Maintaining Optimal Delivery Using Automatic Titration of Oxygen in Preterm Infants Receiving High Velocity Nasal Insufflation Therapy
Phase: NA
Conditions: Infant, Premature, Neonatal Respiratory Distress, Oxygen Saturation, Bronchopulmonary Dysplasia
Sponsor: Vapotherm, Inc.

 
 
 
Vapotherm, Inc. 
 Maintaining Optimal Delivery using 
Automatic Titration of Oxygen in Preterm 
Infants receiving High Velocity Nasal 
Insufflation Therapy: MODERATION Neo 
NCT Number:  NCT05030012  
02 JAN 2023 

 
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Protocol Title: 
Maintaining Optimal Delivery using Automatic 
Titration of Oxygen in Preterm Infants receiving High 
Velocity Nasal Insufflation Therapy: MODERATION 
Neo 
Protocol Number: 
 
RP-NIOA2019001Reg 
 
 
Revision: 
 
 
IDE Submission –  02 JAN 2023 
 
 
Chief Investigators:  
Billie Lou Short, MD 
 
 
 
 
Khodayar Rais-Bahrami, MD 
 
 
 
 
 
 
Sponsor: 
 
 
Vapotherm, Inc 
100 Domain Drive 
Exeter, NH  03833 
1 (603) 658-0011 
http://www.vtherm.com 
 
 
Site Monitor:  
 
Jessica Whittle, MD, PhD 
 
 
 
 
 
jwhittle@vtherm.com 
 
 
 
 
 
 
Confidential 
 
Study site should keep protocol, all contents and related information confidential. 
 
 
 
 

 
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Protocol Approval 
 
 
Investigator Statement 
 
As Investigator of the study titled “Maintaining Optimal Delivery using Automatic Titration of Oxygen in 
Preterm Infants receiving High Velocity Nasal Insufflation Therapy : MODERATION Neo (the “Study”), 
I agree to:  
 
(i) conduct the Study in accordance with: this Investigator Agreement; the Study’s Protocol as approved 
by the ethics committee (the “Protocol”); all applicable laws and regulations; and any ethics committee or 
regulatory conditions of approval;   
(ii) await IRB approval for the Protocol before obtaining informed consents (if applicable); 
(iii) ensure that all requirements for informed consent are met and not let any subject participate in the 
Study before obtaining that subject’s informed consent (if applicable);  
(iv) not make modifications to the Protocol as supplied to me by Vapotherm, Inc. (the “Sponsor”), 
without first obtaining the written approval of the Sponsor;  
(v) provide the Sponsor with accurate financial information as required by appropriate regulations; 
(vi) supervise all testing of investigational devices that involves any Study subject;  
(vii) maintain Study documentation for the period of time as required by appropriate regulations; and 
(viii) supply to the Sponsor, as part of this Investigator Agreement, my curriculum vitae. 
 
 
INVESTIGATOR 
 
 
 
 
 
 
Signature: 
_________________________________________________ 
 
Printed Name: _________________________________________________ 
 
 
 
Date:  
____________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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GLOSSARY OF DEFINITIONS AND TERMS ............................................................ 4 
I. BACKGROUND AND SIGNIFICANCE .................................................................... 5 
III. SUBJECT SELECTION .......................................................................................... 10 
IV. STUDY DESIGN ...................................................................................................... 12 
V. STATISTICAL METHODS AND DATA ANALYSES ......................................... 12 
ANALYSIS COHORTS: ................................................................................................................................ 13 
MISSING DATA .......................................................................................................................................... 13 
POOLABILITY ............................................................................................................................................ 14 
PRIMARY SAFETY OBJECTIVE ................................................................................................................... 14 
PRIMARY PERFORMANCE OBJECTIVE ........................................................................................................ 15 
SECONDARY PERFORMANCE OBJECTIVE 1 ................................................................................................ 16 
SECONDARY PERFORMANCE OBJECTIVE 2 ................................................................................................ 16 
ADDITIONAL ANALYSES ........................................................................................................................... 17 
SAMPLE SIZE CALCULATIONS ................................................................................................................... 19 
VI. STUDY PROCEDURES .......................................................................................... 21 
VII. DATA COLLECTION ........................................................................................... 23 
IX. RISKS AND DISCOMFORTS ................................................................................ 25 
X. POTENTIAL BENEFITS ......................................................................................... 26 
XI. MONITORING AND QUALITY ASSURANCE .................................................. 26 
XII.  CONFIDENTIALITY ........................................................................................... 26 
XIII.  SKIN PIGMENTATION COLOR SCALE ....................................................... 26 
XIV. REFERENCES ...................................................................................................... 28 
APPENDIX A:  CASE REPORT FORM (CRF) ......................................................... 29 
APPENDIX B: ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ............. 0 
 
 
 
 
 

 
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Glossary of Definitions and Terms 
 
High Velocity Nasal Insufflation (HVNI): a system consisting of heated and humidified gas mixtures of 
varying FiO2 delivered to a patient using a small-bore nasal cannula, at generally high flow rates imparted 
with increased velocity as compared to other standard large-bore cannulae. The flow rates of respiratory 
gas generally exceed a patient’s normal spontaneous inspiratory flow demand.  HVNI systems must 
maintain adequate heating and humidification of the delivered gas to protect the nasal tissues from 
dryness and provide patient comfort.   
 
Oxygen Assist Module (OAM): this module utilizes a closed loop control algorithm, used in conjunction 
with the HVNI therapy provided by Vapotherm Precision Flow, that maintains patient oxygen saturation 
in an optimally controlled range (90-95%). In the Reynolds study this was labeled as the IntellO2 module. 
  
Pulse oxygen saturation (SpO2; %): Arterial blood oxygen saturation as measured by pulse oximetry. 
 
Fraction of inspired oxygen (FiO2): The fractional proportion (generally presented as a fraction but may 
be spoken of as percentage) of the delivered respiratory gas mixture that is oxygen. 
 
Case Report Form (CRF): The form used to record pertinent patient data to address the study aim.  CRFs 
do not contain patient names or medical record numbers; rather, they will be coded with a patient number 
and the key will be maintained by the site principal investigator at each center.  The CRFs are the property 
of Vapotherm. 
 
 
 
 
  
 

 
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I. Background and Significance 
 
The current study is designed to provide a technical validation for the Oxygen Assist Module (OAM; 
Vapotherm, Exeter, NH, USA) used in conjunction with the Vapotherm Precision Flow for titrating 
oxygen to neonates requiring non-invasive respiratory support.  The Vapotherm OAM product integrates 
proven pulse oximetry and gas delivery technology with an innovative and proprietary algorithm that 
increases or decreases the FiO2 setting to assist the clinical staff in maintaining the patient in a target SpO2 
range.  The Vapotherm OAM product is a module for the Precision Flow device, which communicates 
with the Precision Flow through the serial interface connecting the two products: the device to the 
module.  The Precision Flow is a Class II device and was FDA cleared (K072845) on July 17, 2008.  The 
current Product Code under which the Precision Flow Hi-VNI is marketed is QAV. The initial Vapotherm 
OAM Gen0 design was used in a clinical trial in the UK (2016-2017, REC London-Chelsea 16/LO/1272, 
NCT02074774).1 The Vapotherm OAM, a module to the Precision Flow device, is designed to assist the 
caregiver in optimizing the patients’ oxygen saturation levels, but is not life sustaining as it will not 
replace the standard of care provided to the infant; i.e., standard SpO2 alarms are in place and caregivers 
are instructed to make manual adjustments per standard care procedures.   
 
