Evaluation of Capillary Refill Index
Conditions: Perfusion; Complications
Sponsor: Nihon Kohden

Clinicaltrials.gov: NCT04144166 
Title: Study Protocol and Statistical Plan for CS-011-004 IRB#: 19-0726 
Date: 2 Aug 2019 
 
 

 Clinical investigation plan CS-011-004 Ver.3.1 
 1 / 38 
 
 
Clinical investigation plan 
 
 
EVALUATION OF CAPILLARY REFILL INDEX 
 
 
Reference number: CS-011 
 
Clinical investigation plan number: CS-011-004 
 
Version number: 3.1 Date: August 2, 2019 
 
 
Sponsor: 
Nihon Kohden Corporation 
1-31-4 Nishiochiai Shinjuku-ku, Tokyo, 161-8560 Japan 
 
Nihon Kohden Innovation Center 
237 Putnam Avenue, Cambridge, MA, 02139 
Nihon Kohden America 
15353 Barranca Parkway, Irvine, CA 92618 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality 
Information contained in this clinical investigation plan is owned by Nihon Kohden Corporation and 
is provided only to the principal investigator, other investigators of this clinical investigation and the 
Institutional Review Board. Recipients of this clinical investigation plan shall handle this material as 
confidential information. The recipients shall not disclose the information to any third party who are 
not involved in this clinical investigation without a prior written consent of Nihon Koken Corporation 
except for explaining this clinical investigation to subjects. 

 Clinical investigation plan CS-011-004 Ver.3.1 
 2 / 38 
 
Revision history 
 
Date of revision 
Version 
Summary of revisions made 
February 28, 2019 
1.0 
Initial version 
June 26, 2019 
2.0 
The subject population additionally includes the ICU patients. 
August 1, 2019 
3.0 
Remove CRF from the attachments 
August 2, 2019 
3.1 
Add ICU in the section 1.3 
 
 

 Clinical investigation plan CS-011-004 Ver.3.1 
 3 / 38 
 
Synopsis 
 
Title: 
Evaluation of Capillary Refill Index 
Study type: 
Single-center, cross-sectional study 
 
Subject population: 
Adult emergency department (ED) and intensive care unit (ICU) patients (both 
males and females without regards to ethnic and racial backgrounds) who meet 
the following eligibility criteria will be recruited. 
 
Inclusion criteria 
• Individuals 18 years of age or older 
• Patients who present to the ED or who are admitted to the ICU of North Shore 
University Hospital (NSUH) 
 
Exclusion criteria 
• Pregnant  
• Prisoners 
• Finger, hand or forearm anatomical anomaly or disease that may interfere with 
attaching a pulse oximeter sensor 
• Patients’ deemed clinically unstable by the clinical team 
 
Number of subjects: 
Total number of subjects is up to 60. 
 
Study duration: 
• Expected duration of each subject participation is approximately 15 minutes. 
• The duration of subject recruitment is anticipated for 6 months. 
• The total duration of the study (including data collection and analysis) is 
approximately 1 year. 
 
Investigational device: 
This study will use a non-significant risk combination of two components to 
measure Capillary Refill Index (CRI): 
• Non-FDA-cleared pulse oximeter (OLV-4201A, Nihon Kohden Corporation, 
Tokyo, Japan): OLV-4201A pulse oximeter is intended for use in monitoring 
SpO2 and pulse rate (PR) using a finger sensor. It conforms to the safety 
standard 
of 
IEC 
60601-1:2005+A1:2012, 
and 
the 
electromagnetic 
compatibility standard of IEC 60601-1-2:2007 and ISO 80601-2-61:2011 
(clause202). The CRI measurement function is embedded in OLV-4201A. 

 Clinical investigation plan CS-011-004 Ver.3.1 
 4 / 38 
 
• FDA-cleared SpO2 sensor probes (TL-271T3, Nihon Kohden Corporation, 
Tokyo, Japan): The sensors are disposable and intended for single patient 
use. 
 
Note: the pulse oximeter is a class II device and is not used for life support or as 
a life sustaining device, thus the risk of this investigational use is considered 
extremely low. Furthermore, the device will not be used for any clinical diagnoses 
and any data obtained from the device will be blinded from the treating physicians 
and thus will not have any impact on the patient’s clinical care. Therefore, the 
investigational device qualifies as a non-significant risk (NSR) device and 
does not require an Investigational Device Exemption (IDE) approval from 
the FDA. 
 
Objectives: 
(1) Primary objective 
The primary objective is to evaluate the capability of Capillary Refill Index (CRI) 
measured by the investigational device to predict altered peripheral perfusion 
determined with visual Capillary Refill Time (CRT) test. Predictive capability of 
CRI needs to be assessed to achieve a goal to provide clinicians with an 
alternative method to the traditional CRT test. 
 
(2) Secondary objective(s) 
The secondary objective is to assess the correlation between CRI and CRT 
values. Although both CRI and CRT reflect time required for reperfusion of 
fingertip after the compression, measured absolute numerical values will be 
different since the mechanisms to assess peripheral perfusion are different 
between CRI and CRT. 
 
Endpoint(s): 
(1) Primary endpoint 
The primary endpoint is the area under the curve (AUC) of the receiver operator 
characteristic (ROC) curve analysis on CRI values to predict the altered 
peripheral perfusion determined with the CRT test. A specific cutoff value for CRI 
has not yet been determined, then the AUC value will be used to summarize 
comprehensive capability of CRI to detect the altered peripheral perfusion. 
 
(2) Secondary endpoint(s) 
The secondary endpoints include the followings: 
• Sensitivity and specificity of CRI in differentiating altered peripheral perfusion 
determined with the CRT test. An optimal cutoff value for CRI will be 

 Clinical investigation plan CS-011-004 Ver.3.1 
 5 / 38 
 
determined with the ROC analysis for the primary endpoint. 
• Pearson’s or Spearman’s correlation coefficient to assess the correlation 
between CRI and CRT values. 
Table of Contents 
Revision history ......................................................................................................................................... 2 
Synopsis .................................................................................................................................................... 3 
List of Abbreviations .................................................................................................................................. 9 
1 
General ............................................................................................................................................ 10 
1.1 
Introduction ............................................................................................................................... 10 
1.2 
Sponsor ..................................................................................................................................... 10 
1.3 
Principal investigator and investigation site(s) .......................................................................... 10 
2 
Investigational device ..................................................................................................................... 11 
2.1 
Summary description of the investigational device and its intended purpose ............................ 11 
2.2 
Manufacture of the investigational device ................................................................................. 12 
2.3 
Name or number of the model/type including software version and accessories ...................... 12 
2.4 
Traceability ................................................................................................................................ 12 
2.5 
Intended purpose of the investigational device in this clinical investigation .............................. 12 
2.6 
Populations and indications for which the investigational device is intended ............................ 12 
2.7 
Materials of the investigational device contacting with tissues or body fluids ............................ 13 
2.8 
Necessary training and experience needed to use the investigational device .......................... 13 
2.9 
Specific medical or surgical procedures involved in the use of the investigational device ........ 13 
3 
Justification for the design of the clinical investigation ............................................................. 13 
3.1 
Evaluation of the results of the relevant pre-clinical testing/assessment carried out to justify the 
use of the investigational device in human subjects ............................................................................ 13 
3.2 
Evaluation of clinical data relevant to this clinical investigation ................................................. 13 
4 
Risks and benefits of the investigational device and the clinical investigation ....................... 14 
4.1 
Anticipated clinical benefits ....................................................................................................... 14 
4.2 
Anticipated adverse device effects ............................................................................................ 14 
4.3 
Residual risks associated with the investigational device identified in the risk analysis ............ 14 
4.4 
Risk associated with participation in the clinical investigation ................................................... 14 
4.5 
Possible interactions with concomitant medical treatments ...................................................... 14 
4.6 
Steps that will be taken to control or mitigate the risks.............................................................. 14 
4.7 
Risk-to-benefit rational .............................................................................................................. 15 
5 
Objectives and hypotheses of the clinical investigation ............................................................ 15 
5.1 
Primary and secondary objectives ............................................................................................ 15 
5.1.1 
Primary objective ............................................................................................................... 15 
5.1.2 
Secondary objective(s) ...................................................................................................... 15 

