Determination of SpO2 and PR Accuracy Specifications at Rest / Accuracy of Pulse Oximeters With Profound Hypoxia / Pulse Oximeter Accuracy Evaluation Protocol
Conditions: Hypoxia
Sponsor: Nihon Kohden

NK IRB No.: 70Ag_Vital-00013 
Date: December 16, 2022  
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Identifiers: NCT05745662 Protocol ID: 70Ag_Vital-00013 
Title: Accuracy of Pulse Oximeters With Profound Hypoxia At Rest (NIHO17) 
Original Date: 16 Dec 2022 
Redaction: 1 Sep 2025 
 

NK IRB No.: 70Ag_Vital-00013 
Date: December 16, 2022  
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Determination of SpO2 and PR accuracy specifications at rest 
ACCURACY OF PULSE OXIMETERS WITH PROFOUND HYPOXIA NIHO 17 
Pulse Oximeter Accuracy Evaluation Protocol 
 
Study Site: The UCSF Hypoxia Research Laboratory, 513 Parnassus Ave San Francisco, CA 94133 
Principal Investigator (PI): Philip E. Bickler, M.D 
Study Period: February 1-2, 2023 
 
Breathe-down Test at Rest 
 
1. Objective 
 
This study is intended to evaluate performance of the following pulse oximeter (test devices: recorded 
oximeters), shown in Table 1, manufactured by Nihon Kohden Corporation (1-31-4, Nishiochiai, Shinjuku-ku, 
Tokyo, 161-8560, Japan) sufficiently to support performance claims for an FDA 510K submission or ISO 
technical file. These claims include accuracy at rest. 
 
Table 1. Test devices: *recorded oximeters 
Device name 
Model name 
Pulse oximeter 
OLV-4000 series, OLV-4202 (SW version: 01-15) 
SpO2 Connection Cord 
JL-400T 
*Finger Probe 
TL-631T3 (Group 1) 
*Finger Probe 
TL-631T3 (Group 2) 
Attachment tape 
- (option for TL-631T3 (Group 1 & Group 2)) 
 
Description of the tested devices is attached as Appendix A. 
 
Bedside monitor, PVM-4763 (SW version 01-10) will be used for monitoring heart rate for reference.  
 
The following requirements are to be met at rest: 
• 
SpO2 value range 70% to 100% 
• 
At least 10 subjects, with 3 of dark pigment (Fitzpatrick Scale Type V or VI) 
• 
At least 200 data points 
 
Success criteria is as follows: 
Primary outcome measure 
SpO2 accuracy 
Rms of within ±2 [%SpO2] (70 to 100 [%]) 
Pulse rate accuracy 
Rms of within ±3 [1/min.] (30 to 300 [1/min.]) 
Secondary outcome measure 
SpO2 accuracy 
Rms of within ±2 [%SpO2] (80 to 100 [%]) 
Rms of within ±3 [%SpO2] (70 to 80 [%]) 
 
Safety of the test devices will be evaluated by assessing adverse events occurred to subjects. 
 
This test is designed in response to the 2013 FDA Guidance on Pulse Oximeters – Premarket Notification 
Submissions and by ISO 80601-2-61:2017 on Pulse Oximeters, specifically the sections listed below. 
 
• 2013 FDA Guidance on Pulse Oximeters – Premarket Notification Submissions:  
o   4.1 
Accuracy of Pulse Oximeters 
o   4.1.1 In vivo testing for SpO2 accuracy under laboratory conditions 
o   4.1.5 Testing for Pulse Rate Accuracy claims 
• ISO 80601-2-61:2017 Annex EE.2 and clause 201.12.1.101.2 
o   201.12.1.101 SpO2 accuracy of pulse oximeter equipment  
o   201.12.1.101.2 
Determination of SpO2 accuracy  
o   201.12.1.104 Pulse rate ACCURACY  
 
NOTE: This study has been designed per ISO 80601-2-61:2017, and it has been also designed to respond to 
the recommendations on subject safety added on ISO 80601-2-61:2011.  Since ISO 80601-2-61:2011 has 
been updated as ISO 80601-2-61:2017 with no changes in the requirements for conducting the study and 
demonstrating SpO2 and PR accuracy, this study results can be referred for demonstrating SpO2 and PR 
accuracy per ISO 80601-2-61:2011 as well as per ISO 80601-2-61:2017. 

