FlowMet-R Blood Flow Measurement for the Diagnosis of Peripheral Artery Disease (PAD) and Critical Limb Ischemia (CLI)
Conditions: Peripheral Artery Disease
Sponsor: Medtronic Endovascular

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Clinical Investigation Plan 
Clinical Investigation Plan/Study Title  
FlowMet-R Blood Flow Measurement for the 
Diagnosis of Peripheral Artery Disease (PAD) and 
Critical Limb Ischemia (CLI) 
Study Product Name 
FlowMet-R 
Sponsor/Local Sponsor 
Medtronic Vascular, Inc. 
3576 Unocal Place 
Santa Rosa, CA 95403 
Document Version 
3.1 
Version Date 
25-JUN-2020 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of 
Medtronic. Any distribution, copying, or disclosure without the prior written authorization of 
Medtronic is strictly prohibited. Persons to whom the information is disclosed must know that it is 
confidential and that it may not be further disclosed by them. 
NCT Number: NCT04120610

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Table of Contents 
Table of Contents.................................................................................................................... 2 
1. 
Glossary........................................................................................................................... 5 
2. 
Synopsis .......................................................................................................................... 6 
3. 
Introduction .................................................................................................................... 9 
3.1 Background..................................................................................................................... 9 
3.2 Purpose .........................................................................................................................10 
4. 
Objectives and/or Endpoints ......................................................................................... 10 
4.1 Objectives......................................................................................................................10 
4.1.1 
Primary Objective(s) .............................................................................................10 
4.1.2 
Secondary Objective(s) .........................................................................................11 
5. 
Study Design ................................................................................................................. 12 
5.1 Duration ........................................................................................................................13 
5.2 Rationale .......................................................................................................................13 
5.2.1 
Prior Benchtop and Animal Studies .........................................................................13 
5.2.2 
Prior Clinical Studies .............................................................................................13 
5.3 Study Oversight ..............................................................................................................14 
6. 
Product Description ....................................................................................................... 14 
6.1 General .........................................................................................................................14 
6.2 Device Risk ....................................................................................................................16 
6.3 Product Accountability .....................................................................................................17 
7. 
Study Site Requirements ............................................................................................... 17 
7.1 Study Site Activation .......................................................................................................17 
8. 
Selection of Subjects ..................................................................................................... 17 
8.1 Study Population.............................................................................................................17 
8.2 Subject Enrollment ..........................................................................................................18 
8.3 Inclusion Criteria.............................................................................................................18 
8.4 Exclusion Criteria ............................................................................................................18 
9. 
Study Procedures........................................................................................................... 19 
9.1 Schedule of Events..........................................................................................................19 
9.2 Data Collection ...............................................................................................................23 
9.3 Scheduled Follow-up Visit Windows ...................................................................................24 

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9.4 Subject Consent..............................................................................................................24 
9.5 Baseline Visit ..................................................................................................................25 
9.5.1 
Relevant Medical History and Demographics............................................................25 
9.5.2 
QoL Assessment...................................................................................................25 
9.5.3 
Rutherford Classification / Visual Assessment ..........................................................25 
9.6 FlowMet-R Assessment ....................................................................................................26 
9.6.1 
Product Equipment ..............................................................................................27 
9.7 Standard Noninvasive Vascular Assessments .......................................................................28 
9.7.1 
Toe brachial index (TBI).........................................................................................28 
9.7.2 
Ankle brachial index (ABI)......................................................................................28 
9.7.3 
Postexercise ankle brachial index (ABI)....................................................................28 
9.7.4 
Duplex ultrasound................................................................................................29 
9.7.5 
X-Ray Angiography ...............................................................................................29 
9.8 Intraprocedural Data Collection .........................................................................................29 
9.9 Deviation Handling ..........................................................................................................30 
9.10 Subject Exit, Withdrawal or Discontinuation ........................................................................30 
10. 
Risks and Benefits ...................................................................................................... 31 
10.1 Potential Risks ................................................................................................................31 
10.2 Risk Minimization ............................................................................................................31 
10.3 Potential Benefits ............................................................................................................32 
10.4 Risk-Benefit Rationale ......................................................................................................32 
11. 
Adverse Events and Device Deficiencies ..................................................................... 32 
11.1 Adverse Events ...............................................................................................................32 
12. 
Statistical Design and Methods .................................................................................. 33 
12.1 General Aspects of Analysis ..............................................................................................33 
12.1.1 
Sample Size .........................................................................................................33 
12.1.2 
FlowMet-R data analysis and diagnostic model.........................................................33 
12.1.3 
Analysis of Stenosis ..............................................................................................34 
13. 
Ethics ......................................................................................................................... 34 
13.1 Statement(s) of Compliance .............................................................................................34 
14. 
Study Administration.................................................................................................. 35 

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14.1 Monitoring .....................................................................................................................35 
14.2 Data Management...........................................................................................................35 
14.3 Direct Access to Source Data/Documents ...........................................................................35 
14.4 Confidentiality ................................................................................................................36 
14.5 Liability .........................................................................................................................36 
14.6 CIP Amendments ............................................................................................................36 
14.7 Record Retention ............................................................................................................36 
14.8 Suspension or Early Termination .......................................................................................37 
14.8.1 
Planned Study Closure ..........................................................................................37 
14.8.2 
Early Termination or Suspension ............................................................................37 
15. 
References ................................................................................................................. 37 
16. 
Appendices ................................................................................................................. 39 
17. 
Version History ........................................................................................................... 39 
 

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1. Glossary  
Term 
Definition 
ABI 
Ankle brachial index 
AE 
Adverse event 
ATK 
Above the knee 
AUC 
Area Under the (ROC) Curve 
BTK 
Below the knee 
CCD 
Charge coupled device  
CDU 
Color duplex ultrasound imaging 
CI 
Confidence interval  
CLI 
Critical limb ischemia  
Cm 
Centimeter 
CMOS 
Complementary Metal-oxide Semiconductor 
CRF 
Case report form 
EDC 
Electronic Data Capture 
FDA 
Food and drug administration  
Hr 
Hour 
ICF 
Informed consent form 
IRB 
Institutional review board 
Nm 
Nanometer 
OHRP 
Office of Human Research Protection 
PAD 
Peripheral artery disease 
PPG 
Photoplethysmography 
ROC 
Receiver operating characteristic  

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Term 
Definition 
SAE 
Serious adverse event  
TBI 
Toe brachial index 
US 
United states  
2. Synopsis 
Title 
FlowMet-R Blood Flow Measurement for the Diagnosis of Peripheral 
Artery Disease (PAD) and Critical Limb Ischemia (CLI) 
Product Name 
FlowMet-R 
Sponsor  
Medtronic Vascular, Inc. 
3576 Unocal Place 
Santa Rosa, CA 95403 
External Organizations 
 
Investigation Purpose 
The purpose of the investigation is to assess the efficacy of the 
FlowMet-R device in diagnosing PAD and CLI in patients scheduled for 
peripheral vascular examination.  The results of the assessment of the 
FlowMet-R device will be compared to gold standard diagnostics 
including ABI, TBI, and Doppler Ultrasound.    
Primary Objective(s) and/or 
Endpoint(s)s 
The primary objective is to determine the efficacy of FlowMet-R 
measurements in diagnosing PAD and CLI in patients during initial 
visit, three month, and six month follow-up. 
Secondary Objective(s) 
and/or Endpoint(s) 
The secondary objectives are to determine the capability of the 
FlowMet-R in prognosis of requiring vascular intervention or 
amputation within three and six months following the initial visit.  
Additionally, to investigate the correlation between FlowMet-R 
measurements and peripheral artery stenosis.  Finally, to assess the 
correlation between changes in ABI/TBI/Rutherford Classification and 
changes in FlowMet-R data between any two time points.  
Study Design 
Multi-center, non-randomized, longitudinal study with three and six 
month follow-up.  
Sample Size 
PAD Cohort: Cohort will consist of 240 limbs with PAD including a 
minimum of 54 limbs with claudication and a minimum of 100 limbs 
with CLI.  All comers - any patient scheduled for peripheral vascular 

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assessment who is not subject to exclusion may be approached for 
enrollment in the disease positive arm.  Exclusion criteria are detailed 
in Section 8.4.  This will include patients in the registry who have a 
planned endovascular or surgical intervention to address their PAD.  
 
Healthy Cohort: Cohort will consist of 160 control limbs.  Any patient 
over 40 years old and without suspected PAD may be approached for 
enrollment in the healthy control arm.  Healthy subjects may be 
enrolled from other departments within the clinic/hospital, can be 
from the local community, or can be actively recruited for 
participation (such as researchmatch.com or active volunteers). 
 