Risk of both hyperoxia and hypoxia in preterm infants have been well described. The NeoProm 
Collaboration Meta-analysis confirmed that a lower SpO2 range was associated with a higher risk of death 
and necrotizing enterocolitis.2 Poets, et al., studied SpO2 values in 1019 infants born with a mean 
gestational age of 25.8 weeks, and birthweight of 855g who had hypoxemic episodes of less than 80% 
SpO2 for longer than 1 minute had a significantly greater odds ratio (OR, 95%CI) for late-death or 
disability (3.4, 1.95-5.83), cognitive/language delay (2.88,  1.65-5.02), motor impairment (5.20, 2.48-
10.92), and severe ROP (2.95, 1,47-5.90) versus episode length equal to or less than 50 seconds3. As a 
result, many neonatal units target a higher range of SpO2, for example, 90%–95%. For staff, maintaining 
SpO2 targets presents a compliance challenge.4 Avoiding both hypoxia and hyperoxia is an important 
goal.5 While additional training improves compliance6 manual maintenance of the target range 90%–95% 
may only be achieved less than 50% of the time.7 
 
Based on prior studies, it is anticipated that the Vapotherm OAM will allow patients to spend more time 
in the target SpO2 range, with the potential for other benefits. 1-7 In practice, the clinician sets the target 
SpO2, and the OAM uses a validated algorithm that combines analysis of real-time measurements and 
trending to choose the appropriate O2 delivery.  The use of smart averaging and hysteresis algorithms 
protects the system from artifact causing too-rapid cycling of O2 delivery.  The system alerts the health 
care provider if it is unable to maintain the target within the healthcare provider’s set FiO2 limits or if 
maintaining the target requires a significant percentage change in the O2 percentage delivered.  In the case 
of system detection of inadequate SpO2 signal, the module will alarm and revert to a clinician-set FiO2 
setting. The Vapotherm OAM maintains trend data for both SpO2 readings and FiO2 settings that is 
captured every second. 
 
 

 
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Closed loop control of inspired oxygen concentration has been in use since at least 1979 using indwelling 
PaO2 electrodes and since at least 1992 using pulse oximetry (SpO2).8 Claure and Bancalari discuss the 
use of algorithms and trend data in closed loop FiO2 control systems for keeping SpO2 at “the target level 
or range set by the clinician” and summarize that “available data indicate the feasibility of automated 
closed loop control of FiO2 in this population [premature infants] and suggest potential benefits by 
achieving a better oxygenation control while limiting oxygen exposure.” 9  
 
In a paper from 2009, Claure and colleagues conducted a pilot clinical trial to evaluate a system for 
automated control of FiO2 in maintaining SpO2 within an intended range in preterm infants with erratic 
fluctuations in SpO2.10  The study involved sixteen infants with frequent hypoxia episodes and compared 
maintenance of SpO2 within the intended range during one 4-hour period of manual adjustment and one 4-
hour period of automatic adjustment.  This randomized study was conducted using the Avea ventilator 
with a built-in automated FiO2 adjustment function.  The authors conclude that this system of automated 
FiO2 adjustment improved maintenance of SpO2 with reduced exposure to supplemental O2, but that 
studies of longer duration and with standard clinical conditions are warranted. 
 
Claure and colleagues later conducted a larger randomized trial as documented in “Multicenter Crossover 
Study of Automated Control of Inspired Oxygen in Ventilated Preterm Infants.”11  This study involved 
thirty-two infants studied during two consecutive 24 hr periods in random sequence; manual FiO2 
adjustment by clinical staff and automated adjustment.  This study was, again, conducted using the Avea 
ventilator and SpO2 measured with a neonatal pulse oximeter (Radical, Masimo, Irvine, CA).  This study 
showed that automatic FiO2 adjustment improved maintenance of an intended SpO2 range, but increased 
time spent with SpO2 between 80% and 86%.  Moreover, automatic FiO2 adjustments led to reduced 
exposure to high SpO2 values, overall lower inspired oxygen concentration and reduced staff effort 
compared with manual adjustment.   
 
The module examined during the aforementioned clinical studies is a currently CE-marked product 
(Avea-CLiO2 (Vyaire [previously ‘Care-Fusion’], Mettawa, IL, USA).  Maria Wilinska MD, PhD and 
Anna Wasco, MD documented their routine use of the CliO2 for approximately a year and reported the 
module to be very effective in a broad range of patients.12  The Vapotherm OAM product has the same 
intended function as the Avea CliO2 module, namely to maintain the patient in the target SpO2 range, but 
instead of building the automated FiO2 into a ventilator, the control algorithm and pulse oximetry is 
incorporated into a separate system that communicates with Vapotherm’s Precision Flow Hi-VNI unit.  
Similar to the CliO2, the Vapotherm OAM is using Masimo’s pulse oximetry technology to monitor SpO2. 
 
The Vapotherm OAM product initially featured the control loop algorithm developed by John Taube 
(Columbia Life Systems, Chapel Hill, NC, USA), and it has since been improved. The foundation for the 
algorithm has been licensed by Vapotherm, Inc.  The original algorithm was validated in animal studies, 
before use in human infants.13  In 1992, Dr. Bhutani and colleagues published a study using the Taube 
algorithm to manage oxygen delivery for infants using an oxygen hood system.14  In this study, the 
patients’ SpO2 was maintained within a steady target range for a much greater percentage of time with the 

 
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automated system (81%; p < 0.01) compared to routine management (54%) or intense manual control 
with adjustments every 2 to 5 min (69%).  This original algorithm was used in a clinical study conducted 
at Cooper University Hospital in conjunction with Vapotherm’s 2000i device (the predicate to the 
Precision Flow) interacting with a ‘Smart Blender’. In the report of the Cooper study, Drs. Saslow and 
Pyon demonstrated in 14 subjects studied, using each patient as their own control, that patients spent 80% 
of the time within their predetermined saturation range versus 60% during the manual mode (p < 0.001).  
Furthermore, the authors reported no adverse events associated with the use of the SmartBlender in either 
mode.15 
 
The Vapotherm OAM initial version (named IntellO2 at the time) was evaluated in a prospective order-
randomized crossover clinical trial of 30 infants demonstrating at least moderate FiO2 requirement 
lability.1 The trial was conducted in the UK (John Radcliffe Hospital, Oxford University, Oxford, and St. 
Peter’s Hospital, Chertsey) under the direction of Drs. Peter Reynolds and Kevin Ives, respectively. This 
study consisted of identification of preterm infants requiring HVNI therapy for ventilatory support. 
Patients’ parents were approached for consent, and the study was performed under ethical approval and 
monitored by an independent Data Safety Monitoring Committee. Each baby was randomized to receive 
24 hours of therapy during which the OAM (or IntellO2 at the time) was set to either Automatic or 
Manual Mode. For both modes, the nursing staff were instructed to continue standard monitoring of the 
baby and make all necessary FiO2 adjustments necessary to maintain SpO2 within the range of 90 to 95%. 
At 24 hours, the baby was crossed over to the alternative mode of OAM (or IntellO2 at the time) control 
for an additional 24 hours of data collection under the same instructions. The primary outcome was 
proportion of time spent within the target SpO2 range. Similar to the Saslow experience, Reynolds, et al. 
found the median proportion of time spent in target range was 49% (IQR 40-57%) under manual control 
versus automated control time in range of 80% (IQR 70-87%), p<0.0001.1 No adverse events were noted 
in either arm of the study. This was the longest duration data collection of any automated controller using 
an open (cannula) system.   
 
In this proposed study, the algorithm is incorporated into latest generation hardware (OAM) working in 
conjunction with the latest generation Vapotherm HVNI system, which incorporates a precision blender 
(Precision Flow Hi-VNI).  The updated hardware employs improved user interface characteristics but uses 
a similar algorithm as with the UK Reynolds study, and imparts no new risk in administration. 
 