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Date: December 16, 2022  
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This study will be conducted in accordance with this protocol and the ethical principles that have their origin in 
the Declaration of Helsinki, ISO 14155: 2011 and :2020.  The study will not begin until the UCSF IRB 
approval is received.  
 
2. Subjects 
 
This study is performed on volunteers who have previously been determined to be healthy enough for this 
study, have signed an informed consent form and met the following IRB requirements.  These volunteers are 
compensated by the laboratory for their participation.  Point of enrolment is defined as time at which subjects 
sign and date the informed consent form and screening based on subject demography and 
inclusion/exclusion criteria is complete. Expected enrolment period is 1 week. Expected duration of each 
subject’s participation will be about 45 minutes.  The total expected duration of this study is 2 days. 
 
The inclusion criteria for the test subjects are: 
 
1. 
Both male and female subjects who can give written informed consent 
2. 
Healthy subjects capable of undergoing controlled hypoxemia to the levels outlined in the desaturation 
profile below 
3. 
Meeting the demographic requirements listed above. 
 
The exclusion criteria for the test subjects are: 
 
1. 
Age below 18 or over 50 
2. 
Pregnant women 
3. 
Significant arrhythmia 
4. 
Blood pressure above 150 systolic or 90 diastolic 
5. 
Carboxyhemoglobin levels over 3% 
6. 
Subjects whom the investigator consider ineligible for the study. 
 
At least 10 subjects will be recruited to complete the test.  Of these 3 will be dark pigment.  If the number 
of samples is less than the required 200 or if less than 2 of dark pigment successfully complete the test, 
subjects will be added to include 2 of dark pigment and at least 200 data points. 
 
 
3. Desaturation 
 
Each subject will have an arterial catheter inserted in the left or right wrist. 
 
For each subject, a series of desaturation runs are performed.  Run 1 starts with a stabilized period at 
room air and is followed by stabilized plateaus at various lower saturation levels.  Run 2 starts with a 
stabilized period at 100% and is followed by stabilized plateaus at various lower saturation levels.  The 
following are value targets: 
 
Run 1   
Room Air, 97, 87,77 
Run 2  
92, 82, 72 
 
The objective of these targets is to spread the data points evenly over the desired range.  Achieving them 
exactly is not important, though every effort will be made to be within 2%.  Saturation level at each plateau 
and the number of plateaus can vary depending on the subject’s condition. 
 
The SpO2 value is reduced by delivering a mixture of medical air and nitrogen, controlled by 2 manually 
controlled needle valve flowmeters.  The operator controls the SpO2 by observing the breath-by-breath 
arterial saturation, which is in turn computed from end tidal PO2 and PCO2.  FiO2 is reduced suddenly at first 
then adjusted to achieve a stable plateau value at the desired target.  A plateau is defined as stable when 
the readings of the sponsor Control instrument have not changed more than 1 % for 20 seconds (they do not 
have to agree with each other).  Each desaturation plateaus should not exceed 10 minutes. When the 
sponsor confirms that stability is achieved, a blood draw is taken to flush the tubing, then the first sample is 
taken using a 2.5 cc syringe.  At the time when the gas operator thinks the SpO2 is stable, the sponsor can 
ask that the blood sample be delayed for up to 90 seconds.  If the stability of a plateau cannot be confirmed 
in the data analysis, the Sponsor may discuss with the PI the validity of the data collected at such plateau.  
The second, third and fourth sample are taken by intervals of 30 seconds.  The number of blood samples 
can vary depending on the subject’s condition.  Extra samples may be required at the discretion of the PI, in 

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Date: December 16, 2022  
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which case the total number of blood samples should not exceed 32.  The gas mixture is then changed for 
the next value.  This is then repeated for each plateau value.  
 
For each subject, this allows 25 samples to be taken when Room air sat is considered.  So, with for 
example 12 subjects in the study, this produces 300 samples.  This ensures that even if one or two subjects 
and some data points are thrown out, the results will meet the FDA norm of 10 subjects and 200 data points. 
 
During this procedure, the subject is coached on breathing.  If he/she appears to fall asleep, he/she is 
woken up.  At any signs of distress, he/she is given 100% oxygen. 
 
