Clinical trial NCT01999179
Conditions: Venous Thrombosis Neoplasms
Keywords: catheter related thrombosis upper extremity deep venous thrombosis central venous catheters cancer Catheters
Sponsor: Medical College of Wisconsin
Start date: 2014-06-01; Completion date: 2022-04-26
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of the pilot study is to determine if a multicenter prospective cohort study of cancer patients with blood clots associated with catheters is feasible. Cancer patients with catheter-related thrombosis treated with one month of anticoagulation will be evaluated for for post-thrombotic syndrome. Laboratory biomarkers will be evaluated as predictors of recurrent thrombosis.

Detailed description:
Participants may be referred for screening at Medical College of Wisconsin (MCW) in two possible mechanisms: participant contact study staff from information on Clinical Trials Science Institute (CTSI) FACT website or referral from treating Hematologist or Oncologist. At MCW, an EPIC report will be generated to identify people with catheter related thrombosis (CRT). The treating provider would then be contacted to determine if referral to the study was appropriate. Subjects at Ohio State University (OSU) will be referred from the treating Hematologist or Oncologist. A report generated in Epic will be used to identify people with CRT. The treating provider would then be contacted to determine if referral to the study was appropriate. Participants will be given printed information about the study or verbal explanation using the informational flyer. Verbal consent will be obtained to be screened for participation and contacted by study personnel. Screening will be completed by BloodCenter of Wisconsin (BCW) nurse coordinator. We aim to consent and enroll patients after diagnosis of catheter-related thrombosis and prior to catheter removal. Consent and enrollment (Visit 1) must occur prior to discontinuation of anticoagulation. Participants will be treated with either enoxaparin for one month following catheter removal, or direct oral anticoagulant treatment (apixaban, rivaroxaban, dabigatran, or edoxaban). Anticoagulation will be continued for 1 month after catheter removal. The minimum duration of anticoagulation will be one month and maximum duration is 7 months. The cost of enoxaparin will be the responsibility of the participant as use of the medication is part of routine care. Subjects will be contacted by telephone prior to discontinuation of anticoagulation to review study protocol, assess for bleeding, and see if any continuation rules apply and arrange for research visit 2 in the following 1-2 weeks. Visits 3 and 4 will occur 3 and 6 months after catheter removal, respectively. At visits 3 \& 4, Medical history, cancer history, and medications will be updated. At each visit, participants will be assessed for post-thrombotic syndrome using the modified Villalta scale and functional limitation using the DASH questionnaire. At MCW, surveys will be administered by the research coordinator and/or Translational Research Unit (TRU) staff and physical examination will be completed by BCW nurse coordinator. At OSU, surveys will be administered by research coordinators and physical examination will be administered by research nurse coordinator. Laboratory samples will be obtained for MCW participants only.

Arms: arm 1: Enoxaparin 1 mg/kg subcutaneously every 12 hours for one month following catheter removal or alternate enoxaparin dose or interval based on anti-factor Xa testing that was obtained by clinical team.

Apixaban, rivaroxaban, dabigatran, or edoxaban at standard dosing per FDA package insert for direct oral anticoagulants.
Interventions: intervention 1: Heparin, Low-Molecular-Weight, or direct oral anticoagulants
Intervention descriptions: intervention 1: Cancer patients will be treated with enoxaparin 1 mg/kg subcutaneously every 12 hours for one month following catheter removal or alternate enoxaparin dose or interval based on anti-factor Xa testing obtained by the clinical team or either apixaban, rivaroxaban, dabigatran, edoxaban following a catheter related blood clot

Protocol documents:
Prot_SAP_000.pdf: 
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Title: Post-thrombotic Syndrome and Predictors of Recurrence in Catheter-Related 
Thrombosis 
NCT01999179 
Date: 11/5/18 
 
 


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Post-thrombotic Syndrome and Predictors of Recurrence in Catheter-
Related Thrombosis 
Protocol Version 10.0 
Principal Investigator: Lisa Baumann Kreuziger, MD, MS 
Co-Investigators: Alan Mast, MD, PhD; Parameswaran Hari, MD and Tzu-Fei Wang, 
MD 
Study Coordinators:  
Zora Jovanovic, BSN, RN, BloodCenter of Wisconsin 
Conducted by: 
BloodCenter of Wisconsin and Froedtert Hospital, Milwaukee, Wisconsin 
 
The Ohio State University, Wexner Medical Center, Columbus, Ohio 
 
 
 
 
 
 
 
 
 
 
 
 


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1. Background and Significance  
Over 5 million central venous catheters (CVCs) are inserted annually in the United 
States.1  CVCs improve quality of life in cancer patients by allowing safe administration 
of chemotherapy and easy access for phlebotomy. Despite these benefits, long-term 
presence of CVCs are associated with infectious and thrombotic risks.1 The incidence of 
catheter-related thrombosis (CRT), or thrombosis in the vein housing the catheter, will 
occur in up to a third of patients with an indwelling catheter.2 CRT account for 
approximately 80% of upper extremity thrombosis, and pulmonary emboli have been 
detected in 15% of patients with symptomatic CRT.3,4 A systematic review and meta-
analysis has reported rates of post-thrombotic syndrome (PTS) in an average of 15% of 
adults with upper extremity thrombosis. Retrospective studies of patients with upper 
extremity thrombosis report PTS rates between 7-47% and prospective studies report 
PTS rates of 15-25%. These studies contain a limited number of patients with catheter-
related thrombosis.5 Presence of a catheter as the etiology of the upper extremity 
thrombosis is suggested to decrease the risk of PTS, but the outcomes of patients with 
catheter-related thrombotic events alone have not been well defined. Residual 
thrombosis after treatment and thrombosis of the axillary and/or subclavian vein 
increase the risk of PTS development5; however, no prospective studies have evaluated 
if duration of anticoagulation in CRT influences the development of PTS. Patients with 
PTS have significantly worse quality of life and limb function;6 thus PTS is a patient 
important outcome to evaluate.  
Anticoagulant treatment of CRT is used to improve patient symptoms and decrease 
recurrent thrombosis and pulmonary embolism. Low molecular weight heparin (LMWH, 
enoxaparin) has been the anticoagulant of choice for cancer patients with catheter-
related thrombosis.7 Enoxaparin is the only LMWH FDA approved for treatment of acute 
venous thrombosis (enoxaparin product insert attached). However, in recent years, 
direct oral anticoagulants such as dabigatran, rivaroxaban, apixaban, and edoxaban 
have offered a more convenient alternative for anticoagulation. A randomized control 
trial and prospective cohort study of cancer patients with venous thromboembolism 
treated with a direct oral anticoagulant have been published.8 Two small studies have 
also been published in using rivaroxaban to treat CRT in cancer patients.9,10  Therefore 
direct oral anticoagulants have become part of clinical practice to treat cancer patients 
with thrombosis in addition to LMWH. The FDA package inserts can be found at the 
follow websites: 
Rivaroxaban (Xarelto®): http://www.accessdata.fda.gov/drugsatfda_docs/label 
/2011/202439s001lbl.pdf 
Apixaban (Eliquis®): http://www.accessdata.fda.gov/drugsatfda_docs/label 