 
 

 
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II. Objectives 
 
The overall objective of this study is to demonstrate that the Vapotherm OAM, when coupled with the 
Precision Flow device, provides safe and efficacious automated control of fraction of inspired oxygen 
(FiO2) adjustments in spontaneously breathing infants with fluctuating arterial blood oxygen saturation 
levels in the routine clinical environment.  
 
Primary Safety Objective 
To demonstrate that safety is not worse than standard practice.  Specifically, to demonstrate that the 
Vapotherm OAM, used in conjunction with the Vapotherm Precision Flow Hi-VNI to treat infants with 
heated, humidified high velocity nasal insufflation (HVNI), is not inferior to standard practice for time 
that infants’ arterial blood oxygen saturation exceed or drop below a target range, thus minimizing the 
proportion of time the subject is exposed to elevated or reduced levels of oxygen in the inspired gas. 
 
Primary Performance Objective 
To demonstrate that percent time oxygen saturation is maintained in a target range is higher than standard 
practice.  More specifically, to demonstrate that Vapotherm OAM used in conjunction with Vapotherm 
Precision Flow Hi-VNI is superior to standard practice for maintaining infants’ arterial blood oxygen 
saturation in a target range, thus minimizing the proportion of time the subject is exposed to elevated or 
reduced levels of oxygen in the inspired gas. 
 
Secondary Performance Objective 1 
To demonstrate that the percent time oxygen saturation is maintained in a target range is higher than 
standard practice for both weight categories (1000g-2500g, 2501g-3500g).  
 
Secondary Performance Objective 2 
To demonstrate that the percent time SpO2 is maintained in a target range is higher than standard practice 
for subjects with both light and dark skin pigmentation.  
 
Additional Objectives 
To quantify and compare OAM to standard practice performance with additional measures including:  
• Proportion of Time, Number of Episodes, and Average Duration of Episodes in both high and low 
SpO2 ranges (with or without FiO2 at or above 21%)  
o SpO2 below target range  
o SpO2 below 80% for episodes ≥60s  
o SpO2 below 80%  
o SpO2 above target range at FiO2>0.21 (not at air)  
o SpO2 below 70%  
o SpO2 in 80% to 86% range  
o SpO2 in target range at FiO2=0.21  
o SpO2 above 98% at FiO2>0.21 (not at air) 

 
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o SpO2 below target range at FiO2=0.21  
• Number of manual adjustments to FiO2 in manual mode compared to automated control (manual 
override). 
• Proportion of Time at or below FiO2 ranges compared between study arms 
o FiO2 at 0.21 (air)  
o FiO2 below 0.25  
• SpO2 fluctuations auto compared to manual control 
o Coefficient of variance for SpO2 for the study arm 
o Standard deviation of SpO2 for the study arm 
• FiO2 fluctuations Auto compared to manual control 
o Coefficient of variance for FiO2 for the study arm 
o Standard deviation of FiO2 for the study arm 
• Index of overshoot (an elevated SpO2 resulting from the FiO2 titration response to a low SpO2) and 
characterization of such excursions. 
o The proportion of time, number of episodes, and average duration per episode of 
Overshoot, defined as SpO2 > range following SpO2 < range for ≥10 seconds duration. 
o The proportion of time, number of episodes, and average duration per episode of 
Overshoot, defined as SpO2 > range for 70s following SpO2 < range. 
• Number of Episodes of hypoxia (below range) within 60-180s after a return to FiO2=0.21 
compared between arms. 
• Number of Episodes of hypoxia (below range) within 60-180s after a return to FiO2=0.21 followed 
by hyperoxia (above range) within 60-180s after a return to FiO2=0.21 compared between arms. 
• The mean FiO2 of the study arms 
• Number of overall adjustments (or adjustments/hour) to FiO2 in manual mode compared to 
automated control. 
• The care ratio (i.e., Nurse:Baby) will be recorded, patients will be separated to care ratio, and each 
care ratio group will be compared between study arms for the proportion of time, number of 
episodes, and average duration of episodes 
o SpO2 in target range  
o SpO2 below target range  
o SpO2 below 80% for episodes ≥60s  
o SpO2 below 80%  
o SpO2 below 70%  
o SpO2 in 80% to 86% range  
o SpO2 above target range at FiO2>0.21 (not at air)  
o SpO2 in target range at FiO2=0.21  
o SpO2 above 98% at FiO2>0.21  
o SpO2 below target range at FiO2=0.21  
• Comparison between Day versus Evening/Overnight of the Proportion of Time, Number of 
Episodes, and Average Duration of Episodes in target, high, and low SpO2 ranges (with or without 
FiO2 at or above 21%) by study arm 

 
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o SpO2 in target range  
o SpO2 below target range  
o SpO2 below 80% for episodes ≥60s  
o SpO2 below 80%  
o SpO2 below 70%  
o SpO2 in 80% to 86% range  
o SpO2 above target range at FiO2>0.21 (not at air)  
o SpO2 in target range at FiO2=0.21  
o SpO2 above 98% at FiO2>0.21  
o SpO2 below target range at FiO2=0.21  
• CONSORT Diagram will be used to articulate the patient numbers 
• For each arm of the study will aggregate the proportion of time for SpO2 for data bins from <80% 
to 100%, and displayed using a histogram. 
• For each arm of the study will aggregate the proportion of time for FiO2 for data bins 0.21 to 1.0, 
and displayed using a histogram. 
• Adverse events as reported on the CRFs (Summarized by seriousness and relatedness to therapy) 
o Specific Serious Adverse Event  
▪ Death 
▪ Necrotizing enterocolitis or focal intestinal perforation 
▪ Microbiologically-confirmed or clinically suspected late-onset invasive infection 
▪ Intracranial abnormality (hemorrhage or focal white matter damage) on cranial 
ultrasound scan or other imaging 
▪ Pulmonary hemorrhage 
o Specific Adverse Event Related to Therapy 
▪ Adverse Event from SpO2 Probe 
▪ Related to the oxygen delivery mode, either automated or manual 
 
 
III. Subject Selection 
 
The subjects in this study are infants in neonatal intensive care units, born prematurely and requiring 
respiratory support via HVNI. The inclusion criteria are designed to identify infants who require 
supplemental oxygen and who therefore present an oxygen titration challenge by demonstration of 
spontaneous fluctuations in SpO2 requiring adjustment of FiO2.  
 
As part of the interim analyses done by the data safety monitoring committee (defined below under Safety 
Monitoring), a review of data after every ten patients will confirm subject inclusion/exclusion criteria.  
 
Inclusion Criteria 
1. 
Infants delivered at a gestational age of less than or equal to 35 6/7 weeks (Preterm) being treated 
with high velocity nasal insufflation therapy for the management of respiratory distress syndrome 

 
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2. 
Patients that clinically require SpO2 maintenance within the target range of 90-95% 
3. 
A need for supplemental oxygen as demonstrated by a required FiO2 > 0.25 at enrollment 
4. 
Requiring a flow rate of greater than 2 L•min-1 such that the assumed inspired oxygen fraction 
matched delivered oxygen fraction (definition of HVNI). 
5. 
A minimum of 6 manual FiO2 adjustments in the 24hr period prior to trial enrollment. 
6. 
Willing/Able to complete informed consent. 
 
 
Exclusion Criteria 
1. 
Current patient weight of <1000g or >3500g at time of study 
2. 
Major congenital abnormalities 
3. 
Hemodynamic instability, defined as being outside of a normotensive range based on an infant’s 
individual characteristics by clinician 
4. 
Persistent unresolved apnea defined as: requiring 6 stimulations or more per 6 hours  
5. 
Seizures 
6. 
Ongoing sepsis 
7. 
Meningitis 
8. 
Clinician’s concern regarding stability of the infant 
 
Infants who meet the inclusion criteria and none of the exclusion criteria will be considered.  Informed 
consent will be obtained from the infant’s Parent or guardian prior to enrollment in the study, following 
which appropriate profile and baseline data will be recorded on the subject’s Case Report Form (CRF).   
 