Each run should take Between 15 and 25 minutes.  It is normal to schedule as many as 10 subjects per 
day. 
 
Trained Nihon Kohden personnel will be present at the procedure.  The role of the Nihon Kohden person is 
to give technical support relative to the use of the test pulse oximeters including applying the sensors to the 
subjects and to perform study monitoring. All these actions will be done under the careful direction of the 
investigator. 
 
Data of the test devices will be automatically recorded simultaneously with measurement in an SD card 
inserted into the pulse oximeter OLV-4202.  Subject’s demographic data, time of blood draw, and Co-
oximeter values will be collected using specific data collection forms. 
 
4. Reference Data 
 
The reference blood samples will be analyzed using two Radiometer ABL90 co-oximeters (ABL-A and 
ABL-B).  Readings of two ABLs will be used to determine the validity of the readings of each other.  When 
two ABLs are determined to be valid, the SaO2 reference value is the average of the SaO2 measurements of 
the two ABLs.  The validity of ABL measurements is determined by the following procedure: 
- 
Check if the difference between two ABL readings is within 2% 
- 
If the difference between two ABL readings is within 2%, the readings of two ABLs are valid. 
- 
Readings of two ABL differed by more than 2% saturation will be excluded from the analysis. 
- 
If only one ABL returns the value, the value will be assumed to be correct. 
 
The co-oximeters should be quality control checked and calibrated at the study site to be functioning 
properly before use. 
The heart rate will be measured using a Nihon Kohden PVM-4763 as an ECG monitor.  The monitor 
should be quality control checked using a Fluke Prosim8 at the study site to be functioning properly before 
use. 
 
5. Sensor Placements 
 
A 3-lead ECG will be taken on each subject with the sponsor Control instrument.  The electrodes for the 
sponsor Control instrument will be the L-150X disposable ECG electrodes. 
 
The probes for the primary test instruments will be the TL-631T3 finger probe for adults and children.  
Probes will be attached to the study subjects by Nihon Kohden engineers who are well trained to use the test 
devices under the supervision of PI or co-investigator.  These probes will be arranged as follows: 
 
On the left-hand side 
 
Subject 1 + 4 + 7 + 10 
Subject 2 + 5 + 8 + 11 
Subject 3 + 6 + 9 +12 
TL-631T3 
(Group 1) 
Index 
Middle 
Ring 
TL-631T3 
(Group 2) 
Middle 
Ring 
Index 
 
6. Subject Safety 
 
1. The sensors will be isolated as follows500V between the sensor and earth ground 
2. 4 KV between AC mains power and the low voltage power supply and 1.5 KV between the low 
voltage power supply and the sensor, OR 5 KV between AC mains and the sensor. 
 

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Non-invasive blood pressure will be measured at a screening.  EtCO2, respiratory rate, and FiO2 of the 
subjects will be monitored.  In addition, the laboratory maintains criteria for subject selection that have been 
proven to minimize the risk of any problems during the study. 
 
Adverse event and serious adverse event will be assessed throughout the study by the PI and co-
Investigator, or research nurse designated by the PI.  If any adverse event occurs during the study, an 
appropriate medical treatment will be provided to the subject by a medical staff at the laboratory.  Nihon 
Kohden may suspend or prematurely terminate the study when there are serious violations and deviations 
from the GCP which could adversely affect subject’s safety and correct data recording. 
 
The test will be discontinued when a subject requests to withdraw from the study, or the PI or co-
investigator will terminate the desaturation procedure and/or a subject’s participation in the study because of 
the reasons including: 1) the subject experiences unexpected oxygen desaturation or 2) the subject loses 
consciousness. 
 
Risks and anticipated adverse device effects associated with participation in the study that are to be 
assessed include the following: 
a. 
Risks of arterial cannulation include bleeding, infection, nerve injury and bruising at the site of catheter 
insertion.  There are also remote risks of an allergic reaction from the lidocaine used for local 
anesthesia, or the development of arterial spasm, dissection, or thrombosis. 
b. 
The risks of the brief exposures to hypoxia are include feeling short of breath, headache, and 
dizziness.  Brief loss of consciousness may occur but is not expected at the levels of oxygen targeted 
for these tests. 
c. 
The risks of hyperventilating include feeling light-headed or dizzy. The risks of breathing air with 
increased amounts of carbon dioxide include feeling short of breath and developing a headache. 
d. 
The risks of burns and skin problems from poor blood circulation.  Poor circulation can be avoided by 
not putting SpO2 probes too tightly. 
 