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/2012/202155s000lbl.pdf 
Edoxaban (Savaysa®): http://www.accessdata.fda.gov/drugsatfda_docs/label 
/2015/206316lbl.pdf 
Dabigatran (Pradaxa®): http://www.accessdata.fda.gov/drugsatfda_docs/label 
/2011/022512s007lbl.pdf 
The catheter is removed if it is non-functioning or is no longer needed.7 The duration of 
anticoagulation in patients with catheter-related thrombosis has not been studied in a 
systematic fashion and is not standardized in clinical practice. A delicate balance exists 
between thrombosis and bleeding in cancer patients because cancer patients have 3 
times higher risk of recurrent thrombosis and 2.5 times higher risk of major hemorrhage 
compared to non-cancer patients.11 Consensus guidelines have a weak 
recommendation for anticoagulation for 3 months after catheter removal in patients with 
upper extremity CRT (ACCP and ISTH guidelines attached).12,13 These 
recommendations are extrapolated from data on provoked lower extremity thrombosis, 
retrospective case series and two prospective cohort studies.12,13  Review of the 
literature reports treatment of catheter-related thrombosis ranging from catheter removal 
without anticoagulation to treatment with anticoagulation up to 6 months.14-16  In cancer 
patients, upper extremity CRT are often treated with anticoagulation for 4-6 weeks to 
balance the risks of thrombotic recurrence with bleeding. Additionally, extraction of the 
catheter removes an inciting factor for thrombosis which may allow for shorter duration 
of therapy. In a survey of MCW Heme/Onc physicians, treatment of patients with CRT 
ranged from 4 weeks to 3 months. A retrospective review of patients with hematologic 
malignancies from 2009-2011 found 85 patients with catheter-related thrombosis 
treated at MCW.  Three patients (4%) were not treated for their CRT and 20 patients 
(24%) had the catheter removed only. Of the patients that underwent anticoagulation, 
the median total treatment duration was 42 days (range 3-1485 days). Of patients who 
had their catheter removed, the median treatment duration after catheter removal was 
44 days (range 4-453 days). The retrospective study was not able to assess 
development of PTS due to lack of assessment as a part of routine practice. Overall, 
there is no standard treatment duration for patients with catheter-related thrombosis and 
1 month of anticoagulation after catheter removal is within clinical practice at both 
locations. This multicenter prospective cohort pilot study project defines the duration of 
anticoagulation after catheter removal at one month to balance the risk of thrombosis 
with the risk of bleeding, patient cost and discomfort of injecting enoxaparin twice a day. 
The project will assess feasibility and obtain estimates of clinical outcomes including 
PTS, thrombosis recurrence, and bleeding. The feasibility outcomes will assess accrual, 
enrollment, and retention procedures. The data obtained from the pilot study will be 
used to provide sample size estimates for a larger definitive study. Additionally the 


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estimates will allow an appropriate comparison of duration of anticoagulation to be 
selected for a future randomized trial.  
Table 1: Care of patients with CRT in practice vs. research protocol 
 
Typical Care Approach 
Research protocol 
Catheter removal 
Not needed or malfunction 
Not needed or malfunction 
Anticoagulation Type 
LMWH (enoxaparin or 
dalteparin) 
Direct oral anticoagulant 
 
Enoxaparin or direct oral 
anticoagulant 
Duration of 
anticoagulation 
1-3 months after catheter 
removal 
1 month after catheter 
removal 
 
A clinical scoring system or biomarker to predict recurrent catheter-related thrombosis in 
cancer patients do not exist. Currently patients are treated with anticoagulation for 
varying amounts of time based on local practice and extrapolation from clinical trials in 
lower extremity thrombosis. Development of biomarkers predictive of thrombosis would 
allow targeting of anticoagulation strategies in cancer patients at highest risk of 
thrombosis. The Ottawa score allows prediction of recurrent thrombosis in cancer 
patients and is based upon gender, history of thrombosis, cancer type and stage.17,18 
The Khorana score integrates site of cancer, body mass index, and pre-chemotherapy 
platelet, leukocyte and hemoglobin levels to predict initial thrombosis.19 The Khorana 
score has not been evaluated as a predictor of thrombotic recurrence and will be 
assessed from clinical information at the time of CRT diagnosis. Validations of the 
Khorana score have also added biomarkers including D-dimer to expand the ability to 
detect high risk groups.20 Additionally, high levels of thrombin generation have been 
associated with increased risk of initial thrombosis in cancer patients.21 Elevated D-
dimer and peak thrombin generation have been shown to be risk factors for recurrent 
thrombosis in non-cancer patients, but the association has not been evaluated in cancer 
patients.22,23 Tissue Factor Pathway Inhibitor (TFPI) functions to limit the activation of 
factor X by the tissue factor/Factor VIIa complex.  TFPI has been shown to be a 
predictor of thrombosis with low levels of TFPI antigen associated with twice the risk of 
thrombosis.24 Platelet TFPI may also play a role in thrombotic risk as platelets 
accumulate at the site of injury. Platelet TFPI has not been assessed as a risk factor for 
thrombosis. Lastly, extracellular DNA released from neutrophils (NETs-neutrophil 


