BIOCARDIA, INC

Randomized Controlled Pivotal Trial of Autologous Bone Marrow

Mononuclear Cells Using the CardiAMP™ Cell Therapy System in
Patients with Post Myocardial Infarction Heart Failure

IPv10-January 13, 2021

CardiAMP™ Cell Therapy for

Heart Failure Trial

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THE CARDIAMP TRIAL
BioCardia’s Study Team
Clinical Research Associates (CRAs)
• Vicki Duffy
• Monique Harris Field Engineering / Procedure Support Staff
• Michelle McVay • Larry Lobacz
• Ken Manley
• Michelle McVay

Data Monitoring / In House Management

• CRO’s DM Unit
• Divya Tuppad
• Annette Iglecia
Medical Monitoring for Study
• Tami Shipman
• CRO’s Safety Unit
• Debby Holmes-Higgin
• Suji Shetty, MBBS
• Hans-Peter Stoll, MD

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Agenda
§ Background
§ Intramyocardial Autologous Bone Marrow Mononuclear Cell (ABM MNC) Therapy
§ Why the CardiAMP™ Cell Therapy Trial?
§ Investigational Devices - CardiAMP™ Cell Therapy System
— Helix ™ Transendocardial Delivery Catheter
— CardiAMP Cell Separator ™
§ Study Design, Eligibility Criteria, Overview of Study Visits
§ Good Clinical Practice, Investigator and Sponsor Responsibilities
§ Study Blinding Plan
§ Protocol Review
§ Patient Screening / Baseline
§ Six-Minute Walk Test (6MWT)
§ Core Labs
§ Study Procedure, Discharge, Follow-Up, Cross-Over
• Device Accountability
• Safety and Reporting Requirements
• Study Binders and Administrative Items
• Questions and Wrap-up
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 Background

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 Intramyocardial Autologous Bone Marrow Mononuclear
Cell Therapy
q Bone marrow harbors a heterogenous mononuclear cell population
q committed cell populations (endothelial progenitor cells)
q uncommitted hematopoietic progenitor & stem cells, mesenchymal stromal/stem cells and lymphoblasts
q Shown to promote many beneficial effects in ischemic cardiomyopathy
q Believed general mechanism of action is release of proteins (microRNAs, cytokines)

Dzau, VJ et al. (2011); J MolCell Cardiol. 50(2): 280-289.

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 Intramyocardial Autologous Bone Marrow
Mononuclear Cell Therapy
Bone marrow cells support enhancement of microvascular function
§ Preclinical evidence supports
this is achieved via:
1. reduced inflammation
2. reduced oxidative stress
3. reduced cell apoptosis
4. increased angiogenesis
5. limiting reactive fibrosis
and adverse remodeling
§ Autologous bone marrow
mononuclear cells (ABM
MNC) home to heart in injury Behfar, A. et al. (2014) Nat. Rev. Cardiol. 11: 232–246

§ ABM MNC have important cell populations (CD34+, mesenchymal stem cells (MSCs))
that have each shown benefit in preclinical/clinical studies for treating the heart.
§ Cells do not turn into heart cells; this underlies clinical safety as new heart cells have a
propensity to trigger life threatening arrhythmias.
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Why the CardiAMP (ABM MNC) Cell Therapy Trial?
§ Significant evidence of clinical benefit across
many studies1.
§ Meta-analysis of 1,255 patients (23 studies)
showed evidence of reduced incidence of
mortality and reduced hospitalizations, along
with improved LVEF and quality of life with
autologous cell therapy.
§ Current Phase III trial builds on previous work, including Phase II experience (TAC HFT)
of ABM MNC with enhanced patient selection, cell processing, delivery, and dosing2.
Efficacy Active Placebo Treat. Favors P-value
Endpoints (n=20) (n=10) Difference Active Group
(Mean) (Mean)
6 minute walk (meters) +14.3 -42.0 +56.3 ü 0.049
MLwHF questionnaire -7.7 +9.7 -17.4 ü 0.038

LV End Systolic Volume (ml) +3.2 +47.2 -44 ü 0.129 NS

LV Ejection Fraction (%) +0.97 -2.38 +3.35 ü 0.252 NS

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Phase III Roll-in Cohort: Month 12 Results

Change in Wall Motion Score

0
Improvement in Quality of Life Self
Assessment (MLHFQ) Versus Baseline -2 -3.0
13
Points Improvement

14
-4
12 10 10 -5.9
10
8
-6
6 5
4
-8
2
0 -10
3 Months 6 Months 9 Months 12 Months Baseline 6 Months 12 Months
Note: Change in Akinetic Wall Segments similar
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Evidence from Past Studies for Successful Phase III
Key factors differentiating Phase III study from previous work

Cell Analysis Screening Criterion

v Subjects must meet a proprietary cell
marker evaluation criterion
v Increased cell markers such as CD34+,
MSCs have been found to be
associated with better clinical
response
Point of Care Treatment Approach
v Same day collection of cells for study
treatment
v Cell processing in Cath/EP lab
v ~15 minutes
Cell Delivery Method
v Catheter tip (helical design) promotes
optimized delivery of therapy into the
myocardium

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CardiAMP Cell Therapy System

Cell
Separator Morph Guide
Catheter

Helix
Transendocardial
Therapy Delivery
Catheter

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Study Design, Eligibility, Overview of
Study Visits

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Study Design
• Multi-center prospective, randomized, double-blind (RCT) trial to
evaluate autologous bone marrow mononuclear cell (ABM MNC)
therapy delivered using the CardiAMP Cell Therapy System in subjects
with ischemic heart failure and left ventricular systolic dysfunction

• 260 subjects enrolled at up to 40 centers in the US and Canada

• Subjects randomized in 3:2 ratio:

• Treatment group – left heart ventriculography and receive ABM MNC
• Control group – left heart ventriculography but receive no ABM MNC

Follow-Up
• Blinded (subject and assessment team) through 24 months
• At 24 months, control arm subjects may elect to cross-over and
receive the study treatment
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Primary Outcome Measure
• Composite measure assessed using a 3-tiered Finkelstein-
Schoenfeld (FS) hierarchical analysis for the Month 12 visit

• The tiers, in chronological order, are:

1) All cause death, including cardiac death equivalents such as heart
transplant or left ventricular assist device (LVAD) placement,
ordered by time to event
2) Non-fatal MACCE (heart failure hospitalization, stroke or MI),
excluding those deemed procedure-related and occurring within
the first 7 days, ordered by time to event
3) Change for 6MWD from Baseline to Month 12

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Secondary Outcome Measures
Secondary Hierarchical Endpoints (statistically evaluated in order)
1. Overall survival at 12 months (non-inferiority)
2. Time to first MACE (non-inferiority)
3. Change in quality of life as measured by Minnesota Living with Heart
Failure (MLwHF) questionnaire at 12 months (superiority)
4. Time to first MACE (superiority)
5. Overall survival at 12 months (superiority)

