Randomized Comparative Evaluation of Midline Catheters for Thrombophlebitis
Phase: NA
Conditions: Catheter Infection, Catheter Thrombosis, Catheter Complications
Sponsor: Corewell Health East

TITLE:  
Randomized Comparative Evaluation of Midline Catheters for 
Thrombophlebitis 
NCT03725293 
Approval date: 04/30/2019 
 
Protocol and Statistical Analysis Plan 

04.19.2019 V 3.0 
Randomized Comparative Evaluation of Midline Catheters for thrombophlebitis 
 
Introduction  
  
Establishment and maintenance of intravenous (IV) access are core processes in  
providing medical care for hospitalized patients. For patients requiring extended 
duration of therapy, the peripherally inserted central catheter (PICC) Team is often 
consulted for patient assessment and vascular access device placement at many 
hospitals. PICCs are central catheters that are placed via peripheral vein under 
ultrasound guidance and may be used for patients with difficult venous access for 
long-term central or peripheral infusion therapies as well as central venous pressure 
monitoring in a critical care setting. Although PICCs provide a great option for some 
patients, these catheters have known complications including catheter- related 
bloodstream infection, catheter-related venous thrombosis, malfunction,  
and high cost. Midline catheters represent a potentially attractive alternative to  
PICCs for peripheral infusions. These catheters have been utilized since the mid  
1980s but fell out of favor in the early 1990s due to reports of acute life threatening 
hypersensitivity reactions. In the last few years, midlines have made a resurgence in 
the market and are FDA cleared for use in patients requiring intermediate to long- 
term infusion therapies. Advances in midline catheters offer the potential for reduced 
complications. As midlines have increased in popularity and new midlines have been 
introduced into the market, it is necessary to better understand complication profiles 
of various midline catheters, as it is likely that all catheters are not created equal. 
Specifically, the incidence of symptomatic catheter-related thrombosis is of interest. 
While this complication has been researched extensively for PICCs with an incidence of 
1.8 – 8.4%, data on this complication for midlines represents a gap in the literature. 
One recent publication cited a 4.5% rate of all symptomatic catheter-related venous 
thrombosis (combined superficial venous thrombosis (SVT) and deep venous 
thrombosis (DVT)) in patients with midline catheters. Another study found a catheter-
related venous thrombosis rate of 2.5% when limiting measured outcomes to 
occurrence of DVT . Internal retrospective  
data at our institution suggests a rate closer to 12-15% for all symptomatic catheter-
related venous thrombosis (SVT and DVT). Some midline catheters are coated to 
provide protection against catheter-related venous thrombosis and/or catheter-
related bloodstream infection. The theoretical benefit(s) of these catheters need 
further validation in human subjects.  
  
Objective  
  
We aim to understand the difference in symptomatic catheter-related upper extremity 
venous thrombosis (CR-UEVT) comparing the Teleflex Arrowg+ard Blue Advance 4.5 F 
single lumen midline catheter to the AngioDynamics BioFlo 4 F single lumen midline 
catheter. Both catheters are inserted using a modified seldinger technique (MST). The 
AngioDynamics product has Endexo technology with claims of reduced platelet 
aggregation and favorable thrombus accumulation profile. The Teleflex catheter is a 
chlorhexidine coated device that claims to be both antithrombogenic and 
antimicrobial.  
 
IRB NUMBER: 2018-379
IRB APPROVAL DATE: 04/30/2019

04.19.2019 V 3.0 
Specific Aim 1: To compare incidence of symptomatic CR-UEVT between the 
AngioDynamics Bioflo midline catheter and the Teleflex Arrowg+ard Blue Advance 
midline catheter.  
  
For Aim 1, we will measure incidence of all symptomatic CR-UEVT inclusive of   
superficial thrombophlebitis (SVT) and deep venous thrombosis (DVT) confirmed by 
upper extremity venous doppler evaluation, to assess whether Arrowg+ard midline 
catheters offer a reduction in the incidence of symptomatic CR-UEVT.                
  
Specific Aim 2: To compare incidence of catheter-related bloodstream infection 
between the AngioDynamics BioFlo midline catheter to the Teleflex Arrowg+ard Blue 
Advance midline catheter.  
  
For Aim 2, we will identify cases of infection per the laboratory confirmed bloodstream 
infection criteria published by the Center for Disease Control (CDC), to assess whether 
Arrowg+ard Blue Advanced midline catheters offer reduction in catheter-related 
bloodstream infection.  
  
Alternatively, for Aim 1 and Aim 2, to further examine the incidence of overall  
complications in the light of the differing catheter dwell times, catheter days data 
(including multiple insertions of midline catheters per patient in the study period) will 
be analyzed.  
  
Specific Aim 3: To compare catheter survival rate data between the AngioDynamics  
BioFlo midline catheter and the Teleflex Arrowg+ard Blue Advance midline catheter.  
  