 Clinical investigation plan CS-011-004 Ver.3.1 
 6 / 38 
 
5.2 
Hypotheses to be tested by statistical data from the clinical investigations ............................... 15 
5.3 
Claims and intended performance of the investigational device that are to be verified ............. 15 
5.4 
Risks and anticipated adverse device effects to be assessed .................................................. 15 
6 
Design of the clinical investigation .............................................................................................. 16 
6.1 
General ..................................................................................................................................... 16 
6.1.1 
Type of the clinical investigation ........................................................................................ 16 
6.1.2 
Measures to be taken to minimize or avoid bias, including randomization and 
blinding/masking .............................................................................................................................. 16 
6.1.3 
Primary and secondary endpoints...................................................................................... 16 
6.1.4 
Methods and timing for assessing, recording and analyzing variables .............................. 17 
6.1.5 
Equipment to be used for assessing, recording and analyzing variables and arrangements 
for monitoring maintenance and calibration...................................................................................... 17 
6.1.6 
Any procedures for the replacement of subjects ................................................................ 17 
6.2 
Investigational device(s) and comparator(s) ............................................................................. 18 
6.2.1 
Description of the exposure to the investigational device(s) or comparator(s), if used ...... 18 
6.2.2 
Justification of the choice of comparator(s) ........................................................................ 18 
6.2.3 
Other medical device or medication to be used during the clinical investigation ................ 18 
6.2.4 
Number of investigational devices to be used .................................................................... 18 
6.3 
Subjects .................................................................................................................................... 18 
6.3.1 
Inclusion criteria for subject selection ................................................................................ 18 
6.3.2 
Exclusion criteria for subject selection ............................................................................... 19 
6.3.3 
Criteria and procedures for subject withdrawal or discontinuation ..................................... 19 
6.3.4 
Point of enrollment ............................................................................................................. 19 
6.3.5 
Total expected duration of the clinical investigation ........................................................... 19 
6.3.6 
Expected duration of each subject’s participation .............................................................. 19 
6.3.7 
Number of subjects required to be included in the clinical investigation ............................ 19 
6.3.8 
Estimated time needed to select this number (i.e. enrolment period) ................................ 19 
6.3.9 
Subject compensation ........................................................................................................ 19 
6.4 
Procedures ................................................................................................................................ 20 
6.4.1 
All the clinical-investigation-related procedures that subjects undergo during the study ... 20 
6.4.2 
Activities performed by sponsor representatives (excluding monitoring) ........................... 22 
6.4.3 
Any known or foreseeable factors that may compromise the outcome of the clinical 
investigation or the interpretation of results ...................................................................................... 22 
6.5 
Monitoring plan ......................................................................................................................... 23 
7 
Statistical considerations .............................................................................................................. 23 
7.1 
Statistical design, method and analytical procedures ............................................................... 23 
7.2 
Sample size .............................................................................................................................. 24 
7.3 
The level of significance and the power of the clinical investigation .......................................... 24 

 Clinical investigation plan CS-011-004 Ver.3.1 
 7 / 38 
 
7.4 
Expected drop-out rates ............................................................................................................ 25 
7.5 
Pass/fail criteria to be applied to the results of the clinical investigation ................................... 25 
7.6 
Provision for an interim analysis ............................................................................................... 25 
7.7 
Criteria for the termination of the clinical investigation on statistical grounds ............................ 25 
7.8 
Procedures for reporting any deviation(s) from the original statistical plan ............................... 25 
7.9 
Specification of subgroups for analysis ..................................................................................... 25 
7.10 Procedures that take into account all the data .......................................................................... 25 
7.11 
Treatment of missing, unused or spurious data, including drop-outs and withdrawals .............. 25 
7.12 Exclusion of particular information from the testing of the hypothesis ....................................... 25 
7.13 In multicenter clinical investigations, the minimum and maximum number of subjects to be 
included for each center ...................................................................................................................... 25 
8 
Data management .......................................................................................................................... 26 
8.1 
Procedures used for data review, database cleaning, and issuing and resolving data queries . 26 
8.2 
Procedure for verification, validation and securing of electronic clinical data system ............... 27 
8.3 
Procedure for data retention ..................................................................................................... 27 
8.4 
Specified retention period ......................................................................................................... 27 
8.5 
Other aspects of clinical quality assurance ............................................................................... 27 
9 
Amendments to the clinical investigation plan ........................................................................... 28 
10 
Deviation from the clinical investigation plan .......................................................................... 28 
10.1 Statement specifying that the investigator is not allowed to deviate from the CIP .................... 28 
10.2 Procedures for recording, reporting and analyzing CIP deviations ........................................... 28 
10.3 Notification requirements and time frame .................................................................................. 28 
10.4 Corrective and preventive actions and principal investigator disqualification criteria ................ 28 
11 
Device accountability ................................................................................................................. 28 
11.1 
Labeling and packaging of the investigational device ............................................................... 28 
11.2 
Receipt of the investigational device ......................................................................................... 29 
11.3 
Identification of each investigational device (batch number, serial number or unique code) ..... 29 
11.4 
Expiry date of use ..................................................................................................................... 29 
11.5 
Use and storage of the investigational device ........................................................................... 29 
11.6 
Subject identification ................................................................................................................. 29 
11.7 
Investigational device which is returned/explanted from subject, if applicable .......................... 30 
11.8 
Return of unused, expired or malfunctioning investigational devices, if applicable ................... 30 
12 
Statement of compliance ........................................................................................................... 30 
12.1 Declaration of Helsinki .............................................................................................................. 30 
12.2 International standard and any regional or national regulations ................................................ 30 
12.3 IRB and/or regulatory authorities .............................................................................................. 30 
12.4 Insurance .................................................................................................................................. 31 
12.5 Conflict of interest ..................................................................................................................... 31 

 Clinical investigation plan CS-011-004 Ver.3.1 
 8 / 38 
 
13 
Informed consent process ......................................................................................................... 31 
13.1 General process for obtaining informed consent ....................................................................... 31 
13.2 Informed consent process if the subject is unable to give it ...................................................... 32 
14 
Adverse events, adverse device effects and device deficiencies .......................................... 32 
14.1 Definitions of adverse events and adverse device effects ......................................................... 32 
14.2 Definition of device deficiencies ................................................................................................ 32 
14.3 Definition of serious adverse events, serious adverse device effect and unanticipated serious 
adverse device effects ......................................................................................................................... 32 
14.4 Definition of unanticipated problems involving risk to subjects or others................................... 33 
14.5 Time periods for reporting adverse events and device deficiencies .......................................... 33 
14.6 Process for reporting adverse events and device deficiencies .................................................. 34 
14.7 Foreseeable adverse events and anticipated adverse device effects ....................................... 36 
14.8 Emergency contact for reporting serious adverse events and serious adverse device effects . 36 
14.9 Information regarding the data monitoring committee ............................................................... 36 
15 
Vulnerable population ................................................................................................................ 36 
16 
Suspension or premature termination of the clinical investigation ....................................... 36 
16.1 Criteria and arrangements for suspension or premature termination ........................................ 36 
16.2 Criteria for access to and breaking the blinding/masking code in the case of suspension or 
premature termination of the clinical investigation ............................................................................... 37 
16.3 Requirements for subject follow-up ........................................................................................... 37 
17 
Publication policy ....................................................................................................................... 37 
18 
Bibliography ................................................................................................................................ 37 
19 
Attachments ................................................................................................................................ 38 
 
 
 

 Clinical investigation plan CS-011-004 Ver.3.1 
 9 / 38 
 
List of Abbreviations 
 
CRI 
Capillary Refill Index 
CRT 
Capillary Refill Time 
CIP 
Clinical investigation plan 
PI 
Principal investigator 
FDA 
Food and Drug Administration 
IDE 
Investigational Device Exemption 
NSR 
Non-significant risk  
°C 
Degrees Celsius 
°F 
Degrees Fahrenheit 
SpO2 
Peripheral capillary oxygen saturation 
PR 
Pulse rate 
NKC 
Nihon Kohden Corporation 
FIMR 
Feinstein Institute for Medical Research 
NSUH 
North Shore University Hospital 
IRB 
Institutional Review Board 
ED 
Emergency department 
ICU 
Intensive care unit 
AE 
Adverse event 
PHI 
Personal Health Information 
CRF 
Case Report Form 

 Clinical investigation plan CS-011-004 Ver.3.1 
 10 / 38 
 
1 
General 
1.1 Introduction 
Capillary refill time (CRT) test is a simple and noninvasive method typically used to assess peripheral blood 
perfusion at the bedside. CRT is defined as the time required for a distal capillary bed (e.g., fingertip) to regain 
its color after having received enough compression to cause blanching [1]. A prolonged CRT (e.g. over 2 
seconds) suggests a decrease in peripheral perfusion and is used to identify hemodynamically compromised 
patients in the critical care setting. Several observational studies have reported the clinical usefulness of CRT 
and the relevance between prolonged CRT and critical conditions. In intensive care patients, prolonged CRT 
was associated with diminished tissue perfusion as well as an increase in organ dysfunction with high blood 
lactate levels [2]. Prolonged CRT was also associated with the development of severe complications in patients 
following abdominal surgery [3]. However, the conventional CRT test has limitations in objectivity given that the 
measurement depends on clinicians’ subjective visual assessment. Since the repeatability and inter-rater 
agreement of the CRT test has been questioned over the last few decades [4, 5], there is great demand for the 
creation of objective methods to assess peripheral blood perfusion [5, 6]. 
 
We developed a new analytic method to assess peripheral blood perfusion quantitatively using pulse oximetry 
waveforms to provide clinicians with an alternative method to the traditional CRT test. The method calculates 
the time it takes for blood to return to the fingertip after release from compression by algorithmically analyzing 
the light intensity waveform of a normal pulse oximeter sensor attached to a patient’s fingertip [7,8]. Since the 
mechanisms to assess peripheral blood perfusion are different from the traditional CRT tests, we differentiate 
the calculated number by our method from CRT and named it Capillary Refill Index (CRI). The CRI measurement 
function is embedded in our investigational device OLV-4201A pulse oximeter. 
 
1.2 Sponsor 
• 
Nihon Kohden Corporation, 1-31-4 Nishiochiai Shinjuku-ku, Tokyo, 161-8560, Japan 
• 
Nihon Kohden Innovation Center, 237 Putnam Avenue, Cambridge, MA, 02139, USA 
• 
Nihon Kohden America: 15353 Barranca Parkway, Irvine, CA 92618, USA 
 
The sponsored research agreement for funding this study is to be made by and between Northwell Health 
and Nihon Kohden Corporation (NKC). 
 