Registry: Patients diagnosed with PAD at baseline procedure who are 
scheduled to undergo an endovascular treatment of the lower limbs 
will be included in the registry data for this study.  The registry will be 
established to record FlowMet-R measurements, angiographic films, 
and any additional relevant information immediately prior to, during, 
and immediately following peripheral vascular interventional 
procedures for enrolled patients.  
Inclusion/Exclusion Criteria 
INCLUSION CRITERIA 
PAD Positive Cohort: 
− Subject meets PAD positive criteria set forth in Section 8.4 
− Subject is willing and able to provide informed consent 
− Subject is willing and able to comply with the study procedures 
− Subject is able to understand the study procedures 
− Subject is scheduled for vascular examination that includes 
noninvasive assessments as standard of care: ABI, TBI, and 
either a Duplex Ultrasound or Angiogram 
Healthy Cohort: 
− Subject is willing and able to provide informed consent 
− Subject is willing and able to comply with the study procedures 
− Subject is able to understand the study procedures 
− Subject has no history of positive PAD diagnosis and is not 
currently suspected of having PAD 
EXCLUSION CRITERIA 
PAD Positive Cohort: 
− Subject is under 40 or unable to consent 

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− Subject has any medical condition, which, in the judgement of 
the Investigator and/or designee, makes the subject a poor 
candidate for the investigational study 
− Subject is excluded from analysis if no stenosis is found during 
Dopper Ultrasound, but Tibial disease is suspected and Tibial 
ultrasound is not able to be performed 
− Subject does not have a suitable finger to attach the FlowMet-
R probe 
− Subject does not have a suitable 1st or 2nd digit to attach the 
FlowMet-R probe on the limb of interest 
− Subject has undergone revascularization within the last 90 
days 
− Subject cannot lay safely in a supine position 
 
Healthy Cohort Exclusion: 
− Subject is under 40 or unable to consent 
− Subject has any medical condition, which, in the judgment of 
the Investigator and/or designee, makes the subject a poor 
candidate for the investigational study 
− One or more of the limbs has a prior or current diagnosis of 
PAD, or is reasonably suspected of having a diagnosis of PAD 
− Subject does not have a suitable finger to attach the FlowMet-
R probe 
− Subject does not have a suitable 1st or 2nd digit to attach the 
FlowMet-R probe 
− Subject has undergone revascularization within the last 90 
days 
Study Procedures and 
Assessments 
Primary Cohort: 160 control limbs (Healthy Cohort) will be measured 
according to Event Schedule C, 240 limbs with PAD, including a 
minimum subset of 54 limbs with claudication and 100 limbs with CLI, 
will be measured according to Event Schedule A.  PAD patients will be 
measured at three and six month follow-up (as measured from the 
baseline visit), according to Event Schedule A.  
 
Registry: Will be active according to Event Schedule B until data from 
at least 25 interventional procedures is reached.  

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3. Introduction 
3.1 Background 
It is well established in the literature and in clinical practice that diminished blood flow to the 
extremities, as a result of peripheral artery disease (PAD) or otherwise, may impair wound healing and 
overall tissue viability [1-5].  PAD is labeled a “large personal, social, and economic burden in the United 
States” by the American Heart Association and American College of Cardiology. PAD is estimated to 
affect 8-10 million in the US alone, while having a significant mortality rate (30% mortality in 5 years) [6, 
7]. Over $5B is spent annually treating peripheral vascular patients, the majority of which results from 
late diagnoses, ineffective interventions, and resulting lower limb amputations [8].     
One end-stage manifestation of PAD is critical limb ischemia (CLI) [9, 10].  Generally, CLI is defined as: 
“any patient with chronic ischemic rest pain, ulcers, or gangrene attributable to objectively proven 
arterial occlusive disease” [9]. Early detection and treatment has the potential to keep PAD from 
reaching the point of CLI.  However, traditional methodologies for quantifying extremity blood flow have 
limitations that prevent widespread clinical adoption. For example, laser Doppler has been used to 
assess cutaneous blood flow, but measurements are limited to a penetration depth of <1 mm, 
precluding measurement of the complete microvascular system [11].  Plethysmography can be used to 
measure relative changes in digital blood volume, but is unable to quantitatively measure perfusion.  
Doppler ultrasound can be used to quantify flow velocity in the major peripheral arteries, but is unable 
to measure perfusion rates in the microvasculature.  Additionally, the time and cost required for 
widespread application of ultrasound imaging across large patient populations is restrictive. 
Transcutaneous oxygen tension has been correlated to CLI severity, but data quality is highly user and 
position dependent and data acquisition is time-consuming [12, 13].  Angiography is the gold standard 
for anatomical visualization of blood vessel structure and stenosis.  However, angiographic information 
does not provide simple and functional metrics of blood flow, especially in the case of multiple stenoses.  
As such, the relationship between extremity blood flow and PAD/CLI cannot be elucidated without a 
more appropriate methodology for quantifying peripheral perfusion. 
The ankle brachial index (ABI) is perhaps the most widely used screening technique to diagnose PAD. 
While the ABI is relatively simple to perform, it is a ratio of systolic blood pressures rather than a direct 
measurement of blood flow, and, despite its widespread usage, is only a proxy of direct perfusion 
measurements. Generally, a cutoff of ABI<0.91 is used to predict the presence of PAD, and a cutoff of 
ABI<0.4 is used to predict the presence of severe PAD indicating CLI [14].  In diagnosing >50% stenosis of 
lower limb arteries, researchers have found the ABI to have relatively high specificity, ranging from 
approximately 83%-99%, but highly variable sensitivity, ranging approximately 15%-79% [15].  In 
patients with partially non-compressible arteries, ABI values may be inflated and appear normal, despite 
the presence of significant disease.  When the ABI is in a normal range but PAD is suspected, a 
postexercise ABI may be used to provide additional confirmation.  A drop in >30mmHg ankle pressure or 

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ABI of >20% after exercise indicates the presence of significant disease [16].  The postexercise ABI may 
be performed with a treadmill test or repeated heel-raises [16]. 
While ABI has a relatively good sensitivity and specificity for claudication, recent data has shown that 
over 30% of patients with documented CLI have a normal ABI or ABI consistent with non-compressible 
blood vessels [17-19]. Therefore, in patients with wounds and/or gangrene, TBI is often used to assist in 
confirmation [20]. 
Color duplex ultrasound (CDU/CDI) imaging is often considered the gold standard when assessing 
arterial stenosis in a vascular laboratory, and good agreement has been shown between duplex and 
digital subtraction angiography (DSA) [21].  Generally, when assessing the performance of other 
diagnostic metrics such as ABI, Duplex ultrasound may be used as a gold standard to determine 
presence of >50% stenosis, indicating significant PAD [15, 22]. 
While the noninvasive technologies mentioned above are considered standard of care in vascular 
medicine, there remains a lack of simple and continuous methods to assess PAD severity. A portable 
technology capable of quantifying disease severity simply and in real time could significantly ameliorate 
diagnosis, surgical treatment, and follow up care.  
. 
 
This study has many clinical implications.  FlowMet-R is the first noninvasive technology to provide 
accurate and continuous quantification of microvascular perfusion.  Hence, this technology may provide 
improved diagnostic and/or prognostic capabilities during procedures and in outpatient settings. The 
current study will set the foundation for future indications of FlowMet-R technology in vascular care. 
3.2 Purpose 
The purpose of the investigation is to assess the efficacy of the FlowMet-R device in diagnosing PAD and 
CLI in patients scheduled for peripheral vascular examination.  The results of the assessment of the 
FlowMet-R device will be compared to gold standard diagnostics including ABI, TBI, and Doppler 
Ultrasound.    
4. Objectives and/or Endpoints 
4.1 Objectives 
4.1.1 Primary Objective(s) 
The primary objective of this study is to determine the efficacy of FlowMet-R measurements in 
diagnosing PAD and CLI. To accomplish this objective, FlowMet-R data (comprised of blood flow 

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measurements and/or feature analysis of the blood flow waveform) will be used to create a predictive 
model of PAD severity. This model will then be used to generate diagnostic ROC curves for PAD and, 
independently, CLI, at multiple time points. The following endpoints will be used to assess fulfillment of 
this objective: 
4.1.1.1 Primary Endpoints 
Employ a predictive model based upon FlowMet-R data to generate ROC curves for the diagnosis of PAD 
and, independently, CLI.  ROC curves will be generated at the initial, three month, and six month time 
points, and will be used to compute the peak sensitivity, peak specificity, and area under the curve 
(AUC). 
4.1.1.1.1 
Definitions of PAD and CLI 
• Two types of positive diagnosis of PAD will be explored according to published literature: (1) ABI≤0.9 
or ABI>1.4 and secondary verification of TBI≤0.7 with exhibition of at least mild claudication 
(Rutherford Category > 0), or (2) ABI≤0.9 or ABI>1.4 and secondary verification of TBI≤0.7 without 
exhibition of symptoms. In either case, if the patient displays normal ABI but PAD is suspected, then a 
postexercise ABI will be performed using a 1-minute treadmill test or heel-raises.  A postexercise 
drop of ABI ≥ 20% or pressure drop ≥ 30mmHg will be considered a positive diagnosis [16]. 
• A positive diagnosis of CLI will be defined by exhibition of chronic rest pain and active wounds, 
verified by TBI < 0.3. 
• Patients that are enrolled in the PAD positive cohort but are not positively diagnosed for PAD using 
the above definition (either because their disease is improving or they were screened incorrectly) will 
be considered PAD negative but will not be grouped into the healthy cohort. 
4.1.2 Secondary Objective(s) 
The secondary objectives seek to discover the relationship between FlowMet-R measurements and 
several additional metrics important in vascular medicine.  First, the capability of FlowMet-R in the 
prognosis of requiring a vascular intervention or amputation within three and six months following 
initial visit will be determined.  Additionally, the correlation between FlowMet-R measurements and 
peripheral artery stenosis will be investigated.  Finally, the correlation between changes in 
ABI/TBI/Rutherford Classification and changes in FlowMet-R data between any two time points will be 
assessed. 
4.1.2.1 Secondary Endpoints 
− Utilize FlowMet-R data to create a predictive model for the prognosis of vascular intervention 
within a three and six month timeframe from initial visit. 
− Employ the predictive model of PAD severity to generate an ROC curve for diagnosis of significant 
stenosis (>50%) in the iliac, femoral, popliteal, peroneal, or tibial arteries. 
− Conduct a correlation test between the predictive model of PAD severity and greatest percent 
stenosis in the iliac, femoral, popliteal, peroneal, or tibial arteries.  