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extracellular traps) has been shown to form a scaffold for venous thrombosis in animal 
models. Circulating plasma free DNA is a marker for NET formation and will be 
assessed in our patients.25 Overall, the proposed project will evaluate novel assays 
(platelet TFPI, plasma free DNA, and thrombin generation with platelet-rich plasma) and 
apply techniques that predict incident thrombosis (Khorana score, D-dimer and thrombin 
generation with platelet-poor plasma) to predict the risk of recurrent thrombosis. Overall, 
identification of a biomarker to predict thrombosis would allow a personalized approach 
to anticoagulation that would avoid unnecessary bleeding risk, cost and lifestyle 
burdens in patients who do not require more prolonged courses of anticoagulation. 
 
2. Study Objectives 
 2.1 
Feasibility Objectives:  
1) To determine the feasibility of a multicenter prospective cohort study of 
cancer patients with catheter-related thrombosis treated with 1 month of 
anticoagulation.  
a. Feasibility will be defined as accrual of 56 patients in 1 year and 80% 
completion of PTS assessments 
2) To determine the feasibility of obtaining plasma samples for biomarker 
analysis to predict recurrent venous thrombosis 
a. Feasibility will be defined as obtaining 80% of plasma samples for 
biomarker analysis 
 2.2 
Clinical Objectives:  
3) To determine the incidence of post-thrombotic syndrome, thrombotic 
recurrence and bleeding in cancer patients with catheter-related 
thrombosis treated with 1 month of anticoagulation 
a. Success of the study will be defined as an incidence of post-thrombotic 
syndrome <20%. 
3. Study Population 
The intended study population is any adult with cancer and catheter-related thrombosis. 
Children will not be included as the involved institutions do not care for children. No 
gender or ethnic group will be excluded or targeted in the study. 
3.1 Study Sites 


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1) BloodCenter of Wisconsin, Medical College of Wisconsin (MCW) and 
Froedtert Hospital, Milwaukee, Wisconsin 
The primary study site will be in Milwaukee. Patients will be recruited from 
MCW/Froedtert Hospital. Laboratory testing will be completed at the 
BloodCenter of Wisconsin in the laboratory of Dr. Alan Mast.  
2) Ohio State University, Wexner Medical Center, Columbus, Ohio 
Ohio State University (OSU), Wexner Medical Center, will be a second 
site for the study.  Patients from OSU will be followed with clinical 
assessments only. 
 
 
3.2 Inclusion Criteria:  
1. Upper extremity venous thrombosis involving the axillary, subclavian, brachiocephalic, 
superior vena cava, and/or internal jugular veins associated with an indwelling catheter 
documented by ultrasound, CT or venography 
2. Current hematologic or solid tumor malignancy undergoing chemotherapy, surgery, 
radiation or hormonal therapy for malignancy and bone marrow transplant if within 100 
days of transplant 
3. ≥18 years of age 
4. Platelet count >50,000 
5. Creatinine clearance >30 ml/min 
6. Ability to provide informed consent 
3.3 Exclusion Criteria:  
1. Underlying medical condition or chemotherapy requiring long-term anticoagulation 
2. Known underlying higher risk thrombophilias including antiphospholipid antibody 
syndrome, antithrombin, protein C or protein S deficiencies, or homozygosity or 
compound heterozygosity for prothrombin G20210A or Factor V R506Q mutations. 
3. Inability to remove venous catheter 
4. Anticipated replacement of central venous catheter within 3 months after enoxaparin or 
direct oral anticoagulant therapy has been discontinued 
5. Personal history of deep vein thrombosis or pulmonary embolism 
6. Concurrent acute deep vein thrombosis of the leg or pulmonary embolism 
7. Major bleeding or clinically relevant non-major bleeding in the preceding 60 days 
8. Participation in another clinical trial that requires anticoagulation 
9. Treatment with thrombolysis 
10. Catheter removal >1 month prior to enrollment 


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11. Use of anticoagulation >6 months prior to catheter removal 
3.4 Study Discontinuation Criteria 
Subjects may be removed from the study by the Investigator for any of the 
following reasons: 
1. Subject’s condition has changed after entering the study so that they 
no longer meet inclusion criteria, or develop any of the exclusion 
criteria. 
2. Subject experiences an adverse event that warrants withdrawal from 
the study. 
3. Principal investigator determines subject is non-compliant. 
4. Subject requires placement of an alternate central venous catheter 
after discontinuation of enoxaparin or direct anticoagulant therapy. 
3.5 Continuation of anticoagulation criteria  
Participants will be continued on anticoagulation longer than one month after catheter 
removal if any of the following criteria exist: 
1. Development of thrombosis other than the CRT 
2. Extension of the catheter-related thrombosis (i.e. additional vein occlusion 
on imaging obtained for clinical reasons) 
If an enrolled subject at MCW requires anticoagulation longer than 1 month after 
catheter removal, laboratory assessments will not be completed as the testing can be 
affected by the presence of an anticoagulant. The participant will not be removed from 
the study and will be followed for PTS outcomes. 
 