1.3 Principal investigator and investigation site(s) 
• 
Principal investigator: 
Timmy Li 
Administrative Director of Clinical Research for Emergency Medicine 
Northwell Health, 300 Community Drive, Manhasset, NY, 11030 
 
• 
Investigation site(s) 

 Clinical investigation plan CS-011-004 Ver.3.1 
 11 / 38 
 
Emergency Department (ED) and Intensive Care Unit (ICU) 
North Shore University Hospital (NSUH) 
Northwell Health, 300 Community Drive, Manhasset, NY, 11030 
  
2 
Investigational device 
2.1 Summary description of the investigational device and its intended purpose 
This study will use a non-significant risk combination of two components: 
• Non-FDA-cleared pulse oximeter (OLV-4201A, Nihon Kohden Corporation, Tokyo, Japan): See Attachment 
1 Operator’s Manual of OLV-4201. OLV-4201A pulse oximeter is intended for use in monitoring SpO2 and 
pulse rate (PR) using a finger sensor. It conforms to the safety standard of IEC60601-1:2005+A1:2012, and 
the electromagnetic compatibility standard of IEC 60601-1-2:2007 and ISO 80601-2-61:2011 (clause202). 
See Attachment 2 and 3 Certificate of Safety/EMC Test. 
• FDA-cleared SpO2 sensor probe (TL-271T3, Nihon Kohden Corporation, Tokyo, Japan; K151080, K120888, 
K080342, K001693, K946175, K945578, K043517, K082785): See Attachment 4 Operator’s Manual of 
SpO2 sensor probe. The sensor is disposable and intended for single patient use. 
 
The investigational device passes light of two wavelengths (red: 660 nm, infrared: 940 nm) through the fingertip 
and measures the light intensity at each wavelength, allowing it to determine the different concentrations of two 
types of hemoglobin (oxy-hemoglobin and deoxy-hemoglobin). The CRI measurement uses a wavelength of 
infrared (940 nm) to trace change of blood volume in the fingertip. To measure CRI, a patient’s fingertip with a 
pulse oximeter sensor probe attached is briefly compressed by an operator. The light intensity transmitted 
through the fingertip increases during compression as blood, which is the major absorber of the light, is 
squeezed out of the fingertip. The compression phase is followed by the release phase during which the light 
intensity decreases with return of blood to the fingertip. The curve describing the recovery phase of the intensity 
waveform is modeled as an exponential decay using the least squares method. The time for returning to a 
predetermined level of the intensity is calculated as CRI (Figure 1). The detailed operation of the CRI function 
of OLV-4201A is described in Attachment 5 Operator’s Manual of the CRI function. 
 
Figure 1: Calculation of CRI using a pulse oximeter waveform 

 Clinical investigation plan CS-011-004 Ver.3.1 
 12 / 38 
 
 
Note: the pulse oximeter is a class II device and is not used for life support or as a life sustaining device, thus 
the risk of this investigational use is considered extremely low. Furthermore, the device will not be used for any 
clinical diagnoses and any data obtained from the device will be blinded from the treating physician and thus 
will not have any impact on the patient’s clinical care. Therefore, the investigational device qualifies as a non-
significant risk (NSR) device and does not require an Investigational Device Exemption (IDE) approval 
from the FDA. 
 
2.2 Manufacture of the investigational device 
Manufacture: Nihon Kohden Corporation 
Address: 1-31-4 Nishiochiai Shinjuku-ku, Tokyo, 161-8560, Japan 
 
2.3 Name or number of the model/type including software version and accessories 
(1) Model number: OLV-4201A 
(2) Name: Pulse Oximeter 
(3) Software version: 01-06 
(4) Composition 
No. 
Name 
Model number 
1 
Pulse Oximeter 
OLV-4201A 
 
(5) Accessories and disposables 
No. 
Name 
Model number 
1 
Power cord 
 
2 
SpO2 connection cord 
JL-400T 
3 
Disposable SpO2 sensor probe 
TL-271T3 
 
2.4 Traceability 
• 
OLV-4201A Pulse Oximeter: identify with assigned serial numbers 
• 
TL-271T3 SpO2 sensor probe: identify with assigned lot numbers 
 
2.5 Intended purpose of the investigational device in this clinical investigation 
• 
Measurement of CRI 
 
2.6 Populations and indications for which the investigational device is intended 
• 
Adult ED and ICU patients both males and females aged 18 years or older 
 

 Clinical investigation plan CS-011-004 Ver.3.1 
 13 / 38 
 
2.7 Materials of the investigational device contacting with tissues or body fluids 
Material of the investigational device that will be in contact with tissues is as follows: 
 
TL-271T3 SpO2 sensor probe 
Name of parts 
Material 
Sensor portion 
Polyester 
 
There is no material that will be in contact with body fluids. 
 
2.8 Necessary training and experience needed to use the investigational device 
Investigators will be trained by sponsor representatives about operations and cleaning of the investigational 
device following the operator’s manual of the investigational device. 
 
2.9 Specific medical or surgical procedures involved in the use of the investigational device 
There is no medical nor surgical procedure involved in the use of the investigational device. 
 
3 
Justification for the design of the clinical investigation 
3.1 Evaluation of the results of the relevant pre-clinical testing/assessment carried out to justify 
the use of the investigational device in human subjects 
OLV-4201A Pulse Oximeter conforms to the safety standard of IEC60601-1:2005+A1:2012, and the 
electromagnetic compatibility standard of IEC 60601-1-2:2007 and ISO 80601-2-61:2011(clause202). See 
Attachment 2 and 3 Certificate of Safety/EMC Test. The part of the investigational device that will be in contact 
with the human subjects is the FDA-cleared TL-271T3 SpO2 probe. There has been no issue regarding 
biocompatibility of the material of the SpO2 probe described in the section 2.7. Therefore, the use of the 
investigational device in human subjects in this clinical investigation is considered to be justified. 
 
3.2 Evaluation of clinical data relevant to this clinical investigation 
Attachment 6 is a report of a previous clinical study conducted at the ED of NSUH. In this preliminary clinical 
study, the term “Blood Refill Time (BRT)” was used, which is the same as CRI, and a prototype device was used 
to measure BRT. The prototype device is a non-FDA-cleared pulse oximeter (OLV-3100, Nihon Kohden 
Corporation, Tokyo, Japan) which is a previous model of OLV-4201A. OLV-3100 was used to record the pulse 
oximetry waveforms, and the recorded waveforms were analyzed thereafter. The calculation of CRI used in the 
analysis is the same as the CRI function embedded in the investigational device. A convenience sample of thirty 
adult ED patients were enrolled as subjects. Visual CRT values were measured by an ED physician using a 
stopwatch. Area under the receiver operator characteristic curve of BRT to predict whether the visual CRT was 
greater than 2.0 seconds was 0.84 (95% CI 0.70-0.98). There was a strong correlation between BRT and CRT 
(r=0.723, p<0.001). The results suggest that BRT measurements with the prototype device successfully 
identified subjects with altered peripheral perfusion determined by the conventional visual assessment of CRT. 

 Clinical investigation plan CS-011-004 Ver.3.1 
 14 / 38 
 
 
4 
Risks and benefits of the investigational device and the clinical investigation 
4.1 Anticipated clinical benefits 
This study is not expected to directly benefit the subjects, but it will provide information that may assist in 
improving the method to assess peripheral blood perfusion quantitatively. 
 
4.2 Anticipated adverse device effects 
There is no particular anticipated adverse device effect since the applied part of the investigational device (TL-
271T3 SpO2 sensor probe) is equivalent to standard pulse oximeter sensors and has a FDA approval. A well-
known potential adverse effect of pulse oximeters is thermal injuries due to temperature rise at the applied part 
of the sensor. 
 
4.3 Residual risks associated with the investigational device identified in the risk analysis 
There is no residual risk associated with the investigational device which is judged unacceptable. 
 
4.4 Risk associated with participation in the clinical investigation 
There is a potential risk of breach of confidentiality, which will be minimized by following the procedures set forth 
in the section 8 “Data management” of this CIP. 
The study procedures are no greater than minimal risk. The pulse oximeter is a class II device and is not used 
for life support or as a life sustaining device, thus the risk of this investigational use is considered extremely low. 
Furthermore, the device will not be used for any clinical diagnoses and any data obtained from the device will 
be blinded from treating physicians and thus will not have any impact on the subject’s clinical care. The 
application of the sensor probe on the subject’s finger is not expected to cause pain. If the study procedure 
becomes too uncomfortable, the procedure will be stopped immediately. The investigator (qualified ED 
physician) will assess the clinical status of the subject prior to enrollment to determine eligibility when the subject 
is recruited. 
 
4.5 Possible interactions with concomitant medical treatments  
There is no possible interaction with concomitant medical treatments. 
 
4.6 Steps that will be taken to control or mitigate the risks 
All data and records generated during this study will be kept confidentially in accordance with policies of the 
study site(s) and HIPAA on subject privacy, and the investigator and other site personnel will not use such data 
and records for any purpose other than conducting the study. All subjects will be given a unique study number. 
The PI will be responsible for ensuring the safety of the subjects participating in this study. The study team will 
report to the PI any time that the sensor has to be removed prematurely, and the PI will track this information. 
Thermal injuries which are the potential adverse effect of the pulse oximeter will be assessed after the 
measurements with the investigational device. 

 Clinical investigation plan CS-011-004 Ver.3.1 
 15 / 38 
 
 
4.7 Risk-to-benefit rational 
Based on the discussions above and the minimal risk involved with the study, the scientific benefits of this study 
outweigh the risks, even though no benefit for each individual study participant is expected. 
 