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− Conduct a correlation test between changes in the predictive model of PAD severity and 
corresponding changes in ABI, TBI, and Rutherford Classification between any two study time 
points. 
5. Study Design 
This is a non-randomized, multi-center, longitudinal study of healthy subjects and subjects with PAD 
who are scheduled for ABI, TBI, and either Duplex ultrasound or Angiographic assessments in a vascular 
clinic.  As detailed in the Event Schedules (Section 9.1), subjects will first be evaluated for study 
inclusion/exclusion. If the subject meets the inclusion criteria and wishes to enroll in the study, they will 
be asked to sign an informed consent form (ICF) and considered for enrollment. If the subject meets 
inclusion criteria and is enrolled, the subject will undergo approximately 3 minutes of FlowMet-R blood 
flow measurements in addition to their routine standard of care examination. 
Subjects enrolled in the PAD cohort will be assessed according to Event Schedule A at approximately 0, 3 
months, and 6 months.  Subject follow ups must meet the scheduled time window within +/- 30 days. 
Subjects that require a vascular (re)intervention for PAD-related treatment before the final 
measurement (6 month follow up) will have pertinent data collected and saved in the study registry.  
The vascular procedure may change the timing with respect to the amount of months after baseline that 
the follow up visits occur.  In that case, the standard of care follow up visits post intervention will be 
adhered to, and data will be collected from the follow up visits that correspond most closely to 
timepoints at 3 and/or 6 months post baseline visit.   
Subjects enrolled in the Healthy cohort will be assessed according to Event Schedule C at a single time 
point.  Imaging outside standard of care will not be performed on the healthy subjects, and healthy 
cohort subjects with normal ABI and TBI values will be assumed not to have significant peripheral 
arterial stenosis. 
A registry will be established to store measurements acquired from patients who are enrolled in this 
study and who undergo surgical (re)intervention to address PAD-related symptoms.  The collection of 
data during intervention may occur at any time following the initial and up to the final visit (6 month 
follow-up).  Collected information will include, at minimum, a digitized copy of the intraprocedural 
record log, all timestamped angiographic films collected during the procedure, and continuous FlowMet-
R data collected from the digits of the treated limb.  This portion of the study is exploratory and 
considered hypothesis-generating.  Therefore, no objectives or endpoints are currently established for 
data collected in the registry.  For any subject undergoing (re)intervention during the course of this 
study, the treating physician and all associated site personnel will be blinded to the FlowMet-R outputs 
during the course of the procedure to eliminate any bias or procedural-based determinations on any 
outputs not validated.    

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5.1 Duration 
The expected study duration is approximately 6-12 months.  The duration of individual subject 
participation will vary based on timing of their enrollment and completion of the final follow-up visit; 
however, at a minimum, participation of an individual subject will be at least 6 months.  
5.2 Rationale 
The study will assess the FlowMet-R’s ability to provide a simple and continuous method of assessing 
PAD severity.    To achieve the objectives defined in Section 4.1, FlowMet-R measurements will be 
acquired from the limbs of enrolled patients and the relationship between the FlowMet-R data and 
positive diagnosis of PAD and CLI will be evaluated at multiple time points (initial measurement, 3 
month follow up, and 6 month follow up). Resulting sensitivity, specificity, accuracy, and receiver 
operating characteristic (ROC) curves will be generated to demonstrate diagnostic capability. FlowMet-R 
measurements, along with additional pertinent surgical data, will be collected during revascularization 
procedures from enrolled patients who require surgical intervention. Additionally, changes in FlowMet-R 
data for enrolled patients at each study time point  will be compared to corresponding changes in ankle 
brachial index (ABI), toe brachial index (TBI), or patient symptoms. Finally, the prognostic capability of 
FlowMet-R data will be assessed by calculating the sensitivity and specificity of predicting whether 
surgical (re)intervention will be necessary following initial assessment. 
5.2.1 Prior Benchtop and Animal Studies 
The FlowMet-R has been validated on the benchtop using an artificial digit coupled with a syringe pump. 
When the FlowMet-R was used to measure the flow of a blood-simulating fluid through the artificial 
digit at controlled volumetric flow rates representing the known physiological range, the FlowMet-R 
output exhibited a linear response with respect to the known volumetric flow rate (R2=0.999).   
Additionally, the FlowMet-R has been tested in animal studies  on New Zealand white rabbits and 
Yorkshire pigs.  New Zealand white rabbits (n=5) undergoing cyanide poisoning and resuscitation have 
been monitored using the FlowMet-R for the purpose of assessing peripheral blood flow. Yorkshire pigs 
(n=3) undergoing anesthesia have been monitored using the FlowMet-R to assess blood flow within 
various regions of the pig’s core and extremities. In both studies, the FlowMet-R was used to detect 
increased blood flow during periods of known vasodilation and decreased blood flow during periods of 
known vasoconstriction and periods of measured decreases in cardiac output.  
 
5.2.2 Prior Clinical Studies 
The FlowMet-R has been used previously as a non-significant risk device to study peripheral blood flow 
in five IRB-approved studies without adverse events. The first study (n=37) was a validation study 
performed at the University of California, Irvine (UCI IRB HS# 2006-4876).  The protocol compared blood 
flow measurements during before, during, and after brachial artery occlusion using both the FlowMet-R 
and a laser Doppler system (Perimed Periflux). The study demonstrated a significant correlation 
between FlowMet-R and the laser Doppler systems (all trials showed R > 0.7). A second study (n=47) 

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aimed to correlate the FlowMet-R to the degree of wound in healing in patients with chronic wounds.  
This study was performed as Good Samaritan Hospital, San Jose CA (GSH FWA# 00006889). A third study 
(ongoing) at UCI (HS#: 2016-3286) is designed to measure blood flow dynamics in patients under 
anesthesia.  A fourth study at the Vascular and Interventional Specialists of Orange County (VISOC) 
outpatient clinic in Orange, CA, collected correlative data between FlowMet-R, Rutherford category, ABI, 
and TBI in 100 patients (WIRB #1177294). A fifth study was conducted at the Cleveland Clinic, with 
results presented at ACC March 2018. The final two aforementioned studies found that FlowMet-R data 
could be used to produce a metric which is significantly correlated to TBI and ABI. In totality, these 
studies suggest that FlowMet-R measurement are correlated to existing standards used to assess 
vascular functionality and they provide evidence supporting the safety for FlowMet-R. No adverse 
events have been reported in any study. 
5.3 Study Oversight 
The FlowMet study will be monitored by the sponsor and a third-party research organization,
 and 
made available for monitoring, auditing, IRB review and regulatory inspection by providing direct access 
to study related source data.  
 
Table 1: Clinical Research Organization 
CRO  
Contact Information 
 
 
 
6. Product Description 
6.1 General  
Device trade name: FlowMet-R 
The FlowMet-R is a non-invasive, optical device designed to measure the blood circulation or perfusion 
rate in peripheral tissue such as the fingers and toes. It comprises a control unit with a digital touch 
screen user interface, and a measurement device (resembling a pulse oximeter) that easily clips onto the 
patient’s finger or toe. An image of the FlowMet-R system can be seen in Figure 1. 

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Figure 1: FlowMet-R System Comprised of Digit-Worn Probe and Touchscreen Display 
 
The FlowMet-R instrument head is a compact toe clip designed to be portable and simple to operate.  
The clip consists of three main primary components: a low-power near infrared laser diode, a 
complementary metal–oxide–semiconductor (CMOS) digital camera sensor, and device housing. 
During FlowMet-R operation, light from the laser diode illuminates and diffuses into the tissue.  The 
diffusion of light is governed by the amount of scattering and absorption within the tissue [23-25]. 
Diffuse light transmits through the medium and onto a camera sensor. This creates a well-defined 
pattern, called “laser speckle,” which is recorded by the camera sensor and used to quantify blood flow 
in real-time. Image processing techniques are used to convert collected images into a single value 
representing the average microvascular blood flow within the tissues being measured. These techniques 
have become ubiquitous within the biomedical optics research literature [26]. 
The FlowMet-R received 510(k) clearance from the FDA in March, 2019.  It has been certified by 
 
, an independent medical device testing and certification agency to be compliant with IEC 60601-1 
and IEC 60825-1, which are standards relating to requirements for electrical safety of medical devices 
and the safety of laser products, respectively. The laser diode power is below the IEC 60825-1 maximum 
permissible exposure limits for skin, meaning it does not pose a risk to the tissue being measured. The 
FlowMet-R has been certified to be compliant as Class I laser product, meaning that it can be safely 
viewed during use without use of any eye protection. Compliance with IEC 60601-1 indicates that the 
FlowMet-R does not pose an electronic or mechanical risk to the patient or user. Lastly, skin-contacting 

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materials on the FlowMet-R have been tested by 
, an independent testing and certification 
agency, to be biocompatible via compliance with ISO 10993-5 and ISO 10993-10 (standards relating to 
biocompatibility of medical devices). These results indicate that the FlowMet-R does not induce harmful 
cytotoxicity, sensitization, or irritation when in contact with skin.  
The FlowMet-R should not be used in an MR environment or in a hyperbaric oxygen chamber. This could 
result in unexpected behavior and bodily harm. This FlowMet-R is not defibrillation proof per IEC 60601-
1 clause 8.5.5.  Personnel involved in this study should review the user manual and instructions for use 
for the FlowMet-R which describes proper use of the FlowMet-R prior to use.  There are no other 
potentially dangerous elements. 
 