For Aim 3, an improved survival of Arrowg+ard Blue Advanced midline catheters will 
be evaluated by functionality of catheter for intravenous therapy prior to patient 
discharge.  The event is failure of functionality identified during follow-up assessment 
during hospitalization. Duration of dwell and functional failure of the  catheter will be 
employed to estimate catheter survival.  
  
Study Design   
  
We propose a prospective single-site, parallel, two-arm, randomized investigation to 
assess catheter-related symptomatic UEVT, catheter-related bloodstream infection, 
and  functionality of two single lumen midline catheters: AngioDynamics BioFlo 4 F 
and Teleflex Arrowg+ard Blue Advance 4.5 F. The research protocol was approved  
by the Institutional Review Board of Beaumont Research Institute. Written informed  
consent will be obtained from all participants.  
  
All inpatients 18 years of age and older that require midline catheter placement by  
the bedside vascular access team will be eligible participants. Patients will be excluded 
if: Do not meet inclusion criteria 2. Multiple lumens required 3. Alternative diameter of 
catheter used 4. If already enrolled once prior 5. Withdraw voluntarily from the study 
6. Are receiving oral, intravenous, or subcutaneous treatment dose anticoagulation 
(prophylaxis with anticoagulant is permissible).
IRB NUMBER: 2018-379
IRB APPROVAL DATE: 04/30/2019

04.19.2019 V 3.0 
  
Research staff of Beaumont Health Institute will allocate two midline catheters to 
eligible participants according to a pre-generated randomized list at a 1:1 ratio in block 
randomization to AngioDynamics BioFlo or Teleflex Arrowg+ard Blue Advanced 
midline catheters. Participant enrollment will take place from November  
2018 until patient recruitment is complete. Demographic and health-related 
information will be obtained from electronic medical records during enrolled period at 
William Beaumont Hospital.  
  
  
Practitioner Participation/Training  
  
Advanced Practice Providers within the bedside PICC/Midline service at the Royal  
Oak campus are eligible to place catheters for this study. A cohort of fifteen providers 
are possible volunteers to be trained to place catheters for this study. Placing catheters 
for this study is not required and will be carried out on a strictly voluntary basis. All 
advanced practice providers are credentialed in placing PICCs and midlines by 
institutional policy and have greater than one year of experience in these procedures. 
None of the providers have previous experience with the Teleflex Arrowg+ard Blue 
Advance midline catheter. The clinical team from Teleflex will be expected to develop 
an educational/training pathway for providers to achieve proficiency prior to subject 
recruitment. A possible training/credentialing pathway may consist of: 1 hour didactic 
training followed by phantom training on a vein block and required successful 
placement of 2-4 catheters on real patients.  
  
Initial Assessment   
  
After written informed consent is obtained, investigators will carry out additional 
evaluation at the bedside. The research team will capture and save images of vessel 
depth and vessel diameter in short axis using the Sonosite S1 ultrasound equipment. 
Ultrasound guidance will be used for the initial assessment and procedure. The high 
frequency linear array transducer will be used for all procedures. Inserters will 
evaluate the vessel for valves, thrombosis, trajectory, and collapsibility per routine 
care. If the vein is appropriate for cannulation, the practitioner will continue with  
the procedure. Post-cannulation and post securement, functionality is confirmed  
with blood sampling (10 cc) and flush without resistance.   
  
The research team also will document practitioner details, the vascular access device 
(VAD) used, the time of VAD placement, number of attempts, need for a rescue inserter, 
the vein that was cannulated, depth and diameter of the vein, and the indication for 
VAD placement. An attempt is defined as each time the needle punctures the skin. Data 
will be collected from the electronic medical record and  
includes: age, gender, BMI, vital signs, relevant past medical history. Specific medical 
history of interest includes: 1. VTE 2. Cancer (within past 6 months) 3. Hypercoaguable 
state 4. Current pregnancy/up to 8 weeks postpartum 5. Major surgery/major trauma 
within past 4 weeks 6. Estrogen supplementation 7. Long 
IRB NUMBER: 2018-379
IRB APPROVAL DATE: 04/30/2019

04.19.2019 V 3.0 
travel > 6 hours within past 4 weeks 8. Inflammatory Conditions (IBD, SLE) 9. 
Immobilization >72 hours 10. Other. Indication for catheter placement will also be 
recorded: 1. DIVA 2. Antibiotics  3. Incompatible Medications 4.  Other   
  