 

 
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IV. Study Design 
 
This study will be a prospective, multi-center, randomized, crossover trial of automated oxygen titration 
versus manual titration (conventional method). Patients enrolled will have their FiO2 managed by two 
mechanisms of titration (study arms) for two consecutive 24-hour periods in random order.   
• Automated control (OAM), where the FiO2 is adjusted by the OAM system with clinical staff 
ability to override FiO2 when required, and instructed to do so – regardless of the mode 
• Manual control (Manual), where FiO2 is only adjusted by the clinical staff  
 
In both arms, the infants will be receiving high velocity nasal insufflation treatment using the Vapotherm 
Precision Flow Hi-VNI.  
 
The study model does not change the nature of care that is provided by the clinical staff, and the clinical 
staff will be largely naive to the function of the OAM mode.  Therefore, if the clinical staff see fit to 
change FiO2 during the Automated arm of the study they may override the module by changing the setting 
on the Precision Flow (without interacting with the OAM).  Any manual override, and the justification for 
the override, will be noted on the subject’s Case Report Form (CRF). SpO2 will continue to be monitored 
on the ICU patient monitors per standard of care.   
 
In both study arms, data for FiO2, nasal cannula HVNI flowrate, gas temperature, SpO2 and pulse rate will 
be logged every 1 sec by the OAM, as well as being displayed / logged by the usual patient monitoring 
systems in each unit.  Note that the OAM can log any manual adjustments during auto mode (overrides) 
as well as all data while in manual mode (Auto mode off). Offline computerized analysis will reduce the 
recorded data for both periods to assess time spent in the specified SpO2 range, time spent above and 
below the specified SpO2 range as well as other benchmark SpO2 values (see Data Collection and 
Statistical Analysis).  Time spent below benchmark FiO2 values will be assessed (e.g., FiO2 at 21%, 
<25%).  OAM data will be analyzed based on a modified intention-to-treat, whereby for any time the 
automated system is manually overridden in the 24-hour window, these outcomes data will be included 
into the analysis as well as the number of occurrences where manual manipulation is needed. 
 
This study will be conducted at multiple sites, consisting of Academic Level III and IV Neonatal 
Intensive Care Units with proven record of experience in management of Preterm Infants requiring HVNI 
therapy delivered using the Precision Flow Hi-VNI technology.  Each arm of the study will be assessed 
for 24 hours under routine clinical conditions. All staff members will be trained on the OAM operation 
and will have the ability to discontinue the study should the clinical condition of the patient require it. 
 
V. Statistical Methods and Data Analyses 
 
 
Descriptive statistics will be used to summarize data including mean, standard deviation, median, range 
and interquartile range for continuous data, and counts and percent for categorical data.  Hierarchical 

 
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testing will be used to test the secondary objective(s).  If both primary safety non-inferiority endpoints are 
passed and the primary performance endpoint is passed, we will test the secondary endpoint(s) for 
potential labeling claims. Analyses will be performed using SAS version 9.2 or higher, or comparable 
statistical software. Data from technically compromised data collection shall not be included in the 
analysis but will be described in detail if there are any instances. 
 
Technical Definition of Analyzed Target Range – To be in line with common practice, for all data 
analyses the term ‘target range’ is defined as an SpO2=90%–95% or an SpO2=90%–100% if FiO2=0.21. 
The analyzed targeted oximetric blood oxygen saturation range denoted as ‘target range’ in the safety 
performance, primary performance, secondary performance, and additional objectives/analyses is defined 
here, to include those babies who are not hypoxic (<90% SpO2) whilst on room air (FiO2=0.21). Thus, at 
FiO2=0.21, an SpO2=90%-100% is deemed within target range. These are not clinically deemed ‘out of 
target range’ when FiO2=0.21 (at air, Eupoxia), even when the SpO2 is greater than 95%. This definition 
of the analyzed target range does not change the clinical practice, as clinicians still target babies to a 
target range of SpO2=90%–95% by adjusting FiO2 accordingly.  
 
Analysis Cohorts: 
Full Analysis Set (FAS) – Subjects that are randomized and receive any period of time on at least one 
treatment will be included in the adverse event summary. 
 
Modified Intent to Treat (mITT) – Subjects that are randomized and receive any period of time on both 
treatments will be included in the primary safety and performance endpoints.  
 
Per Protocol (PP) – Subjects that are randomized, receive both the treatments as randomized (in the 
correct order) and without any major deviations (e.g., inclusion/exclusion violations, informed consent 
not obtained) will be included in the primary safety and performance endpoints as a supplemental 
analysis. 
 
Challenge Population – Subjects in the PP with at least 6 FiO2 adjustments in the manual arm will be 
identified as sufficiently labile subjects and will be included in supplemental analysis for safety and 
performance endpoints. 
 
Missing Data 
The impact of missing data due to loss to follow-up prior to completing both arms will be assessed by 
sensitivity analyses using several methods of imputation including multiple imputations for the primary 
performance and primary safety endpoints. Details will be specified in a separate statistical analysis plan. 
 

 
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Poolability 
A poolability analysis will be performed to assess the poolability of sites with respect to the primary 
performance endpoint measure in the mITT subjects. A Student’s t-test will be used to test for a difference 
in performance across sites. A significance level of 0.15 will be used to determine whether the sites are 
poolable. If a significant difference is found between sites, additional analyses will be done to identify 
factors that may be associated with this difference. Additionally, if a significant difference is observed, a 
random site adjusted estimate of the performance endpoint, along with 95% CI, will be provided. 
 
Although enrollment will be monitored in an effort to strive for even allocation between sites, for 
purposes of the poolability analysis those sites with less than five (5) evaluable patients enrolled will be 
combined into a pseudo-site for purposes of analysis.   
 
Primary Safety Objective  
Objective: To demonstrate that safety is not worse than standard practice.  Specifically to demonstrate that 
the Vapotherm OAM, used in conjunction with the Vapotherm Precision Flow Hi-VNI to treat infants 
with heated, humidified high velocity nasal insufflation (HVNI), is not inferior to standard practice for 
time that infants’ arterial blood oxygen saturation exceed or drop below a target range, thus minimizing 
the proportion of time the subject is exposed to elevated or reduced levels of oxygen in the inspired gas. 
 
Endpoint: There are two safety endpoints: the proportion of time spent above the target SpO2 range and 
the proportion of time spent below. The proportion of time expressed as a percentage will be measured by 
pulse oximetry (SpO2), abstracting and analyzing recorded data over two contiguous 24-hour study 
periods; one 24-hour period with automated control (OAM) and one 24-hour period with manual control.  
 
Subjects to Analyze:  Subjects in the mITT cohort will be the primary analysis. Additional supplemental 
analyses will repeat this analysis using the FAS, the PP and Challenge cohorts. This will be used to 
provide an Adverse Event(s) summary. 
 
Hypotheses: 
Non-inferiority, proportion of time above range: 
Ho:  D ≥ δ 
Ha:  D < δ,  
where D = difference in proportion of time above range (OAM – standard practice) and δ is the 
non-inferiority margin of 5. 
Non-inferiority, proportion of time below range: 
Ho:  D ≥ δ 
Ha:  D < δ,  
where D = difference in proportion of time below range (OAM – standard practice) and δ is the 
non-inferiority margin of 5. 
 

 
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If both of the non-inferiority tests below reject the null and conclude non-inferiority is achieved, we will 
test for superiority.  
 