6.2 Device Risk 
The FlowMet-R is FDA cleared and Medtronic (previously LAS) has determined that the FlowMet-R 
should be classified as a non-significant risk device. The following table, Table 1, outlines the US Food 
and Drug Administration’s description of a significant risk device as per 21 CFR 812.3(m) and why these 
qualities do not apply to the FlowMet-R. 
Under 21 CFR 812.3(m), a 
significant risk device means an 
investigational device that: 
Does the FlowMet-R 
meet this criterion? 
Rationale 
Is intended as an implant and 
presents a potential for serious 
risk to the health, safety, or 
welfare of a subject  
No 
The FlowMet-R is not intended as an 
implant. It is used external to the body 
to measure blood flow using light.  
Is purported or represented to  
be for use supporting or sustaining 
human life and presents a 
potential for serious risk to the 
health, safety, or welfare of a 
subject  
No 
The FlowMet-R will be used to 
measure extremity blood flow, and 
does not perform any life-sustaining 
functions in doing so.  
Is for a use of substantial 
importance in diagnosing, curing, 
mitigating, or treating disease, or 
otherwise preventing impairment 
of human health and presents a 
potential for serious risk  
to the health, safety, or welfare of 
a subject 
No 
The FlowMet-R will be used to collect 
extremity blood flow measurements 
for comparison against existing 
standard assessments of vascular 
health. FlowMet-R data will not be 
used in any way to diagnose, cure, 
mitigate, treat, or change the 
treatment of enrolled subjects. 
Otherwise presents a potential for 
serious risk to the health, safety, 
or welfare of a subject 
No 
FlowMet-R measurements are 
performed non-invasively using light 
and do not present a serious risk to the 
health, safety, or welfare of enrolled 
subjects.   

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Table 1: FDA Non-Significant Risk Designation as per 21 CFR 812.3(m) 
6.3 Product Accountability 
The FlowMet-R received 510(k) clearance from FDA and product supply will be managed in a manner 
consistent with other market-released products.   
7. Study Site Requirements 
7.1 Study Site Activation 
Study site activation is managed by 
.  During the activation process (prior to subject enrollment), 
 will train study site personnel on the clinical investigation plan, relevant standards and regulations, 
informed consent, and data collection and reporting tools.   
Prior to performing study related activities, all regulatory requirements shall be fulfilled, including, but 
not limited to the following: 
− IRB approval of the current version of the clinical investigation plan and informed consent 
− Fully executed clinical trial agreement 
− Financial Disclosure 
− CV of investigators and key members of the investigation study site 
− Documentation of delegated tasks 
− Documentation of study training 
In addition, all participating study site staff must be trained on the current version of the CIP as well as 
on the applicable study requirements depending on their role and must be delegated by the principal 
investigator to perform study-related activities.  
Each study site will be provided with documentation of study site/investigator readiness; this 
notification must be received prior to performing study-related activities.  
8. Selection of Subjects 
8.1 Study Population 
Subjects shall be enrolled until the following number of limbs have been measured under Event 
Schedule A (Section 9.1): 
− 160 control limbs (no diagnosed PAD) 
− 240 limbs with PAD 
− Of the limbs with PAD, a subset >100 limbs with CLI 
− Of the limbs with PAD, a subset >54 limbs without CLI 
Any patient being seen for diagnosis of suspected PAD may be screened for enrollment in the PAD 
cohort.  For patients undergoing intervention, supplemental data will be taken within a catheterization 
laboratory. Control data from a healthy cohort will also be gathered.  Recruitment of healthy subjects is 
at the site's discretion.  Third party recruitment services such as researchmatch.org may be used.   

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8.2 Subject Enrollment 
First, the patient will be asked if he/she would like to participate in the study.  If so, they will undergo 
the informed consent procedure.  
When a subject and the principal investigator or authorized designee, as required, have personally 
signed and dated the IC, the subject is considered to be enrolled in the study.  The date the subject 
signed the IC must be documented in the subject's medical records.   
Subjects will be screened to ensure they meet all of the inclusion and none of the exclusion criteria prior 
to study enrollment.   
8.3 Inclusion Criteria 
Candidates for this study must meet ALL of the following inclusion criteria: 
PAD Positive Cohort 
− Subject meets PAD positive criteria set forth in Section 8.3 
− Subject is willing and able to provide an informed consent. 
− Subject is willing and able to comply with the study procedures. 
− Subject is able to understand the study procedures. 
− Subject is scheduled for vascular examination that includes noninvasive assessments as standard 
of care: ABI, TBI, and either a Duplex ultrasound or Angiogram. 
Healthy Cohort 
− Subject is willing and able to provide an informed consent. 
− Subject is willing and able to comply with the study procedures. 
− Subject is able to understand the study procedures. 
− Subject has no history of positive PAD diagnosis and is not currently suspected of having PAD.   
8.4 Exclusion Criteria 
Candidates for this study who meet any of the following criteria at the time of the baseline visit are NOT 
eligible to be enrolled in this study: 
PAD Positive Cohort Exclusion 
− Subject is under 40 or unable to consent. 
− Subject has any medical condition, which, in the judgment of the Investigator and/or designee, 
makes the subject a poor candidate for the investigational study. 
− Subject is excluded from analysis if no stenosis is found during Doppler but Tibial disease is 
suspected and Tibial ultrasound is not able to be performed. 
− Subject does not have a suitable finger to attach the FlowMet-R probe. 
− Subject does not have a suitable 1st or 2nd digit to attach FlowMet-R probe on the limb of 
interest. 
− Subject has undergone revascularization within the last 90 days 

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− Subject cannot lay safely in a supine position. 
Healthy Cohort Exclusion 
− Subject is under 40 or unable to consent. 
− Subject has any medical condition, which, in the judgment of the Investigator and/or designee, 
makes the subject a poor candidate for the investigational study. 
− One or more limbs has a prior or current diagnosis of PAD, or is reasonably suspected of having a 
diagnosis of PAD. 
− Subject does not have a suitable finger to attach the FlowMet-R probe. 
− Subject does not have a suitable 1st or 2nd digit to attach FlowMet-R probe. 
− Subject has undergone revascularization within the last 90 days 
9. Study Procedures  
9.1 Schedule of Events 
Patients will follow the below event schedules based on their cohort.  PAD patients will follow Event 
Schedule A, Registry patients will follow Event Schedule B, and the Healthy Cohort subjects will follow 
Event Schedule C.   
 
 
Initial and Follow-Up Visits: Event Schedule A 
 

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 Interventional Procedure: Event Schedule B 
 
 
 
 
 

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Healthy Cohort Single Visit: Event Schedule C 
 

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9.2 Data Collection 
Data collection requirements are summarized in Table 2 below.  
Table 2: Data collection and study procedure requirements at subject visits 
Study Procedure 
Baseline 
Registry 
Entry (if 
applicable) 
 
3 month 
6 month 
Study Exit 
Informed Consent 
X 
 
 
 
 
Inclusion/exclusion assessment  
X 
 
 
 
 
Medical History/Demographics 
X 
 
X 
X 
 
Rutherford Grade 
X 
 
X 
X 
 
QoL Survey 
X 
 
X 
X 
 
FlowMet Collection 
X 
 
X 
X 
 
FlowMet Collection 
Intraprocedure 
 
X 
 
 
 
ABI/TBI 
X 
 
X 
X 
 
Exit subject 
 
 
 
 
X 
AEs 
As they occur 
Study deviations 
As they occur 
 

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9.3 Scheduled Follow-up Visit Windows 
The target dates and windows for each visit are detailed in the table below.  Should a subject miss a visit 
or the visit fall outside the pre-specified window, a study deviation must be reported and the original 
follow-up schedule maintained for subsequent visits.   
Data analyses include follow-up visits regardless of whether the visit occurs within the window.  
Therefore, a late visit is preferred over a missed visit, but must be accompanied by a deviation report.  
Follow-up visit windows are listed in Table 3, and are based on days post-FlowMet-R assessment.   
Table 3: Data collection and study procedure requirements at subject visits 
Study Follow-up Visit 
Window 
(Calculated days post-FlowMet-R Assessment) 
Window Start 
Target 
Window End 
Follow-up Visit 1 
2 months 
3 months 
4 months 
Follow-up Visit 2 
5 months 
6 months 
7 months 
9.4 Subject Consent 
Informed consent is defined as a legally effective documented confirmation of a subject's voluntary 
agreement to participate in a particular study. This process includes obtaining an Informed Consent 
Form that has been approved by the study site's IRB and signed and dated by the subject.  A subject may 
only consent after information has been given and explained to the subject on all aspects of the clinical 
investigation that are relevant to the subject's decision to participate.   
Prior to enrolling subjects, the informed consent must be approved by the site's IRB.  The document 
must be controlled to ensure it is clear which version was approved by the IRB.  Any adaptation of the 
sample informed consent must be reviewed and approved by Medtronic and the IRB reviewing the 
application prior to enrolling subjects.   
The investigator must notify the subject of any significant new findings about the study that become 
available during the course of the study which are pertinent to the safety and well-being of the subject, 
as this could impact a subject's willingness to participate in the study.  If relevant, consent may be 
requested from subjects to confirm their continued participation.   
Prior to initiation of any study-specific procedures, informed consent must be obtained from the 
subject.  The informed consent process must be conducted by the principal investigator or an authorized 
designee, and the informed consent form must be given to the subject in a language he/she is able to 
read and understand.  The process of informed consent must be conducted without using coercion or 
undue improper influence on or inducement of the subject to participate by the investigator or other 
study site personnel.  The informed consent process shall not waive or appear to waive subject's legal 
right.  The language used shall be as non-technical as possible and must be understandable to the 
subject and the impartial witness, where applicable.  
The subject must have ample time and opportunity to read and understand the informed consent form, 
to inquire about details of the study, and to decide whether or not to participate in the study.  All 
questions about the study should be answered to the satisfaction of the subject.   