4. Study Design 
4.1 
Study Overview 


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Figure 1 shows the overall study design of the multicenter prospective cohort of cancer 
patients with catheter-related thrombosis. Participants may be referred for screening at 
MCW in two possible mechanisms: participant contact study staff from information on CTSI 
FACT website or referral from treating Hematologist or Oncologist. At MCW, an EPIC 
report will be generated to identify people with CRT. The treating provider would then be 
contacted to determine if referral to the study was appropriate.  Subjects at OSU will be 
referred from the treating Hematologist or Oncologist.    A report generated in Epic will be 
used to identify people with CRT.  The treating provider would then be contacted to 
determine if referral to the study was appropriate. Participants will be given printed 
information about the study (Appendix A) or verbal explanation using the informational flyer. 
Verbal consent will be obtained to be screened for participation and contacted by study 
personnel. Screening will be completed by BCW nurse coordinator (Script Appendix B; 
Screening form Appendix C). We aim to consent and enroll patients after diagnosis of 
catheter-related thrombosis and prior to catheter removal. Consent and enrollment (Visit 1) 
must occur prior to discontinuation of anticoagulation. Enrollment will be limited to patients 
undergoing anticoagulation with either enoxaparin or a direct oral anticoagulant at the 
discretion of the treating provider. The study will follow patients treated with anticoagulation 
for one month after catheter removal. Prior to discontinuation of anticoagulation, patients 
will be contacted via telephone to review study protocol, assess for bleeding, and arrange 
for Visit 2 in the following 1-2 weeks. Appendices D-H include the background information 
that will be collected. Visits 3 and 4 will occur 3 and 6 months after catheter removal, 
respectively. At visits 3 & 4, Medical history, cancer history, and medications will be 
updated (Appendices E-G). At each visit, participants will be assessed for post-thrombotic 


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syndrome using the modified Villalta scale (Appendix I) and functional limitation using the 
DASH questionnaire (Appendix J).  At MCW, surveys will be administered by the TRU staff 
and physical examination will be completed by BCW nurse coordinator, Zora Jovanovic. At 
OSU, surveys will be administered by research coordinators trained to complete the 
assessment. Laboratory samples will be obtained for MCW participants only and processed 
as noted in section5.6 and section 6.  
 
4.2 
Selection of Subjects  
Subjects will be recruited at MCW and OSU through referral from their treating 
Hematologist or Oncologist. The patient’s treating physician will give potential 
participants the informational flyer (Appendix A) or use the flyer to verbally describe the 
study and receive permission for the patient to be screened for eligibility and contacted 
by the research coordinator. Additionally at Milwaukee and Columbus, an electronic 
alert will be created that identifies a person with catheter-related thrombosis through the 
results of their radiology report.  The research coordinator will review the report and 
then contact the treating physician to inform them of the study and receive permission to 
contact the subject. In 2012, 2350 new patients were seen in the Heme/Onc and BMT 
clinics at Froedtert Hospital and 1003 had a Port-A-Cath placed. Estimating a catheter-
associated thrombotic rate of 15%,5,26 this predicts approximately 150 patients annually 
with CRT due to a Port-A-Cath. Additional patients are anticipated due to CRT from 
peripherally inserted central catheters (PICC). A survey was conducted among the 
Heme/Onc and BMT physicians at MCW with a 60% response rate (21/35). The 
physicians estimated that 63 patients had been seen with CRT in the last 3 months (252 
annual). 86% of physicians reported that they would refer patients to a study of CRT 
treated with 4 weeks of anticoagulation; 14% were uncertain. MCW physicians also 
noted a variety of treatment practice from 4 weeks to 3 months of anticoagulation after 
catheter removal. We estimate a 10% drop out rate due to reinsertion of a catheter or 
inability to remove a catheter. We also estimate that we will need to screen and 
approach 3 patients for every participant. Therefore, we will plan to screen and 
approach 250 patients to enroll 56 patients (36 BCW and, OSU 20,) and have 50 
complete the study as the overall target. 
4.3 
Sample Size Estimates 
Sample size estimates were based on the confidence interval method and were based 
upon the feasibility endpoints. With 50 patients completing the study, we would have 
95% confidence that completion of 80% of PTS assessments in the pilot study would 
correspond to 66-90% completion in another study. Completion of 90% of assessments 


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would correspond to between 78-96% of assessments. We estimate a 10% drop-out 
rate so will plan to enroll 56 patients over 1 year.  
Evaluation of 50 patients would provide 95% confidence that if the feasibility study 
found a PTS incidence of 10% that the true proportion in a larger study would not be 
greater than 20%.  
5. Clinical Procedures 
 
5.1  Enrollment and Consent 
We aim to consent and enroll participants after diagnosis of catheter-related thrombosis 
and prior to catheter removal. Participants must be consented and enrolled prior to 
anticoagulation discontinuation. Screening will be completed using Appendix B (Script 
Appendix B; Screening form Appendix C). Medical history, family history, and medications 
will be reviewed after consent is obtained (Appendices D-H).Consent for medical record 
release will be obtained to determine cancer staging and laboratory information from the 
time of CRT diagnosis.  
  
5.2   Anticoagulation 
Participants will be treated with either enoxaparin for one month following catheter 
removal, or direct oral anticoagulant treatment (apixaban, rivaroxaban, dabigatran, or 
edoxaban). Dosing an alternate enoxaparin dose or interval based on anti-factor Xa 
testing that was obtained by clinical team, at standard dosing per FDA package insert. 
Anticoagulation will be continued for 1 month after catheter removal. The minimum 
duration of anticoagulation will be one month and maximum duration is 7 months. The 
cost of enoxaparin or direct oral anticoagulant treatment will be the responsibility of the 
participant as use of the medication is part of routine care. Subjects will be contacted by 
telephone prior to discontinuation of anticoagulation to review if any continuation rules 
apply and arrange for research visit 2.    
5.3   Concomitant medications 
The decision of which anticoagulant to prescribe for the thrombotic event will be made 
by the patient’s physician per standard of care. The patient’s prescribing physician will 
be responsible for assessing the potential drug interactions between anticoagulant 
therapy and other medications as he or she would in their normal medical practice. For 
example, direct oral anticoagulant therapy medications have drug interactions with 
CYP3A4 inhibitors and inducers. Use of anti-platelet agents will be allowed and 
recorded. We anticipate the use of antiplatelet agents to be low because of the risk of 
thrombocytopenia associated with many chemotherapeutic agents.  
 
