Assessment of Lavare Cycle Implementation Among Patients Following HeartWare Left Ventricular Assist Device Implantation: A Prospective Randomized Controlled Pilot Study
Phase: NA
Conditions: Thromboembolism, Hemolysis, Stroke
Sponsor: Vanderbilt University Medical Center

Lavare Cycle in Patients Receiving HeartWare Left Ventricular Assist Device
NCT04199793
August 31, 2020

Protocol Version #: 2
Protocol Date: August 31, 2020 
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Protocol Title: Assessment of LAVARETM cycle implementation among 
patients following HeartWare left ventricular assist device implantation: A 
prospective randomized controlled pilot study 
Sponsor:  
Sandip Zalawadiya, MD 
Vanderbilt University Medical Center 
1215 21st Ave., South, MCE, Suite 5209 
Nashville, TN 37232 
Phone:  615-322-2318 
Email:  Sandip.zalawadiya@vumc.org 
NCT:  NCT04199793 

Protocol Version #: 2
Protocol Date: August 31, 2020 
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Table of Contents: 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Inclusion/Exclusion Criteria 
4.0 
Enrollment/Randomization 
5.0 
Study Procedures 
6.0 
Risks of Investigational Agents/Devices (side effects) 
7.0 
Reporting of Adverse Events or Unanticipated Problems involving 
Risk to Participants or Others / Protocol Deviations 
8.0 
Monitoring Plan 
9.0 
Data Management 
10.0 Study Withdrawal/Discontinuation 
11.0 Statistical Considerations 
12.0 Privacy/Confidentiality Issues 
13.0 Follow-up and Record Retention 

 
 
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1.0 
Background 
 
Left ventricular assist device (LVAD) patients remain at risk for pump thrombus 
and thromboembolic events through multiple mechanisms. The HeartWare® 
Ventricular Assist System (HVAD®, HeartWare Inc., Framingham, MA, USA) 
includes a novel speed modulation feature called Lavare™ cycle. It consists of 3 
phases: phase 1 – a 200 rpm decrease from baseline speed for 2 seconds, 
phase 2 – a 100 rpm increase from baseline for 1 second and phase 3 – return of 
speed to baseline; this cycle repeats itself once every minute. The LavareTM 
Cycle is aimed to promote washing of left ventricle to decrease blood stasis and 
subsequent risk of thrombus formation, ingestion and/or expulsion. In a post-hoc 
analysis of ReVOLVE registry, which includes 248 patients implanted with the 
HVAD following Conformité Européenne Mark in nine centers in Europe and 
Australia, no adverse impact on survival was observed with Lavare™ cycle. 
Additionally, lower risk of stroke, sepsis and right heart failure was observed 
among those with Lavare™ cycle in the abovementioned study. However, no 
prior study has prospectively evaluated the impact of Lavare™ cycle on patient 
outcomes in a randomized fashion. 
 
 
2.0 
Rationale and Specific Aims 
 
Primary objective: To assess feasibility of conducting a future larger trial that 
investigates whether, among patients receiving HeartWare LVAD, Lavare cycle 
results in lower risk of pump-related complications.  
 
Outcomes of interest: 
 
1. Primary 
a. Composite endpoint of total ischemic events, thrombotic or 
thromboembolic events/Pump Hemolysis/Pump Thrombosis/ Pump 
exchange 
2. Secondary 
a. All-cause mortality 
b. Survival to transplantation  
c. LVAD related complications 
i. Stroke 
ii. Transient ischemic attack 
iii. Mucocutaneous bleeding 
iv. Right ventricular failure 
v. Infection: LVAD system related  
vi. Moderate or Severe aortic insufficiency 
d. Changes in biomarkers 

 
 
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e. Re-hospitalizations 
f. Echocardiographic changes in myocardial structure and function   
g. Functional status   
i. NYHA functional class 
ii. 6-minute walk test 
h. Quality of life   
i. KCCQ  
 
Design:  This is a pilot 2-arm prospective randomized controlled trial. Both 
treatment strategies, Lavare cycle on and off, are consistent with standard of 
care.   
 