Superiority, proportion of time above range: 
Ho:  D ≥ 0 
Ha:  D < 0,  
where D = difference in proportion of time above range (OAM – standard practice) 
 
Superiority, proportion of time below range: 
Ho:  D ≥ 0 
Ha:  D < 0,  
where D = difference in proportion of time below range (OAM – standard practice) 
 
Analysis Method:  The difference (OAM – standard practice) of the proportion of time in range will be 
tested using a paired t-test using a one-sided alpha of 0.025 to test non-inferiority.  If both are passed, 
testing for superiority will be performed again using a one-sided alpha of 0.025.  Both superiority tests 
must be passed in order to claim superiority. 
 
Primary Performance Objective 
Objective: To demonstrate that percent time oxygen saturation is maintained in a target range is higher 
than standard practice.  More specifically, to demonstrate that Vapotherm OAM used in conjunction with 
Vapotherm Precision Flow Hi-VNI is superior to standard practice for maintaining infants’ arterial blood 
oxygen saturation in a target range, thus minimizing the proportion of time the subject is exposed to 
elevated or reduced levels of oxygen in the inspired gas. 
 
Endpoint: The proportion of time (expressed as a percentage) spent in the targeted arterial blood oxygen 
saturation range. The percentage will be measured by pulse oximetry (SpO2), to determine the ability of 
the OAM to effectively titrate FiO2 to the needs of the infant.  This value will be assessed by abstracting 
and analyzing recorded data over two contiguous randomized 24-hour study periods; one period with 
automated control (OAM) and one 24-hour period with manual control.   
 
Subjects to Analyze:  Subjects in the mITT cohort will be the primary analysis. Additional supplemental 
analyses will repeat this analysis using the FAS, the PP and Challenge cohorts. This will be used to 
provide an Adverse Event(s) summary. 
 
Hypothesis: 
Ho:  D ≤ 0 
Ha:  D > 0,  
 
Where D = difference in proportion of time in range (OAM – standard practice) 
 

 
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Analysis Method:  The difference (OAM – standard practice) of the proportion of time in range will be 
tested using a paired t-test using a one-sided alpha of 0.025. 
 
Secondary Performance Objective 1 
Objective: To demonstrate that the percent time SpO2 is maintained in a target range is higher than 
standard practice for subjects in each of the weight category subgroups (1000g-2500g, 2501g-3500g). 
 
Endpoint: The proportion of time (expressed as a percentage) spent in the targeted arterial blood oxygen 
saturation range. The percentage will be measured by pulse oximetry (SpO2), to determine the ability of 
the OAM to effectively titrate FiO2 to the needs of the infant.  This value will be assessed by abstracting 
and analyzing recorded data over two contiguous randomized 24-hour study periods; one period with 
automated control (OAM) and one 24-hour period with manual control. 
 
Subjects to Analyze:  Subjects in the mITT cohort will be the primary analysis. Additional supplemental 
analyses will repeat this analysis using the FAS, the PP and Challenge cohorts. This will be used to 
provide an Adverse Event(s) summary. 
 
Hypothesis: 
Ho:  D ≤ 0 
Ha:  D > 0,  
 
Where D = difference in proportion of time in range (OAM – standard practice) 
 
Analysis Method:  The difference (OAM – standard practice) of the proportion of time in range will be 
tested using a paired t-test using a one-sided alpha of 0.025 for subjects in each category using a 
Hochberg adjustment to control alpha.  
 
Secondary Performance Objective 2 
Objective: To demonstrate that the percent time SpO2 is maintained in a target range is higher than 
standard practice for subjects with both light and dark skin pigmentation.  
 
Endpoint: The proportion of time (expressed as a percentage) spent in the targeted arterial blood oxygen 
saturation range. The percentage will be measured by pulse oximetry (SpO2), to determine the ability of 
the OAM to effectively titrate FiO2 to the needs of the infant.  This value will be assessed by abstracting 
and analyzing recorded data over two contiguous randomized 24-hour study periods; one period with 
automated control (OAM) and one 24-hour period with manual control.   
 
Subjects to Analyze:  Subjects in the mITT cohort will be the primary analysis. Additional supplemental 
analyses will repeat this analysis using the FAS, the PP and Challenge cohorts. This will be used to 
provide an Adverse Event(s) summary. 

 
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Hypothesis: 
Ho:  D ≤ 0 
Ha:  D > 0,  
 
Where D = difference in proportion of time in range (OAM – standard practice) 
 
Analysis Method:  The difference (OAM – standard practice) of the proportion of time in range will be 
tested using a paired t-test using a one-sided alpha of 0.025 for subjects in each skin pigmentation (light 
or dark) category using a Hochberg adjustment to control alpha. Skin pigmentation classification will be 
based upon assessing the subject’s skin tone as specified in Section XIII.  Additionally, summaries by 
individual classification of skin pigmentation will be provided by each level using descriptive statistics 
along with a 95% confidence interval. 
 
 
Additional Analyses 
These exploratory analyses will use descriptive statistics to quantify values in each arm and the difference 
(OAM – standard practice).  These analyses will use the mITT and PP populations except for adverse 
event summaries  
 
To quantify and compare OAM automatic mode to standard manual practice performance with additional 
measures including:  
• Proportion of Time, Number of Episodes, and Average Duration of Episodes in both high and low 
SpO2 ranges (with or without FiO2 at or above 21%)  
o SpO2 below target range  
o SpO2 below 80% for episodes ≥60s  
o SpO2 below 80%  
o SpO2 above target range at FiO2>0.21 (not at air)  
o SpO2 below 70%  
o SpO2 in 80% to 86% range  
o SpO2 in target range at FiO2=0.21  
o SpO2 above 98% at FiO2>0.21 (not at air) 
o SpO2 below target range at FiO2=0.21  
• Number of manual adjustments to FiO2 in manual mode compared to automated control (manual 
override). 
• Proportion of Time at or below FiO2 ranges compared between study arms 
o FiO2 at 0.21 (air)  
o FiO2 below 0.25  
• SpO2 fluctuations compared to manual control 
o Coefficient of variance for SpO2 for the study arm 
o Standard deviation of SpO2 for the study arm 

 
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• FiO2 fluctuations compared to manual control 
o Coefficient of variance for FiO2 for the study arm 
o Standard deviation of FiO2 for the study arm 
• Index of overshoot (an elevated SpO2 resulting from the FiO2 titration response to a low SpO2) and 
characterization of such excursions. 
o The proportion of time, number of episodes, and average duration per episode of 
Overshoot, defined as SpO2 > range following SpO2 < range for ≥10 seconds duration. 
o The proportion of time, number of episodes, and average duration per episode of 
Overshoot, defined as SpO2 > range for 70s following SpO2 < range. 
• Number of Episodes of hypoxia (below range) within 60-180s after a return to FiO2=0.21. 
• Number of Episodes of hypoxia (below range) within 60-180s after a return to FiO2=0.21 followed 
by hyperoxia (above range) within 60-180s after a return to FiO2=0.21. 
• The mean FiO2 of the study arms 
• Number of overall adjustments (or adjustments/hour) to FiO2 in manual mode compared to 
automated control. 
• The care ratio (i.e., Nurse:Baby) will be recorded, patients will be separated to care ratio, and each 
care ratio group will be compared between study arms for the proportion of time, number of 
episodes, and average duration of episodes 
o SpO2 in target range  
o SpO2 below target range  
o SpO2 below 80% for episodes ≥60s  
o SpO2 below 80%  
o SpO2 below 70%  
o SpO2 in 80% to 86% range  
o SpO2 above target range at FiO2>0.21 (not at air)  
o SpO2 in target range at FiO2=0.21  
o SpO2 above 98% at FiO2>0.21  
o SpO2 below target range at FiO2=0.21  
• Comparison between Day versus Evening/Overnight of the Proportion of Time, Number of 
Episodes, and Average Duration of Episodes in target, high, and low SpO2 ranges (with or without 
FiO2 at or above 21%) 
o SpO2 in target range  
o SpO2 below target range  
o SpO2 below 80% for episodes ≥60s  
o SpO2 below 80%  
o SpO2 below 70%  
o SpO2 in 80% to 86% range  
o SpO2 above target range at FiO2>0.21 (not at air)  
o SpO2 in target range at FiO2=0.21  
o SpO2 above 98% at FiO2>0.21  
o SpO2 below target range at FiO2=0.21  

 
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• CONSORT Diagram will be used to articulate the patient numbers 
• For each arm of the study will aggregate the proportion of time for SpO2 for data bins from <80% 
to 100%. 
• For each arm of the study will aggregate the proportion of time for FiO2 for data bins 0.21 to 1.0. 
• Adverse events as reported on the CRFs (Summarized by seriousness and relatedness to therapy) – 
See Appendix B for the list of adverse events and classification criteria.  
Sample Size Calculations 
The sample size was initially based upon data from the Reynolds trial looking at a subset of 
subjects expected to be enrolled in this trial (enrollment weight initially 1000g-2500g, now 
1000g – 3500g).  These data are presented in Tables 1 and 2 below. While we are requesting 
with this IDE Study to now enroll larger babies, the Study sample size will not be changing. 
 