5 
Objectives and hypotheses of the clinical investigation 
5.1 Primary and secondary objectives 
5.1.1 Primary objective 
The primary objective is to evaluate the capability of CRI to predict altered peripheral perfusion determined 
with the CRT test. Predictive capability of CRI needs to be assessed to achieve a goal to provide clinicians 
with an alternative method to the traditional CRT test. Receiver operator characteristic (ROC) curve analysis 
will be performed and area under the curve (AUC) will be calculated for this objective. An optimal cutoff value 
for CRI will be determined with the ROC analysis and the sensitivity and the specificity in differentiating altered 
peripheral perfusion will also be calculated. 
 
5.1.2 Secondary objective(s) 
The secondary objective is to assess the correlation between CRI and CRT values. Although both CRI and 
CRT reflect time required for reperfusion of fingertip after the compression, measured absolute numerical 
values will be different since the mechanisms to assess peripheral perfusion are different between CRI and 
CRT. Pearson’s correlation coefficient will be calculated to assess the correlation between CRI and CRT 
values. If the values are not normally distributed, Spearman’s correlation coefficient will be used instead. 
 
5.2 Hypotheses to be tested by statistical data from the clinical investigations 
CRI is capable to detect subjects with altered peripheral perfusion determined with the CRT test. 
 
5.3 Claims and intended performance of the investigational device that are to be verified 
(1) 
Capillary Refill Index (CRI) 
• Display range: 0.1 ~ 99.9 seconds 
 
*CRI will not be claimed as an intended for use in a regulatory application for FDA clearance of OLV-
4201A Pulse Oximeter. CRI will be included in the regulatory application as an index intended for clinical 
research only, not for diagnosis. 
 
5.4 Risks and anticipated adverse device effects to be assessed 
(1) 
Thermal injuries due to temperature rise at the applied part of the sensor probe 
 

 Clinical investigation plan CS-011-004 Ver.3.1 
 16 / 38 
 
6 
Design of the clinical investigation 
6.1 General 
6.1.1 Type of the clinical investigation 
Single-center, cross-sectional study: 
In this clinical investigation, CRI and CRT measured at a same time point for each will be compared. 
 
6.1.2 Measures to be taken to minimize or avoid bias, including randomization and blinding/masking 
• 
The investigator who will measure the visual CRT will be blinded from the CRI values measured with 
the investigational device. 
• 
CRI and CRT measurements will be alternately repeated for 3 times each per a subject, and each 
averaged value will be used as measured CRI and CRT values for each subject. 
 
6.1.3 Primary and secondary endpoints 
(1) 
Primary endpoint 
The primary endpoint is the area under the curve (AUC) of the receiver operator characteristic (ROC) curve 
analysis on CRI values to predict the altered peripheral perfusion determined with the CRT test. A specific 
cutoff value for CRI has not yet been determined, then the AUC value will be used to summarize 
comprehensive capability of CRI to detect the altered peripheral perfusion. Procedures of the measurement 
of CRI and CRT, and statistical methods are described in the section 6.4 "Procedures” and the section 7 
“Statistical considerations”, respectively. 
 
(2) 
Secondary endpoints 
The secondary endpoints include the followings: 
• Sensitivity and specificity of CRI in differentiating altered peripheral perfusion determined with the CRT 
test. An optimal cutoff value for CRI will be determined with the ROC analysis for the primary endpoint. 
• Pearson’s or Spearman’s correlation coefficient to assess the correlation between CRI and CRT values. 
 
 

 Clinical investigation plan CS-011-004 Ver.3.1 
 17 / 38 
 
6.1.4 Methods and timing for assessing, recording and analyzing variables 
The study team will perform assessments and measurements according to the following table: 
 
Study Phase 
Screening 
and 
registration 
Study 
measurement 
at the bedside 
Follow up 
Review the inclusion and the exclusion criteria 
X 
 
 
Informed consent/assent 
X 
 
 
Assigning a unique study subject number 
X 
 
 
Measurements for subject’s basal 
characteristics 
 
X 
 
Applying a SpO2 sensor probe on the finger 
 
X 
 
Measurements of CRI and CRT 
 
X 
 
Adverse event assessment 
 
X 
 
Medical record review for subject’s basal 
characteristics 
 
 
X 
 
The study procedures listed in the table are described in the section 6.3 “Subjects”, the section 6.4 
“Procedures” and the section 13 “Informed consent process”. 
 
6.1.5 Equipment to be used for assessing, recording and analyzing variables and arrangements for 
monitoring maintenance and calibration 
Equipment to be used in this study are described in the section 2 “Investigational device” and the section 6.4 
“Procedures”. 
 
6.1.6 Any procedures for the replacement of subjects 
No replacement condition is foreseen. Subjects who withdraws early will not be replaced as we plan to recruit 
up to 60 subjects to achieve at least 54 subjects to be analyzed as described in the section 7.2 “Sample size”. 
 

 Clinical investigation plan CS-011-004 Ver.3.1 
 18 / 38 
 
6.2 Investigational device(s) and comparator(s) 
6.2.1 Description of the exposure to the investigational device(s) or comparator(s), if used 
(1) 
Investigational device 
The SpO2 sensor probe will be applied to a subject’s fingertip. 
 
(2) 
Comparator 
The comparator is the visual CRT. There is no physical exposure for the CRT test. 
 
6.2.2 Justification of the choice of comparator(s) 
The comparator is the visual CRT, which is typically used to assess peripheral blood perfusion at the bedside. 
The CRI measurement has been developed to assess peripheral blood perfusion quantitatively as an 
alternative method to the visual CRT test. Therefore, comparisons between CRI and CRT need to be 
performed. 
 
6.2.3 Other medical device or medication to be used during the clinical investigation 
A standard patient monitor used in the ED will be used to collect information of patient’s basal characteristics 
as listed below: 
• 
Noninvasive blood pressure 
• 
SpO2 
• 
Pulse rate or heart rate 
• 
Respiratory rate (if available) 
• 
Body temperature 
 
There is no medication to be used during the investigation. 
 
6.2.4 Number of investigational devices to be used 
• 
OLV-4201A Pulse Oximeter: 
1 unit 
• 
TL-271T3 SpO2 sensor probe: 
1 sensor per subject 
 
6.3 Subjects 
6.3.1 Inclusion criteria for subject selection 
Adult ED and ICU patients (both males and females without regard to diverse ethnic and racial backgrounds) 
who meet the following inclusion criteria will be recruited. 
• 
Individuals 18 years of age or older 
• 
Patients who present to the ED or who are admitted to the ICU of North Shore University Hospital 
(NSUH) 
 

 Clinical investigation plan CS-011-004 Ver.3.1 
 19 / 38 
 
6.3.2 Exclusion criteria for subject selection 
• 
Pregnant 
• 
Prisoners 
• 
Finger, hand or forearm anatomical anomaly or disease that may interfere with attaching a pulse 
oximeter sensor 
• 
Patients’ deemed clinically unstable by the clinical team 
 
6.3.3 Criteria and procedures for subject withdrawal or discontinuation 
All subjects are free to withdraw from the study at any time and for any reason. Subject safety will be 
monitored by the investigator who is a qualified ED physician. The primary safety concern is ensuring the 
patients are not distressed by the study procedures. All the procedures that subjects will receive are non-
invasive, but if the subject reports any adverse effects during the course of the study, the investigators will 
immediately discontinue any procedures and remove any research instruments from the subject. Data 
collected up to the point of the subject’s withdrawal will continue to be used and analyzed. No further data 
will be collected after the subject’s withdrawal. 
 
6.3.4 Point of enrollment 
Adult patients who present to the ED of NSUH who meet the eligibility criteria will be recruited. Importantly, 
patients will only be approached who are physically available to participate in the study, as to not delay or 
interrupt the patient’s care for recruitment. Informed consent will be obtained directly from the subject prior to 
all procedures. Then, a unique study subject number will be assigned, and the subject will be registered for 
this study. 
 
6.3.5 Total expected duration of the clinical investigation 
The duration of the study (including data collection and analysis) is approximately 1 year. 
 
6.3.6 Expected duration of each subject’s participation 
Expected duration of each subject’s participation is approximately 15 minutes. 
 
6.3.7 Number of subjects required to be included in the clinical investigation 
Total number of subjects is up to 60. Detail of the required sample size calculation is described in the section 
7.2 “Sample size”. 
 
6.3.8 Estimated time needed to select this number (i.e. enrolment period) 
The duration of subject enrollment is anticipated for 6 months. 
 
6.3.9 Subject compensation 
Each subject will receive a $15 gift card as compensation for their participation in this study. 

 Clinical investigation plan CS-011-004 Ver.3.1 
 20 / 38 
 
 
6.4 Procedures 
6.4.1 All the clinical-investigation-related procedures that subjects undergo during the study 
Adult ED patients aged 18 years and older will be recruited for this study. Informed consent will occur prior to 
the study enrollment. Patients will be assigned a unique study subject number. All data mentioned below will 
be recorded on paper forms. Raw data measured by the investigational device will be recorded digitally on a 
SD card inserted in the device. Data recoded on paper forms will be entered into REDCap so that it can be 
analyzed.  
 
Patient’s basal characteristics will be collected as shown below. Noninvasive blood pressure, SpO2, pulse 
rate, respiration rate and body temperature will be measured by a standard patient monitor used in the ED.  
 