Study Population: This trial will enroll patients undergoing their first HeartWare 
LVAD implantation as well as those chronically supported with HeartWare LVAD. 
Clinical data will be collected at baseline and at regular post-enrollment follow-up 
until trial ends. For chronically supported patients, minimum support duration of 
3-months will be required.    
 
Duration of follow-up: 180-days; follow-up visits will be logged at 30-days, 90-
days and 180-days. 
 
 
3.0 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria: 
1. Age ≥18 years  
2. Approved for or supported with HeartWare durable left ventricular assist 
device 
3. Capable of giving informed consent 
 
Exclusion Criteria: 
1. New implantation:  
a. Age <18 years 
b. INTERMACS profile 1 at the time of implantation 
c. Presence of intra-cardiac thrombus  
d. History of thromboembolic event within previous 3 months of 
enrollment 
e. Chronic Kidney disease stage 4 or 5, or on any form of dialysis 
(eGFR must be consistently documented <30 for 30 days) 
 
 

 
 
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2. Previous HeartWare implant with active support: 
a. Support duration <3 months 
b. History of prior LVAD pump exchange 
c. History of LVAD pump hemolysis or thrombosis as defined by 
INTERMACS criteria 
d. History of stroke or transient ischemic event within previous 3 
months of enrollment 
e. History of post-LVAD severe right ventricular failure as defined by 
INTERMACS criteria within previous 3 months of enrollment 
f. History of pump-related infection treated within previous 3 months 
of enrollment or those on chronic antibiotics suppressive therapy for 
pump related infection 
g. History of post-LVAD intra-cardiac or arterial thrombus or 
thromboembolic event within previous 3 months of enrollment 
h. INR <2 within previous 30-days from the date of enrollment 
i. Aspirin dose <325 mg/day 
j. LDH levels ≥ 3 times the upper normal limit in previous 3 months 
k. Chronic kidney disease stage 4 or5, or any form of dialysis (eGFR must 
be consistently documented <30 for 30 days).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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4.0 
Enrollment/Randomization 
Number of subjects: N=100; 50 patients undergoing their first HeartWare LVAD 
implantation and 50 patients with chronic HeartWare LVAD support will be 
included.  This multi-center study will be conducted at up to 4 sites.   
 
 
 
 
 
 
Procedures for randomization 
Using REDCap, participants will be randomly assigned in a 1:1 ratio.  
Participants will receive a randomization number.  The randomization number 
identifies the participant for all procedures occurring after randomization.  Once a 
randomization number is assigned to a participant, it cannot be re-assigned to 
another participant. 
 
There are 2 arms:  
1) LavareTM Cycle - On  
      OR     
2) LavareTM Cycle – Off 
 
 
 
 
 

 
 
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5.0 
Study Procedures 
Screening Visit: Visit 1 (prior to new LVAD implantation for New Implants and at 
the time of consent for Previous Implants) 
• Informed Consent 
• Demographics  
• Review of Medical History 
• Blood sampling for biomarkers (approximately 20mLs) 
• KCCQ questionnaire 
• 6-minute walk test (Can be deferred if patient is on inotropic or MCSD 
support) 
• NYHA functional class assessment defined as follows: 
1. Class I - No symptoms and no limitation in ordinary physical activity, e.g. shortness of 
breath when walking, climbing stairs etc. 
2. Class II - Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity. 
3. Class III - Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g. walking short distances (20-100 m). Comfortable only at rest. 
4. Class IV - Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 
5. No NYHA class listed or unable to determine. 
 
 
Data will be collected on the following tests that were likely performed as part of 
the standard LVAD evaluation.  The participant will not be required to undergo 
these tests for the purposes of this trial: 
• Echocardiogram  
• Right heart catheterization or Swan-Ganz Catheterization 
 
The Screening Visit and the Randomization Visit can occur on the same day, if 
all study criteria have been met.  
 