5.4   Catheter removal 
The timing and mechanism of catheter or port removal will be directed by the subjects’ 
treating physician. The practitioner type (ex. MD Interventional Radiologist vs RN PICC 


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Team) will be recorded. Additionally, the reason for catheter removal will be recorded. In 
a patient that requires catheter or port re-insertion while on enoxaparin or direct oral 
coagulant therapy, the enoxaparin or direct oral coagulant therapy will be continued for 
30 days following removal of all catheters or ports provided the time of anticoagulation 
does not exceed 6 months duration. If a patient requires re-insertion of a catheter or 
port after discontinuation of enoxaparin or direct oral anticoagulant therapy, they will be 
removed from the study at that time because a new catheter would be an additional 
thrombotic inciting factor. 
 
5.5   Post-thrombotic syndrome assessments 
Visit 2 will occur within 2 weeks of discontinuation of anticoagulation. Visit 3 will be at 3 
months after catheter removal plus or minus 2 weeks and Visit 4 within 6 months plus or 
minus 2 weeks after catheter removal. At each visit, medical history and medication will 
be reviewed (Appendices E-G). The subjective assessment of the modified Villalta 
(page 1 and 2 of Appendix I) and the DASH questionnaire (Appendix J) will be 
administered by the Translational Research Unit (TRU) staff or the clinical nurse 
coordinator after completing the objective assessment. The objective assessment of the 
modified Villalta score will be completed by trained clinical nurse coordinators blinded to 
the subjective assessment (page 3 and 4 of Appendix I). The subjective assessment of 
the modified Villalta (page 1 and 2 of Appendix I) and the DASH questionnaire 
(Appendix J), will be administered by the research coordinator at OSU. 
 
5.6   Blood measurements 
Blood will be collected by venipuncture using a 20G needle or larger from patients at the 
BCW site at Visit 2, 3 and 4. A 21G needle may be used for collection of blood via 
venipuncture if blood cannot be obtained with a 20G needle or larger. The first 2 ml of 
blood will be discarded due to tissue factor activation with the venipuncture. Three BD 
Vacutainer citrated tubes (0.105M sodium citrate) with 4.5 ml blood will be collected. 
Thrombin generation, D-dimer, plasma total TFPI and TFPIα, and platelet TFPIα, will be 
assayed using platelet-poor plasma (PPP). Thrombin generation will also be assayed 
using platelet rich plasma (PRP). Laboratory procedures as noted in section 6. 
 
Table  2. Study Schedule of Procedures  
Procedure 
Screening 
Visit 1 
(Consent) 
Visit 2 
Visit 3 
Visit 4 
Review Eligibility criteria 
X 
X 
 
 
 
Consent for research 
participation 
 
X 
 
 
 
Documentation-medical 
history, medications, & 
 
X 
X 
X 
X 


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clinical data 
Physical Examination 
 
 
X 
X 
X 
PTS Assessment: 
modified Villalta, DASH 
 
 
X 
X 
X 
Blood draw- D-dimer, 
thrombin generation, TFPI, 
plasma free DNA 
(MCW Only) 
 
 
X 
X 
X 
 
6. Laboratory Procedures  
 
6.1 
Plasma preparation 
Tube 1 of citrated blood will be used to prepare PRP and tubes 2 and 3 of citrated blood 
will be used to prepare PPP. Tube 1 will be centrifuged at 130 g at room temperature for 
10 minutes within 30 minutes of blood collection.27 After centrifugation, the PRP will be 
pipetted off without disturbance of the white blood cell layer (buffy coat). 200 ul of PRP 
will be used to assess the platelet count via a Coulter counter. Approximately half of the 
PRP will be placed into centrifuge tubes for preparation of PPP by centrifugation at 
2000g for an additional 10 minutes. Tubes 2 and 3 will undergo centrifugation at 2000g 
for 10 minutes and centrifugation at 14,000 g for 5 minutes at room temperature.27 PPP 
will be obtained from the upper half volume of plasma supernatant. PPP will be used to 
adjust the platelet count of the PRP to 150,000/uL. The unused PPP will be frozen to 
allow batched processing of thrombin generation, D-dimer, plasma free DNA and TFPI 
testing. 
  
6.2 
Thrombin Generation 
 
Thrombin generation will be measured through a calibrated automated thrombogram 
system (CAT, Thrombinoscope bv, Maastricht, The Netherlands) with and without tissue 
factor activation using both PRP and PPP. Each well of the 96-well plate will contain 20 
ul of reagent (PPP-Reagent or PRP-Reagent), 20 ul of thrombin calibrator, and 80 ul of 
plasma. Plasma samples will be measured in duplicate. 
 
6.3 
D-Dimer 
The Stago Asserachrom® D-Di ELISA assay will be used to determine D-dimer levels. 
The Asserachrome ELISA has similar sensitivity and specificity as other D-dimer assays 
in clinical use.28 Batched laboratory testing will prevent clinical decisions from being 
altered by the D-dimer results.  


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6.4 
TFPI Assay 
Levels of platelet TFPI (TFPIα), plasma total TFPI and TFPIα will be assessed through 
TFPI AlphaLISA assays. AlphaLISAs are a washless, bead based assay system. When 
the two beads are brought into close proximity by antigen binding, a singlet oxygen is 
released from the donor bead to the acceptor bead, resulting in light emission. Two 
AlphaLISAs are established in the lab to measure TFPI, one for total TFPI (full length 
TFPIα, truncated TFPIα, and TFPIβ) and one specifically for TFPIα. Both assays use a 
common acceptor bead to which mouse anti-human TFPI antibody (directed toward the 
second Kunitz domain) is conjugated. The total TFPI AlphaLISA uses biotinylated 2H8 
(directed toward the first Kunitz domain) to detect all forms of TFPI, while the TFPIα 
AlphaLISA uses a biotinylated anti-K3 antibody to detect only TFPIα. A streptavidin-
conjugated donor bead is added to bind these antibodies. Each well of the 96-well plate 
will contain 5ul of plasma and 20 ul mixture of anti-K2 conjugated acceptor bead and 
either the biotinylated 2H8 to measure total TFPI or biotinylated anti-K3 to detect TFPIα.  
Plasma samples will be measured in duplicate. 
6.5 Plasma Free DNA 
Levels of plasma free DNA will be assessed using the Quant-iT PicoGreen dsDNA kit 
and the Sytox Green fluorescent dye.25 The Victor microplate reader will be used to 
determine the fluorescence omitted from the samples. The DNA concentration will be 
determined through comparison to a standard curve. 
  