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When the subject decides to participate in the study, the informed consent must be signed and 
personally dated by the subject and investigator or authorized designee, as required by the informed 
consent, and ensured by the principal investigator or his/her authorized designee.    
A copy of the informed consent, signed and dated as required by law, must be provided to the subject.   
If the informed consent is obtained the same day the subject begins participating in study-related 
procedures, it must be documented in the subject's case history that consent was obtained prior to 
participation in any study-related procedures.   
In the event that the subject cannot read and/or write, the informed consent process shall be obtained 
through a supervised oral process.  An independent and impartial witness must be present during this 
process.  This informed consent and any other information must be read aloud to the prospective 
subject.  Whenever possible, the subject shall sign and personally date the informed consent form.  The 
witness signs and personally dates the informed consent attesting that the information was accurately 
explained and that informed consent was freely given.   
The original signed informed consent must be filed in the hospital/clinical chart and/or with the 
subject's study documents.  The informed consent must be available for monitoring and auditing.   
 
9.5 Baseline Visit 
9.5.1 Relevant Medical History and Demographics 
The clinician will document demographics and medical history on the associated Case Report Forms and 
enter them into the Electronic Data Capture (EDC) system. 
For patients that are seen for a vascular (re)intervention and are part of the registry portion of the 
study, standard information about the patient’s scheduled intervention, treatment plan, and follow up 
schedule will be contained in the record log and uploaded as a digital copy. 
9.5.2 QoL Assessment 
Quality of Life (QoL) assessments are an important reporting standard for PAD patients.  The VascuQoL 
is a questionnaire that has been used frequently by clinical studies in the past in evaluating QoL in CLI 
and Claudication patients [28]. Here, we choose to use the abbreviated VascuQoL-6, a 6 item survey that 
has been shown to be as effective as the standard VascuQoL, but with reduced time burden on patients 
and clinicians [29].    
9.5.3 Rutherford Classification / Visual Assessment  
The Rutherford scoring system is commonly used in vascular assessment of PAD patients. Grade and 
category will both be recorded for enrolled patients on the CRF.  The clinician will also note visual 
inspection of limbs for evidence of ulcers or wounds.  If present, wound grade and foot infection grade 
will be noted as well as wound healing trajectory. 

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9.6 FlowMet-R Assessment 
FlowMet-R measurements will be taken before noninvasive testing as detailed in Event Schedule A.  
Clinical personnel must be trained on use of the FlowMet-R device prior to measurement. Details of the 
measurement acquisition procedure are as follows: 
− A patient rest period shall be performed in accordance with standard ABI collection before 
FlowMet-R or ABI measurement.  Extremity blood flow measurements will be performed using 
the FlowMet-R device in the following order: index finger of the upper right hand (if the index 
finger is unavailable another finger may be used), and on the great toe (if the great toe is not 
available the 2nd toe may be used, and this will be noted in the CRF) of the limbs being 
measured.  If measuring bilaterally, the right side will be performed first. 
− Once the probe is placed on the digit, flow will be allowed to equilibrate for approximately 30 
seconds before checking signal quality to allow transient changes in perfusion to diminish.  Signal 
quality will be confirmed by observing the presence of a pulse waveform (if one is expected), or 
by the stability of the flatline (in the case of complete occlusion). The clinician will also ensure 
that an appropriate amount of light is detected by the FlowMet-R device. The following light 
intensity values are acceptable: maximum intensity greater than 30 but less than 255 and 
average intensity greater than 25 but less than 200. The FlowMet-R device will indicate to the 
clinician if the intensity is outside of proper bounds by displaying a warning. The clinician should 
then adjust the probe until the warning disappears.   
− The patient shall be instructed not to move, laugh, talk, etc. during the measurement. These 
actions can cause erroneous FlowMet-R measurements due to movement artifact. If this occurs, 
the measurement will need to be repeated and this should be noted in the CRF. 
− Following the 30 second equilibration period, the clinician will then record FlowMet-R blood flow 
data for approximately 30 seconds using the data acquisition software, which will save the data 
on the local hard drive.  Once data collection is complete, the clinician will note the “flow value” 
and waveform fidelity displayed in the software on the CRF. 
− A post-hoc data quality check must be performed before taking the next flow measurement. 
Data fidelity will be assessed by observing the recorded waveform using the analysis tab of the 
software.  The flow waveform should appear periodic without large unexpected spikes 
(indicating motion artifact) or sections that are missing (indicating over- or under- exposure).  
See Figure 3 (top) for examples of high quality flow waveform data and compromised data. In 
cases of advanced disease, the waveform may be severely dampened or not be present at all.  In 
cases where advanced disease has occluded blood flow and a waveform is not expected, the user 
will check the flow measurement to ensure the flow graph is relatively flat and there are no 
major motion artifacts in the flow recording.  See Figure 3 (bottom) for examples of high quality 
and compromised data from patients with advanced disease. 
− If the post-hoc data quality check reveals poor quality or missing data, steps 2-5 must be 
repeated until acceptable data has been recorded.  This may require a repositioning of the 
probe.  If 5 or more repeated attempts are made and poor quality data persists, the clinician will 
choose the optimal record to the best of their knowledge.  

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Figure 3: Example illustrations of high fidelity flow measurements (left column) compared 
with flow measurements that are corrupted by artifact (right column).   
 
 
9.6.1 Product Equipment 
9.6.1.1 FlowMet-R 
The FlowMet-R is a non-invasive optical device that measures real time blood flow/perfusion rate in the 
extremities using the principles of laser speckle imaging (LSI). To perform LSI, tissue is illuminated with 
coherent laser light, which scatters off moving red blood cells and produces a speckle pattern.  The 
pattern is recorded on an image sensor and the characteristics can be used to measure blood 
flow/perfusion, as demonstrated in prior literature [26]. 
During use, the FlowMet-R probe is affixed onto the toes using a spring-loaded clip, with the light source 
(laser diode) and image sensor (digital camera) on opposite sides.  The image sensor and readout 
circuitry are custom designed for a compact profile and adequate spatial sampling of the speckle pattern 
[27].  Molded, biocompatible silicone pads are used within the FlowMet-R probe in locations where the 
device contacts skin.  Data acquisition, processing, display, and user interaction is performed using 
custom software run on a computer with Windows 10 operating system. Between uses, the skin-
contacting silicone pads and probe housing can be sanitized using alcohol wipes or germicidal wipes, 
such as PSI Inc. Sani-Cloths, which are commonly used in hospitals and which are bactericidal, 
tuberculocidal, and virucidal. The FlowMet-R has been used in NSR-designated IRB approved studies on 

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more than 100 patients without adverse events. The FlowMet-R was 510(k) cleared by the FDA in early 
March, 2019. 
If the FlowMet-R system malfunctions and/or needs to be serviced, this will be reported on the EDC and 
to Medtronic.  Medtronic will provide technical assistance within 48 hours.  If the system requires repair 
or replacement, Medtronic will provide a new unit to the site within 5 business days.   
9.6.1.2 Automatic ABI System 
Medtronic will provide an automated PAD system, the Flolab (Parks Medical Electronics, Inc., Aloha, OR) 
which will be provided to each site by Medtronic and used to perform ABI and TBI measurements. An 
automated device can improve measurement consistency between sites and help reduce inter-operator 
differences.  The system includes a 4 Piece set of standard 8½"-14" (22 cm-36 cm) cuffs, a PPG monitor, 
and a control unit, which is used to automatically perform bilateral ABI and TBI measurements.  
Measurements results will be printed out and included in the CRF.  If the automated system cannot be 
used or is unavailable, manual ABI and TBI measurements will be performed.  Clinical personnel must be 
trained on use of the Flolab device prior to taking ABI and TBI measurements with the system. 
9.7 Standard Noninvasive Vascular Assessments 
Noninvasive testing and Duplex imaging results will be evaluated on the same leg(s) used to collect 
FlowMet-R data with the patients lying supine. The results will be recorded on the CRF.  If color duplex 
imaging is not scheduled as standard of care, angiographic images taken within 30 days prior to the 
noninvasive measurements may be used for calculation of stenosis percentage.   
9.7.1 Toe brachial index (TBI)  
A patient rest period shall be performed in accordance with standard ABI/TBI collection before 
FlowMet-R or ABI/TBI measurement.  Brachial pressures and toe pressures on both lower limbs (if 
applicable) will be measured according to the 2016 guidelines provided by the ACC/AHA using an 
automated TBI system. A PPG device will be used to detect the toe waveform. Measurement results will 
be recorded on the CRF. 
9.7.2 Ankle brachial index (ABI)  
A patient rest period shall be performed in accordance with standard ABI/TBI collection before 
FlowMet-R or ABI/TBI measurement.  Brachial pressures and ankle pressures on both lower limbs (if 
applicable) will be measured according the 2016 guidelines provided by the ACC/AHA using an 
automated sphygmomanometer-based system. Measurement results will be recorded on the CRF. 
9.7.3 Postexercise ankle brachial index (ABI)  
If an enrolled patient’s ABI and TBI measurements classify that patient as not having PAD/CLI as per the 
definitions in Section 8.4, but it is suspected that the patient may have PAD based upon medical history 
or clinical symptoms, a postexercise ABI measurement will be performed. For such patients, guidelines 