Obtained from medical record: 
• 
Age 
• 
Gender 
• 
Race  
• 
Height 
• 
Body weight 
• 
Past general medical history (diabetes mellitus, hypertension, smoking, heart disease, lung disease, 
others) 
• 
Initial vital sign data (blood pressure, SpO2, pulse rate/heart rate, respiratory rate and body 
temperature) 
• 
Core body temperature (if available) 
• 
Red blood cell count (RBC), Hematocrit (Ht) and Hemoglobin (Hb) (if available) 
• 
Lab data: Blood lactate levels, Cre/BUN and TP/Alb (if available) 
• 
Primary diagnosis 
• 
Disposition (Discharged home, admitted, left against medical advice, skilled nursing facility, other 
hospital, expired, unknown or other) 
• 
Time of events (ED arrival, ED encounter, ED discharge and admission, etc.) 
 
Obtained at the bedside: 
• 
CRT 
• 
CRI 
• 
Noninvasive blood pressure 
• 
SpO2 
• 
Pulse rate or heart rate 
• 
Respiratory rate (if available) 
• 
Fitzpatrick skin tone scale 

 Clinical investigation plan CS-011-004 Ver.3.1 
 21 / 38 
 
 
• 
Body temperature (axillary) 
• 
Forearm and fingertip temperatures 
• 
Room temperature 
 
The surface temperature of the patient’s hand will be measured by a non-contact infrared thermometer. To 
address the reliability of the subjective assessment of peripheral perfusion by the investigator, we will also 
measure forearm-to-fingertip skin temperature difference (Tskin-diff), as well as central-to-fingertip 
temperature difference (Tc-diff). The Tskin-diff will be obtained from the index/middle finger temperature and 
the temperature on the radial side of the forearm, midway between the elbow and the wrist.  
 
The CRT and the CRI measurements will be conducted with following methods for each subject in a relaxed 
position (seated or lying down) with relaxed hands. The subject’s most accessible hand (right or left) will be 
used. Each measurement will be performed alternately and will be repeated three times each for a total of six 
compressions per subject. If the subject is wearing nail polish, the investigator will measure CRI/CRT after 
removing the subject’s nail polish. If the subject is wearing a ring on their finger, CRI/CRT will be measured 
after removing the ring(s). 
 
Visual CRT measurement using a stopwatch  
An investigator (an ED physician) will compress the fingertip of the subject’s index or middle finger for five 
seconds, signaled by “start compression” and “release compression” beep sounds. When the fingertip is 
released from the compression, the investigator will begin the visual CRT measurement. The investigator will 
hold a stopwatch in the hand that does not perform the compression and use this stopwatch to measure CRT. 
 
CRI measurement by the investigational device 
The SpO2 sensor probe will be applied to either the index or middle fingertip of the same hand of the subject 
used in the CRT measurement, depending upon which fingertip was compressed in the CRT measurement. 
For example, if the index fingertip was used in the CRT measurement, then the sensor will be applied to the 
middle fingertip. With the sensor on it, the investigator will compress the subject’s fingertip for five seconds 
by the investigator’s finger as same way of the traditional CRT test. The sensor is flexible and thus, the 
investigator is able to compress the fingertip by compressing the sensor (Figure 2). The compression will be 
performed with signals from the device, and then the device will measure CRI. 

 Clinical investigation plan CS-011-004 Ver.3.1 
 22 / 38 
 
 
Figure 2: Compression for the CRI measurement 
 
The investigator will confirm the sensor probe is properly applied to the fingertip by measuring CRI and 
checking whether the shape of the CRI measurement waveform is proper. With proper application of the 
sensor probe, the measurement waveform is convex upward as shown in Figure 3. If the sensor probe is not 
properly applied, the investigator will replace the sensor probe. 
 
Figure 3: Proper shape of the CRI measurement waveform 
 
The investigator will be blinded from the measured value of the CRI measurement. 
 
All subjects are free to withdraw from the study at any time and for any reason. The investigators will 
immediately discontinue any procedures and remove any research instruments from the subject. Data 
collected until the subject’s point of withdrawal from the study will be analyzed. The estimated duration of the 
subject’s participation is approximately 15 minutes in total. 
  
6.4.2 Activities performed by sponsor representatives (excluding monitoring) 
There is no activity performed by sponsor representatives. 
 
6.4.3 Any known or foreseeable factors that may compromise the outcome of the clinical investigation or 
the interpretation of results 
• 
Improper application of the sensor probe to the fingertip will cause inappropriate results of the 
measurement. The investigator will confirm the sensor probe is properly applied to the fingertip with 
the procedure described in the section 6.4.1. If the sensor probe is not properly applied, the 
investigator will replace the sensor probe. 
 

 Clinical investigation plan CS-011-004 Ver.3.1 
 23 / 38 
 
6.5 Monitoring plan 
Since this is a single site study, there is no plan for external site monitoring. 
 
The principal investigator is tasked with ensuring the safety and data integrity of the study. The PI will 
continuously review the aggregate data to determine if any aspects of the study need to be changed or stopped. 
In addition, the PI will review any and all CIP deviations, adverse events, and unanticipated problems that may 
occur to determine their relatedness to the study, their severity, and whether they require study changes. Any 
unanticipated problems or instances of non-compliance will be reported to the IRB as per their reporting 
requirements. If any changes of CIP are needed, an investigator will submit a modification request to the IRB. 
CIP changes will not be implemented prior to IRB approval unless necessary to eliminate apparent immediate 
hazards to the research subjects. In such a case, the IRB will be promptly informed of the change following 
implementation. 
 
The sponsor and/or representative may conduct periodic on-site monitoring visits during the course of the study, 
including study initiation and close-out to ensure appropriate documentation is present and completed. The 
investigator will permit study-related monitoring, audits, and inspections of all study related documents (e.g. 
source documents, regulatory documents, data collection instruments, study data etc.) by the IRB, the sponsor, 
government regulatory bodies, and compliance and quality assurance groups of the study site. The investigator 
will ensure the capability for inspections of applicable study-related facilities. 
 
Participation as an investigator in this study implies acceptance of potential inspection by government regulatory 
authorities and applicable compliance and quality assurance offices of the study site. 
 
7 
Statistical considerations 
7.1 Statistical design, method and analytical procedures 
In order to assess the study aims and hypotheses, we will describe the study sample using descriptive statistics 
such as frequencies, proportions, means, standard deviations, 95% confidence intervals, medians, and 
interquartile ranges. The mean of the three repeated CRI and CRT measurements will be considered as the 
values for each subject.  
 
The primary and secondary endpoints are described in the section 6.1.3. Receiver operator characteristic (ROC) 
curve analysis will be performed and area under the curve (AUC) will be calculated to demonstrate capability of 
CRI to predict altered peripheral perfusion determined with the CRT test. An optimal cutoff value for CRI will be 
determined with the ROC analysis and the sensitivity and the specificity in differentiating altered peripheral 
perfusion will be calculated. Pearson’s, or Spearman’s correlation coefficient will be calculated to assess the 
correlation between CRI and CRT values. 
 

 Clinical investigation plan CS-011-004 Ver.3.1 
 24 / 38 
 
7.2 Sample size 
The primary endpoint of this study is an AUC of the ROC curve analysis on CRI values to predict altered 
peripheral perfusion determined with the CRT test. Sample size for subjects with altered peripheral perfusion 
required to obtain desired AUC is calculated with the following equation [9]: 
 
𝑛𝑛= 
𝑍𝑍𝛼𝛼
2
2 × 𝑉𝑉(𝐴𝐴𝐴𝐴𝐴𝐴)
𝑑𝑑2
 
 
where, Z is the standard normal deviate determined with probability of type I error: α, d is the desired width of 
one-half of the confidence interval (CI), and V(AUC) is variance of AUC which is derived from the following 
equation [10]: 
 
𝑉𝑉(𝐴𝐴𝐴𝐴𝐴𝐴) = (0.0099 × 𝑒𝑒−𝑎𝑎2 2
⁄ ) × {(5𝑎𝑎2 + 8) + (𝑎𝑎2 + 8)/𝜅𝜅} 
 
where,  𝑎𝑎= 𝜑𝜑−1(𝐴𝐴𝐴𝐴𝐴𝐴) × 1.414; 𝜑𝜑−1 is inverse of standard cumulative normal distribution; and 𝜅𝜅 is the ratio 
of the number of subjects without the altered peripheral perfusion to the number of subjects with the altered 
peripheral perfusion. Based upon our preliminary data: 
• 
The prevalence of the subjects with altered peripheral perfusion is expected to be 30%, and then 𝜅𝜅 
is 2.33. 
• 
We hypothesize that the AUC will be 0.84, and then 𝑎𝑎= 𝜑𝜑−1(0.84) × 1.414 = 1.406.  
 
Therefore, V(AUC) can be calculated as follow: 
 
𝑉𝑉(𝐴𝐴𝐴𝐴𝐴𝐴) = ൫0.0099 × 𝑒𝑒−1.4062 2
⁄ ൯× {(5 × 1.4062 + 8) + (1.4062 + 8)/2.33} = 0.0816 
 
To achieve an AUC of at least 0.70 which is considered as fair [11], one-half of the CI: d should be 0.14 with the 
hypothesized AUC of 0.84. At the significance level of 5% (probability of type I error: α = 0.05), the number of 
subjects with altered peripheral perfusion is derived as: 
 
𝑛𝑛= 
𝑍𝑍𝛼𝛼
2
2 × 𝑉𝑉(𝐴𝐴𝐴𝐴𝐴𝐴)
𝑑𝑑2
= 1.962 × 0.0816
0.142
= 15.99 ≈16 
 
The total number of required sample size given by 𝑛𝑛(1 + 𝜅𝜅) is 54. Considering possible early withdrawals of 
subjects, we plan to recruit up to 60 subjects to achieve 54 evaluable subjects (10% of drop-out rate). 
 