7.  Subject Remuneration 
 
For their time and efforts in study activities, research subjects will receive $25 for each 
of the following patient visits: 
• Study visit 2, 1 month after catheter removal 
• Study visit 3, 3 months after catheter removal 
• Study visit 4, 6 month after catheter removal 
 
A total of $75 will be paid to subjects completing all study visits to cover travel to the 
research site, parking, and time of the visits. The subject will be paid $25 for each 
completed study visit whether they withdraw, the investigator withdraws them or they 
complete all study activities.  Payment will occur when they are no longer an active 
participant in the study.  Remuneration for study visits will only take place at the BCW 
site. 
 
7.1 
Potential benefit to subjects 
Our protocol will treat participants with anticoagulation for 1 month after catheter 
removal. There are no definite direct benefits to subject participation. Because the 


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duration of anticoagulation varies in clinical practice, treatment with one month of 
anticoagulation could have lower risk of hemorrhage in comparison to 3 or 6 months of 
anticoagulation. Additionally, the cost and discomfort associated with use of injected 
anticoagulant could be lower. The study may also benefit others with CRT if the study is 
able to identify biomarkers that will predict thrombosis to allow a tailored approach to 
treatment of CRT.   
 
8.  Human Subjects Protection 
 
8.1 
Informed Consent: Subjects are required to sign an informed consent prior 
to enrollment, and before undergoing any study procedures or assessments. 
When substantial modifications are made to the informed consent, the IRB 
may require that all subjects currently enrolled in the study will be re-
consented.   
 
Subjects will be provided with a copy of the signed informed consent form 
used in the study, procedures, and assessments.  Subjects will also be 
provided with the contact telephone numbers of the investigator and qualified 
personnel who can assist with their questions and concerns.   
 
8.2  
Protected Health Information 
 
Protected health information that will be collected as part of this study 
includes name, date of birth, date of catheter placement, date of thrombosis 
diagnosis, date of bleeding event, and date of thrombosis recurrence.  This 
information will be stored for 10 years beyond the completion of the study. 
After blood is used for study testing it will be discarded.  
 
8.3 
Confidentiality 
Loss of confidentiality is always a potential risk when collecting protected 
health information. Research records will remain confidential. Subject’s 
records will be available to the study staff and to each site’s IRB and for audit 
purposes. Only authorized personnel will have access to the protected health 
information and research records. The investigators, clinical research nurses, 
and TRU nurses will have access to the patient identifying code. In order that 
confidentiality can be maintained, the PI/study staff will keep records in locked 
cabinets/room and results of tests will be coded to prevent association with 
volunteers’ names. All electronic data will be entered into a secured, website 
data management system, REDCap, that requires training and is password 
protected. Identifying information will not be included on laboratory samples, 


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faxes, or correspondence. Laboratory samples and printed surveys will only 
have participant number and not identifying information. 
All study team members are trained in HIPAA privacy regulations and other 
applicable site privacy policies. No information will be released, nor will 
participation in the research be acknowledged, to any party except where 
compulsory according to law or intuitional policy. The results of the research 
study may be published, but volunteers’ names or identities will not be 
revealed.  
 
9. Adverse Event Monitoring 
 
9.1 
Definitions 
 
Adverse Event (AE) – Any untoward or unfavorable medical occurrence in a 
human subject related to bleeding or thrombosis, including any abnormal sign 
(for example, abnormal physical exam or laboratory finding), symptom, or 
disease, temporally associated with the subject’s participation in research, 
whether or not considered related to the subject’s participation in research. 
 
Serious Adverse Event (SAE) – Any adverse event temporally associated 
with the subject’s participation in research and related to bleeding or 
thrombosis that meets any of the following criteria: 
• Results in death; 
• Is life-threatening (places subject at immediate risk of death from 
the event as it occurs); 
• Requires inpatient hospitalization or prolongation of existing 
hospitalization; 
• Results in a persistent significant/incapacity; 
• Results in a congenital anomaly/birth defect; or 
• Any other adverse event that, based upon appropriate  medical 
judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent on the other outcomes 
listed in this definition 
Note that seriousness and severity are separate concepts. The term “severe” 
refers to the intensity of a specific event; a severe event may be of minor 
medical significance (e.g., a severe leg cramp). The term “serious” is based 
on an outcome or action criteria that are usually associated with events that 
pose a threat to the patient’s life or functioning. An event that is mild in 
severity is serious if it leads to one of the outcomes defined above. 
 


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Grade 4 and 5 events will always be considered Serious Adverse Events. 
Many Grade 3 and some Grade 1 and 2 events may meet the definition of a 
Serious Adverse Event. 
 
Unexpected Adverse Event- Any adverse event occurring in one or more 
subjects in a research protocol, the nature, the severity, or frequency of which 
is not consistent with either: 
• The known of foreseeable risk of adverse events associated 
with the procedures involved in the research that are described 
in; 
o  the protocol related documents or the current IRB-
approved informed consent document and;  
o other relevant sources of information, such as a product 
labeling or package insert or; 
• The expected natural progression of any underlying disease, 
disorder, or condition of the subject(s) experiencing the adverse 
event and the subject’s predisposing risk factor profile for the 
adverse event. 
 
Unanticipated problem involving risks to subjects or others (UP) - Any 
incident, experience or outcome that meets all the following criteria: 
• Unexpected (in terms of nature, severity, or frequency) given: 
o The research procedures that are described in the 
protocol related-documents, such the IRB-approved 
research protocol and the informed consent form 
document and, 
o The characteristics of the subject population being 
studied;  
• Related or possible related to the subject participation in 
research; and 
• Suggests that the research places subjects or others at a 
greater risk of harm (including physical, psychological, 
economic, or social harm) related to the research than was 
previously known or recognized. 
 
