Conditions: Central Venous Catheter Thrombosis Central Venous Catheter Associated Bloodstream Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: no

Brief summary:
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) 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.

Detailed description:
This pilot study Children's Hospital of Wisconsin will be a prospective, blinded, randomized controlled trial enrolling 20 patients in the pediatric intensive care unit (PICU) with a newly placed central venous catheter (CVC) to receive t-PA or heparin (current standard of care and defined as placebo 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 central line associated blood stream infection (CLABSI) or venous thromboembolism (VTE). Secondary outcomes would be episodes of CVC dysfunction, off study use of t-PA, and bleeding.

Any patient admitted to the PICU and meeting the inclusion criteria will be approached for consent within 72 hours CVC placement. Randomization and administration of study drug/placebo treatment will be initiated within 24 hours of enrollment.

After randomization, study drug/heparin will be infused in the CVC for a dwell duration of 30 minutes-4 hours and then withdrawn (lock therapy) every 3 days until discharge from the PICU, CVC removal or a maximum of 10 doses received.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.

This single center, pilot study will enroll 20 subjects.

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 placebo arm (heparin lock). Randomization will be stratified by age (\<5 or ≥5 years old). To maintain the blind, randomization will be done in the investigational pharmacy prior to the dispensing of the study drug/heparin.

Study Treatment and Dosing In subjects randomized to the t-PA, dosing and administration will comply with the Children's Hospital and Health System (CHHS) Policy and Procedure Protocol t-PA Administration for Central Venous Access Devices (CVAD); subjects randomized to the standard of care heparin group will receive an equivalent volume for weight of heparin 10U/ml. The CVC should be flushed with normal saline prior to infusion of study drug/placebo. After dwelling time of 30 minutes-4 hours, study drug/placebo 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 PICU, removal of CVC, or a maximum of 10 doses of study drug/placebo are received.

Patient weight Volume Study drug/Placebo 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 to assess for asymptomatic thrombosis in the blood vessel of the CVC location.

Arms:
arm 1: patients will receive 30 min-4 hours dwells of alteplase (recombinant t-PA) (2mg/2ml, up to 2mg per dose) to central venous catheter every 3 days (maximum 10 doses) arm 2: patients will receive 30 min-4 hours heparin (10U/ml, up to 2 ml per dose) dwells to central venous catheter every 3 days (maximum 10 doses)

Interventions: intervention 1: alteplase (recombinant t-PA) intervention 2: Heparin
Intervention descriptions: intervention 1: Medication administered to dwell in central venous catheter intervention 2: Medication administered to dwell in central venous catheter

Protocol document:
Prot_SAP_000.pdf: 
 
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. 
BIBLIOGRAPHY 
1. Malec LM, Cooper J, Rudolph J, Michaels MG, Ragni MV. Prophylactic rtPA in the prevention of line-
associated thrombosis and infection in short bowel syndrome. J Pediatr Gastroenterol Nutr 2017;  
 
2. Ragni MV, Journeycake JM, Brambilla DJ. Tissue plasminogen activator to prevent central venous access 
device infection: a systematic review of CVAD thrombosis, infection, and 
thromboprophylaxis. Haemophilia 2008; 14:30–38. 
 


 
 
TOPCAT Protocol 
3.  Hemmelgarn B.R., Moist L.M., Lok C.E., et al: Prevention of dialysis catheter malfunction with 
recombinant tissue plasminogen activator. N Engl J Med 2011; 364: pp. 303-312 
 
4. Baskin JL, Pui CH, Reiss U, et al. Management of occlusion and thrombosis associated with long-term 
indwelling central venous catheters. Lancet 2009; 374:159. 
 
5. Dillon PW, Jones GR, Bagnall-Reeb HA, et al. Prophylactic urokinase in the management of longterm 
venous access devices in children: a Children's Oncology Group study. J Clin Oncol 2004; 22:2718–2723. 
 
6. Balestreri L, De CM, Atovic M, et al. Central venous catheter-related thrombosis in clinically 
asymptomatic oncologic patients: a phlebographic study. Eur J Radiol 1995; 20:108–111. 
 
7. Journeycake JM, Buchanan GR. Thrombotic complications of central venous catheters in children. Curr 
Opin Hematol 2003; 10:369–374. 
 