The following will happen: 
 
• Randomization: Randomly assigned by REDCap to one of the two groups:  
1LavareTM Cycle - On  
      OR     
2 LavareTM Cycle – Off 
• Study intervention: Changes in LavareTM Cycle will be made by the study staff 
according to the group you are assigned.  
• LVAD data: standard parameters displayed on the screen upon routine 
interrogation of the LVAD will be collected.  
 
 
 
 
 

 
 
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Visit 2: Day 30 (+/- 14 Days) 
• Review of Medical History 
• Blood sampling for biomarkers 
• 6-minute walk test (Can be deferred if patient is on inotropic or MCSD 
support) 
• NYHA functional class assessment defined as follows: 
1. Class I - No symptoms and no limitation in ordinary physical activity, e.g. shortness of 
breath when walking, climbing stairs etc. 
2. Class II - Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity. 
3. Class III - Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g. walking short distances (20-100 m). Comfortable only at rest. 
4. Class IV - Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 
5. No NYHA class listed or unable to determine. 
 
• LVAD data: Standard parameters displayed on the screen upon routine 
interrogation of the LVAD will be collected. We will also ask Medtronic to 
provide trends in the LVAD parameters over past 30 days utilizing log-files 
that are stored in their data bank. Please send log-files to Medtronic with a 
title: Lavare Trial Log-Files for appropriate storage and analysis.   
• Adverse Events  
 
Data will be collected on the following tests that were likely performed as part of 
the standard LVAD evaluation.  The participant will not be required to undergo 
these tests for the purposes of this trial: 
• Echocardiogram 
• Right heart catheterization or Swan-Ganz Catheterization  
 
 
Visit 3: Day 90 (+/- 14 Days)  
• Review of Medical History 
• Blood sampling for biomarkers (approximately 20 mLs) 
• KCCQ questionnaire 
• 6-minute walk test (Can be deferred if patient is on inotropic or MCSD 
support) 
• NYHA functional class assessment defined as follows: 
1. Class I - No symptoms and no limitation in ordinary physical activity, e.g. shortness of 
breath when walking, climbing stairs etc. 
2. Class II - Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity. 
3. Class III - Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g. walking short distances (20-100 m). Comfortable only at rest. 
4. Class IV - Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 
5. No NYHA class listed or unable to determine. 
 

 
 
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• LVAD data: Standard parameters displayed on the screen upon routine 
interrogation of the LVAD will be collected. We will also ask Medtronic to 
provide trends in the LVAD parameters over past 30 days utilizing log-files 
that are stored in their data bank. Please send log-files to Medtronic with a 
title: Lavare Trial Log-Files for appropriate storage and analysis.  
• Adverse events 
 
Data will be collected on the following tests that were likely performed as part of 
the standard LVAD evaluation.  The participant will not be required to undergo 
these tests for the purposes of this trial: 
• Echocardiogram 
• Right heart catheterization or Swan-Ganz Catheterization  
 
 
Visit 4: Day 180 (+/- 30 Days)  
• Review of Medical History 
• Blood sampling for biomarkers (approximately 20 mLs) 
• KCCQ questionnaire 
• 6-minute walk test (Can be deferred if patient is on inotropic or MCSD 
support) 
• NYHA functional class assessment defined as follows:  
1. Class I - No symptoms and no limitation in ordinary physical activity, e.g. shortness of 
breath when walking, climbing stairs etc. 
2. Class II - Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity. 
3. Class III - Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g. walking short distances (20-100 m). Comfortable only at rest. 
4. Class IV - Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 
5. No NYHA class listed or unable to determine. 
 