Grading of Adverse Events – Events will be graded by using the Common 
Terminology Criteria for Adverse Events (CTCAE) Criteria version 4.0. 
 
Attribution – the determination and documentation of whether an adverse 
event is related to a medical procedure. 
 
Attribution Categories: 
1. Not Related –Event clearly related to other factors (e.g., clinical state, 
other therapies; concomitant drugs) 


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2. Possible Related – Sequence of event is compatible with study drug, 
device, or procedure, but could have been produced by other factors 
3. Probably Related - Sequence of event is compatible with study drug, 
or procedure and cannot be explained by other factors without much 
doubt 
4. Definitely Related - Sequence of event is compatible with study drug, 
or procedure and beyond doubt cannot be explained by other factors 
 
 
9.2  
Site Monitor Physician 
A site monitor physician will be identified at each site. Lisa Baumann 
Kreuziger is the site monitor physician at MCW.  Tzu-Fei Wang will be the site 
monitor physician at OSU.  
The site monitor physician will: 
1)  Assess all adverse events and the frequency of adverse events 
2)  Report directly to the IRB in the event of a serious adverse event    
 
9.3  
Study Staff 
Information on all adverse events, whether reported by the subject, directly 
observed, or detected by physical examination, laboratory test or other 
means, will be collected, recorded, followed, and reported as described in the 
following sections. If follow-up or clinical intervention is required, the treating 
provider will be informed and will provide treatment or follow-up as needed.  
The PI will monitor and review adverse events monthly or more often as 
needed.   
 
9.4 
Timeline for Reporting of Adverse events, Serious Adverse Events, 
Unexpected Adverse Events and Unanticipated Problems 
  
  
All serious adverse events, all unexpected adverse events, and all 
unanticipated problems will be reported to the IRB and DSMC as per 
standard operating procedure by phone, email or SAE form regardless of 
attribution.  
 
 
9.5 
Reporting Events to Local Institutional Review Boards 
All serious adverse events will be reported to the institutional review board 
(IRB). Each site will comply with their institution’s standard operating 
procedures for reporting adverse events. Subjects will be instructed to report 
any adverse event(s) during the study and post-study .The investigator will 


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notify the IRB and any other applicable regulatory agency of any 
unanticipated death or adverse event occurring after a participant has 
discontinued or terminated study participation that may reasonably be related 
to the study.  
9.6  
Data Safety Monitoring Committee (DSMC) 
 
This study will be reviewed by the Medical College of Wisconsin Cancer Center Data 
Safety Monitoring Committee (MCW CC DSMC). A summary of the MCW CC DSMC 
activities are as follows: 
• Review the clinical trials for data integrity and safety 
• Review all adverse events requiring expedited reporting as defined per 
protocol 
• Review all DSM reports 
• Submit a summary of any recommendations related to study conduct 
• Terminate the study if deemed unsafe for patients 
A copy of the MCW CC Data and Safety Monitoring Plan and membership roster will 
be maintained in the study research file and updated as membership changes. The 
committee will review reports from the study PI twice annually (or more frequently if 
needed) and provide recommendations on trial continuation, suspension or 
termination as necessary.  Any available DSMC letters will be submitted to the IRB 
of record as required.  
 
9.7 
Potential Risks to Volunteer 
 
Likely:   
Blood Sampling: Venipuncture can cause pain and discomfort at the needle 
puncture site 
Physical Exam: Pain associated with movement of arm and assessment of 
swelling. 
Anticoagulation: Use of injected anticoagulation can cause pain and 
bruising at the injection site. Cost associated with anticoagulation will be the 
responsibility of the participants and/or their insurance companies. The cost 
of enoxaparin (lovenox) will range in price from $24 to $119 a 
dose depending on the dosage necessary for each person. The cost of direct 
oral anticoagulant treatment averages $11-15 a dose. The amount of 


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insurance copays will depend on the insurance plan. Some insurance 
companies do not cover costs associated with research studies. 
Use of aspirin, clopidogrel (Plavix) and NSAIDs [ex. ibuprofen (Motrin), 
naproxen (Aleve)], while using anticoagulation will increase your risk of 
bleeding.  The physician prescribing aspirin, clopidogrel or NSAIDs will 
determine if these medications should be continued while you receive 
enoxaparin or direct oral anticoagulant therapy.  If needed, aspirin, 
clopidogrel, and NSAIDs can be safely resumed the day after anticoagulation 
is discontinued. 
Due to risk of bleeding, spinal procedures should be avoided while using 
anticoagulation. 
Less Likely: 
Blood Sampling: Venipuncture can cause, bruising, fainting or local infection 
at the needle site. 
Survey: Filling out the surveys could cause stress or anxiety to the participant 
Physical Exam: Examining the chest cause participant embarrassment  
Anticoagulation: Use of anticoagulation is known to cause an increased risk 
of bleeding that can occur at the injection site or systemically. Use of 
anticoagulation is known to cause an increased risk of bleeding that can 
occur at the injection site or systemically. Participants will have had 
anticoagulation for 0-6 months prior to catheter removal and one month after 
catheter removal. Usual care would include anticoagulation between 1-3 
months after catheter removal. With a shortened course of anticoagulation, an 
increased risk of thrombosis or post-thrombotic syndrome could occur. 
Potential side effects of enoxaparin include fever, nausea, diarrhea, fluid 
retention, elevated LFTs, decreased platelets, decreased RBCs, local 
irritation, hematoma and redness. 
A potential side effect of all direct oral anticoagulant treatment includes 
bleeding. Edoxaban also reported a rash, abnormal liver function tests, and 
anemia. Dabigatran is also associated with gastritis-like symptoms in 15% of 
patients.  
Rare:  