Table 1. Summary of unpublished Reynolds data for infants with enrollment weight 
1000g or greater. 
  
  
Auto (OAM) 
Manual (Standard Practice) 
Difference 
SpO2 % 
time  
N 
Mean 
SD 
Median 
Mean 
SD 
Median 
Mean 
SD 
Median 
In range 
18 
76.0 
12.3 
79.1 
47.6 
14.0 
50.4 
28.4 
10.8 
27.1 
Above 
18 
13.5 
5.7 
12.4 
28.5 
17.5 
23.4 
-15.0 
16.2 
-10.0 
Below 
18 
14.4 
7.1 
12.6 
27.0 
8.9 
27.4 
-12.6 
10.8 
-11.5 
 
Table 2. Summary of unpublished Reynolds data for infants by weight category. 
 
 
 
Auto (OAM) 
Manual (Standard 
Practice) 
Difference 
 Weight 
SpO2 % 
time 
N 
Mean 
SD 
Median 
Mean 
SD 
Median 
Mean 
SD 
Median 
1000-
1500g 
In range 
11 
74.4 
11.3 
77.0 
47.4 
11.9 
50.2 
26.9 
6.5 
26.4 
Above 
11 
14.2 
5.4 
13.6 
26.8 
15.1 
23.3 
-12.6 
12.6 
-10.2 
Below 
11 
15.3 
6.6 
13.9 
28.7 
9.5 
29.4 
-13.4 
11.3 
-14.5 
1500g-
2500g 
In range 
7 
78.5 
14.1 
83.2 
47.8 
17.8 
52.1 
30.7 
15.8 
27.1 
Above 
7 
12.3 
6.5 
9.5 
31.2 
21.6 
29.0 
-18.9 
21.3 
-8.9 
Below 
7 
13.1 
8.1 
10.5 
24.4 
7.8 
22.4 
-11.3 
10.8 
-10.0 
 
For sample size calculations comparing the difference of values in the same subject, the 
sample size is driven by the standard deviation.  We will identify what difference the trial is 
powered to detect with the specified sample size and standard deviation. 
 
Safety co-Endpoints – Time Above Target Range and Below Target Range: 
The safety co-endpoints will be powered to detect superiority even though we will first test for 
non-inferiority.  The change in proportion of time SpO2 was above and below range was     

 
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-15.0% ± 16.2% and -12.6% ± 10.8%, respectively.  Using the largest standard deviation of 
16%, again using PASS 14, a sample size of 38 will be adequate with at least 95% power for 
each test with a one-sided alpha of 0.025 to detect a difference as small as 10%.  Both safety 
endpoints are powered at 95% ensure overall power is at least 90%. 
 
Primary Performance Endpoint – Time in Target Range: 
The change in proportion time SpO2 was in target range is 28.4% ± 10.8%.  Rounding the 
standard deviation up to 11, using PASS 14 test for paired means with a nonparametric 
adjustment, a two-sided alpha of 0.05, with at least 90% power, a sample size of 40 will detect 
a difference from zero with a mean change as small as 6%. Our expected difference far 
exceeds this amount. 
 
Secondary Performance Endpoint 1 – Time in Target Range by weight subgroup: 
For the secondary performance endpoint (weight stratification subgroups of primary 
performance endpoint), using the maximum standard deviation from the Reynolds data, a 
standard deviation of 15.8% will be rounded to 16% for sample size calculations.  Using PASS 
14, with a two-sided alpha of 0.05 and at least 90% power, a standard deviation of 16, the 
sample size of 17 subjects per weight stratification will be adequate to detect differences as 
small as 14% for time in range with adequate power.   
 
Secondary Performance Endpoint 2 – Time in Target Range by skin pigmentation: 
For the secondary performance endpoint (stratification subgroups of primary performance 
endpoint by skin pigmentation [light or dark]) pilot data are unavailable by skin pigmentation, 
but we will assume the performance is similar to the maximum standard deviation from the 
Reynolds data, a standard deviation of 15.8% will be rounded to 16% for sample size 
calculations.  Using PASS 14, with a two-sided alpha of 0.05 and at least 90% power, a 
standard deviation of 16, the sample size of 17 subjects per skin pigmentation stratification 
(light or dark) will be adequate to detect differences as small as 14% for time in range with 
adequate power.   
 
Overall sample size will be driven by goal of at least 17 subjects per weight group and an 
overall sample size of at least 40 subjects per the primary performance endpoint.  Allowing up 
to 15% attrition, expected enrollment will be 47 subjects. 
 
 
 
 
 

 
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VI. Study Procedures 
  
Necessary staff at each center will be trained on the study objectives, including the target SpO2 ranges, 
alarm limits and operation of the OAM. Care of the infants is not altered, and clinical staff have the option 
of overriding the OAM to make manual adjustment to FiO2 as needed throughout the study. During the 
Manual arm of the study, staff will be instructed to adjust FiO2 as per normal protocol and to respond to 
SpO2 alarms (titrating FiO2 up or down) in a typical manner. Sites will be selected which are already 
familiar with clinical use of the HVNI therapy.  
 
After informed consent is received and the infant is enrolled, the descriptive data will be completed on the 
CRF and the order of providing FiO2 control will be randomly assigned (i.e. OAM in Automated mode 
followed by manual mode, or vice versa).  The baby will remain instrumented to provide standard clinical 
monitoring (including SpO2). A second pulse oximetry probe will be put in place to send an SpO2 signal 
to the OAM without interrupting the SpO2 signal used for the standard patient monitoring, and the 
placement of the OAM SpO2 probe will be confirmed to be in the right hand (for pre-ductal values) and 
that the signal is valid.   
 
The patient file will be created in the OAM and the OAM configured in recording mode; the start time 
will be noted in the CRF.  For the manual arm, the OAM will be set to record but the automatic control 
setting will be left in the OFF configuration. For the automated arm, again the module will be set to 
record, but the automatic control setting will be selected to the AUTO mode.  When the nurses conduct 
their routine hourly charting of SpO2 and FiO2, they are to confirm that the SpO2 reading on the OAM 
matches that on the standard patient monitor and that the FiO2 reading on the OAM matches that 
displayed on the Precision Flow.   
 
During the study, these hourly records of SpO2 and FiO2 are to also be recorded on the CRF.  The alarm 
limits and any adjustments to the alarm limits will be recorded with date/time on the CRF. The time that 
the study switches modality-arm will be recorded on the CRF (i.e., after the first 24-hours), and the OAM 
configured to preserve the prior recorded data and allow for a new recording period.  During the Auto-arm 
of the study, any manual overrides will be recorded on the CRF along with the justification for the 
override. The time when the study has ended will be recorded on the CRF and the recording of data by the 
OAM halted.   The recorded data files will be exported from the OAM onto a specified USB memory 
drive and delivered to the site principal investigator along with the CRF. 
 