8. Blaney M, Shen V, Kerner JA, et al. Alteplase for the treatment of central venous catheter occlusion in 
children: results of a prospective, open-label, single-arm study (The Cathflo Activase Pediatric Study). J 
Vasc Interv Radiol 2006; 17:1745–1751. 
 
9. Macrae JM, Loh G, Djurdjev O, et al. Short and long alteplase dwells in dysfunctional hemodialysis 
catheters. Hemodial Int 2005;9:189-195 
 
10. Onyeama SN, Hanson SJ, Dasgupta M, Baker K, Simpson PM, Punzalan RC. Central Venous Catheter-
associated Venous Thromboembolism in Children with Hematologic Malignancy. J Pediatr Hematol 
Oncol. 2018 May 31. doi: 10.1097/MPH.0000000000001229. [Epub ahead of print] 
 
11. Cathflo Activase: Prescribing Information: 
https://www.gene.com/download/pdf/cathflo_prescribing.pdf 
 
12. CHHS Patient Care Protocol- tPA Administration for Central Venous Access Devices (CVADs): 
https://connect.chw.org/-/media/DocumentLibrary/Policies-and-Procedures/Protocol---tPA-
Administration-for-Central-Venous-Access-Devices---CVADs.ashx 
 
13. Deitcher SR, Fesen MR, Kiproff PM, et al; for the Cardiovascular Thrombolytic to Open Occluded 
Lines-2 Investigators. Safety and efficacy of alteplase for restoring function in occluded central venous 
catheters: results of the Cardiovascular Thrombolytic to Open Occluded Lines trial. J Clin Oncol. 
2002;20(1):317-324. 
 
14. Ponec D, Irwin D, Haire WD, et al; Recombinant tissue plasminogen activator (alteplase) for 
restoration of flow in occluded central venous access devices: A double-blind placebo-controlled trial—
the cardiovascular thrombolytic to open occluded lines (COOL) efficacy trial. JVIR. 2001;12:915-955. 
 
15. Firwana BM, Hasan R, Ferwana M et al. tissue Plasminogen activator versus heparin for locking 
dialysis catheters; A systematic review. Avicenna J Med. 2011; 1(2) 29-34. 


 
 
TOPCAT Protocol 
 
16. Schenk P, Rosenkranz AR, Woflfl G, et al. Recombinant tissue plasminogen activator is a usefu 
alternative to heparin in priming quinton permacath. Am J Kidney Dis 2000; 35:130-6. 
 
17. Gittins NS, Hunter-Blair YL, Matthews JN, et al. Comparison of alteplase and heparin in maintain the 
patency of paediatric central venous haemodialysis lines: A randomized controlled trial. Arch Dis Child. 
2007; 92: 499-501. 
 
18. Infusion Nurses Society. Infusion therapy standards of practice. J Infus Nurs. 2016;39(suppl 1):S1-
S159 
 
19. Camp-Sorrell D, ed. Access Device Standards of Practice for Oncology Nursing. 4th ed. Pittsburgh, PA: 
Oncology Nursing Society; 2017:1-85. 
 
20.Haire WD, Herbst SF. Consensus conference on the use of alteplase (t-PA) for the management of 
thrombotic catheter dysfunction. J Vasc Access Devices. Summer 2000:1-8. 
 
21. AVA. Study Guide for Vascular Access Certification. Association for Vascular Access;2011:iii-164. 
 
22. Cummings-Winfield C, Mushani-Kanji T. Restoring patency to central venous access devices. Clin J 
Oncol Nurs. 2008;12(6):925-934. 
 
 
 
 
 
 
 
 
 

ICF_001.pdf: 
 
t-PA Prophylaxis to Reduce Central Venous Catheter Associated 
Infection and Thrombosis (TOPCAT) 
 
NCT03672006 
 
November 20, 2019 


 
Page 1 of 8 
 
 
 
 
Statement of Volunteer Consent and Health Insurance Portability  
and Accountability Act (HIPAA) Authorization for Research Study 
 
 
Study Title:  t-PA Prophylaxis to reduce Central Venous Catheter Associated Infection 
and Thrombosis 
 
Principal Investigator(s) / Study Leader(s): Sheila J. Hanson, MD 
The Principal Investigator is the Study Leader for this research. 
 