7.3 The level of significance and the power of the clinical investigation 
All statistical tests will be assessed at the significance level of 5% (probability of type I error: α = 0.05). 
 

 Clinical investigation plan CS-011-004 Ver.3.1 
 25 / 38 
 
7.4 Expected drop-out rates 
Although the drop-out rate for this study is unknown, relatively high drop-out rate can be expected since the 
study site is the ED and the subjects may need early withdrawals due to disposition (admission to the hospital 
or discharge). Therefore, we use 10% of drop-out rate and will recruit up to 60 subjects to achieve 54 evaluable 
subjects. 
 
7.5 Pass/fail criteria to be applied to the results of the clinical investigation 
The hypothesis to be tested in this study is that CRI is capable to detect subjects with altered peripheral 
perfusion determined with the CRT test, as described in the section 5.2. A criterion to accept the hypothesis is 
that the AUC value described in the section 6.1.3 (1) “Primary endpoint” is at least 0.70 which is considered as 
fair [11]. 
 
7.6 Provision for an interim analysis 
No interim analysis is planned. 
 
7.7 Criteria for the termination of the clinical investigation on statistical grounds 
As no interim statistical analysis is planned, no criteria for the termination of the study is defined. 
 
7.8 Procedures for reporting any deviation(s) from the original statistical plan 
Any modification to the statistical analysis plan will be documented in the final study report if applicable. 
 
7.9 Specification of subgroups for analysis 
Not applicable. 
 
7.10 Procedures that take into account all the data 
Not applicable. This study is the observational study and no allocation of subjects is planned. 
 
7.11 Treatment of missing, unused or spurious data, including drop-outs and withdrawals 
• 
Data collected up to the point of the subject’s withdrawal will continue to be used and analyzed. 
• 
If just one value of CRI/CRT out of the three repeated measurements is missing, the mean of the 
remaining two values will be used as the value for the subject. 
 
7.12 Exclusion of particular information from the testing of the hypothesis 
• 
Data of a subject in which two or more values of CRI/CRT out of the three repeated measurements are 
missing will be excluded from the analysis. 
 
7.13 In multicenter clinical investigations, the minimum and maximum number of subjects to be 

 Clinical investigation plan CS-011-004 Ver.3.1 
 26 / 38 
 
included for each center 
Not applicable. 
 
8 
Data management 
8.1 Procedures used for data review, database cleaning, and issuing and resolving data queries 
(1) Identification of source document and source data 
All data and information obtained in the study will be recorded on paper forms of case report form (CRF). 
The CRFs are considered as original source documents and the data recorded in the source documents is 
considered as original source data. 
 
(2) Case Report Form (CRF) 
The CRFs are the primary data collection instruments for the study. All data requested on the CRFs must 
be recorded. All missing data must be explained. If a space on the CRF is left blank because the procedure 
was not done, or the question was not asked, write “N/D”. If the item is not applicable to the individual case, 
write “N/A”. All entries should be printed legibly in ink. If any entry error has been made, to correct such an 
error, draw a single straight line through the incorrect entry and enter the correct data above it. All such 
changes must be initialed and dated. DO NOT ERASE OR WHITE OUT ERRORS. For clarification of 
illegible or uncertain entries, print the clarification above the item, then initial and date it. 
The PI is responsible for ensuring the data and information are properly recorded on each subject’s CRF 
and related documents. The PI and an investigator who completes the recording will sign the CRF to validate 
that the data and the information are recorded on the CRF correctly and completely.  
 
(3) Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a signed 
subject authorization informing the subject of the following:  
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization. For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect 
at least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
 
(4) Data review 
The PI will continuously review the aggregate data to ensuring integrity of the study data. The PI is 

 Clinical investigation plan CS-011-004 Ver.3.1 
 27 / 38 
 
responsible for identifying missing data and exclusion of data described in the section 7.11 and 7.12. 
 
8.2 Procedure for verification, validation and securing of electronic clinical data system 
The data and the information will also be input into the secure database REDCap, with access granted to study 
investigators only. There are procedures and processes in place by Northwell Health to safeguard the 
authenticity, integrity and confidentiality of the data in REDCap. And there are procedures for training, technical 
support, and auditing to ensure the system is functioning and being used in the manner intended. 
 
8.3 Procedure for data retention 
Signed consent forms and paper forms used to collect data will be stored in a locked research office at North 
Shore University Hospital and/or The Feinstein Institute for Medical Research. This data will also be input into 
the secure database REDCap, with access granted to study investigators only. 
 
When data is sent out of the Northwell Health system to the sponsor, the data shall be de-identified and the 
data file will be encrypted. In this data file, each subject will be assigned a unique study subject number. No 
names or other direct identifiers will be included in the data file. The date when the data was collected and the 
information on past or current medical history are the only indirect identifiers that will be included in the data file. 
Only the PI will obtain a list that links the study subject numbers that are sent to the sponsor to the original 
subject information. This list will remain stored in the locked research office.  
 
Any study records that identify subjects will be kept private. Participants will not be identified in publications 
disclosed outside of Northwell Health, except as detailed below. Investigators will share information collected 
from this research study with: 
• 
Study sponsor and/or its agents, 
• 
Other researchers,  
• 
Regulatory agencies, such as the Food and Drug Administration (FDA) and the Department of Health 
and Human Services (DHHS), and 
• 
Clinical staff not involved in the study who may be involved in the participant's treatment. 
 
8.4 Specified retention period 
The investigator and the sponsor shall retain all the records of the study during the study and for a period of 2 
years after the latter of the following two dates: 
• 
The date on which the study is terminated or completed 
• 
The date that the records are no longer required for purposes of supporting applications for FDA 
clearance of the investigational device. 
 
8.5 Other aspects of clinical quality assurance 
Not applicable. 

 Clinical investigation plan CS-011-004 Ver.3.1 
 28 / 38 
 
 
9 
Amendments to the clinical investigation plan 
If any changes on this CIP are needed, an investigator will submit a modification request to the IRB. CIP changes 
will not be implemented prior to IRB approval unless necessary to eliminate apparent immediate hazards to the 
study subjects. In such a case, the IRB will be promptly informed of the change following implementation. 
 
10 Deviation from the clinical investigation plan 
10.1 Statement specifying that the investigator is not allowed to deviate from the CIP 
The Investigators are not allowed to deviate from the CIP, excepted under emergency circumstances, to protect 
the rights, safety and well-being of the subjects. In this case, such deviations shall be documented and reported 
to the sponsor and the IRB as soon as possible. 
 
Any exceptions from the CIP must receive approval from both the sponsor and the IRB before they are initiated. 
 
10.2 Procedures for recording, reporting and analyzing CIP deviations 
Any CIP deviations initiated without the sponsor and IRB approval that may affect the scientific soundness of 
the study, or affect the rights, safety, or welfare of study subjects, must be recorded and reported to the sponsor 
and to the IRB. If any CIP deviations are observed during the monitoring visit, all such observations must be 
documented in reports of the monitoring visits. All CIP deviations will be discussed during the data review which 
occurs before the data analysis, and then the discussion will be documented in the final study report. 
 
10.3 Notification requirements and time frame 
Any CIP deviations must be reported to the sponsor and the IRB as soon as possible, but no later than 5 working 
days after the CIP deviation occurs. If any CIP deviations are observed during the monitoring visit, all such 
observations must be documented in reports of the monitoring visits. An investigator shall report to the sponsor 
in a case of withdrawal of IRB approval as soon as a possible, but no later than 5 working days of the IRB 
notification of withdrawal of approval. 
 
10.4 Corrective and preventive actions and principal investigator disqualification criteria 
The PI will check whether the same deviation occurred in other subjects which are unreported. If other deviations 
are observed, all the deviations must be recorded and reported. The PI and/or the sponsor will warn the 
investigator of the importance to respect the CIP. An investigator who continuously violates the CIP despite the 
warnings could be excluded from the investigation after agreement of the sponsor. 
 
11 Device accountability 
11.1 Labeling and packaging of the investigational device 
The study device or its immediate package will bear a label with the following information: 
• 
The name and place of business of the manufacturer, packer, or distributor 

 Clinical investigation plan CS-011-004 Ver.3.1 
 29 / 38 
 
• 
The quantity of contents, if appropriate 
• 
The statement, "CAUTION -- Investigational device. Limited by Federal (or United States) law to 
investigational use." 
 
The label will also describe all relevant contraindications, hazards, adverse effects, interfering substances or 
devices, warnings, and precautions, if applicable. The labeling of the device will not contain any false or 
misleading statements nor imply that the device is safe or effective for the purposes being investigated. 
 
The study device will be packaged in accordance with the manufacturer’s recommendations. The sensor probes 
will be shipped as bulk orders of 24 probes individually packaged. Only one probe will be used for each patient, 
and then it will be discarded. 
 
11.2 Receipt of the investigational device 
Upon receipt of the investigational device supplies, an inventory will be performed, and a device tracking log 
will be filled out and signed by the person accepting the devices from the manufacture’s carrier. Any damaged 
or unusable devices will be documented in the study files. The investigator will notify the sponsor of any 
damaged or unusable devices that were supplied to the investigator’s site. 
 