Nihon Kohden has determined that there is no residual risk associated with the test devices. Nihon Kohden 
will be responsible for maintaining the test devices. 
 
Monitoring will be performed by Nihon Kohden.  Any adverse events (serious and non-serious) and 
adverse device effects will be documented in case report forms and reported to Nihon Kohden by PI in a 
timely manner. 
 
7. Data Analysis 
 
Collected data used for data analysis will be reviewed by PI and Nihon Kohden. Data will be retained by the 
laboratory and Nihon Kohden per their SOPs and policies. Nihon Kohden has no access to subject’s 
personally identifiable information. 
 
Data from subjects who did not complete the protocol will be thrown out.  Also, if subject’s 
carboxyhemoglobin level is confirmed to be over 3% during or after the study, data from the subject will be 
thrown out.  Missing data will not be supplemented. 
 
Data that meets the following conditions will be also thrown out: 
- 
The CO-oximeter experienced error conditions 
- 
Two CO-oximeter readings differed by more than 2% saturation 
- 
The first data points at a plateau where a co-oximeter output differs over 2% saturation from the 
second points at the same plateau 
- 
Data points at a plateau where a co-oximeter output changes over 2% saturation from the 
previous points at the same plateau 
- 
Data points which are the only ones at a plateau 
- 
Data points from unstable pulse wave signal where the motion artifact red p-p amplitude is over 
the PPG p-p amplitude of the subject 
- 
Data points from unstable pulse wave signal where the respiratory artifact red p-p amplitude is 
over the PPG p-p amplitude of the subject 
- 
PR readings where heart rate changes over 4bpm for 10 seconds 
- 
PR readings at a plateau where heart rate changes over 19bpm for 10 seconds 
SpO2 data will be reduced using the ARMS method and accuracy will be reported as the ARMS deviation 
between the co-oximeter and the test instruments for all points gathered from each sensor. 
 
 

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PR data will be reduced using the ARMS method and accuracy will be reported as the ARMS deviation 
between the ECG monitor and the test instruments for all plateaus gathered from each sensor. Accuracy will 
be determined by comparing the noninvasive pulse rate measurement of the pulse oximeter (PRi) to the heart 
rate obtained from an electrocardiography reference device (HRRi) and calculating the arithmetic root mean 
square (Arms) error value as follows: 
 
 
 
 
 
All records of this study related to TL-631T3 (Group 1), TL-631T3 (Group 2) will be retained by Nihon 
Kohden for at least 3 years after the date of release for commercial distribution of the test devices. 
 
Data will be statistically analyzed by the laboratory per UCSF SOP. The laboratory will provide a 
summarized report for TL-631T3 (Group 1), TL-631T3 (Group 2), using the data recorded by the sponsor 
suitable for FDA 510K submission. Any deviation from the protocol will be reported promptly using case report 
forms and reported in the report. 
 

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Appendix A Description of the investigational device 
A.1. Test devices: *recorded oximeters 
Device name 
Model name 
Quantity 
Intended populations 
Materials that will be in contact 
with subject’s skin 
Approved for market in 
Japan 
Appearance 
Pulse oximeter 
OVL-4000 
series, OLV-
4202 (SW 
version: 01-15) 
6 
Adult/Child/Neonate 
- 
Yes 
 
SpO2 Connection 
Cord 
JL-400T 
11 
- 
- 
Yes 
 
*Finger Probe 
TL-631T3 
(Group 1) 
1 
Adult/Child 
Polyurethane 
Yes 
 
*Finger Probe 
TL-631T3 
(Group 2) 
1 
Adult/Child 
Polyurethane 
Yes 
 
Attachment tape 
- (option for TL-
631T3 (Group 1 
& Group 2)) 
24 
Adult/Child/Neonate 
Polyvinyl chloride, Acrylic 
adhesive 
Yes 
 
The safety assessment per section 201.11 of ISO 80601-2-61:2011 has been conducted for all the test devices and confirmed that the test devices can be 
used on human subjects. 
All test devices can be identified by serial number or lot number.  Nihon Kohden will be responsible of keeping records documenting the delivery, use, 
return, and disposal of the test devices.