Phone Number(s): 414-266-3728 
 
Full Street Address: 9000 W. Wisconsin Avenue, MS 681, Milwaukee, WI 53226 
 
E-Mail Address: shanson@mcw.edu 
 
 
 
 
 
 
Co-Investigator(s): Rowena Punzalan, MD 
 
414-937-6896 
 
 
 
Rainer Gedeit, MD 
 
 
414-266-3360 
 
 
“You” refers to you or your child throughout the consent form. 
 
 
 
 
 
 
 
 
 
 
 
A. 
Why are we asking you to be in this research study? 
We invite you to take part in this research study to learn more about people like 
you who have central lines placed while they are in the hospital. A central line is a long, 
thin, flexible tube in your body that gives you medicine, fluids, nutrients or blood. 
Sometimes central lines can stop working well because they are clogged with the material 
that makes up blood clots (fibrin), sometimes the blood vessel the central line is in can 
get a blood clot.  Both fibrin and blood clots can increase the risk of an infection in the 
 
We are asking you to be in a research study. 
 
You do not have to be in the study. 
 
If you say yes, you can stop the study at any time. 
 
Your health care will not change in any way if you say no. 
 
Feel free to ask questions. 
 
Take as much time as you need to make your choice. 
 
Only sign this form if you want to be in the study. 
Effective Date: November 20, 2019 
Expiration Date: November 19, 2020 
Children's Hospital of Wisconsin IRB 


 
Page 2 of 8 
 
 
central line.  There is a medication, a tissue plasminogen activator, which is used to 
unclog central lines when they stop working.  This medicine is also called t-PA, 
Alteplase, or Activase®. We don’t know the best way to prevent these clogs from 
occurring but wonder if this medicine, t-PA, used ahead of time while the line is working 
well would help prevent blood clots, line blockage, and line infections. Because it will 
take many children with central lines at many hospitals to get enough data to answer this 
question, this first study is called a ‘pilot study,’ where we will only include children at 
Children’s Hospital, to see if our way of doing the study is smooth for the patients and 
investigators before expanding to other hospitals. 
 
This study will help us learn more about how to keep central lines working well. 
We will study 20 children, less than or equal to 18 years old who have central lines while 
they are in the pediatric ICU at Children’s Hospital of Wisconsin. We will see if t-PA 
works better than the medicine used now (heparin) in to prevent line blockage, blood 
clots and line infections. We will decide if this is the best study design for a bigger study 
for these problems. 
.  
B. 
What happens if you say yes, you want to be in this study?   
 
 If you say yes, you will be “randomized” into one of the two study 
described below. Randomization means that you are put into a group by 
chance.  It is like flipping a coin.  Which group you are put in is done by a 
computer. You will have an equal chance of being in each group.  Using 
randomization improves the chance of determining which (if either) 
treatment is better.  Whichever group you are in, a medicine will be put 
into the central line and let sit for 30 min-4 hours depending on when your 
next medicine through the line needs to be given.   
o If you are in Study group 1: you will get t-PA in your central line 
 
o If you are in Study group 2: you will get heparin in your central 
line.   
 
o We will not know which group you are in. 
 
 The study medicine will be put in your central line every 3 days until you 
leave the ICU, a month has passed, or you no longer need your central line 
and it is taken out of your body. 
o If you do get a line clot or infection or any reaction to the 
medicine, the study will stop at that time, and your providers will 
care for you as normal clinical care. 
o At the end of the study, you will have an ultrasound of your body 
where your central line is to see if there are any blood clots. 
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o Ultrasound is a painless picture that can see if your blood vessels 
look normal. 
 
 
How long will the study take? 
 
You will be actively participating in the study until you receive 10 doses of either 
heparin or t-PA, are discharged from the PICU or have the CVC removed. We will then 
monitor your medical chart for 30 days following the last dose of either heparin or t-PA 
or 7 days after the CVC is removed, whichever occurs first. If you are discharged home 
from the hospital with the CVC in place we will follow your medical chart for 7 days 
after discharge. 
 
 
 
If you turn 18 years old while still participating in this research study, we will 
have you sign a consent form as an adult if you wish to continue study participation. 
 