 Follow-up Assessment   
  
Investigators will perform a follow-up assessment on all catheters within 24 hours  
of insertion and then daily for the life of the VAD. Generally all follow-up evaluations 
will occur between 8 am and 10 am. At each follow-up interval, the researcher will 
document the time of evaluation and assessment of functionality as well as review the 
patient chart for signs and symptoms of catheter-related bloodstream infection and 
document the presence of localized site infection.  A catheter is functional if the 
investigator is able to withdraw 3-5 ml of blood or if the VAD flushes without 
resistance with 5 mL of saline. Even if the line is actively infusing upon evaluation, the 
investigator will stop the infusion and assess for functionality by drawing blood and 
flushing.  Data specific to blood sampling will be collected daily. If the catheter was 
identified to have failed during follow-up assessment the date and time of  
failure and the reason for failure will be documented. If the catheter failed or was 
removed prior to the follow-up assessment then the VAD failure time and the 
assessment of failure and reason for line removal will be obtained through chart 
review. For all failed catheters, re-insertion attempt data will be tracked through the 
medical record in the nursing section for venous lines and need for reinsertion of  
the midline or escalation to a PICC, or CVC will be noted. If the patient is discharged 
prior to the time of follow-up assessment then the time of discharge will be 
documented and the VAD will be presumed functional until time of discharge unless 
otherwise noted in the chart.  
 
Some patients may leave the hospital with the midline in place for additional 
intravenous therapies. If the patient is discharged with the midline, the research team 
will discuss the infusion plan with the care management team. Patients will also be 
provided detailed contact information of the Vascular Access Team (standard practice) 
at the time of hospital discharge in case any questions or complications arise. If the 
patient develops any concerning signs or symptoms for the venous thromboembolism, 
the Vascular Access Team will instruct the patient to return to the outpatient clinic for 
an evaluation with a member of the Vascular Access Team, schedule an urgent 
appointment with the medical doctor, or check into the Emergency Department for 
further evaluation. The research team will document imaging results from these 
encounters. All patients will receive follow-up phone call assessments by the research 
team. Patient disposition options include: discharge home/residence or to a skilled 
nursing facility or transfer to another hospital. If the patient is discharged home, 
infusion and catheter care occurs via home care or at an infusion center. For patients 
discharged to a skilled nursing facility, catheter care and infusion is managed by 
nursing staff at these centers. These patients will continue to be followed in the post-
hospital setting, specifically to assess for the complication of thrombosis. The research 
staff will follow-up via telephone call with staff managing the infusion within 48 -72 
hours of discharge and weekly including the last day of therapy to inquire about the 
VAD site and function of the catheter and document any complications/results to 
radiographic imaging. Once therapy is completed and the catheter is removed, the 
research team will follow up with the patient or designated legally authorized 
representative/next of kin via phone to inquire about the access site at 30 days post 
IRB NUMBER: 2018-379
IRB APPROVAL DATE: 04/30/2019

04.19.2019 V 3.0 
line removal. All patients will receive the 30 day follow-up phone contact. Patients will 
specifically be asked if they developed redness, swelling, or pain at the catheter 
insertion site and had radiographic evaluation for a blood clot or pulmonary embolism. 
If the patient has a concern, the research team will forward the concern to Dr. Bahl and 
Emily Diloreto for further evaluation per routine.  
 
 
SVT and DVT rates will be calculated based on upper extremity proven diagnosis of 
SVT and/or DVT in symptomatic cases. Researchers will review all study subject 
records in EPIC, the electronic medical records system, and screen enrolled subject 
data for all upper extremity venous Doppler examinations. Radiology interpretations 
will be reviewed for findings consistent with CR-UEVT. This review will occur thirty 
days post patient discharge. Symptoms and rationale for imaging will be documented. 
This information will be obtained by reviewing the order/provider documentation in 
EPIC. If the patient is diagnosed with thrombophlebitis, the location of the thrombus 
will also be documented. 
IRB NUMBER: 2018-379
IRB APPROVAL DATE: 04/30/2019

04.19.2019 V 3.0 
Infection rate will be tracked using confirmed catheter-related blood stream infection 
data from the surveillance team within the epidemiology department. The team 
utilizes the CDC definition of laboratory-confirmed blood-stream infection (LCBSI). See 
Appendix A for LCBSI definitions and pathway for diagnosis.  
 
The medication administration record will be queried for all medications given 
through each catheter. Vesicants that are generally given via central line or considered 
caustic to the vessel will be noted in both groups. Number of doses will be recorded. 
See Appendix B for full list of non-neoplastic vesicants.  We will also collect data on 
patients that received alteplase for occlusion. We will specifically evaluate the 
relationship of alteplase use and how it relates to catheter-related thrombosis, 
catheter-related bloodstream infection, and functionality of catheter.   
  