• LVAD data: Standard parameters displayed on the screen upon routine 
interrogation of the LVAD will be collected. We will also ask Medtronic to 
provide trends in the LVAD parameters over past 30 days utilizing log-files 
that are stored in their data bank. Please send log-files to Medtronic with a 
title: Lavare Trial Log-Files for appropriate storage and analysis.  
• Adverse events 
 
Data will be collected on the following tests that were likely performed as part of 
the standard LVAD evaluation.  The participant will not be required to undergo 
these tests for the purposes of this trial: 
• Echocardiogram 
• Right heart catheterization or Swan-Ganz Catheterization  
 

 
 
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Schedule of Events 
 
 
At the time of 
randomization 
30-
day 
Visit 
(+/-14 
days) 
90-
day 
Visit 
(+/-
14 
days) 
180- 
day 
Visit 
(+/- 
30 
days) 
Demographics 
Age, gender, race 
x 
 
 
 
Comorbidities 
Etiology of heart failure, Atrial arrhythmia, 
Ventricular arrhythmia, Hypertension, 
Diabetes, Hyperlipidemia, Cerebrovascular 
event 
Peripheral arterial disease, Cancer, 
Chronic kidney disease and its stage, 
Dialysis, COPD, Obesity, Presence of 
pacemakers/ ICD (BiV/ dual/ single), Prior 
cardiac surgery, History of sternotomy, 
Number of sternotomies, History of 
hypercoagulable disease, History of prior 
DVT, History of prior PE, History of HIT 
x 
 
 
 
Laboratory values 
Basic chemistry panel, Complete 
blood count with differential, Liver 
function test, INR, LDH, Urine analysis 
x 
x 
x 
x 
Biomarkers 
NT-pro-BNP, ST-2, GDF-15, Galactin-
3, Hs-CRP, TNF-alpha, IL-6, NGAL, 
KIM-1, TIMP-2, IGFBP-7, Ang-2, Ang-
1, Soluble Tie-2, VEGF, Thrombin, 
vWF,   
x 
x 
x 
x 
Functional 
parameters  
6-minute walk test, NYHA functional 
class 
x 
x 
x 
x 
Echocardiogram 
 
x 
x 
x 
x 
Review of Medical 
History 
 
X 
X 
X 
X 
Pulmonary artery 
catheter data  
 
x 
X 
X 
X 
VAD specific 
variables 
Implantation indication (DT/BTT), Implant 
Technique (sternotomy/ thoracotomy), 
INTERMACS class, Inotropes (presence, 
types and duration), Temporary support 
device (presence, type and duration), 
diuretics (types, doses) 
x 
 
 
 
VAD parameters  
(power, PI, flow, speed, hematocrit), 
log-files 
x 
x 
x 
x 
Quality of life 
KCCQ score 
x 
 
x 
x 
Post Implant VAD 
related AE’s 
Arterial and venous thromboembolic 
events, neurological dysfunction, bleeding, 
pump hemolysis/thrombosis/exchange, 
pump malfunction, myocardial infarction, 
infection, right heart failure, aortic 
regurgitation, re-hospitalizations, cardiac 
arrhythmia, hypertension, major renal, 
respiratory or hepatic dysfunction and 
other major adverse events. 
 
 x 
x 
x 

 
 
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6.0 
  Risks                                                                                                                  
We do not have data to detail potential risks and their chances arising from 
participation in this study. This study aims at understanding this very question.  
 
Hypothetically, conditions that lead to decreased blood volume in the left side of 
the heart (such as dehydration, excessive bleeding, right HF, fluid around the 
heart, etcetera) can increase the chances of suction events or low flow alarms 
with implementation of the LavareTM Cycle.  
1. Suction event occurs when decreased blood volume in the left side of 
heart causes part of left heart wall sucked over the LVAD pump’s 
inflow cannula; the result of this event is reduction in LVAD pump 
speed to reduce the suction pressure and free up the sucked over left 
heart wall.    
2.  Low flow alarm is triggered when average flow through the pump drops 
below the set limit.   
 
  
7.0 
Reporting of Adverse Events or Unanticipated Problems          
involving Risk to Participants or Others 
 
Definition of Adverse Event (AE) 
An AE is any untoward medical occurrence (e.g., noxious or pathological 
changes) in a subject compared with pre-existing conditions that may occur 
during any part of the clinical study. An AE is defined as being independent of 
assumption of any causality (e.g., primary or concomitant disease or study 
design).  AEs are evaluated by the Investigator and maintained in the research 
records at the site.  
 