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Blood Sampling: In rare circumstances venipuncture can cause blood clots, 
peripheral nerve injury or an arterial puncture.   
Anticoagulation: The anticoagulation medication prescribed from the 
treating provider as planned treatment for catheter-related thrombosis can 
rarely cause bleeding requiring hospital admission, transfusion, or death. 
Breach of confidentiality: personal health information will be collected and 
rarely a breach of confidentiality may lead to disclosure of that information. 
In addition to the above possible risks, there is always the risk of developing 
previously unknown side effects. 
10. Data 
10.1 Data Management 
The data gathered will be entered into REDCap data system with each ID 
having a unique identifier for each participant. REDCap is a secure, web-
based application for building and managing online databases. All data will be 
de-identified and samples will only have a unique identifier that will link the 
unique identifier with the patient’s name.  
10.2 Data Collection 
Research information, including consent forms and PTS assessments will be 
maintained secure as described in the Confidentiality section 8.3. 
 Each participant will be identified with a unique identifier number in REDCap. 
This unique identifier will be linked to the same unique identifier for a 
biological specimen sample stored in the Dr Alan Mast’s laboratory or the 
TRU to allow batched testing.   
10.3 Data Monitoring 
The PI or study staff will review all data collection forms on an ongoing basis 
for data completeness, accuracy, and protocol compliance.  The data will be 
continuously monitored by the principal investigator of the study.  The 
regulatory officer that is a part of the BCW Clinical Trials Office will assist with 
internal and external audits as appropriate.  If protocol compliance or data 
accuracy comes into question study PI will request a study review. 
Subject accrual, compliance with the protocol, status of enrolled subjects, 
adherence data regarding study visits, and adverse events will be 
summarized on a quarterly basis (or more frequently if needed) and reviewed 
by the PI.  Serious adverse events will be reviewed at the time of the 


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occurrence by the PI and reported to the DSMC and IRB as per standard 
operating procedure. 
A biannual safety and progress report will be submitted to the DSMC.  The 
report will include the number of patients entered, number of patients treated, 
summary of all adverse events reported to date using standardized grading, a 
specific list of all serious adverse events [SAEs]. 
Data safety and monitoring activities for each study will continue until all 
patients have completed their treatment and the 6 months of follow-up.  In the 
event that data and safety monitoring results in the suspension or termination 
of enrollment and/or treatment of patients, the principal investigator, the MCW 
CCC Director, the MCW Associate Director for Clinical Medical College of 
Wisconsin Cancer Center Research, the MCW IRB will be notified per MCW 
Office of Research Standard Operating Procedure. 
The PI is responsible for the overall conduct of the project. Prior to start of the 
project at OSU, the PI will visit the site to ensure staff training, data 
management, and monitoring procedures are in place.  Weekly or as needed 
teleconferences will be arranged between the study staff and investigators 
between OSU and WI to discuss enrollment, monitoring, concerns and trouble 
shoot any problems that arise.  Audits of study procedures will be completed 
through WI institutional review boards and BCW clinical trials offices. 
10.4 Stopping Rules 
The DSMC can consider stopping the study prior to completion if: 
1. The intervention is associated with adverse events that call into question 
the safety of the intervention 
a. Interim analysis after 20 patients shows an incidence of thrombotic 
recurrence >40% (8/20 patients) 
i. 
Rationale: A retrospective review of CRT in patients with 
hematologic malignancy at MCW found development of 
thrombosis other than CRT or extension of the catheter-related 
thrombosis in 20/141 (14%) of patients.  Recurrent thrombosis 
has been reported in other studies in 20% of cancer patients.1 If 
after half of patients are recruited, the thrombotic incidence has 
doubled over the reported incidence in the literature, the study 
will be stopped.  This level was chosen because it would be 
unlikely that if 8 events in the first 20 patients occur that no 
thrombotic events would occur in the next 20 patients to have 
an overall 20% (8/40) recurrent thrombosis incidence. 


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2. Difficulty in study recruitment or retention will significantly impact the ability 
to evaluate the study endpoints 
3. New information becomes available that necessitates stopping the trial 
11. Statistical Considerations 
11.1    Description of Endpoints: 
1. 11.1.1 Feasibility Endpoints:  
a. Recruitment of 56 patients in 1 year and 80% completion of PTS 
assessments by enrolled patients.  
b. Feasibility of obtaining plasma samples for biomarker analysis as 
determined by obtaining 80% of samples from enrolled patients. 
11.1.2 : Clinical Endpoint 
2. Incidence of post-thrombotic syndrome <20% at 6 months. 
11.1.3: Secondary Endpoints  
1. Recurrent thrombosis  
2. Incidence of major and clinically relevant non-major bleeding  
3. Reliability of QuickDASH questionnaire in patients with catheter-related 
thrombosis 
11.2 Statistical Analysis 
 
The incidence of PTS, thrombotic recurrence, major bleeding and clinically relevant 
non-major bleeding will be reported as proportions. These outcomes will be compared 
at 3 and 6 months using Chi-square or Fisher’s exact tests. A Cox-proportional hazards 
model will be utilized to calculate the risk of PTS and thrombosis recurrence. Chi-square 
or Fisher’s exact tests will be used to determine if clot presentation or location predicts 
PTS or thrombotic recurrence. Agreement between the DASH and QuickDASH scales 
will be assessed using the intraclass correlation coefficient. To compare the 
discriminating ability of the DASH and QuickDASH on the level of PTS, receiver 
operating curves will be developed using the scale scores at 6 months as the test 
variable and dichotomized PTS assessment as the classifying variable. Levels of D-
dimer, thrombin generation, and TFPI will be reported as means. Logistic regression will 
evaluate if D-dimer, thrombin generation or TFPI levels at 1 month or % change from 
baseline predict thrombotic recurrence. Where necessary, for parametric assumption, 
we will employ appropriate transformations with justifications. For example, the log of 
some of the biomarkers data may be used if the data range is >1000. Statistical 


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significance will be determined with p<0.05. SAS version 9.13 and JMP 10 Statistical 
software will be employed for data analysis. 
 
An interim analysis will be completed after 20 patients complete 6 months of follow-up. 
The interim analysis will allow assessment of thrombotic recurrence by the DSMC. 
11.3 Follow-up and Record Retention 
 
The current proposal involves on-going data collection for the duration of the study at 
each site. The records will be maintained per site policy. 
 
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