11.3 Identification of each investigational device (batch number, serial number or unique code) 
Each investigational device will be identified with the following numbers as described in the section 2.4 
“Traceability”: 
• 
OLV-4201A Pulse Oximeter: identify with assigned serial numbers 
• 
TL-271T3 SpO2 sensor probe: identify with assigned lot numbers 
 
11.4 Expiry date of use 
Not applicable. 
 
11.5 Use and storage of the investigational device 
When in use, the device will remain in the possession of the study team. The device must be used only for the 
purpose of this study. The OLV-4201A Pulse Oximeter will be cleaned following the manufactures instructions 
(cleaned by hand with a mild detergent), and the standard hygiene and infection control procedure in the ED. 
The SpO2 sensor probes that come into contact with the subject’s finger will be properly disposed after each 
use. The device will immediately be returned to the locked research office at NSUH and/or FIMR when not in 
use. The research team will follow product instructions and operator’s manuals. There are no specific storage 
requirements nor special handling requirements during storage for the study device. 
 
11.6 Subject identification 
The serial number of the Pulse Oximeter and the lot number of the sensor probe which are used for each subject 

 Clinical investigation plan CS-011-004 Ver.3.1 
 30 / 38 
 
will be documented in the CRF of each subject. With this record, the dates of using the device are also traceable. 
 
11.7 Investigational device which is returned/explanted from subject, if applicable 
Not applicable. 
 
11.8 Return of unused, expired or malfunctioning investigational devices, if applicable 
At the completion of the study, there will be a final reconciliation of the study devices. This reconciliation will be 
logged on the device tracking log. Any discrepancies noted will be investigated, resolved, and documented prior 
to returning the device to the manufacture. 
 
12 Statement of compliance 
12.1 Declaration of Helsinki 
This study is to be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki. These principles protect the rights, safety and well-being of human subjects, which are the most 
important considerations and shall prevail over interests of science and society. These principles shall be 
understood, observed, and applied at every step in the clinical investigation. 
 
12.2 International standard and any regional or national regulations 
This study is to be conducted in accordance with US and international standards of Good Clinical Practice: 
International Conference on Harmonization ICHE6, ISO 14155, the Code of Federal Regulations Title 21 parts 
803 and 812, and other applicable government regulations and institutional research policies and procedures. 
 
12.3 IRB and/or regulatory authorities 
This CIP and any amendments on the CIP will be submitted to the Northwell Health IRB for formal approval of 
the study conduct. The decision of the IRB concerning the conduct of the study will be made in writing to the 
investigator and a copy of this decision will be provided to the sponsor before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. This consent form 
will be submitted with the CIP for review and approval by the IRB for the study. The formal consent of a subject, 
using the IRB-approved consent form, must be obtained before that subject undergoes any study procedures. 
The consent form must be signed by the subject and the investigator-designated research professional obtaining 
the consent. A waiver of documentation of consent will be used for any subjects that have a physical limitation 
preventing them from signing the consent form but have the ability to understand and express a reasoned choice. 
In this case, HIPAA authorization will be obtained verbally, and only in cases where there is a physical limitation 
preventing the subject from signing his/her name. Both the waiver of documentation of consent and the verbal 
HIPAA authorization will be documented in the enrollment note. 
 

 Clinical investigation plan CS-011-004 Ver.3.1 
 31 / 38 
 
12.4 Insurance 
The sponsor shall hold an insurance contract to cover the liability according to the arrangement of the sponsored 
research agreement for this study. 
 
12.5 Conflict of interest 
All Northwell Health Investigators will follow the Northwell Health Policy on Conflicts of Interest Related to 
Research. 
 
13 Informed consent process 
13.1 General process for obtaining informed consent 
Adult patients who present to the ED of NSUH who meet the eligibility criteria will be recruited. Informed consent 
will be obtained directly from the subject prior to all procedures. Some individuals may be assessed to have 
difficulty writing but have the ability to understand and express a reasoned choice. For example, such limitations 
in writing may result from a broken arm, an infusion line causing pain when moving the arms or writing fingers, 
or a high fever that may induce feelings of lethargy that prohibits them from providing a written signature, etc. 
As such, we request a waiver of documentation of consent for individuals who have a physical limitation 
preventing them from signing the consent form. The consent process will be performed as follows: 
(1) The subject will be given consent forms to read and be given an opportunity to ask questions. If the 
subject has a visual impairment, the consent will be read to them. 
(2) One impartial witness will be present during the entire informed consent discussion. 
(3) After the written consent is provided to the subject, if capable of doing so, the subject will sign or mark 
an X to signify consent and will personally date the consent document. If that is not possible, the subject 
will provide verbal consent. 
(4) After consent has been obtained from the subject, the person obtaining consent and the impartial 
witness will sign and date the written study consent form with a statement that documents that an oral 
process was used and, if necessary, that the subject provided verbal consent. By signing the consent 
document, the witnesses attest that the information in the consent document and any other written 
information were accurately explained to the subject. 
(5) The consent process will also be documented in the medical record or in accord with the Institution’s 
policy. 
(6) Signed copies of the consent form will be given to the subject. 
 
HIPAA authorization will be obtained verbally, and only in cases where there is a physical limitation preventing 
the subject from signing his/her name. Both the waiver of documentation of consent and the verbal HIPAA 
authorization will be documented in the enrollment note. 
 
If, at any point, the participant no longer wishes to be in this study, he/she may notify the study investigators (as 
outlined in the consent form) and be withdrawn from the study. 

 Clinical investigation plan CS-011-004 Ver.3.1 
 32 / 38 
 
 
13.2 Informed consent process if the subject is unable to give it 
Not applicable. If a patient approached for the study is assessed to have a cognitive impairment based on their 
inability to understand and express a reasoned choice, they will be unable to provide informed consent and thus 
will be excluded from participation in the study. 
 
14 Adverse events, adverse device effects and device deficiencies 
14.1 Definitions of adverse events and adverse device effects 
(1) Adverse event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including 
abnormal laboratory findings) in subjects, users, or other persons, whether or not related to the 
investigational medical device. This definition includes events related to the investigational medical 
device or comparator, and events related to the procedures involved. For users or other persons, this 
definition is restricted to events related to investigational medical devices. 
 
(2) Adverse device effect (ADE) 
Adverse event related to the use of an investigational medical device. This definition includes adverse 
events resulting from insufficient or inadequate instructions for use, deployment, implantation, 
installation, or operation, or any malfunction of the investigational medical device as well as any event 
resulting from use error or from intentional misuse of the investigational medical device. 
 
14.2 Definition of device deficiencies 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety, or performance. 
Device deficiencies include malfunctions, use errors, and inadequate labeling. 
 
14.3 Definition of serious adverse events, serious adverse device effect and unanticipated serious 
adverse device effects 
(1) Serious adverse event (SAE) 
Adverse event that: 
a) led to death,  
b) led to serious deterioration in the health of the subject, that either resulted in 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, or  
3) in-patient or prolonged hospitalization, or  
4) medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function,  
c) led to fetal distress, fetal death, or a congenital abnormality or birth defect 
 

 Clinical investigation plan CS-011-004 Ver.3.1 
 33 / 38 
 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, without 
serious deterioration in health, is not considered a serious adverse event. 
 
(2) Serious adverse device effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a serious adverse 
event. 
 
(3) Unanticipated serious adverse device effects (USADE) 
Serious adverse device effect which by its nature, incidence, severity, or outcome has not been 
identified in the current version of the risk analysis report. 
 
NOTE: anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, 
severity or outcome has been identified in the risk analysis report. 
 
14.4 Definition of unanticipated problems involving risk to subjects or others 
Any incident, experience, or outcome that meets all of the following criteria:  
• 
Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such as the 
IRB-approved protocol or consent form, the investigators brochure, etc.) 
• 
Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• 
Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
14.5 Time periods for reporting adverse events and device deficiencies 
(1) Notifying the PI and the sponsor 
Any adverse event that qualifies as a serious adverse event or a serious adverse device effect, and any 
type of unanticipated adverse device effect, regardless of seriousness or severity, must be reported 
immediately to the PI and to the sponsor by telephone within 24 hours of the event. Within the 
following 48 hours, the PI shall provide further information, as applicable, on the adverse event or the 
unanticipated problem in appropriate forms of a written narrative. This should include a copy of 
completed reporting forms, and any other diagnostic information that will assist the understanding of 
the event. 
 
(2) Notifying the IRB 
The Northwell Health IRB requires the investigators to submit reports of the following problems within 
5 working days from the time the investigators become aware of any adverse event that occurs any 
time during or after the study, which in the opinion of the PI is: 

 Clinical investigation plan CS-011-004 Ver.3.1 
 34 / 38 
 
• 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed consent document 
and other relevant sources of information, such as product labeling and package inserts.) 
AND 
• 
Related to the research procedures (An event is “related to the research procedures” if in the 
opinion of the PI or the sponsor, the event was more likely than not to be caused by the research 
procedures.) 
The above is required regardless of whether the event is serious or non-serious, on-site or off-site. 
 
All unanticipated adverse device effects and all serious adverse device effects reported by the 
investigator to the sponsor must also be reported to the IRB as soon as possible, but within 5 
business days. 
 
14.6 Process for reporting adverse events and device deficiencies 
(1) Notifying the PI and the sponsor 
At each contact with the subject, the investigator must seek information on adverse events including 
adverse device effects by specific questioning and, as appropriate, by examination. Information on all 
adverse events including adverse device effects must be recorded immediately in the source 
documents, and also in appropriate adverse event case report forms. All clearly related signs, symptoms, 
and abnormal diagnostic procedures results should be recorded in the source documents, though 
should be grouped under one diagnosis. 
 