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provided by the ACC/AHA will be followed.  A treadmill or heel-raise test will be considered an 
acceptable challenge for measurement of postexercise ABI.  
9.7.4 Duplex ultrasound 
Color duplex ultrasound measurements shall be used to determine stenosis percentage and location, 
either during the visit itself or within 30 days prior of the patient visit.  Duplex shall be acquired from all 
limbs enrolled in the study with PAD/CLI as defined via the definitions in Section 8.4. If duplex 
ultrasound is not available, X-ray angiography will be considered a suitable alternative for calculation of 
stenosis and location.  Color duplex ultrasound imaging will be performed in a similar fashion as the 
study by Lewis, et al. [30].  First, the distal common femoral artery (CFA) will be imaged and the Doppler 
waveform (DW) assessed visually for any loss of triphasic flow due to significant iliac disease. If the DW 
shows indications of this, then the iliac arteries will be assessed for the presence of atherosclerotic 
disease. The scan will continue distally from the CFA assessing the superficial femoral artery (SFA), 
popliteal, anterior tibial, posterior tibial, and peroneal arteries in the longitudinal plane. The extent and 
severity of any arterial disease are assessed by measuring the peak systolic velocity (PSV) from the DW 
just proximal to and distal through the stenosis. For each measured artery, if perceptible stenosis exists, 
the location of maximum stenosis will be identified and PSV values distal and proximal to the arterial 
stenosis will be noted on the CRF. The shape of the waveform (i.e. monophasic, biphasic, or triphasic) 
measured distal to the stenosis shall also be noted. If no stenosis is noted, this will indicated on the CRF. 
9.7.5 X-Ray Angiography 
Peripheral angiography may be used as an alternative to duplex ultrasound in the assessment of arterial 
stenosis percentage and location, and may be performed during the visit itself or within 30 days prior.  
Angiography is an imaging technique to diagnose narrowed or blocked peripheral arteries, the hallmark 
of PAD.  Angiograms may or may not include dye for improving image contrast. Angiograms have been 
used for decades and are considered the gold standard for evaluating vascular disease.  Advanced 
techniques, such as the computed tomographic angiogram (CTA), and digital subtraction angiography 
(DSA) have gained popularity in recent years and have shown reliable sensitivity and specificity for 
differentiating extend of disease [31]. 
9.8 Intraprocedural Data Collection 
Patients enrolled in the study who undergo revascularization surgery to address PAD/CLI will have 
pertinent data collected immediately before, during, and immediately after the surgical procedure. The 
schedule of events is summarized in Event Schedule B above (section 9.1). The following steps shall be 
followed: 
− Prior to the start of the procedure, the FlowMet-R probe will be attached to the upper extremity 
for a 30-second recording.  Next, the probe will be moved to the great toe of the limb being 
treated. If this digit is not usable, another digit may be used.  
− Once the probe is placed on the digit, flow will be allowed to equilibrate for 30 seconds before 
checking signal quality to allow transient changes in perfusion to diminish.  Signal quality will be 

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confirmed by observing the presence of a pulse waveform (if one is expected), or by the stability 
of the flatline (in the case of complete occlusion). The clinician will also ensure that an 
appropriate amount of light is detected by the FlowMet-R device. The following light intensity 
values are acceptable: maximum intensity greater than 30 but less than 255 and average 
intensity greater than 25 but less than 200. The FlowMet-R device will indicate to the clinician if 
the intensity is outside of proper bounds by displaying a warning. The clinician should then adjust 
the probe until the warning disappears.  After proper placement and collection of the FlowMet-R 
and sensor have been confirmed, the physician shall be blinded to all outputs during and after 
the course of the intervention. 
− Movement of FlowMet-R probe should be minimized during the procedure to prevent motion 
artifact and measurement errors.  
− If the FlowMet-R probe is accidently removed during the procedure or if a data quality warning is 
displayed by the FlowMet-R software (i.e. too much or too little light is being detected), the 
probe shall be replaced or reseated on the digit it was originally placed on (if possible). If this is 
not possible, a different digit may be used and this change shall be noted.  
− The digit being measured and patient ID should be entered into the Patient Data section of the 
FlowMet-R software.  
− FlowMet-R data saving shall be initiated prior to state of surgery. Therapies and notable events 
for each procedure, including timing, shall be recorded.   
− The surgical procedure shall take place as per the standard of care.  
− At the end of the procedure, FlowMet-R data saving shall be ceased.  
− FlowMet-R data, along with angiographic films, and other pertinent information related to the 
surgical procedure such as patient symptoms and visual assessment shall be uploaded to the 
registry EDC.  
 
9.9 Deviation Handling 
A study deviation is defined as an event within a study that did not occur according to the clinical 
investigation plan or clinical trial agreement.   
Prior approval by Medtronic is expected in situations where the investigator anticipates, contemplates, 
or makes a conscious decision to deviate. Prior approval is not required when a deviation is necessary to 
protect the safety, rights or well-being of a subject in an emergency or in unforeseen situations beyond 
the investigator’s control (e.g. subject failure to attend scheduled follow-up visits, inadvertent loss of 
data due to computer malfunction, inability to perform required procedures due to subject illness). 
Any deviation from this protocol will be noted and described in the EDC system under the deviations 
from protocol section.  
9.10 Subject Exit, Withdrawal or Discontinuation 
The study exit form should be completed at the time a subject is exited from the study.  A subject will be 
considered to have exited from the study for any of the following reasons.  
− Subject completes follow-ups required by the investigational plan 
− Subject dies 

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− Subject requests to be withdrawn 
− Physician requests that patient be withdrawn to protect the welfare of the patient 
− Subject is lost to follow-up 
A subject may elect to withdraw from the study at any time.  The subject should notify the investigator.  
The investigator and research staff should encourage all subjects to return for required follow-up visits.  
Every attempt must be made to ensure all subjects complete the follow-up schedule.  For subjects who 
fail to appear for a scheduled study visit, the site must contact the subject in a timely manner to 
reschedule the visit and associated required evaluations within the subject's window, if possible.   
10. Risks and Benefits 
10.1 Potential Risks 
The FlowMet-R is FDA cleared and Medtronic (previously LAS)has determined that the FlowMet-R 
should be classified as a non-significant risk device. There are no incremental risks introduced to the 
subject as a result of participation in this study.   
10.2 Risk Minimization 
The potential risks associated with the FlowMet-R have been successfully mitigated.  Any potential risks 
associated with this study are further minimized by selecting qualified investigators and training study 
personnel on the CIP.   
Prior benchtop, animal, and clinical studies have been performed previously.   
The FlowMet-R has been validated on the benchtop using an artificial digit coupled with a syringe pump. 
When the FlowMet-R was used to measure the flow of a blood-simulating fluid through the artificial 
digit at controlled volumetric flow rates representing the known physiological range, the FlowMet-R 
output exhibited a linear response with respect to the known volumetric flow rate (R2=0.999).   
Additionally, the FlowMet-R has been tested in animal studies on New Zealand white rabbits and 
Yorkshire pigs.  New Zealand white rabbits (n=5) undergoing cyanide poisoning and resuscitation have 
been monitored using the FlowMet-R for the purpose of assessing peripheral blood flow. Yorkshire pigs 
(n=3) undergoing anesthesia have been monitored using the FlowMet-R to assess blood flow within 
various regions of the pig’s core and extremities. In both studies, the FlowMet-R was used to detect 
increased blood flow during periods of known vasodilation and decreased blood flow during periods of 
known vasoconstriction and periods of measured decreases in cardiac output. 
The FlowMet-R has been used previously as a non-significant risk device to study peripheral blood flow 
in five IRB-approved studies without adverse events The first study (n=37) was a validation study 
performed at the University of California, Irvine (UCI IRB HS# 2006-4876).  The protocol compared blood 
flow measurements during before, during, and after brachial artery occlusion using both the FlowMet-R 
and a laser Doppler system (Perimed Periflux). The study demonstrated a significant correlation 
between FlowMet-R and the laser Doppler systems (all trials showed R > 0.7). A second study (n=47) 
aimed to correlate the FlowMet-R to the degree of wound in healing in patients with chronic wounds.  
This study was performed as Good Samaritan Hospital, San Jose CA (GSH FWA# 00006889). A third study 
(ongoing) at UCI (HS#: 2016-3286) is designed to measure blood flow dynamics in patients under 
anesthesia.  A fourth study at the Vascular and Interventional Specialists of Orange County (VISOC) 

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outpatient clinic in Orange, CA, collected correlative data between FlowMet-R, Rutherford category, ABI, 
and TBI in 100 patients (WIRB #1177294). A fifth study was conducted at the Cleveland Clinic, with 
results presented at ACC March 2018. The final two aforementioned studies found that FlowMet-R data 
could be used to produce a metric which is significantly correlated to TBI and ABI. In totality, these 
studies suggest that FlowMet-R measurement are correlated to existing standards used to assess 
vascular functionality and they provide evidence supporting the safety for FlowMet-R. No adverse 
events have been reported in any study. 
10.3 Potential Benefits 
There are no anticipated benefits from participation in this study.  The information gained from this 
study could result in improved management and diagnosis of PAD and CLI.   
10.4 Risk-Benefit Rationale 
The FlowMet-R is FDA cleared and has been classified as a non-significant risk device.   
11. Adverse Events and Device Deficiencies 
11.1 Adverse Events 
Investigators shall submit a report of any device-related or suspected device-related adverse or serious 
adverse event to the sponsor and IRB as soon as possible, but in no event later than 5 business days 
after the investigator first learns of the event (§ 812.150(a)(1)).  These reports shall be uploaded to the 
EDC system and will only include adverse events that could reasonably be associated with use of the 
FlowMet device.  All Adverse Events reported to the Sponsor during the study will be reviewed and 
adequately reported to comply with applicable regulations (ISO 14155:  
 and vigilance requirements. All adverse events will be classified according, at a minimum, to ISO 14155: 
. Medtronicwill also determine whether a reported Adverse Event is anticipated or unanticipated. 
Investigators will be asked to classify whether an adverse event is considered serious or non-serious and 
whether it is considered device related.  If an event is determined to be Serious and device related, 
investigators will be asked to make a determination as to whether or not the study can remain an NSR 
study. If needed, this determination will be submitted to the IRB. Potential complications are listed in 
section 6.2.  Unexpected complications are also possible, as any electronic device carries some medical 
risk.  Potential complications include slight discomfort due to warming of the interrogated tissue during 
normal function of the internal components (approximately <1% probability).   
Potential complications include slight discomfort due to warming of the interrogated tissue during 
normal function of the internal components (approximately <1% probability).   
 