Other Secondary Outcomes

• Tx-emergent SAEs at 30 days • Freedom from SAEs
• Heart failure death • NYHA functional class
• Heart failure hospitalization • 6MWD, repeated measures
• All-cause hospitalizations • Echocardiography measures
• Overall survival at 24 months • Technical success defined as successful
• Days alive out of hospital delivery of ABM MNC at study procedure
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Inclusion Criteria (Slide 1 of 2)
1. >21 and <90 years of age

2. NYHA Class II or III

3. Ejection fraction 20%-40% measured by transthoracic 2-D echocardiogram

• Eligibility determined by echo core lab
• Not in the setting of a recent ischemic event ( >6 months)

4. A diagnosis of chronic ischemic left ventricular dysfunction (HF) secondary to myocardial

infarction (MI) >6 months before screening, documented by clinical history, defined by:
• Elevation of cardiac enzymes and/or ECG changes consistent with MI
• Treated with thrombolytic therapy, CABG, or percutaneous coronary revascularization

5. Able to complete two to three 6-minute walk distance (6MWD) tests with distance between
100-450m
• Third test required if there is >10% difference between 6MWD-1 and 6MWD-2

6. Screening bone marrow cell analysis score of 3

• Proprietary score with screening sample analysis performed by Core Lab

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Inclusion Criteria (2 of 2)
7. 3-months prior to randomization, on stable guideline-directed medical therapy (GDMT)
i. A transition between ACE inhibitors and ARBs is allowed within 3 months of
randomization
ii. Changes not exceeding halving or doubling the following medications:
• Angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor
blockers (ARB) for patients with ACE inhibitor intolerance or
nitrate/hydralazine at the investigator’s discretion
• Beta blockers – If treated with beta blockers, they should be specifically
approved for treating heart failure, except for those subjects with prior
intolerance or if justified by their cardiologist
• Diuretics, aldosterone inhibitors, ARNI, SGL2I
iii. When applicable, for guideline directed device- based therapies, the CRT device
must be placed > 3 months prior to randomization:
• If subject is eligible to receive a CRT device within 6 months of
randomization, the patient should not be enrolled in the study

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 Exclusion Criteria (Slide 1 of 3)
Cardiovascular:
1. Coronary artery revascularization within 3 months of randomization
2. Acute coronary syndrome within 3 months of randomization
3. Documented in patient’s medical records or detected by echo core lab:
a. Left ventricular thrombus
b. Severe mitral or tricuspid regurgitation
c. Aortic stenosis graded as > 2+ or orifice area < 1.5 cm2
d. Aortic insufficiency graded as > 2+
4. Mechanical aortic valve or heart constrictive device
5. Screening visit 24 hr ambulatory heart monitor detects life-threatening ventricular arrhythmias:
a. Non-sustained ventricular tachycardia (NSVT) > 20 consecutive beats
b. Sustained ventricular tachycardia (SVT) or short run > 20 consecutive beats
c. Patient has a pacemaker or ICD:
i. A copy of the device’s interrogation may be used lieu of the 24 hr ambulatory heart monitor if it
captures and identifies atrial and ventricular arrhythmias
6. 12- lead ECG: complete heart block or QTc interval > 550 ms (Intrinsic Rhythm)
7. Not a candidate for cardiac catheterization
8. Peripheral artery disease of the aorta or iliac/femoral system that would preclude patient safety during the
study procedure; such as stenotic/ aneurysmal/embolic disease or symptoms of claudication
9. ICD delivers therapy within 60 days of the study procedure
10. Medical condition that may limit the patient's ability to perform the 6MWD test:
a. Bronchospastic lung disease (such as asthma, COPD), PAD, orthopedic, muscular, neurological conditions
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Exclusion Criteria (2 of 3)
Labs: Screening visit and Day-0
13. Baseline glomerular filtration rate < 30 ml / min / 1.73m2
14. Hematological abnormality: (Without explanation)
a. Hematocrit < 30%,
b. White blood cell < 4,500/µl
c. Platelet < 100,000/µl
15. Liver dysfunction with enzymes (AST and ALT) > three times the ULN
16. INR ≥ 1.5 related to bleeding or clotting disorders (not due to a reversible cause i.e.,
Coumadin)
• Patients who are unable to discontinue Coumadin prior to the procedure will not be
eligible to participate in the study

Labs: Screening visit

17. Serum positive for hepatitis B/C and/or HIV
• Unless patient is a carrier for hepatitis B/C, but has never had an active flare

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Exclusion Criteria (3 of 3)
Other:
18. History of drug or alcohol abuse within the past 24 months
19. Non-cardiac condition that limits lifespan to < 1 year
20. Currently participating (or participated within the past 30 days) in an
investigational therapeutic or device trial
21. Participated in the treatment arm of a gene or stem cell therapy trial within the
past 12 months
22. Unwilling or unable to comply with follow-up
23. Serious allergy to lidocaine, local anesthetics or radiological contrast
24. Females that are:
a. Pregnant or nursing
b. Childbearing potential and not using effective contraceptive 30 days
prior to study procedure
25. Be an organ transplant recipient
26. History of malignancy within past 2 years (patients must be disease free for 2
years), except for curatively-treated basal cell carcinoma, squamous cell
carcinoma, or cervical carcinoma

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 Overview of
Screening/Baseline Visit
• Consent, 3 months stable HF medications prior to randomization
• History, Physical Examination, Labs, Pregnancy Test

Study Visits •
•
•
12 lead ECG ,NYHA, 24 hr Holter Monitor or device interrogation
6MWD (exclude <100meters, >450meters)
Echocardiogram with contrast
• Minnesota Living with HF Questionnaire, Adverse Events
Study Population: • 5mL bone marrow aspirate for Cell Potency Assay
• NYHA class II-III
• Ischemic Heart Failure
• EF 20-40% Treatment (Day 0)
• Pre-procedure echo, PE, labs, UA, 12 Lead ECG, Pregnancy Test
• 60 mL bone marrow aspirate, CardiAMP cell centrifugation
• Arterial access and biplane ventriculography
• 3:2 (Treatment: Sham) Randomization, post-procedure echo
Point
of
Care Transendocardial Injection of BMMNC’s
• 0.5 mL each injection for a total of 8-10 injections Control Procedure
• Helix/Morph catheter injection system, LV gram • Investigators follow pre-specified script
• Estimated total dose 200 million BMMNC’s • Left Ventricular gram
• Post-procedure Echo, Troponins • Post-procedure Echo, Troponins

Discharge (Day-1)
Physical Exam, Labs, UA, 12 lead ECG

Blinded Follow-up
• Clinic Visits 1, 3, 6, 9, 12, 24 months
• 6MWD 3, 6, 9, 12, 24 months
• Echocardiogram with contrast 6, 12, 24 months
• Holter Monitor 1, 3 months
• PPM/ICD interrogation 1, 3, 6, 9, 12, 24 months
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• MLWHFQ 3, 6, 9, 12, 24 months THE CARDIAMP TRIAL
• Cross-Over option for Control group
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Good Clinical Practice, Investigator and
Sponsor Responsibilities

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Good Clinical Practice

GCP is an international ethical and scientific quality standard for designing,

conducting, recording, and reporting trials that involve the participation of
human subjects.