Definition of Serious Adverse Event (SAE) 
An SAE is an AE occurring during any study phase (i.e., run-in, treatment, follow-
up), that fulfills one or more of the following criteria:  
• Results in death  
• Is immediately life-threatening  
• Requires in-patient hospitalization or prolongation of existing 
hospitalization  
• Results in persistent or significant disability or incapacity  
• Is a congenital abnormality or birth defect  
• Is an important medical event that may jeopardize the patient or may 
require medical intervention to prevent one of the outcomes listed above.  
 
Procedures for Reporting Adverse Events (AEs) 
All SAEs are be reported to the Vanderbilt University Medical Center (VUMC) 
Clinical Research Enterprise, whether or not considered causally is related. The 

 
 
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site investigator is responsible for informing their local IRB as per local 
requirements.  
 
Investigators and other center personnel must inform appropriate Clinical 
Research Enterprise representatives via REDCap of any SAE that occurs in the 
course of the study within 1 day (i.e., immediately but no later than the end of the 
next business day) of when he or she becomes aware of it. Follow-up information 
on SAEs must also be reported by the Investigator within the same time frame.  
 
An automated email alert will be sent to the designated Clinical Research 
Enterprise representative, when the page with SAE information is saved in 
REDCap by the Investigators or other site personnel. If REDCap is not available, 
then the Investigator or other study site personnel reports by fax an SAE to the 
appropriate Clinical Research Enterprise representative. A paper back- up SAE 
report is used for this purpose. The same reporting time frames still apply. The 
investigator is responsible for completing the eCRF as soon as the system 
becomes available again.  
 
The Clinical Research Enterprise representative will work with the Investigator to 
compile all the necessary information and ensure that all the necessary 
information is provided to Vanderbilt University Medical Center within one 
calendar day of initial receipt for fatal and life-threatening events and within five 
calendar days of initial receipt for all other SAEs. 
 
Reporting of serious adverse events to the FDA 
The Sponsor will inform the regulatory authorities of any serious or unexpected 
adverse events that occur in accordance with the reporting obligations of 21 CFR 
312.32.  It is the responsibility of the investigator to compile all necessary 
information and ensure that the FDA receives a report according to the FDA 
reporting requirement timelines. 
 
 
Protocol Deviations 
Investigators are required to adhere to the protocol, applicable federal (national) 
or state/local laws and regulations, and any conditions required by the 
IRB/Medical Ethics Committee (MEC), or applicable regulatory authorities. 
 
A protocol deviation is used to describe situations in which the clinical protocol 
was not followed. All deviations from the protocol must be reported to Vanderbilt 
study staff per 21 CFR §812.150. In addition, all deviations must be reported to 
the reviewing IRB per the IRB’s reporting requirements. The investigator shall 
state any mitigating circumstances or clinical reasoning that resulted in a protocol 
deviation. Examples of deviations would be required testing not done or an 
intervening medical condition preventing return for follow-up during the specified 
window. 

 
 
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The investigator must notify Vanderbilt study staff and the reviewing IRB of any 
deviation from the investigational plan to protect the life or physical well-being of 
a patient in an emergency as soon as possible, but not later than 5 working days 
after the deviation has occurred, or no later than 5 working days after the 
investigator becomes aware of the deviation. 
 
 
8.0 
Monitoring of the study 
During the study, a Clinical Research Enterprise representative will conduct 
regular monitoring visits with the study site. The monitoring visits may be 
conducted by phone, e-mail or by in-person visits to the study site. The 
monitoring visits will:  
 
• Provide information and support to the investigator(s)  
• Confirm that facilities remain acceptable  
• Confirm that the investigational team is adhering to the protocol, that data 
are being accurately and timely recorded in the eCRF.  
• Perform source data verification (a comparison of the data in the eCRF 
with the patient’s medical records at the hospital or practice, and other 
records relevant to the study) including verification of informed consent of 
participating patients.  
 
The Clinical Research Enterprise representative will be available between visits if 
the investigator(s) or other study site personnel need information and advice 
about the study conduct. 
 