 
 
C. 
Can anything bad happen to you because of this study? 
 
 
Yes, there is a chance that: 
 
 You could have an allergy to the medication, or bleeding. The amount of 
study medicine will just fill your central line and so risk to your body is low. 
The risk of the study medicine, t-PA, is the same as the standard medicine, 
heparin. If you have significant problems with bleeding, or if you are currently 
taking blood thinners such as coumadin, heparin injections or high dose 
aspirin you should not be part of this study. In addition, this study drug may 
not work for you. 
 During the ultrasound you may feel slight pressure in the area where the 
ultrasound probe is passed over your body.  
 Someone could find out that you are in the study and learn something about 
you that you did not want others to know. 
 You could have a legal problem if you told us about a crime, such as child 
abuse (or other mandatory reporting) that we have to report. 
 
 
We will do our best to protect your privacy. 
 
 
D. 
Will this study help you in any way? 
 
 
We do not know if there will be a direct benefit to you or not. Benefit may include 
a decreased risk of central line infection or blood clots (thrombosis). This study 
will help us to gain knowledge to design a multicenter interventional study to 
develop therapy to reduce the risk of central line infection or thrombosis. There is 
evidence that these complications result in unfavorable outcomes, such as, 
Effective Date: November 20, 2019 
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increased length of mechanical ventilation, increased length of stay, increased 
healthcare cost and increased mortality. 
 
E. 
Will you be paid for being in this study? 
You will not be paid for being in this study.   
 
F. 
Will it cost you anything to be in this study? 
 
There will not be a cost to you for participating in the study. If your doctor 
decides to order an ultrasound for clinical reasons, then this will be charged as a  normal 
expense to your insurance. If we complete the ultrasound for research purposes only then 
the study will cover this cost. The study will also cover the cost of the heparin or t-PA 
treatment. 
 
 
In the event that this research activity results in an injury, the care for such 
injuries will be billed in the ordinary manner to you or your insurance company.  
 
Insurance companies may refuse to pay for injuries sustained while participating 
in a research study. If you think that you have suffered a research-related injury, let the 
study physician know right away so she can evaluate you. We will not give you money to 
treat any injury from the study, but if you are hurt in this study, treatment will be 
provided. 
 
 
G. 
Do you have to participate in this study? 
 
No, you do not have to be in this study.  You can stop being in the study at any 
time.  Just let Dr. Hanson know. 
 
 
If you say no, 
 Your health care will not change in anyway. 
 The other choices if you don’t want to be in this study are to just receive 
heparin or no medicine to try and keep your central line from clogging. 
 
If you stop being in this study, we may still use the study information we have 
already collected as long as it cannot be linked back to you. Any data collected or 
analysis that has been done up to this point will need to be kept due to legal and 
regulatory requirements. The investigator may terminate subject’s participation in the 
study without regard to subject’s consent if attending physician thinks that study 
participation may affect the patient’s health or welfare. 
 
H. 
What if you have questions? 
If you have questions or there is something you do not understand, please call the 
Dr. Hanson 414-266-3728 or Katherine Siegel 414-266-3973.  Please call if you have: 
 
 Any questions about the study. 
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 Concerns that you have been injured in any way by being in this study. Dr. 
Hanson will evaluate you for any research related injuries you report. 
 Questions about how we will use your information. 
 
You can also call the Institutional Review Board (IRB) if you have any questions 
about your rights as a research subject.  The IRB is the committee that has reviewed this 
study.  A member of this committee can talk to you if you have any questions or 
complaints at 414-337-7133. 
 
 
I.  RESEARCH DATA IN MEDICAL RECORD 
 
A copy of the signed consent, assent and HIPAA Authorization will be kept in 
your medical record. We will be collecting information on your condition and 
hospital stay for this study. The ultrasound report performed at the end of the 
study will be part of your medical record. No other data collected for the study 
will be placed in your medical record.  
 
 
J.        Will your information be kept private?  
 
The only people allowed to see your information will be the people who work on 
the study and people who make sure the study is done the right way and hospital rules are 
followed.  Groups or people that might look at and/or copy your research records are: 
 
 Dr. Hanson, the research team and the statisticians who will help figure out 
what the results mean 
 The Institutional Review Board at Children’s Hospital of Wisconsin 
 Food and Drug Administration (FDA) 
 
Your health information, and a copy of this form will be locked in our files.   
When we share the results of the study in a medical journal or at a conference talk we 
will not include any information that identifies you. We will do our best to make sure no 
one outside of the study will know you are a part of the study. As this is FDA-regulated 
research, they may inspect and/or copy your research records for purposes of quality 
assurance and data analysis. 
 