Purpose:
• Public assurance that the rights, safety, and wellbeing of trial subjects
are protected, consistent with the principles that have their origin in
the Declaration of Helsinki, and that the clinical trial data are credible.

• Unified standard for the European Union (EU), Japan, and the United
States to facilitate the mutual acceptance of clinical data by the
regulatory authorities in these jurisdictions.

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Investigator Responsibilities (Slide 1 of 2)
Responsibilities of the Investigator include but are not limited to:
• Study Conduct:
– Per Good Clinical Practice (GCP)
– Comply with the study protocol (Investigational plan)
– Comply with all applicable regulations
– Adhere to the Investigator Agreement
– Obtain written Informed Consent, document, consenting process
• Prior to study-related tests or procedures
– Ensure completion/sign off on eCRFs
• Create account in MediData RAVE to sign off on eCRF’s

– Timely reporting of AEs, SAEs, UADE and protocol deviations as required

– Account for devices used in study
– Oversight of all study personnel
– Notify BioCardia of study personnel changes

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Investigator Responsibilities (Slide 2 of 2)

Ensuring subject recruitment and follow-up:

• Every attempt should be made to contact lost to follow-up (LTFU) subjects
Maintaining Investigator Records:
• Maintain and retain complete and accurate source documents
• Retain records for 2 years after study completion
• Support FDA audits

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Reporting Responsibilities: Notification Time
IRB/EC: Maximum Time of Notification
Type of Report BioCardia Per
Guidelines

Case Report Forms X ---------- Within 14 days of subject enrollment or visit

Serious Adverse Events X X Within 24 hours of knowledge 0f event

UADE X X Within 24 hours of knowledge 0f event

Adverse Events X X Within 21 days of the event

Subject Withdrawal X X Within 5 working days

Withdrawal IRB Approval X ---------- Within 5 working days

Annual Progress Report (IRB/EC annual X X Submitted annually from date of IRB approval
renewal used as site’s report to sponsor)
Protocol Deviation X X Within 5 working days

ICF not Obtained X X Within 5 working days

Final report X X Within 3 Months

Other X X As requested

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Adverse Event (AE) Reporting Requirements
When AE occurs:
• Submit AE form in EDC within 21 days (SAEs within 24 hours) of becoming
aware of event:
1. Medidata RAVE sends an alert to BC and Medical Monitor notifying them
of the event
2. Upload pertinent source documents and PI’s determination of relatedness
to the Device/Procedure/Study into JUDI within 3-7 working days of the
initial report
• Treatment-emergent SAEs and UADEs should be reported within 24 hrs to your
CRA in addition to submitting the AE form into EDC
1. Treatment-emergent SAEs are defined as all SAEs that occur within 72
hours of the procedure and a causal relation with the procedure is
suspected
2. Please note that the CRO Safety group may reach out with questions and
requests for additional documentation

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Sponsor Responsibilities
Ensure the Investigator conducts the study in accordance with:
1. Study Protocol
2. Clinical Study and Investigator Agreement
3. International Conference on Harmonization (ICH)/ Guidelines for GCP
4. ISO 14155:2011(E)
5. The Declaration of Helsinki
6. All applicable country law/regulations

Ensure all research staff are qualified to participate in the study and received required training:
1. Ensure all subjects have signed an IRB/EC approved Informed Consent Form prior to any
study-related activities.
2. Ensure that all Investigational devices are only shipped to sites that have all regulatory
required documentation.
3. Ensure that devices are deployed in subjects that qualify and have signed an Informed
Consent Form.
4. Report adverse events and device performance issues per IRB/EC and national regulatory
requirements.
5. Verify the accuracy of the study data by monitoring and reviewing subject Case Report
Forms against source documents.
6. Conduct monitoring/study visits throughout the duration of the clinical study.

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Monitoring
Interim Monitoring Visits will be conducted as follows:
1. The interim monitoring visits for each site will occur on a regular basis, but no less than annually
2. During the visit, the monitor:
a. Assures Protocol, Regulatory and GCP compliance
b. Answers questions, close queries and ensure site has adequate study supplies
c. Following the visit, a Visit Follow-Up Letter will be provided

3. During the Interim Monitoring Visit, the CRA will review all the following (but not limited to):
• 100% Source Data Verification (SDV) for the first • Monitoring regulatory & GCP compliance
subject, followed by Risk Based monitoring of key
• Proper data collection & query resolution
data points
• Ensuring proper delegation of tasks & site
• Informed consent and process documentation
qualification
• Ensuring protocol compliance
• Adequate training throughout the study
• Regulatory binder review
• Product Accountability
• Meeting with the Principal Investigator
• Review, document collection & proper reporting of
AEs, SAEs, & UADEs through resolution
4. Access to the following:
• Hospital • Copy Machine
• Medical Records • Monitoring Space
• Internet

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 Study Blinding Plan

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Study Teams and Blinding Plan
The unblinded / study procedure team is responsible for:
• Study procedure – discharge care and evaluation (Visit D0/D1)
• Procedure room is prepared identically for each procedure, if
randomized to control, a prescribed procedure script is used, as
though randomized to the treatment arm
• Device ordering, returns, ensure storage and access to devices is
restricted
• Reporting adverse events and protocol deviations

The blinded / assessment team is responsible for:

• Screening, consenting and follow-up visits
• 6MWD test, NYHA classification, physical exams
• Reporting adverse events and protocol deviations

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Blinding Plan Highlights
Restricted access data may be found in many functional areas and physical locations
where the study operations are executed:
• Access to restricted data controlled at each access point to the greatest extent
possible
• Documents (e.g., source documents, interim reports) which contain restricted
data stored in a restricted access location
• Electronic documents containing restricted data sent to secure, workplace email
addresses:
§ It is the sender's responsibility to ensure that recipients of restricted
electronic correspondence are authorized to receive such data
• EMR access: Procedures in place to ensure minimization of unblinding in EMR
records:
§ The study treatment assignment not be documented in procedure reports
(i.e., randomized arm)
§ Blinded study team members instructed not to review the EMR for labs and
AEs that occurred during the study procedure or through hospital discharge
It is the responsibility of all team members to ensure restricted data is not shared
openly in the workplace.
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Breaking the Blind
Planned Unblinding:
• Participating subjects, as well as site and study personnel, unblinded in
accordance with the protocol
• Notification obtained from sponsor of permission to break the blind

Unplanned Unblinding:
• The investigator, BioCardia, or Regulatory Authorities may initiate unplanned
unblinding procedures in the interest of patient safety
• The blinded site staff may also be inadvertently unblinded during the course of
the study
§ If a blinded team member(s) becomes unblinded to subject or aggregate
data, BC must be notified within 5 business days of the unblinding event:
§ BC will obtain required information for documentation of this event and
provide documentation back to the study site for their files
§ Notify IRB