 
9.0  
Data Management  
Data management will be performed by the Clinical Research Enterprise staff. 
Data will be entered into REDCap, a web-based data capture system at the study 
site. Trained site staff will be responsible for entering data on the observations, 
tests and assessments specified in the protocol into REDCap. Data entered in 
the REDCap will be saved to a central database and changes tracked to provide 
an audit trail. The data will then be source data verified, reviewed/queried and 
updated as needed. The Principal Investigator is responsible for electronically 
signing the eCRF. Data queries will be issued for inconsistent, improbable or 
missing data. All entries to the study database will be available in an audit trail. 
The data will be frozen and then locked to prevent further editing. When all data 
have been coded, validated, signed, and locked, a clean file will be declared. Any 
treatment revealing data may thereafter be added and the final database will be 
locked. A copy of the eCRF will be archived at the study site when the study has 
been locked.  
 
 

 
 
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Source data 
The Clinical Trial Agreement (CTA) will specify the location of source data. 
Access to source documents and source data is essential to inspection and 
review of clinical studies by the Food and Drug Administration (FDA). 
 
Recording of data 
The REDCap Web-Based Data Capture system will be used for data collection 
and query handling. The site Principal Investigator will ensure that data are 
recorded in the electronic Case Report Forms (eCRF) and will ensure the 
accuracy, completeness, and timeliness of the data recorded and of the provision 
of answers to data queries according to the Clinical Trial Agreement.  
 
Data will be entered in the eCRF by trained personnel using the REDCap 
system. When data have been entered, reviewed, edited, and source data 
verification has been performed, as appropriate, by a VUMC Clinical Research 
Enterprise representative, the data will be frozen to prevent further editing. The 
site Principal Investigator will be notified to sign the eCRF electronically. A copy 
of the eCRF data will be archived at the study site. 
 
 
10.0 Study Withdrawal/Discontinuation 
Participants may withdraw consent at any time for any reason or be dropped 
from the trial at the discretion of the investigator should any untoward effect 
occur. In addition, a subject may be withdrawn by the investigator or the Sponsor 
if enrollment into the trial is inappropriate, the trial plan is violated, or for 
administrative and/or other safety reasons. 
 
 
11. 0 Statistical analysis 
Statistical analysis will be performed using software STATA version 13 
(StataCorp, College Station, TX).  Baseline characteristics will be compared 
using Wilcoxon-Rank Sum test for continuous variables and Fisher’s exact test 
for categorical variables. Multivariable regression analyses will be performed to 
assess for risk of primary and secondary outcomes with Lavare cycle on and off. 
Changes in laboratory parameters, echocardiographic measures, functional 
status and quality of life will be assessed using multivariable regression 
analyses. Statistical significance will be defined as p<0.05.  
 
 
12.0      Privacy/Confidentiality Issues 
All records and other information about subjects participating in the study will be 
treated as confidential. 
 
The investigator agrees that the Sponsor (or Sponsor representative), 

 
 
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IRB, or regulatory authority representatives may consult and/or copy trial 
documents in order to verify worksheet/case report form data. By signing the 
consent form, the subject agrees to this process. If trial documents will be 
photocopied during the process of verifying worksheet/case report form 
information, the subject will be identified by unique code only; full names/initials 
will be masked prior to transmission to the Sponsor. 
 
The investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.  Data generated by this trial will be considered confidential by the 
investigator. 
 
Information furnished to the investigator by the Sponsor will be maintained in 
confidence, and such information will be divulged to the institutional review 
board, ethics review committee (IRB/ERC); affiliated institution and employees, 
only under an appropriate understanding of confidentiality.  
 
 
13.0  Follow-up and Record Retention 
Duration of follow-up: 180-days; follow-up visits will be logged at 30-days, 90-
days and 180-days.  
 
FDA and ICH-GCP guidelines require that an Investigator retain subject 
identification codes, subject files, and source data for the maximum period of 
time permitted by the hospital, institution, or private practice, but not less than 2 
years. 
 
The investigator will follow the principles outlined in the Clinical Trial Agreement.