 
 
A description of this clinical trial will be available in 
http://www.clinicaltrials.gov, as required by US 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 website at any time. 
 
 
 
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K. 
Permission to collect, use and share your health information.  
 
 
The health information we are asking for is called “Protected Health Information” 
(PHI).  It is protected by a federal law called the Privacy Rule of the Health Insurance 
Portability and Accountability Act (HIPAA).   
 
 
Researchers are required to get written permission from you to use your health 
information in a research study, data registry bank, and/or a tissue bank. As this is FDA-
regulated research, FDA has access to review and copy all relevant records. 
 
   
How will your health information be used? 
 
Your health information will be used to provide information needed for the 
research study. 
 
 
What information will be used? 
 
The following information about your health will be used for this research study: 
medical history, laboratory results, ultrasound results and what happens during this 
hospital stay. 
 
  
Who will use your health information? 
 
The hospital or clinic that holds your medical records will share medical 
information with the researchers.  
 
 
How long will the permission last? 
 
 
This authorization will last until the end of the study. 
 
 
 
You can end this Authorization at any time by withdrawing your permission in 
writing. Beginning on the date your permission ends, no new health information from 
you will be used. Any health information that was shared before you withdrew your 
permission will continue to be used. After this Authorization ends, you can no longer 
actively take part in this research study. 
 
 
 
Withdrawal of your permission should be made in writing to the person whose 
name is listed here: 
 
Sheila Hanson, MD, 9000 W. Wisconsin Avenue, MS 681, Milwaukee, WI 53226 
 
  
How will your health information be protected? 
 
Whenever possible your health information will be kept confidential. Federal 
privacy laws, however, may not apply to some people outside of CHW who  
can 
share your health information without your permission.  
 
 
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Additional information. 
 
You should take as much time as you need to make your decision about giving 
permission for the use of your health information for this research study. The researchers 
are required by law to report child abuse or neglect (or suspicion of abuse or neglect) if 
 
you or your child mention it to the researchers or if it is suspected.  Please ask any 
questions you may have about this authorization. 
 
L. 
Permission for you to participate in this study 
 
 
 
 
This study, consent form and HIPAA Authorization has been explained to 
you by: 
 
             
 
___________________________________  
------------------------------------  
 
Name Of Study Leader or Study Team  
 
Signature of Study Leader  
 
Designee 
 
 
 
 
 
or Study Team Designee 
 
 
___________________________________  
_________  
 
Date  
 
 
 
 
 
Time 
 
            
 
 
 
 
Sign this document if: 
 You have read (or had it read to you) this entire consent form.   
 We have talked with you about the information in this form and have 
answered your questions. 
 You agree to let the study team use and share your health information for 
this study. 
 You agree to let your primary care doctor share your health information 
with us. 
 You agree to be in this study. 
 
 
 
After you sign this document, we will give you a copy of this form. 
 
 
 
___________________________________  
 
--------------------------- 
 
Printed Name of Study Participant or  
 
 
 
Date 
 
Authorized Representative  
 
 
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Children's Hospital of Wisconsin IRB 


 
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___________________________________  
 
--------------------------- 
 
Signature of Study Participant or   
 
 
 
Date 
Authorized Representative  
 
 
 
 
ASSENT OF MINOR: 
 
The above has been explained to me and I agree to participate. 
 
 
___________________________________  
               --------------------------------- 
Signature of Minor  
 
 
 
 
 
Date  / Time 
 
 
 
If child’s assent is not obtained above, please indicate reason below (check one): 
 
 Assent is documented on a separate IRB-approved assent form 
 Child is under the required age range for assent 
 The IRB granted a waiver of assent, please specify: ------------------------------------- 
 
 
__________________________________  
         -------------------------------------- 
Signature of Principal Investigator  
 
 
 
 
Date 
or Research Team Designee 
 
__________________________________  
Time 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Effective Date: November 20, 2019 
Expiration Date: November 19, 2020 
Children's Hospital of Wisconsin IRB