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12. Statistical Design and Methods 
12.1 General Aspects of Analysis 
12.1.1 
Sample Size 
The rate of PAD and CLI within the population seen at a typical vascular clinic is estimated from prior 
investigation (i.e WIRB #1177294). In this previous study, 100 limbs were assessed using the ABI and 
graded using the Rutherford classification scheme. PAD (diagnosed via ABI score of <0.9) was present in 
63% of limbs. CLI (estimated as having a Rutherford category of ≥4) occurred in 15% of limbs. FlowMet-R 
data was also collected from the above limbs, and the data analysis techniques used in the data analysis 
section below were applied to build a diagnostic model for PAD and CLI.  ROC curves were then 
generated for the diagnosis of both Claudication and CLI. The resulting area under the curve (AUC) for 
these ROC curves was 0.67 and 0.80, respectively. However, the Claudicant group AUC had a tighter 
confidence interval due to larger sample size (84 vs. 22). 
Using a conservative estimation that the AUC for distinguishing PAD groups from healthy controls 
remains within +/- 0.05 of the Claudicant group, and +/- 0.2 of the CLI group, an estimate for the 
necessary sampling size can be determined. A standard type I error rate (α) of 0.05 and power of 0.8 is 
desired, thus the following approximate sample size was calculated for statistically significant results 
[32, 33]:  160 control limbs and 240 limbs with PAD, of which at least 54 limbs with Claudication and at 
least 100 limbs with CLI.  Limbs with CLI may be included as a subset of limbs with PAD.  A minimum of 
250 patients (400 limbs) and maximum of 400 patients will be enrolled in the study. 
 
12.1.2 
FlowMet-R data analysis and diagnostic model 
FlowMet-R data is comprised of continuous blood flow data recorded over 30 seconds. Over this time, a 
pulsatile blood flow waveform may be present due to the subject’s cardiac cycle, provided that digital 
blood flow is sufficient to generate such a signal.  Thus, a combination of the flow amplitude and one or 
more features of the waveform may be used as inputs to train the predictive model. 
The target outcome variable for training the model shall be a continuous metric of PAD severity, 
analogous to the ABI or TBI.  The training will be performed as a regression using iterative algorithms 
ubiquitous in machine learning. 
The predicted outputs from the regression model will be used to generate an ROC curve by classifying a 
binary diagnostic (i.e. PAD true/false, CLI true/false), or prognostic (i.e. vascular intervention likely 
within 6 months (true/false)). The classification algorithm which results in the highest diagnostic area 
under the curve for PAD and CLI shall be chosen to compute final sensitivity and specificity.   
A k-fold cross validation scheme will be implemented to gauge model generalization.  k-fold cross 
validation is a statistical sampling method that can be used to train and objectively validate the above 

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classification algorithms [34]. Using this scheme, only a subset of the total body of collected data is used 
to train the model, which is then applied to the remaining data withheld from training prospectively. 
During this validation stage, the performance and generalizability of the model can be assessed. Cross 
validation allows more objective selection of the optimal algorithm because performance assessment is 
based upon applying the model to a data set which it is naïve to (i.e. a prospective application of the 
model). 
12.1.3 
Analysis of Stenosis 
For each artery measured using duplex ultrasound or arterial angiography, the ratio of the PSV distal to 
the most prominent stenosis to the PCV proximal to the stenosis will be computed (if applicable). The 
percent stenosis in such arteries will be computed two ways: (1) Percent stenosis  = 
PSVdistal/PSVproximal, or (2) using the diameter reduction value from Table 3, reprinted from [35]. 
 
 
Table 3: Criteria for determining arterial stenosis using peak systolic velocity (PSV) measurements. 
Classification of the percent stenosis or presence of greater than 50% stenosis for each limb (used to 
generate corresponding ROC curve or correlation coefficient) may be determined by either considering a 
single artery of interest or by considering the artery in each limb with the greatest percent stenosis.  
13. Ethics 
13.1 Statement(s) of Compliance 
This study will be conducted in compliance with Good Clinical Practice. GCP includes review and 
approval by an independent IRB before initiating a study, continuing review of an ongoing study by and 
IRB, and obtaining and documenting the freely given informed consent of a subject before initiating the 
study.   
The FlowMet-R study is compliant with ISO 14155.This includes the protection of the rights, safety and 
well-being of human subjects, controls to ensure the scientific conduct and credibility of the clinical 
investigation and the definition of responsibilities of the sponsor and investigator.  In accordance with 
ISO 14155, the sponsor shall avoid improper influence on, or inducement of, the subject, monitor, any 
investigator or other parties participating in or contributing to the clinical investigation.   

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The principles of the Declaration of Helsinki have been implemented throughout the informed consent 
process, IRB approval, and study training.   
In addition to the regulatory requirements outlined above, the study will be conducted according to 
federal, national and local laws, regulations, standards, and requirements of the United States, where 
the study is being conducted.  These include, but are not limited to: 
− 21 CFR Part 11: Electronic Records, Electronic Signatures 
− 21 CFR Part 50: Protection of Human Subjects 
− 21 CFR Part 54: Financial Disclosure by Clinical Investigators 
− 21 CFR Part 56: IRB 
− Principles of the Declaration of Helsinki 
 
 
14. Study Administration 
14.1 Monitoring 
The FlowMet-R study will be monitored by the sponsor and a third-party research organization, 
, 
and made available for monitoring, auditing, IRB review and regulator inspection by providing direct 
access to study related source data.  Site monitors will visit the site periodically to ensure adherence to 
the protocol.   
14.2 Data Management 
An EDC system will be created that contains the case report forms (CRF) to be filled out for each 
enrolled subject.   The sites may optionally use a paper-based form for collecting key data from the 
patient during the visit, then upload the results to the EDC post-visit. 
All records and other information about subjects participating in this study will be treated as 
confidential. Procedures in the CIP require source documentation. Source documentation will be 
maintained at the study site. Source documents, which may include worksheets and subject medical 
records, , must be created and maintained by the investigational study site team.  
The investigator will clearly mark clinical records to indicate that the subject is enrolled in this clinical 
investigation. The data reported on the CRFs shall be derived from source documents and be consistent 
with these source documents, and any discrepancies shall be explained in writing. 
14.3 Direct Access to Source Data/Documents 
When applicable, the monitors, auditors, the IRB, the Office of Human Subjects Protection (OHRP) of the 
Department of Health and Human Services as well as the Food and Drug Administration (FDA) will be 
granted direct access to medical records for verification of the research procedures and data.  

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14.4 Confidentiality 
The study will be conducted in a manner consistent with the federal Health Insurance Portability and 
Accountability Act (HIPAA).  Only non-identifiable health information will be collected and stored in the 
EDC database.  The research staff at individual sites may use and share information to ensure research 
meets legal, institutional, or accreditation requirements.  If the research team uncovers abuse, neglect, 
or reportable diseases, this information may be disclosed to appropriate authorities.  As part of the 
study, the PI, study team, and others may disclose non-identifiable protected health information to the 
following: 
− The commercial sponsor and/or their representative Medtronic Inc.  
− Contract Research Organization (whose job is to help organizations fulfill their responsibilities in 
the research and development process):
 
− The United States Food and Drug Administration 
− The United States Department of Health and Human Services and the Office of Human Research 
Protection (OHRP). 
In all disclosures outside of individual study sites, no subject shall be identified by name, social security 
number, address, telephone number, or any other direct personal identifier unless disclosure of the 
direct identifier is required by law.  OHRP  and FDA are authorized to remove information with 
identifiers if necessary to complete their task. 
14.5 Liability 
14.6 Liability provisions are expressed in each site clinical trial 
agreement.  CIP Amendments 
− Any revisions or amendments to the CIP or IC document, along with a statement of justification 
for the changes, will be submitted to all affected IRBs.  All amendments to the CIP shall be agreed 
upon between Medtronic and the principal investigator(s), or the coordinating investigator. 
Approval by IRB must be obtained prior to implementing a CIP revision at the study site. 
14.7 Record Retention 
The investigator will maintain complete and accurate study records in an encrypted file located 
exclusively at the clinic for 2 years following study closure. The investigator should take measures to 
prevent accidental or premature destruction of documents. Should the investigator wish to assign the 
study records to another party or move them to another location, advance written notice must be given 
to Medtronic. 
Medtronic will retain the study records according to Medtronic corporate policy and record retention 
schedule. 

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14.8 Suspension or Early Termination 
14.8.1 
Planned Study Closure 
Study Closure is a process initiated by distribution of a study closure letter. Study closure is defined as 
closure of a study that occurs when Medtronic requirements have been satisfied per the CIP. Ongoing 
IRB oversight is required until the overall study closure process is complete.  
14.8.2 
Early Termination or Suspension 
Early Termination is the closure of a study that occurs prior to meeting defined endpoints. This is 
possible for the whole study or a single study site.  
Suspension is a temporary postponement of study activities related to enrollment and distribution of 
the product. This is possible for the whole study or a single study site.  
15. References 
 
1. 
Mosely, L.H. and F. Finseth, Cigarette smoking: impairment of digital blood flow and 
wound healing in the hand. The Hand, 1977(2): p. 97-101. 
2. 
Stadelmann, W.K., A.G. Digenis, and G.R. Tobin, Impediments to wound healing. The 
American journal of surgery, 1998. 176(2): p. 39S-47S. 
3. 
Cronberg, C., et al., Peripheral arterial disease. Acta Radiologica, 2003. 44(1): p. 59-66. 
4. 
Ouriel, K., Peripheral arterial disease. The lancet, 2001. 358(9289): p. 1257-1264. 
5. 
Falanga, V., Wound healing and its impairment in the diabetic foot. The lancet, 2005. 
366(9498): p. 1736-1743. 
6. 
Norgren, L., et al., Inter-society consensus for the management of peripheral arterial 
disease (TASC II). European Journal of Vascular and Endovascular Surgery, 2007. 33(1): p. S1-S75. 
7. 
Hirsch, A.T., et al., ACC/AHA 2005 Practice Guidelines for the management of patients 
with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a 
collaborative report from the American Association for Vascular Surgery/Society for Vascular 
Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular 
Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on 
Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients 
With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and 
Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular 
Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation, 
2006. 113(11): p. e463-654. 
8. 
Hirsch, A.T., et al., National health care costs of peripheral arterial disease in the 
Medicare population. Vascular Medicine, 2008. 13(3): p. 209-215. 

