capability to assent for the study is made by reviewing medical records for that specific information. This 
is always confirmed with attending physician for finalization of assent waiver for the study before 
patient is approached.  Assent will be obtained from the patient if he/she is at least 7 years of age and is 
alert enough or cognitively able to understand the nature of the study. This assent will be obtained for 
all child subjects (7-17 years old) and documented by signing a separate assent form (for 7- 13 years old) 
or by signing an assent line on the parent permission form (for 14-17 years old). If the patient turns 18 
years old while still participating in the study, we will have patient confirm his or her interest in 
continuing participation. If patient is still interested in study participation we will have him or her 
consent during the current admission. 

 
 
TOPCAT Protocol 
 
We plan to enroll only English speaking patients for this 20 patient pilot study. We do not have available 
funds and resources at this time to provide Spanish ICF documents for this pilot study. If we notice a 
large population of Spanish speaking patients being excluded we will consider including Spanish 
Speaking patients in the next phase of this study after the pilot is completed.  
 
O. 
PROCEDURES TO BE EMPLOYED IN ANALYZING DATA AND THE ANTICIPATED SIGNIFICANCE OF 
THE PROPOSED STUDY 
 
Aim 1 Outcomes will include consent rates and determination of sample size to adequately power a 
multicenter trial to determine if t-PA reduces the rate of CVC complications (CLABSI and VTE) by 20%. 
 
Aim 2 Outcomes 
The primary outcome will be rate of clinical diagnosed CLABSI and VTE in each arm.  Secondary 
outcomes will include: episodes of CVC dysfunction (defined as inability to draw blood from line and/or 
inability to flush CVC), off study use of t-PA, and clinical bleeding 
 
Statistical analysis plan  
Analysis will be performed by Quantitative Health Sciences under the direction of Dr. Pippa 
Simpson. Data will be investigated with summary statistics (e.g. frequencies, median and 
inter-quartile range). Where appropriate for a parametric analysis transformation will be 
used or a non-parametric analysis will be used. Differences between t-PA and heparin 
control groups will be examined by using Chi-square and Fisher’s exact tests for categorical 
variables, and a Mann-Whitney test or a t-test for the continuous or ordered variables.  
 
 
P. 
FINANCIAL RELATIONSHIPS  
 
This study has received internal funding from the Department of Pediatrics, Medical College of 
Wisconsin. This funding will be used to pay for t-PA and completion of study procedures.   
 
Q. 
ADVERTISEMENTS / FLIERS 
 
No fliers or advertisements will be used to recruit subjects for this study 
 
R. 
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TOPCAT Protocol 
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