All FiO2 adjustments (both manual and automatic) as well as SpO2 parameters (including SpO2 value and 
quality index) will be recorded by the OAM in the data file.  Following data collection, recorded data will 
be downloaded to a spreadsheet for subsequent analysis. Clinical staff are instructed to perform FiO2 
adjustments as required, regardless of the study arm. 
 

 
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At 7-days post enrollment or at discharge from the hospital or death (if occur earlier), the infants will be 
checked and evaluated for specific or non-specific untoward events, as deemed by the clinical judgement 
of the clinician(s). This will be recorded on the CRF. 
 
Target SpO2 Range 
 
For this study, the target SpO2 range on the OAM will be 90% to 95% in all infants.  The usual site’s 
monitor’s low and high alarm limits will be set to 90% and 95%, respectively.  
 
Safety Monitoring 
 
Care for the infants will be unchanged from normal standard of care during the conduct of this study.  
During the Automated arm, clinical staff has the option of making a manual adjustment to FiO2 if deemed 
necessary per normal clinical decision making.  These manual adjustments, SpO2 and rationale for the 
change will be recorded on the CRF.  
 
The OAM used in the study will be equipped with the following features and alerts: 
• Automatic FiO2 control: selectable ON/OFF 
• User settings for upper and lower SpO2 targets,  
o Alert for Failsafe mode (see below) 
o NOTE: The ALARMS on the standard patient monitoring collected concurrently will be 
set consistent with the target SpO2 range. 
• Percent Oxygen (FiO2) Alarm Limit: The clinician will set a %O2 alarm limit where, if the 
delivered %O2 is equal to or above the clinician-set %O2 alarm limit for 30 seconds continuous, 
the device provides a silent alert message. If the delivered %O2 is above the alarm limit for 1 
minute continuous, it will audibly alarm. 
o NOTE: This FiO2 clinician-set alarm limit value is recorded on CRF 4 at study start and 
date/time when changed during study period. A significant increase in %O2 as commanded 
by the OAM may mask patient deterioration.  Set the %O2 alarm limit appropriate for the 
patient to provide further notification of automatic %O2 increases. 
 
Failsafe Mode 
 
The OAM used in the study will be configured with a failsafe mode that defaults to a clinically-selected 
default FiO2 if the SpO2 signal becomes unreliable.  The OAM will default to a failsafe FiO2 if: 
• >2 min continuous without a SpO2 signal 
 
Failsafe FiO2 will be the highest of following values: 
• Backup FiO2: 21% to 100% FiO2 set by user (for this study, the backup FiO2 value will be left at 
21%) 

 
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• Baseline FiO2: FiO2 setting calculated to keep the patient in the allowable target SpO2 range 
during the period the Automatic FiO2 algorithm was running 
• Median FiO2 of the last 15 seconds Automatic FiO2 control was active  
 
Data Safety Monitoring Committee 
 
An independent data and safety monitoring committee will review the data set after every 10 infants 
enrolled and recommend termination of the study if study related adverse events indicated risk to the 
infants or the primary outcomes are significantly worse for the Automated arm than for the Manual arm.  
During this review, the independent reviewer(s) will identify for the investigators any patients that do not 
meet the subject inclusion/exclusion criteria.  
 
Other Medical Care 
All other pharmaceutical and medical treatment will remain the purview of the medical staff and be 
administered per the current standards of care in each institution.  This study is designed to evaluate only 
the impact of automated oxygen titration via the OAM and it is assumed that the ancillary interventions 
will follow common clinical practice guidelines and convention.   
VII. Data collection 
 
Manually Entered Data 
 
At the point of enrollment, baseline data will be recorded on the CRF, which includes: 
• Weight at birth (grams) 
• Weight at time of the study (grams) 
• Gestational Age at birth (Weeks Days/7) 
• Age at the time of the study (Days) 
• Gender 
• Race / Ethnicity, and Skin Pigmentation Classification 
• Current FiO2  
• Current HVNI flow settings (L•min-1) 
• Diagnoses (Primary and Secondary) 
• Medications  
• Acuity Score 
• Confirm site of SpO2 probe placement (right hand) 
• Caregiver : Patient ratio 
During the study, the clinical staff will record on the CRF the following: 
• Time the study was started and confirm the initial arm (Automatic / manual) 
• Time the study switched arms, and confirm the second arm (Automatic / manual) 
• Hourly SpO2 and FiO2 readings 

 
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• Any overrides during the Automatic arm and the rationale for the override 
• The time and description of any procedures done on the infant that could affect breathing or 
performance of pulse oximetry 
• Medications listing 
 
Automated data collection 
 
Data logged by the data collection module(s) will be abstracted to produce total counts of events per 
recording period, normalized and presented per-hour, the 24-hour average, as well as hourly 
median/mean/stdev/min/max SpO2 and FiO2 values for trending. 
 
Data logged by the data collection module(s) will be abstracted and analyzed for the following 
parameters: 
 
Index 
Mean  
± SD  
Proportion of 
total time spent 
Episodes of 
occurrence 
Duration of 
Episodes 
SpO2 within range 
 
X 
 
 
SpO2 coefficient of variance  
X 
 
 
 
SpO2 within range (any FiO2) and 
between 90-100% whilst FiO2 at 
0.21 
 
X 
X 
X 
SpO2 > range 
 
X 
X 
X 
SpO2 > range w/ FiO2 > 0.21 
 
X 
X 
X 
SpO2 > 98% 
 
X 
X 
X 
SpO2 > 98% w/ FiO2 > 0.21 
 
X 
X 
X 
SpO2 < range 
 
X 
X 
X 
SpO2 in 80% to 86% range 
 
X 
X 
X 
SpO2 < 80% 
 
X 
X 
X 
SpO2 <80% for ≥ 60 sec 
 
X 
X 
X 
SpO2 < 70% 
 
X 
X 
X 
Overshoot: SpO2 > range following 
SpO2 < range ≥10 seconds duration 
 
X 
X 
X 
Overshoot: SpO2 > range for 70 sec 
following SpO2 < range 
 
X 
X 
X 
Time with FiO2 at 0.21 
 
X 
 
 
Time with FiO2 < 0.25 
 
X 
 
 
FiO2 adjustments: Manual & Auto 
X 
 
 
 
Night/Day: SpO2 within range 
 
X 
X 
X 
 

 
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To support patient safety and to serve as an index of adequate oxygenations, pulse rate data will be logged 
from the SpO2 signal and analyzed for stability within a normal range and for the occurrence of 
excursions outside of the normal range.  The determination of normal range will be relative to each 
infant’s clinical status. An episode, considered to be a clinically meaningful excursion, is defined with a 
minimum duration of 5 seconds (or, ≥5 sec) into the specified ‘range of interest,’ unless otherwise noted.  
 
The designated study arm duration of 24 hours each, for a total of 48 hours was determined to reflect a 
normal clinical practice ‘unit of time,’ wherein this would allow for sufficient time to assess manual mode 
oxygen control behavior in at least two care giver’s (e.g. clinicians – MD, RN, and RRT) shifts as well as 
take into account any other diurnal variation in either the patient or the NICU, to allow a reliable 
comparison between both study arms. Furthermore, recent publications have similarly utilized 24-hour 
study arms to compare manual and automated control in neonatal closed loop control algorithms: Claure 
2011, Hallenberger 2014, Waitz 2015, Reynolds 2018, van del Heuvel 2018, and Gajdos 2018. Patient 
data which includes any study arm of less than 12 hours duration will be deemed a major protocol 
violation. Patient data which includes any study arm of between 12 hours and 18 hours duration will be 
deemed a minor study violation. Patient data collection which includes study arm data of greater than 18 
hours will be deemed satisfactory and without protocol deviation.  
 