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 Protocol Review

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Screening/Baseline Visit
1. Physical Exam, 12-Lead ECG, Urinalysis
2. 6MWD test (between 100 m to 450 m)
a. Conduct two, 6-minute walk tests on the same day. If the difference between the two tests is
greater than 10%, conduct a third test and the best test will be used for analysis
b. Recommend a minimum of 1 hour between tests – using clinical judgment based on
assessment of resting heart rate and blood pressure
c. If the subject walks <100 m or >450 m, the subject fails eligibility
3. Labs: Clinical Chemistry, Hematology with differential, NT pro-BNP, Troponin and CK-MB, HIV,
Hepatitis B/C
4. Pregnancy test, if applicable (Urine)
5. 24-Hour Holter monitor (Not required with ICD or Pacemaker)
• Request interrogation from device clinic
6. ICD/Pacemaker Interrogation, if applicable
7. Minnesota Living with Heart Failure (MLWHF) Quality of Life questionnaire
8. Schedule echo with contrast: Image quality impacts the reliability of the LV echo measurements
a. Baseline echo used for study procedure planning – optimized use of contrast is essential
9. Bone marrow aspirate collected
10. Adverse events/protocol deviations documented
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Six-Minute Walk Test (6MWT) (Slide 1 of 3)
Equipment:
• 30-meter walkway to create 60-meter lap course; clearly delineated
start-line and marked every 3 meters
• Turn around points clearly demarcated (i.e., orange traffic cones)
• Stopwatch & lap counter
• Chair that can be moved along the course
• Oxygen supply (Note: technician SHOULD NOT walk with patient
whether they are using supplemental oxygen or not)
• Sphygmomanometer
• Emergency response equipment per site protocol

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Six-Minute Walk Test (6MWT) (2 of 3)
Evaluator:
• Conducted by investigator or research coordinator blinded to the
treatment arm
• If possible, conducted by the same evaluator for each visit
• Conduct according to “American Thoracic Society Statement:
Guidelines for the Six-Minute Walk Test”
• Complete the 6MWT training on Fire Crest

Subject Preparation:
• Comfortable clothing, appropriate shoes
• Usual walking aids, if necessary
• No exercise 2 hours prior to test

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Six-Minute Walk Test (6MWT) (3 of 3)
Method:
• 10 minutes seated rest for patient prior to beginning, no “warm-up”
• Assess baseline pulse and blood pressure – use clinical judgment to
determine if appropriate to conduct test. Contraindicated if resting HR is
>120 bpm, SBP >180 mm Hg and a DBP >100 mm Hg. (consult physician)
• Complete standing assessment of Dyspnea / Fatigue - see Borg Scale
• Instruct patient on walk requirements (see details in SRD-04924)
• Use consistent language and encouragement for each test as (See
suggested script in SRD).
• Conduct two, 6-minute walk tests on the same day
§ A minimum of 1 hour between tests – use clinical judgement
based on assessment of resting heart rate and blood pressure
§ If the difference between the two tests is greater than 10%, conduct a
third test, the best test will be used for analysis

If the subject walks <100 m or >450 m, stop; fails inclusion criterion.

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This form may be used as
source for the 6MWD Test:
(or use your own source)

1st of 4 pages:

*Please ensure you

have a copy of the
Dyspnea and Fatigue
Borg Scale.

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Percent Difference Calculator:

*Please note Percentage difference

calculation must be used in
determining the distance between
Test 1 and Test 2 whether using this
form or your own source.

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Core Laboratories for Echo and Cell Analysis
Core Lab 1 2 3

Echo Lab Yale University School of Med

Cardiovascular Research Group
Project Manager: Mary Jo Rizzo

NOTE: Echo images uploaded

into Intelemage (Medidata
Imaging)
Cell Baylor CAGT Flow Cytometry GenPath BioReference (BRLI) Labs BioCardia Cell Bank
Analysis Attn: Aaron Orozco / Attn. HemPath Processing Attn: Andrew Jacobson
Labs Jacob Couturier 481 Edward Ross Dr., Bldg. 481 320 Soquel Way
1102 Bates Street Elmwood Park, NJ 07407 Sunnyvale, CA 94085
Feign Center, Suite 1640 (201) 233-4758 (720) 987-9188
HOUSTON, TX 77030
(832) 824-4666

NOTE: Sample to assess sterility of Visit Day 0 treatment product sent to Quest Diagnostics
Attn: Specimen Processing; 200 Lewis Drive; Wood Dale, IL, 60191-2800; 630-595-3888

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Echocardiography

Yale Echo Core Lab:

• Responsible for training sonographer on Echo Imaging Protocol
• Yale Echo Core Lab interprets results, determines screening eligibility, uploads PDF report
into Medidata Imaging and enters echo data into EDC

Reminders:
The Screening/Baseline echo is performed with contrast and is used for study procedure
planning:
• Prior to procedure the polar map (show wall motion and thickness) is sent to the
Interventional Cardiologist(IC). On Day-0 the BC FCE reviews the polar map and echo with
IC to determine target segments. The segments are determined by myocardial wall
thickness and motion. Study targets are hypokinetic with a wall thickness of >6 mm.

Study Echos with contrast: Screening/Baseline, 6-M, 12-M and 24-M

Study Echos without contrast (limited): Day-0

• Pre-procedure and Post-procedure
• Local Echocardiography Department to review echo for LV thrombus, pericardial effusion

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Screening: Bone Marrow Aspirate (BMA; SRD-4408)
The procedure is performed under local anesthesia, conscious sedation and takes approximately
15 minutes. The clinician draws 5 ml of bone marrow from the iliac crest (hip bone).

- Monitor all patients who have BMA post-procedure per site’s standard of care
- 24-hours after the BMA, call patient for “well-being/health status check”
- Report any AEs associated with BMA procedure and follow until resolved or stabilized

Refer to the SRD 4400 (for shipping instruction) for the blood and BMA samples.

Box BOX #1 BOX #2 BOX #3

Tube(s) 1- 1.5 ml BMA 1- 1.5 ml BMA 1- 5ml Blood + 1- remaining BMA (~2 ml)
Destination Baylor (CAGT) GenPath BioReference Labs BioCardia
Send FedEx tracking numbers to BioCardia
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Screening BMA Key Points
The following samples are collected:
§ 5 ml bone marrow aspirated from iliac crest into a syringe
• The sample divided into 3 separate tubes for delivery to 3 labs
§ 5 ml venous blood collected, placed into a green top vacutainer tube
§ FedEx (overnight) samples- email FedEx tracking numbers to BioCardia

Upon receiving sample:

§ BC receives results within 1-2 days of the core lab receiving the sample
§ BC informs site of the subject’s eligibility
§ BC enters eligibility results into EDC
§ Baylor enters cell analysis results in EDC

Rescreening may be performed when technical issues are identified (e.g.,

clotting of sample, activation of cold/heat detectors or suspicion of excessive
peripheral blood contamination)

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Visit Day 0: Study Devices and Supplies
Centrifuge