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9. 
Varu, V.N., M.E. Hogg, and M.R. Kibbe, Critical limb ischemia. Journal of vascular 
surgery, 2010. 51(1): p. 230-241. 
10. 
Sprengers, R.W., et al., Quality of life in patients with no-option critical limb ischemia 
underlines the need for new effective treatment. Journal of vascular surgery, 2010. 52(4): p. 
843-849. e1. 
11. 
Jakobsson, A. and G. Nilsson, Prediction of sampling depth and photon pathlength in 
laser Doppler flowmetry. Medical and biological Engineering and Computing, 1993. 31(3): p. 
301-307. 
12. 
Padberg Jr, F.T., et al., Transcutaneous oxygen (TcPO 2) estimates probability of healing 
in the ischemic extremity. Journal of Surgical Research, 1996. 60(2): p. 365-369. 
13. 
Got, I., [Transcutaneous oxygen pressure (TcPO2): advantages and limitations]. Diabetes 
& metabolism, 1998. 24(4): p. 379-384. 
14. 
Belch, J.J., et al., Critical issues in peripheral arterial disease detection and management: 
a call to action. Archives of internal medicine, 2003. 163(8): p. 884-892. 
15. 
Xu, D., et al., Sensitivity and specificity of the ankle—brachial index to diagnose 
peripheral artery disease: a structured review. Vascular Medicine, 2010. 15(5): p. 361-369. 
16. 
Aboyans, V., et al., Measurement and interpretation of the ankle-brachial index: a 
scientific statement from the American Heart Association. Circulation, 2012. 126(24): p. 2890-
2909. 
17. 
Bunte, M.C., et al., Validation of the relationship between ankle–brachial and toe–
brachial indices and infragenicular arterial patency in critical limb ischemia. Vascular Medicine, 
2015. 20(1): p. 23-29. 
18. 
Randhawa, M.S., et al., Prevalence of tibial artery and pedal arch patency by 
angiography in patients with critical limb ischemia and noncompressible ankle brachial index. 
Circulation: Cardiovascular Interventions, 2017. 10(5): p. e004605. 
19. 
Shishehbor, M.H. and G.W. Reed, Personalized approach to revascularization of critical 
limb ischemia, 2014, Am Heart Assoc. 
20. 
Writing Committee, M., et al., 2016 AHA/ACC Guideline on the Management of Patients 
With Lower Extremity Peripheral Artery Disease: A Report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation, 
2017. 135(12): p. e726-e779. 
21. 
Eiberg, J.P., et al., Duplex Ultrasound Scanning of Peripheral Arterial Disease of the 
Lower Limb. European Journal of Vascular and Endovascular Surgery, 2010. 40(4): p. 507-512. 
22. 
Begelman, S.M. and M.R. Jaff, Noninvasive diagnostic strategies for peripheral arterial 
disease. Cleveland Clinic journal of medicine, 2006. 73(4): p. S22. 
23. 
Anderson, R.R. and J.A. Parrish, The optics of human skin. Journal of investigative 
dermatology, 1981. 77(1): p. 13-19. 
24. 
Prahl, S.A., et al., A Monte Carlo model of light propagation in tissue. Dosimetry of laser 
radiation in medicine and biology, 1989. 5: p. 102-111. 

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25. 
Wilson, B. and G. Adam, A Monte Carlo model for the absorption and flux distributions 
of light in tissue. Medical physics, 1983. 10(6): p. 824-830. 
26. 
Boas, D.A. and A.K. Dunn, Laser speckle contrast imaging in biomedical optics. Journal of 
biomedical optics, 2010. 15(1): p. 011109-011109-12. 
27. 
Kirkpatrick, S.J., D.D. Duncan, and E.M. Wells-Gray, Detrimental effects of speckle-pixel 
size matching in laser speckle contrast imaging. Optics letters, 2008. 33(24): p. 2886-2888. 
28. 
Stoner, M.C., et al., Reporting standards of the Society for Vascular Surgery for 
endovascular treatment of chronic lower extremity peripheral artery disease. Journal of 
Vascular Surgery, 2016. 64(1): p. e1-e21. 
29. 
Nordanstig, J., et al., Vascular Quality of Life Questionnaire-6 facilitates health-related 
quality of life assessment in peripheral arterial disease. Journal of Vascular Surgery, 2014. 59(3): 
p. 700-707.e1. 
30. 
Lewis, J.E.A., P. Williams, and J.H. Davies, Non-invasive assessment of peripheral arterial 
disease: Automated ankle brachial index measurement and pulse volume analysis compared to 
duplex scan. SAGE Open Medicine, 2016. 4: p. 2050312116659088. 
31. 
Met, R., et al., Diagnostic performance of computed tomography angiography in 
peripheral arterial disease: a systematic review and meta-analysis. Jama, 2009. 301(4): p. 415-
424. 
32. 
Hulley, S.B., et al., Designing clinical research. 2013: Lippincott Williams & Wilkins. 
33. 
Obuchowski, N.A., ROC analysis. American Journal of Roentgenology, 2005. 184(2): p. 
364-372. 
34. 
Arlot, S. and A. Celisse, A survey of cross-validation procedures for model selection. 
Statistics surveys, 2010. 4: p. 40-79. 
35. 
Gerhard-Herman, M., et al., Guidelines for noninvasive vascular laboratory testing: a 
report from the American Society of Echocardiography and the Society for Vascular Medicine 
and Biology. Vascular Medicine, 2006. 11(3): p. 183-200. 
 
16. Appendices 
Not Applicable 
17. Version History 
 

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Version 
Summary of changes 
Justification of 
changes 
Identification 
of the 
affected 
study 
documents 
Author(s)/Title 
3.1 
MAJOR CHANGES 
Migration to Medtronic 
Template 
Acquisition of LAS 
by MDT complete 
Informed 
Consent Form 
 
 
Changed FlowMet assessment 
procedure to implement the 
standard of care rest period for 
ABI/TBI instead of FlowMet-
specific 5 minute rest period.  
The same rest period may be 
applied for FlowMet and 
ABI/TBI measurements.   
Changed to ensure 
sites can follow 
their own specific 
standard of care for 
ABI/TBI.   
 
 
 
Created a health-cohort 
specific procedures flowchart.   
Improved 
readability 
 
 
Added exclusion of PAD cohort: 
− Subject may not have 
revascularization 
surgery within the last 
90 day  
− Subject cannot lay 
safely in supine position 
Added language to 
avoid ambiguity in 
patient symptoms 
and to avoid 
putting patient in 
supine position 
who may not be 
able to safely be 
supine for required 
length of time. 
 
 
Added exclusion of Healthy 
cohort 
− Subject does not have 
suitable finger or toes 
to attach the probe 
− Subject is under 40 
years old 
 
Added for clarity 
and to ensure 
healthy cohort 
maintains an age-
matched 
population with 
PAD cohort. 
 
 
 

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Changed FlowMet assessment 
procedure to note that if 5 or 
more repeated attempts are 
made with poor-quality data, 
then the clinician will choose 
the optimal record to the best 
of their knowledge. 
Added to ensure 
procedure was in 
place for the rare 
occurrence where 
FlowMet readings 
cannot accurately 
be obtained after 5 
attempts. 
 
 
 
Changed date requirements of 
ultrasound or angiographic 
imaging from within 24 hours 
to 30 days.   
Loosened this 
restriction to 
improve patient 
enrollment.  This 
restriction was 
determined able to 
be reduced because 
very little change is 
expected to occur 
in the stenosis % in 
chronic PAD 
patients over the 
prior 30 days 
before their 
imaging exam.  
Additionally, 30 
days is a commonly 
accepted 
timeframe for 
validity of stenosis 
imaging tests used 
in similar PAD 
studies.   
 
 
MINOR CHANGES 
Created separate event 
schedule C specifically for 
healthy cohort.   
Additional language 
added for 
readability. 
 
 
Specified patients enrolled in 
PAD cohort cannot be grouped 
into healthy cohort, even after 
their PAD is treated.   
Always intended 
this way but 
provided additional 
language for clarity. 
 
 
 
Request digitized copy of 
intraprocedural log for patient 
registry. 
Electronic copy is 
required for storage 
in edc system. 
 
 
 

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Clarification that follow-up 
visits will be conducted as per 
standard of care post-
procedure, and that the visits 
that most closely correspond to 
the 3- and 6- month timepoints 
after initial visit will be used.   
Made follow up 
visit window less 
strict to better 
accommodate 
Covid situation and 
reduce dropout 
rate.  
 
 
 
Inclusion Criteria: Specified 
that PAD cohort must meet 
PAD positive criteria described 
in protocol.   
In practice this has 
always been the 
case, added explicit 
language for clarity 
 
 
Added procedure if FlowMet-R 
system needs servicing or 
replacement. 
Added language to 
improve procedure 
and timeline in case 
FlowMet system 
requires servicing. 
 
 
Specified wound-specific 
information (wound grade, 
infection grade, healing status) 
that is required as part of 
medical history.   
Provided additional 
details on medical 
history questions 
for clarity.  
 
 
 
Added more specific 
information requests about 
adverse even handling 
(whether device related or 
serious).   
Clarification on how 
to treat adverse 
events.   
 
 
 
Added language for protocol 
deviation information.   
Improved details 
for submitting 
protocol deviation.