IX. Risks and Discomforts 
 
This study does not present any significant risk to the infants because infant monitoring during each arm 
of the study will be per normal standard clinical care.  Clinical staff will be instructed to disregard the 
actions of the investigational module in their own clinical decision making and will be able to manually 
adjust FiO2 if required.  
 
Because this Study includes Physiologic Closed Loop Control technology and involves neonate patients, 
FDA has concluded this to be a significant risk study. 
 
During this study any inherent risk of using adaptive control loops to manage FiO2 is mitigated by the fact 
that the adaptive control algorithm that drives the OAM has been previously tested in clinical trials, and 
by the user configurable alarm features built into the OAM.  Moreover, the study protocol calls for all 
medical staff to override the auto-control feature if out-of-range SpO2 values are not corrected, or if 
manual adjustment to FiO2 is clinically indicated.  Lastly, a data safety monitoring committee will be able 
to assess unforeseen patient risk at periodic interim points in the study. 
 
There is no foreseen discomfort associated with the study.  The infants enrolled will not undergo a change 
in their respiratory support modality and adjustments in FiO2 do not affect the comfort of the patient. 
 

 
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X. Potential Benefits 
 
The trial may result in acceptance of a technology that leads to improvements in the ability for clinicians 
to provide high-quality care. Such improvement in providing clinician support may subsequently result in 
improved patient outcomes and the cost of care associated with management of infants’ oxygen delivery 
needs.  However, due to the short duration of the exposure, it is not likely that the patients enrolled in the 
study will themselves benefit from participation in this study, nor is the study intended to provide 
sufficient support for improvement in any specific pathophysiologic outcome.  
 
XI. Monitoring and Quality Assurance 
 
The clinical trial site will be monitored in accordance with policies at Vapotherm and those federal 
regulations that pertain to good clinical practice in clinical research; namely ISO 14155 and others as 
applicable or as directed by the human research ethics committee.  Monitoring will occur at a regular 
frequency, such as to allow ongoing review of data collected, site qualifications and compliance with the 
protocol.  All monitors will be appropriately trained to ensure compliance with the protocol.  
 
XII.  Confidentiality 
 
Rigorous procedures will be followed to maintain confidentiality of subject identification and test-related 
information and to adhere to government regulations concerning privacy.  A unique identification number 
designed to protect the identity of subjects will be used to identify the subject being monitored on case 
report forms, recruitment logs, data forms, and any or other reports containing information or referring to 
a device/module assigned to a particular patient. 
 
This unique identification number will not be linked to identifiable data; no personal or identifiable 
patient data will be collected.  The Vapotherm employee assigned to manage the study will be the only 
person to have knowledge pertaining to the link between the unique identifiable number and the subject.  
All other Vapotherm representatives involved in this study will only have access to the patients’ unique 
identification number.   
                                                                                                                                                                 
XIII.  Skin Pigmentation Color Scale  
 

 
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To provide a plausible and applicable skin pigmentation scale to this study, the Munsell System Soil 
Color Chart (2009 Revision, Munsell Color, Grand Rapids, Michigan), Hue 7.5YR will be utilized to 
describe skin pigmentation. This color scale for skin pigmentation has been previously implemented 
clinically, and most recently in the Foglia 2017 clinical study that evaluated pulse oximetry bias of skin 
pigmentation in infants with hypoxemia.16 Similar to Foglia 2017, and multiple pediatric/adult studies, 
skin pigment stratification will be classified and defined as Light or Dark skin pigment.  
 
Specific to the Munsell Scale: Light skin pigment will be designated as values 7 and 8, Dark skin pigment 
will be designated as 2.5, 3, 4, and 5, and a value of 6 will be considered intermediate and not classified as 
either light or dark pigment.16 
 
 
 

 
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XIV. References 
 
1. 
Reynolds PR, Miller TL, Volakis LI, et al. Randomised cross-over study of automated oxygen control 
for preterm infants receiving nasal high flow. Archives of disease in childhood Fetal and neonatal 
edition. 2018. 
2. 
Askie LM, Darlow BA, Finer N, et al. Association Between Oxygen Saturation Targeting and Death or 
Disability in Extremely Preterm Infants in the Neonatal Oxygenation Prospective Meta-analysis 
Collaboration. JAMA. 2018;319(21):2190-2201. 
3. 
Poets CF, Roberts RS, Schmidt B, et al. Association Between Intermittent Hypoxemia or Bradycardia 
and Late Death or Disability in Extremely Preterm Infants. JAMA. 2015;314(6):595-603. 
4. 
van Zanten HA, Tan RN, van den Hoogen A, Lopriore E, te Pas AB. Compliance in oxygen saturation 
targeting in preterm infants: a systematic review. European journal of pediatrics. 2015;174(12):1561-
1572. 
5. 
Sola A, Golombek SG, Montes Bueno MT, et al. Safe oxygen saturation targeting and monitoring in 
preterm infants: can we avoid hypoxia and hyperoxia? Acta paediatrica. 2014;103(10):1009-1018. 
6. 
van Zanten HA, Pauws SC, Beks EC, Stenson BJ, Lopriore E, Te Pas AB. Improving manual oxygen 
titration in preterm infants by training and guideline implementation. European journal of pediatrics. 
2017;176(1):99-107. 
7. 
van Zanten HA, Pauws SC, Stenson BJ, Walther FJ, Lopriore E, Te Pas AB. Effect of a smaller target 
range on the compliance in targeting and distribution of oxygen saturation in preterm infants. 
Archives of disease in childhood Fetal and neonatal edition. 2018;103(5):F430-F435. 
8. 
Beddis IR, Collins P, Levy NM, Godfrey S, Silverman M. New technique for servo-control of arterial 
oxygen tension in preterm infants. Archives of disease in childhood. 1979;54(4):278-280. 
9. 
Claure N, Bancalari E. Automated closed loop control of inspired oxygen concentration. Respiratory 
care. 2013;58(1):151-161. 
10. 
Claure N, D'Ugard C, Bancalari E. Automated adjustment of inspired oxygen in preterm infants with 
frequent fluctuations in oxygenation: a pilot clinical trial. The Journal of pediatrics. 
2009;155(5):640-645 e641-642. 
11. 
Claure N, Bancalari E, D'Ugard C, et al. Multicenter crossover study of automated control of inspired 
oxygen in ventilated preterm infants. Pediatrics. 2011;127(1):e76-83. 
12. 
Wilinska M, Wasco A. A Challenging Patient: approaches to controlling FiO2 during highly unstable 
oxygen saturation. Neonatal Intensive Care. 2012;25(3):25-26. 
13. 
Taube J. Adaptive control of dog inspired oxygen. IEEE Proc Ninth Ann Conf of Eng in Med and Biol. 
1987. 
14. 
Bhutani VK, Taube JC, Antunes MJ, Delivoria-Papadopoulos M. Adaptive control of inspired oxygen 
delivery to the neonate. Pediatric pulmonology. 1992;14(2):110-117. 
15. 
Saslow JM, Pyon KH. Clinical Trial Report Comparison of SmartBlender and Standard Approach to 
Optimize Oxygenation of Preterm Infants. Cooper University Hospital Document. 2009:1-20. 
16. 
Foglia EE, Whyte RK, Chaudhary A, et al. The Effect of Skin Pigmentation on the Accuracy of Pulse 
Oximetry in Infants with Hypoxemia. The Journal of pediatrics. 2017;182:375-377 e372. 
 

 
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APPENDIX A:  Case Report Form (CRF) 
 
 

 
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APPENDIX B: ADVERSE EVENTS and SERIOUS ADVERSE 
EVENTS