30cc Syringes

1cc Syringes
Counterbalance
BMA Needle
*Cell Separator
3-Way Stop

Morph

*Helix

* Red font denotes Investigational device

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Study Procedure: Important Scheduling Points
In preparation for scheduling the case:
• Review the Screening Visit lab results for troponin
• If above ULN determine if this is the subject’s norm-notify study team
• Schedule case support with BioCardia- No Fridays
• Schedule subject’s arrival time early enough so the lab results may be
reviewed prior to the BMA procedure (ensure subject continues to
meet study eligibility criteria)
• Schedule cardiac catheterization procedure
• Cardiovascular surgeon / staff available if needed for any emergencies
• Echocardiogram <24 hours prior procedure (no contrast required)
• Echocardiogram within 6 hours after procedure (no contrast required)
• Current IRB approved informed consent signed by subject
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Pre-Procedure Day-0: Assessments/Tests
• Confirm subject meets all eligibility criteria, signed current IRB approved ICF
• Physical Exam, Urinalysis, Pregnancy Test (if applicable)
• 12-Lead ECG
• Limited transthoracic echocardiogram: 24 hours prior to procedure
• Labs: Clinical Chemistry, Hematology with differential, PT/PTT, Cardiac Troponins and CK-MB
- Cardiac Troponin and CK-MB prior to procedure:
§ If cardiac troponin measures below the ULN proceed with the study procedure as planned
§ If cardiac troponin is > ULN, repeat cardiac troponin in 4-6 hrs.
§ If the cardiac troponin level has no change or has decreased and the subject
demonstrates no clinical symptoms of acute coronary syndrome, proceed with the study
procedure as planned
§ If cardiac troponin continues to rise over time or the study subject demonstrates
symptoms of an acute coronary syndrome, the study procedure will be postponed, the
subject will be further assessed per site’s standard of care in order to rule out acute
myocardial ischemia and/or acute coronary syndrome. Report as AE(s).
• COVID-19 Screening Questionnaire
• Verify: INR < 1.5 (exclusion criterion #4), eGFR > 30 (exclusion criterion #1)
• Concomitant medications
• AEs, Hospitalizations, Unscheduled Visits
• BMA & cell processing – verify sufficient volume of ABM MNC at least 4.2 ml
• Randomization - performed by an unblinded authorized site personnel

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Day-0 BMA Cell/Blood Samples Overview
Harvest of whole blood and BMA for processing
2x5 cc venous blood samples (Green top Vacutainer tube)
2x5 cc venous blood samples ( 2 Paxgene tubes (1-Red and1-Blue top))
2x5 cc bone marrow from the Iliac Crest (Green top Vacutainer tube)
2x30 cc bone marrow from Iliac Crest to be processed in CardiAMP CS
From processed (concentrated) bone marrow in study procedure:
Obtain sterility sample (Quest)
Post-catheter sample (CAGT, Baylor College Med)
Samples sent by FedEx to Quest and CAGT
Send FedEx tracking numbers to BioCardia
CardiAMP CS processed bone marrow for study procedure
1 x 1 cc syringe aliquoted with 0.7 cc concentrated bone marrow
7-9 x 1 cc syringes aliquoted with 0.5 cc of concentrated bone marrow

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Day-0: BMA Cell /Blood Sample Collection (SRD-4409)
The clinician draws 70 ml of bone marrow from the posterior iliac crest (hip bone)
The procedure is performed under local anesthesia and conscious sedation and takes ~15 minutes.

Bone Marrow Aspiration 2 X 30 ml Syringe for procedure.

60ml for procedure &
10 ml for study samples.

- After the bone marrow aspiration, ensure that adequate hemostasis has occurred before
proceeding with anticoagulation for the cardiac catheterization.

- Refer to SRD-4400 for sample shipping instructions.

- If subject screen fails after the Day-0 BMA call patient 30 days ( ± 1wk) for a “well-being/health
status” check. Report any AEs associated with the BMA procedure and follow until resolved or
stabilized.

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 Processing the BMA Cells (Centrifugation) Refer to SRD: 4410
Step 1. Step 2. Step 3.
2- 30 cc Syringes filled with BMA Inject both 30 cc Place CS (filled with
1-Cell Separator (CS) BMA syringes into 60 cc BMA) and
Cell Separator counterbalance into
Centrifuge.

Run centrifuge for

15 min at 3200
RPM.

Step 4
Step 5
Remove CS from centrifuge.
Draw the concentrated cells out of the
Take a 30 ml syringe and draw
CS with a 10 ml syringe. Must have at
of the plasma. Once plasma
least 4.2 ml of the cells to proceed.
removed shake the CS for 30
sec to mix the nucleated and
Connect the 3-way stop to the 10 ml
RBCs.
syringe and aliquot 0.7 into 1 syringe
and 0.5 ml of cells into the remaining
8-10 1 ml syringes.

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Important Procedural Points (Slide 1 of 2)
Target segments are identified by the site PI/IC and the BC clinical team
• Based on available imaging (baseline echocardiography)
Begin intra-myocardial injections when ACT ≥ 250 seconds
• Re-check ACT every 30 minutes
If ACT <250 seconds during the injection procedure:
• Injection may proceed but administer heparin until ACT ≥250 seconds
• If injections are almost complete it is at the physician’s discretion whether to
administer additional heparin
Procedure will be stopped if one or more of the following occur:
• Sustained drop in blood pressure exceeding 20 mm/Hg & not responsive to fluid
administration
• Clinical signs and symptoms indicating acute coronary syndrome
• Clinical signs and symptoms indicating a cerebrovascular accident
• Two episodes of sustained ventricular tachycardia / ventricular fibrillation
requiring cardioversion

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Important Procedural Points (2 of 2)
• 2 Echocardiograms:
§ Within 24 hours prior to the procedure
§ Within 6 hours after the procedure
• Essential equipment and health care personnel will be available for the procedure:
§ In the event echocardiography is required
§ Peri-cardiocentesis equipment will be immediately available in case of
cardiac perforation and pericardial bleeding
§ Cardiac surgical team on call in case surgical pericardial drainage is required
• 8-10 injections per protocol of 0.5 ml of concentrated BMA per each syringe
§ At least 4.2 cc of concentrated cells, if not additional sample collected or
subject is screen failed
§ 1 X 1 ml syringe with 0.7 ml ABM MNC and 7-9 X 1 ml syringes with 0.5 ml
ABM MNC
• A final left ventriculogram at the end of the procedure (highly recommended)
• Post-procedure monitoring of the arterial closure site per site’s standard of care

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Randomization
• Prior to randomization, ensure that there is sufficient processed ABM
MNC from CardiAMP Cell Separator to fill at least 1 X 1 cc syringe
with 0.7 ml ABM MNC and 7-9 X 1 cc syringes with 0.5 ml ABM MNC

• Unblinded research coordinator obtains the randomization assignment

from EDC and informs the study investigator and unblinded study
team

• Care and attention made not to reveal the treatment allocation to the
subject or to members of the blinded study team
§ Do not document treatment arm in subject medical records.
Document in medical records “ Randomized per protocol”