The clinical course of each event must be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause. Serious adverse events and 
serious adverse device effects that are still ongoing at the end of the study period must be followed up 
to determine the final outcome. Any serious adverse device effects that occur after the study period 
must be recorded and reported promptly. 
 
The minimum initial information to be captured in the subject’s source documents concerning the 
adverse event includes: 
• 
Study identifier 
• 
Study subject number 
• 
Model and serial number/lot number of the investigational device 
• 
A description of the event 
• 
Date of onset 
• 
Investigator assessment of the association between the event and study procedure/treatment 
• 
Current status 

 Clinical investigation plan CS-011-004 Ver.3.1 
 35 / 38 
 
• 
Whether study procedure/treatment was discontinued 
• 
Whether the event is serious and reason for classification as serious 
 
(2) Notifying the IRB 
The investigators should report unanticipated problems to the Northwell Health IRB using the form: 
“Unanticipated Problems Posing Risks to Subjects or Others Including Reportable Adverse Events” or 
as a written report of the event (including a description of the event with information regarding its 
fulfillment of the above criteria, follow-up/resolution and need for revision to consent form and/or other 
study documentation). Copies of each report and documentation of IRB notification and receipt will be 
kept in the Clinical Investigator’s study file. 
 
<Other Reportable events> 
For clinical studies with an investigational device, the following events are also reportable to the 
Northwell Health IRB: 
• 
For device studies that include the delivery of investigational drugs, any adverse experience 
that, even without detailed analysis, represents a serious unexpected adverse event that is rare 
in the absence of drug exposure (such as agranulocytosis, hepatic necrosis, Stevens-Johnson 
syndrome). 
• 
Any adverse event that would cause the sponsor to modify the protocol or the informed consent 
form, or would prompt other action by the IRB to assure protection of human subjects. 
• 
Information that indicates a change to the risks or potential benefits of the research, in terms of 
severity or frequency. For example:  
o 
An interim analysis indicates that participants have a lower rate of response to 
treatment than initially expected. 
o 
Safety monitoring indicates that a particular side effect is more severe, or more frequent 
than initially expected. 
o 
A paper is published from another study that shows that an arm of your research study 
is of no therapeutic value. 
• 
Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used 
in a research protocol. 
• 
Breach of confidentiality 
• 
Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard 
to a research participant. 
• 
Incarceration of a participant when the research was not previously approved under Subpart C 
and the investigator believes it is in the best interest of the subject to remain on the study. 
• 
Complaint of a participant when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
• 
Protocol violation (meaning an accidental or unintentional deviation from the IRB approved 

 Clinical investigation plan CS-011-004 Ver.3.1 
 36 / 38 
 
protocol) that in the opinion of the investigator placed one or more participants at increased risk, 
or affects the rights or welfare of subjects. 
 
14.7 Foreseeable adverse events and anticipated adverse device effects 
There is no particular anticipated adverse device effect since the applied part of the investigational device (the 
sensor probe) is equivalent to standard pulse oximeter sensors. A well-known potential adverse effect of pulse 
oximeters is thermal injuries due to temperature rise at the applied part of the sensor. 
 
14.8 Emergency contact for reporting serious adverse events and serious adverse device effects 
<Sponsor contact information for reporting purposes> 
Report adverse events including adverse device effects and any unanticipated problems by phone and email 
to the following representative of the sponsor: 
Steve Weisner, CEO 
Nihon Kohden Innovation Center 
Phone: 617-318-5900 
Email: Steve_Weisner@nihonkohden.com 
 
14.9 Information regarding the data monitoring committee 
Not applicable. There is no data monitoring committee for this study. 
 
15 Vulnerable population 
Not applicable. The population for this study is not considered as a vulnerable population. 
 
16 Suspension or premature termination of the clinical investigation 
16.1 Criteria and arrangements for suspension or premature termination 
The sponsor may suspend or prematurely terminate either a clinical investigation in an individual investigation 
site (if applicable) or the entire clinical investigation for significant and documented reasons. A principal 
investigator, IRB, or regulatory authority may suspend or prematurely terminate participation in the clinical 
investigation at the investigation sites for which they are responsible. 
 
If suspicion of an unacceptable risk to subjects arises during the clinical investigation, or when so instructed by 
the IRB or regulatory authorities, the sponsor shall suspend the clinical investigation while the risk is assessed. 
The sponsor shall terminate the clinical investigation if an unacceptable risk is confirmed. The sponsor shall 
consider terminating or suspending the participation of a particular investigation site (if applicable) or investigator 
in the clinical investigation if monitoring or auditing identifies serious or repeated CIP deviations. 
 
If suspension or premature termination occurs, the terminating party shall justify its decision in writing and 
promptly inform the other parties. The principal investigator and sponsor shall keep each other informed of any 

 Clinical investigation plan CS-011-004 Ver.3.1 
 37 / 38 
 
communication received from either the IRB or the regulatory authority. If the suspension or premature 
termination was in the interest of safety, the sponsor shall inform all other investigators of other investigation 
sites (if applicable).  
 
When the sponsor concludes an analysis of the reason(s) for the suspension, implements the necessary 
corrective actions, and decides to lift the temporary suspension, the sponsor shall inform the principal 
investigator, the IRB, and where appropriate, the regulatory authority of the rationale and provide them with the 
relevant data supporting this decision. Concurrence shall be obtained from the IRB and, where appropriate, 
regulatory authorities before the clinical investigation resumes. 
 
16.2 Criteria for access to and breaking the blinding/masking code in the case of suspension or 
premature termination of the clinical investigation 
Not applicable. The blinding in this study is used only when CRI and CRT measurements are performed at the 
bed side as described in the section 6.1.2: the investigator who will measure the visual CRT will be blinded from 
the CRI values measured with the investigational device. 
 
16.3 Requirements for subject follow-up 
Any early withdrawal of subject must be fully documented in the case report forms. The subject must be followed 
up to state the reason for the withdrawal and to establish whether the reason is considered as an adverse event 
or not. 
 
17 Publication policy 
The result and the data obtained in this study will be used for applications for FDA clearance of the 
investigational device. A full publication policy is detailed in the sponsored research agreement for this study 
between Northwell Health and NKC. The guiding principles for this are based on the requirements of Northwell 
Health. Authorship and manuscript preparation will be done in accordance with accepted standards. In general, 
this publication policy allows for publication of the result and the data with the requirement that all publications 
and public release must be presented to the sponsor well in advance of any publication or presentation, time 
for the sponsor to respond to the data is encouraged and allowed per the publication policy. 
 
18 Bibliography 
1. Schriger DL, Baraff L: Defining normal capillary refill: variation with age, sex, and temperature. Ann 
Emerg Med 1988; 17:932-935 
2. Lima A, Jansen TC, van Bommel J, et al: The prognostic value of the subjective assessment of 
peripheral perfusion in critically ill patients. Crit Care Med 2009; 37(3):934-938 
3. Van Genderen ME, Paauwe J, de Jonge J, van der Valk RJP, Lima A, Bakker J, et al: Clinical 
assessment of peripheral perfusion to predict postoperative complications after major abdominal 
surgery early: a prospective observational study in adults. Crit Care 2014; 18(3): R114 

 Clinical investigation plan CS-011-004 Ver.3.1 
 38 / 38 
 
4. Alsma J, van Saase JLCM, Nanayakkara PWB, et al: The Power of Flash Mob Research: Conducting 
a Nationwide Observational Clinical Study on Capillary Refill Time in a Single Day. Chest 2017; 
151:1106-1113 
5. Pickard A, Karlen W, Ansermino JM: Capillary refill time: is it still a useful clinical sign? Anesth Analg 
2011; 113:120-123 
6. Lima A, Bakker J: Noninvasive monitoring of peripheral perfusion. Intensive Care Med 2005; 31:1316-
1326 
7. Shinozaki K, Capilupi MJ, Saeki K, et al: Blood refill time: Clinical bedside monitoring of peripheral blood 
perfusion using pulse oximetry sensor and mechanical compression. Am J Emerg Med 2018; 
36(12):2310-2312 
8. Shinozaki K, Capilupi MJ, Saeki K, et al: Low Temperature Increases Capillary Blood Refill Time 
Following Mechanical Fingertip Compression of Healthy Volunteers: Prospective Cohort Study. J Clin 
Monit Comput 2018 [Epub ahead of print] 
9. Hajian-Tilaki, K.: Sample size estimation in diagnostic test studies of biomedical informatics. Journal of 
biomedical informatics 2014; 48:193-204 
10. Obuchowski, N. A., Lieber, M. L., & Wians, F. H.: ROC curves in Clinical Chemistry: Uses, misuses, and 
possible solutions. Clinical Chemistry 2004; 50(7) 
11. E. A. Youngstrom. A primer on receiver operating characteristic analysis and diagnostic efficiency 
statistics for pediatric psychology: we are ready to ROC. J Pediatr Psychol. 2014;39(2):204-221. 
 
19 Attachments 
• 
Attachment 1: Operator’s Manual of OLV-4201 
• 
Attachment 2: Certificate of Safety Test of IEC 60601-1 
• 
Attachment 3: Certificate of EMC Test of IEC 60601-1-2 and ISO 80601-2-61(clause202) 
• 
Attachment 4: Operator’s Manual of SpO2 sensor probe 
• 
Attachment 5: Operator’s Manual of the CRI function 
• 
Attachment 6: Report of Collaborative Research at Northwell