 
Sample Size and Statistical Analysis   
 
Sample Size: For this randomly allocated, two group experiment, the primary outcome 
was complication profile in terms of thrombophlebitis. Under Aim 1, based on the 
preliminary analysis using approximately 13 months of data at William Beaumont 
Hospital, it suggested the incidence of thrombosis between 12-15% from  
1,200 insertions of AngioDynamics BioFlo midline catheters with the diagnosis of  
symptomatic thrombosis. We established a one-sided Fisher’s exact two- 
proportions test with a type I error α = 0.05. In terms of results from previous study 
[1], sample size was designed to have a power of 80% for detecting a 11% lower in the 
incidence of thrombosis using Teleflex Arrowg+ard Blue Advanced midline catheters. 
Based on these criteria, 212 participants will be randomly allocated to 2 study groups 
(106 per group). This sample size included a 20% buffer to account for potential 
sample loss. For Aim 3, this sample size has a power of 0.85 to detect a hazard ratio of 
1.5 for failure of functionality association with AngioDynamics  
BioFlo midline catheters, based on a log rank test with a 0.05 one-sided significant 
level and median time of midline catheter introduction into a vein of 10 days [1]. All 
above calculations were made using the power software PASS 16.  
 
Statistical Analysis: For Aim 1 and Aim 2, we will use descriptive statistics (frequency, 
percent) to summarize the incidence of complication profile in terms of thrombosis 
and infection between these two groups. For Aim 1, a logistic regression model will be 
built to examine the association between midline catheters and the presence of 
thrombosis, adjusting for participant characteristics. The odds ratio  
(OR) associated midline catheters on thrombosis will be estimated. For Aim 2, we  
will further create cases of bloodstream infection per 1000 catheter-days, 
IRB NUMBER: 2018-379
IRB APPROVAL DATE: 04/30/2019

04.19.2019 V 3.0 
accounting for catheter dwell times. A Poisson regression model will be employed to 
assess the relative risk (RR) of AngioDynamics BioFlo and Teleflex Arrowg+ard Blue 
Advanced midline catheters on the presence of infection within any observed catheter 
dwell time, adjusting for participant characteristics. P-values of less than  
0.05 will be considered statistically significant. In addition, for Aim 3, we will create  
data with the first episode of function failure of catheter on IV treatment. To adjust for 
any difference in participant characteristics, Cox proportional hazard models will be 
built. We will evaluate the proportional hazard assumption for each fixed covariate of 
participant characteristics by the log baseline cumulative hazard plot,  
Schonfeld residual plot, and the interaction between the covariate and function time of 
midline catheters. If the assumption is violated, a stratified Cox proportional hazard 
model will be built. Hazard ratio (HR) of two midline catheters for function  
failure will be reported.   
 
 
 
 
Site   
  
William Beaumont Hospital, Royal Oak (RO) campus is a 1,100 bed major academic 
and referral center with Level 1 adult trauma and Level 2 pediatric trauma status. A 
major teaching facility, Beaumont, Royal Oak has 55 residency and fellowship 
programs with 454 residents and fellows. Beaumont is the exclusive clinical partner 
for the Oakland University William Beaumont School of Medicine. The Beaumont 
Research Institute was established more than 30 year ago at Royal Oak and offers 
research support services to clinical investigators.  
  
 
Primary Investigator   
 
I have specialized training in emergency ultrasound and completed fellowship in the 
field in 2008. Since that time, I have served as Director of Emergency Ultrasound for 
Emergency Medicine. I also serve as the Medical Director for the hospital vascular 
access team. Additionally, I have a specific interest in ultrasound-guided vascular 
access with several peer-reviewed publications and national presentations in this  
area.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: 2018-379
IRB APPROVAL DATE: 04/30/2019

04.19.2019 V 3.0 
References:  
   
Lisova K et al. The incidence of symptomatic upper limb venous thrombosis associated 
with midline catheter: Prospective observation. Journal of Vascular Access. 2018. Epub 
ahead of print.  
  
Klungboonkrong et al. Predictors of deep vein thrombosis associated with midline 
venous catheter in hospitalized patients: a single-institute experience. Journal of 
Vascular and Interventional Radiology 2015. 26(2) S146.  
 
Gorski L et al. Development of an evidence-based list of noncytotoxic vesicant  
medications and solutions. J Infus Nurs. 2017;40(1)26-40  
 
National Healthcare Safety Network (NHSN) Patient Safety Component Manual. Center 
for Disease Control. Chapter 4. 2018  
 
https://www.cdc.gov/nhsn/pdfs/pscmanual/pcsmanual_current.pdf  
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
  
IRB NUMBER: 2018-379
IRB APPROVAL DATE: 04/30/2019

04.19.2019 V 3.0 
Appendix A 
 
 
IRB NUMBER: 2018-379
IRB APPROVAL DATE: 04/30/2019

04.19.2019 V 3.0 
IRB NUMBER: 2018-379
IRB APPROVAL DATE: 04/30/2019

04.19.2019 V 3.0 
Appendix B  
  
IRB NUMBER: 2018-379
IRB APPROVAL DATE: 04/30/2019