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Randomized to Control Arm
1. Left ventriculography, similar to treatment arm but no ABM MNC administered
2. Site investigator and all catheterization lab personnel follow a pre-specified
script and follow actions that mimic the actions that would be taken if the
subject was randomized to the Treatment arm.
a. A copy of the recommended pre-specified script is provided in the Study Reference
Manual (SRD 4505)
3. After Control procedure, all remaining ABM MNC is injected through the Helix
trans-endocardial delivery catheter and collected at the helical needle tip into
a green top vacutainer tube.
a. Samples of these cells sent to the Cell Analysis Core Laboratory for cell
count, cell viability and cell analysis, and for storage at the lab or a
separate bio-banking facility.
b. Sterility of the processed bone marrow sample also assessed.
4. Subjects randomized to the Control arm follow the same hospital admission
practice as those randomized to the Treatment arm

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Post-Procedure (Day-0): Assessments/Tests
1. Limited echocardiogram within 6-hours after procedure
2. Cardiac Troponin levels drawn every four to six (4-6) hours after study
procedure until at least two levels demonstrate a plateau or decline
3. Bone Marrow and Blood Samples:
• Bone marrow and blood samples sent by FedEx (overnight) to Core Lab
(Baylor)
• Sterility sample sent by FedEx (overnight) to Quest Diagnostics
• Guide and injection catheters are bagged and returned to BC
• Cell separator destroyed onsite
Refer to the SRD 4400 (shipping instructions) the Treatment Day blood and BMA samples.

Treatment Day-0 BMA Sterility Test- Helix Post-Procedure

Tube(s) 2- 5 ml BMA + 4- 5ml Whole Blood 1- 2-3gtts BMA 1- Remaining BMA
Destination Baylor (CAGT) Quest Diagnostics Baylor (CAGT)

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Study Reference Documents (SRD) for Study Procedure

SRD #04400:
• Packing samples for cell analysis laboratories
SRD #04408:
• Screening BMA and blood sample collection
SRD #04409:
• Treatment day BMA and sample collection
SRD #04410:
• BMA Processing using CardiAMP
SRD #04505:
• Procedure Script for Control subjects

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Discharge (Day-1) Visit: Assessments/Tests
• Physical Exam
• 12 Lead ECG
• Labs: Clinical Chemistry, Hematology w/ differential, Troponin, CK-MB
Troponin:
§ If cardiac troponin levels exceed 50 times the ULN and/or
the subjects displays symptoms of acute coronary syndrome:
―subject evaluated/treated per standard of care
―cardiac troponins every 4-6 hours
§ Report as adverse event(s)
• Urinalysis
• Concomitant Medications
• Adverse Events

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Blinded Follow-up for 24 Months
Clinic Visits 1, 3, 6, 9, 12, 24 months:
• Labs: Chemistry, Hematology (with diff.), Urinalysis, NT-proBNP 1, 3, 6,
12, 24 months
• Troponin & CK-MB 1 month (repeat at subsequent visits as required)
• 6MWD & MLWHFQ, device Interrogation 3, 6, 9, 12, 24 months
• 12-Lead ECG 1, 6, 12, 24 months
• Echocardiogram with contrast 6, 12, 24 months
• Ambulatory cardiac monitor 1, 3 months
• Blinded Assessment Questionnaire 12, 24 months
• Con Medications & COVID Questionnaire 1, 3, 6, 9, 12, 24 months
• Adverse Events & Protocol Deviations 1, 3, 6, 9, 12, 24 months
• Unblinding and potential Cross-Over occurs upon completion of the 24-
month visit

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Cross-Over 24-month Visit/Cross-Over (Control Group)
• Consent, Physical Examination, Labs, Pregnancy Test
Day-0, Day-1 • 12 lead ECG ,NYHA, If applicable, Device Interrogation
• 6MWD, Echocardiogram contrast
and Follow-Up: • Minnesota Living with HF Questionnaire, Adverse Events

Treatment (Day 0)
• Pre-procedure echo, Labs, UA, 12 Lead ECG,
60mL bone marrow aspirate, CardiAMP cell centrifugation
• Arterial access and biplane, ventriculography

Point
of Transendocardial of BMMNC’s
Care • 0.5 mL each injection for a total of 8-10 injections
• Helix/Morph catheter, ventriculography
• Estimated total dose 200 million BMMNC’s
• Post-procedure echo, Troponins

Discharge (Day-1)
Physical Exam, Labs, UA, 12 lead ECG

1-year Follow-up
• Follow-up Call, Con Meds, AE’s, PD’s 1 month
• Clinic Visits 6, 12 months
• 6MWD, NYHA 6, 12 months
• Echocardiogram with contrast 6, 12 months
• MLWHFQ , Con Meds 6, 12 months
• Adverse Events, Protocol Deviations 6, 12 months
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When Can Cross-Over Occur?
Upon completing 24-month visit all subjects/Assessment Team are unblinded
• Control arm eligible to cross-over and receive the study treatment after the subject
has completed the 24-month visit
§ Subjects elect cross-over treatment within 45 days of unblinding
§ Refer to the Study Reference Document
• To qualify for cross-over (Eligibility Criteria):
§ Successfully completed the 12 and 24-Month visits
§ LVEF ≤ 40% by two-dimensional echocardiogram; not in setting of a recent
ischemic event, assessed by the echo core lab at the 24-Month visit
§ Provide written informed consent
• Procedure Day (Day-0) and Discharge (Day-1):
§ The Pre/Post Procedure and Discharge assessments/tests same as the
Treatment arm.
§ Follow-up visit window starts on Day-0

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Cross-Over Subject Exclusion Criteria
Control subject excluded from crossover if they meet any of the criteria listed below:
• Serum positive for hepatitis B/C and or HIV (Unless patient is a carrier for Hepatitis B/C, but has
never had an active flare)
• Female who is pregnant, nursing, or of childbearing potential while not practicing effective
contraceptive methods for at least 30 days prior to randomization
• Not a candidate for cardiac catheterization
• Have left ventricular thrombus, as detected by echocardiography
• Have a mechanical aortic valve or heart constrictive device
• Have a documented presence of aortic stenosis (aortic stenosis graded as > 2+ equivalent to an
orifice area of 1.5cm2 or less), as measured by the echocardiography
• Acute coronary syndrome 3 months prior to procedure
• Have complete heart block or QTc interval > 550 ms on 12-lead ECG
• AICD firing within 60 days prior to the procedure
• Have peripheral artery disease involving the aorta or iliofemoral system that impacts the
feasibility or safety of the study intervention. This includes stenotic or aneurysmal or embolic
disease, and symptom limiting claudication.
• Unwilling or unable to comply with follow-up

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Cross-Over Subjects: 1-Year Follow-Up

Follow-up consists of:

• Follow-up call after procedure, con meds, AEs, PDs 1 month
• Clinic Visits 6, 12 months
• 6MWD, NYHA 6, 12 months
• Echocardiogram with contrast 6, 12 months
• MLWHFQ , Con Meds 6, 12 months
• Adverse Events, Protocol Deviations 6, 12 months

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Unscheduled Visits

Definition:

If subject has a visit with a healthcare provider for a cardiovascular related

issue outside of a standard of care visit or study follow-up visit

• The subject should be evaluated for presence of COVID-19 virus

• Document in EDC any unscheduled visits and COVID-19 testing results

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 Lost to Follow-Up
• Due to the seriousness of the subjects’ condition, it is anticipated that
few subjects enrolled in the trial will become lost to follow-up
• A back-up contact person will be requested at the time of enrollment
• Mailings and non-visit contacts will be encouraged to help maintain
subject engagement
• If the subject is at risk of lost to follow-up, every effort will be made to
locate the subject with at least 3 documented telephone calls and a
registered letter to the subject’s address before considering the patient
lost to follow-up
• BioCardia must be notified immediately after attempts to locate the
subject have failed. This should also be recorded in the subject’s medical
record and in the EDC

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Safety and Reporting Requirements

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Adverse Events (AEs)
Any undesirable clinical occurrence or change from patient’s baseline (or
pre-device procedure) condition, whether it is considered device related or
not:
• Investigator must determine causality of the AE (rate relationship of event
to each catheter and cell separator and to the study procedure as:
§ Unrelated
§ Unlikely Related
§ Possibly Related
§ Probably Related
§ Definitely Related
• All AEs monitored for all consented subjects, and all AE terms translated
into the standard nomenclature dictionary MedDRA
• Reportable within 21 days by submitting AE form in EDC

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Serious Adverse Event (SAE)
An event is considered a Serious Adverse Event if it:
1. Results in death, Is life-threatening
2. Requires hospitalization or prolongation of existing hospitalization
• Complications that occur during hospitalizations are an AE unless it meets the
above criteria
• Hospitalization for elective treatment of pre-existing conditions that did not worsen
from baseline is not considered an AE
3. Results in disability/incapacity
• Event resulted in a substantial disruption of a person's ability to conduct normal life
functions, i.e., significant, persistent or permanent change, impairment, damage or
disruption in the patient's body function/structure, physical activities and/or quality
of life
4. Congenital anomaly or birth defect resulting from exposure to the study product prior
to conception or during pregnancy
5. Requires intervention to prevent permanent impairment or damage
6. Other Serious (Important Medical Events)
• Does not fit above outcomes but may jeopardize the patient and may require
medical or surgical intervention (treatment) to prevent one of the other outcomes
7. Reportable within 24 hours of knowledge of the event by submitting AE form in EDC

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Unanticipated Adverse Device Event (UADE)
Defined as any device-related, Serious Adverse Event, if that event was not previously
identified in the risk analysis, IFU, and consent form in nature, severity, or frequency:

• If a UADE occurs, notify BioCardia within 24-hours of knowledge of the event

• UADEs must be reported by sponsor to FDA, reviewing IRBs and participating
investigators within 10-days of receiving notice (or per local IRB requirements)

• Anticipated adverse events are provided in the protocol, Clinical Risk Benefit
Analysis. The sponsor will evaluate all serious adverse events for reportability as an
UADE in accordance with 21 CFR part 812.46(b)

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Adverse Event Reporting Requirements
If an adverse event occurs:
Submit an AE form into EDC within 21 days (SAEs within 24 hours) of becoming
aware of event
• Medidata RAVE will send an alert to BC and Medical Monitor notifying them of
the event
• Upload pertinent source documents and PI’s determination of relatedness to
the Device/Procedure/Study into JUDI (email ICON) within 3-7 working days
of the initial report
Treatment-emergent SAEs and UADEs should be reported within 24 hours to your
monitor in addition to submitting the AE form into EDC
• Treatment-emergent SAEs are defined as all SAEs that occur within 72 hours
of the procedure and a causal relation with the procedure is suspected
• Please note that the Safety group may reach out with questions and request
additional documentation

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Subject Death
• If a subject’s death occurs during the investigation:
§ An autopsy should be requested if not precluded by signed ICF
§ For patient’s death associated with the procedure:
— The death must be reported via telephone and with written documentation to
BioCardia or designee within 24 hours of knowledge
§ Forms to submit in EDC:
— Submit an AE form for the cause of death. If not known, please document in the
Study Completion form
§ JUDI: Upload all-source documentation related to the death, death certificate, autopsy
report (if available) and PI’s determination of relatedness to Device/Procedure/Study
• These documents should be submitted as soon as possible from the date the investigator
first learns of the subject’s death but no longer than 10-days of learning of the death:
§ Patient death must be reported to the IRB/EC in accordance with the IRB/EC
requirements
§ Please note that the Safety group may reach out with questions and requests for
additional documentation

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Adverse Events Queries/Upload Source
Medidata RAVE
• Queries may be posed by:
§ ICON Safety group
§ BioCardia monitor
• Upload source documentation for SAEs

JUDI
• Upload source documentation for SAEs
• Additional queries may be posed by the Medical Monitor via JUDI following
CEC assessment of source documents

Either the Medical Monitor or Clinical Events Committee (CEC) may request additional
source documentation.

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Device Failures and Malfunctions
DEVICE FAILURE
• If the investigational device does not perform according to its labeling and
negatively impacts the treatment, while used according to the labeling

DEVICE MALFUNCTION
• An unexpected change to the investigational device that is contradictory to
the labeling and may or may not affect device performance

REPORTING
• Report to BioCardia and request return label for the device
• Return devices to BioCardia for evaluation after appropriate
decontamination

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 Device Accountability

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Inventory Management
The following to be accounted for and monitored throughout the life of the study:
1. CardiAMP ™ Cell Separator
2. Helix Transendocardial Delivery Catheter
3. Morph Universal Deflectable Guide Catheter

Note: When these devices are received the Packing Slip should be signed and filed, and
all devices added to the Device Accountability Log

The following supply kits are provided by BioCardia to support the study but are not
monitored:
• Cell Potency Assay Kit
• Sterility Sample Kit
• Delivery System Kit
• Treatment Day BMA Kit

Note: Expired supply kits should not be used and upon expiration the clinical site
should discard the expired kits on-site. The site leads will ensure clinical sites have
adequate supply kits in inventory.

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 Product Disposition
denotes the Comment section for
products initial use. RMA # and any incidental
comments.

Returned to Sponsor: Product

that has not been opened
(Helix, Morph, Cell Separator).

Any product that was opened and

used during the procedure.

Unopened expired product

destroyed onsite (TX Day BMA kit,
Potency Assay kit, Sterility kit,
Delivery Accessory kit).
Good Device Management Practices
• Investigational devices need to be separated from
commercial devices and stored in a locked and secure
location with limited access
• Notify your monitor if the devices are relocated to a new
storage location (include the new address with building and
room number as applicable)
• Your monitor will review the Device Accountability Logs at
each monitoring visit and sign off on any device dispositions
• Any device discrepancy will require site reconciliation;
notification to the monitor, the site IRB and the sponsor
• Contact your site monitor for any questions you may have
about the use of the Device Accountability Log
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 Administrative Items

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Site Activation: Requirements

A fully executed Budget/CTA

All required regulatory documents received by the study team
SIV completed
PI and lead study coordinator completed study required training

Once all required documents are received BioCardia will send a site
activation email/letter:
Begin study activities

No consenting of subjects should occur before

all site activation requirements have been met
and email notification received.

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 Monitoring

ICH-GCP defines monitoring as the act of overseeing the conduct of a clinical trial, that
is, ensuring that the trial is conducted according to protocol, GCP, SOP and regulatory
requirements. It is the responsibility of the sponsor to ensure the trial is adequately
monitored

• Title 21 Code of Federal Regulations (21 CFR): FDA Regulated Products:

• Part 11: Electronic Records/ Electronic Signatures
• Part 50: Protection of Human Subjects
• Part 54: Financial Disclosure – Clinical Investigators
• Part 56: Institution Review Boards
• Part 812: Investigational Device Exemptions
• Additional Guidance:
• FDA Information Sheets

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Site Monitoring Activities

IP Accountability
Subject Consent Meet with PI & Staff
Every visit reconcile IP log
Monitor 100% of ICF’s with shipping Every visit onsite or
records/subject records remote

Onsite Activities
Include:

Access to Source
Regulatory / IRB Documentation/EMR/ MR/eCRF
Documentation/eISF SDV eCRF’s and Review AEs for
Review at each visit completeness and resolution
Close outstanding findings

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 Interim Monitoring Visits: Follow-Up
• Timing and Frequency:
§ Frequency of monitoring visits will be dependent on subject enrollment rate,
subject visits, quality issues, trial site compliance, and other study/ site issues

Visit Type Recommended Frequency/Timing

Initial IMV Approximately 45-65 days following the randomization of the
site’s first subject
IMV’s Monitoring visit should occur every 6 months depending upon
enrollment

• Pre-Visit Communication:
§ Confirmation letter will be forwarded to the study site prior to the visit to
document the date, time, expected duration, and an agenda for the visit

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Interim Monitoring Visits: Compliance
• Protocol Deviations:
§ Protocol deviations should be reported as soon as possible
§ Any protocol exemptions/waivers, granted in rare circumstances only, must be approved by
BC, and must be fully documented in the subject’s source documents

• Compliance Issues:
§ The clinical site will be monitored routinely for adequate enrollment, timeliness of data
submission, and compliance with the Protocol and local regulations
§ Consistent pattern of non-compliance with respect to the above will require a corrective
action plan to be negotiated with the Investigator
§ If corrective actions are not effective in resolving site compliance, the Sponsor may
withdraw the clinical site from the study

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Remote Activities
Activities:
• Monitors will maintain regular contact with the site staff by
telephone and/or email
• Monitor may request more frequent contact, if it is deemed
necessary to address any outstanding issues or ensuring subjects
are scheduled for follow-up visits in window
• Monitor will review remotely the data entered in the EDC system
for any unclear or questionable data and will respond with manual
queries or e-mail communications to the sites for clarification or
correction as needed.

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Close Out Visit
• The COV will be performed:
§ After all subjects enrolled at all sites has completed the study
§ All queries have been resolved prior to the database lock
§ If a site has not enrolled a subject, a COV may be conducted via telephone
• During the COV the CRA will:
§ Ensure that the site staff has completed and submitted all continuing review
and final reports as required by the site's EC/IRB
§ Collect copies of these documents for BioCardia’s Central Files
§ Meet with Site PI to review applicable document retention requirements and
audit preparation procedures
• After the COV:
§ PI is responsible for notifying the reviewing IRB/EC of COV and provide copy of
notification to BioCardia
§ If corrective action, device reconciliation, or other discrepancies remain
outstanding, the CRA will continue to follow up with the Site, in writing, until
deficiencies are resolved

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Common Inspection/Audit Findings

• Non-adherence to the protocol

§ Violation of protocol eligibility criteria
§ Inadequate Investigator Records (source documentation)
§ Informed Consent process
• Inadequate Investigator participation, excessive or inappropriate
delegation of duties

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EDC: Account Activation
• New users will receive a system-generated, ACCESSING THE SYSTEM
email invitation from iMedidata RAVE
containing a link to create a profile • Once an account is activated, the Rave
system can be accessed through the
• On the first visit to the Biocardia URL, new following link:
users will be able to navigate to eLearning.
Upon successful completion of eLearning § HTTPS://LOGIN.IMEDIDATA.COM/LOG
(users must obtain a score of 80% or better), IN
users will be able to activate their Medidata
Rave account and gain access to the study
• If a valid training is currently on file with
iMedidata, the system will automatically
update and provide you with access to the
Biocardia study

• Medidata Imaging: Uploading echo images

(Prior to uploading an image please
remember to enter the subject’s height and
weight on the demographics page)

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EDC Data Entry: Timelines
• Registration form is completed when subject signs consent:
§ Notifies BC that a consent has been signed
§ Triggers the Screening/Baseline forms
• Specific forms required to be completed prior to Randomization:
§ Clinical team reviews the data to determine subject eligibility
§ Registration, Screening/Baseline, Demographics
§ Cell analysis score, Rescreen (only if subject is a rescreen subject)
§ Day of procedure: Day-0 Treatment (visit date), Enrollment/Randomization
• Follow-up Visit:
§ Data should be entered within 10 days from the subject visit

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EDC: Creating/Registering Subjects

• Site numbers are two digits and subject number three: (i.e 06-010)
• Site and subject number will auto-populate/derive in the system
• Subject initials are not collected
• Adding a New Subject:
• From the RAVE home screen, select “your site”
• From the Site home screen, select the “Add Subject” icon
§ In short, you will need to “select the checkbox” associated with the prompt:
“Register Subject “and “save the form”.
§ Additional instructions are provided in the section, “Registration”
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EDC: Randomization occurs on: Day-0 Treatment

Form accessible ONLY to un-blinded team members. This form will dynamically add to the Visit Schedule when the
requirements are met. See Section “Guidelines for Balance System” for details.
• Please note the” XX” in the above screenshot will be auto-populated by the system
• Complete the form as prompted, noting the following clarifications:
§ The only enterable field on this form is “Do you want to randomize this subject?
§ All other fields are derived values, populated automatically by the “Balance” IWRS Randomization tool of
the RAVE EDC

Do you want to randomize this subject?

- If the patient has met all eligibility and randomization criteria, select “YES”, and “Save the form”
- If the patient has not met eligibility and/or randomization criteria (i.e., subject is a Screen Failure) select “NO”
Ø If marked “NO”, complete the ‘Study Completion/Discontinuation’ eCRF, and all other required forms
for screen failure/non-randomized subjects
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Study Binder Review
Regulatory Binder:
o Delegation of Authority Log, Training Log, Visit Log and Screening Log
Device Accountability Binder:
o Device Accountability Logs
Source Worksheets
o 6-minute walk distance
o Study procedure
o COVID 19 questionnaire
Study Reference Manual (SRM):
o Maintained electronically (ie ‘Box’)
o Study procedure and testing guidelines
o Adjunctive protocol procedure instructions
Other:
o Good Documentation Process – source docs
o EMR best practices
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 Thank you!

Questions & Wrap-Up

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