Clinical Efficacy in Relief of Dyspnea by HVNI: Evaluation of New Cannulae Designs
Phase: NA
Conditions: Dyspnea, Hypercapnia, Respiratory Insufficiency
Sponsor: Vapotherm, Inc.

CLINICAL EFFICACY IN 
RELIEF OF DYSPNEA BY 
HVNI:  EVALUATION OF 
NEW CANNULAE 
DESIGNS 
NCT04512781
10 JUNE 2021 

 Vapotherm, Inc
HVNI Cannula Efficacy in Relieving Dyspnea 
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Protocol Title: 
Clinical Efficacy in Relief of Dyspnea by HVNI:  Evaluation of New 
Cannulae Designs  
Protocol Number: 
RP-VTPF2019001Sci 
Revision: 
Rev 1.3 – 10 June 2021 
Principal Investigator: 
Charles W. Atwood, Jr., MD, FCCP, FAASM 
Co-Investigators: 
Sponsor: 
Vapotherm, Inc 
100 Domain Drive 
Exeter, NH  03833 
1 (603) 658-0011 
http://www.vtherm.com 
Site Monitor(s): 
Amanda DeBellis MSc, Clinical Research Assistant 
Sohrab Mayar MSc RRT, Clinical Research Manager 
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 “Assessing clinical effect of HVNI on improving patient ambulation in acute 
care scenarios: a feasibility study” (the “Study”), I agree to:  
 
(i) conduct the Study in accordance with: this Investigator Agreement; the Study’s Protocol as approved by 
the IRB (the “Protocol”); all applicable laws and regulations; and any IRB or FDA 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 without first obtaining consensus from the Vapotherm Science 
and Innovation team and necessary IRB approval;  
(v) maintain Study documentation for the period of time as required by appropriate regulations; and 
(vi) 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 ................................................................................................. 6 
II. OVERALL STUDY OBJECTIVE .......................................................................................................... 7 
III. SUBJECT SELECTION ....................................................................................................................... 8 
IV. STUDY DESIGN ................................................................................................................................. 8 
V. SUBJECT ENROLLMENT ................................................................................................................... 9 
VI. STUDY PROCEDURES .....................................................................................................................10 
VII. DATA COLLECTION .......................................................................................................................14 
VIII. STATISTICAL ANALYSIS ..............................................................................................................15 
IX. RISKS AND DISCOMFORTS ............................................................................................................15 
X. POTENTIAL BENEFITS ....................................................................................................................15 
XI. MONITORING AND QUALITY ASSURANCE ..................................................................................16 
XII. PROTOCOL DEVIATIONS ..............................................................................................................16 
XIII. ADVERSE EVENT REPORTING ....................................................................................................16 
XIV. CONFIDENTIALITY ......................................................................................................................16 
XV. REFERENCES ..................................................................................................................................17 
 
 
 
 
 

            
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Glossary of Definitions and Terms 
 
High Flow Nasal Cannula (HFNC): Nasal cannula system that delivers flow rates of respiratory gas meeting or 
exceeding a patient’s normal spontaneous inspiratory flow demand.  HFNC systems must maintain adequate 
heating and humidification of the delivered gas to protect the airway tissues from dryness. 
 
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.   
 
Non-Invasive Positive Pressure Ventilation (NIPPV): Breathing assist where a mask is strapped tightly to a 
patient’s face and bi-level positive airway pressure is administered at an established frequency to support 
patient ventilation. 
 
Intubation: The placement of an endotracheal tube to facilitate respiratory support and provide airway 
protection. 
 
Respiratory Failure: The inability to maintain sufficient arterial blood oxygen saturation and/or retention of 
carbon dioxide levels during unassisted spontaneous breathing. 
 
Pulmonary Rehabilitation: Exercise regimen for patients with compromised cardio-pulmonary function 
designed to improve pulmonary parameters. 
 
Pulse Oximetry Reading (SpO2):  Indirect measure of a patient’s arterial blood oxygen saturation using pulse 
oximetry technology that utilizes oxygen/hemoglobin concentrations. 
 
Resting SpO2:  SpO2 value the patient demonstrated at rest, while sitting upright and connected to the pulse 
oximetry monitor prior to the start of the study session.  This value will be patient specific and reflect oxygen 
saturation. 
 
Desaturation SpO2: The SpO2 value considered to be the point of desaturation where the value drops below a 
specified threshold.  This value is based on the desaturation requirement for reimbursement of oxygen 
therapy. 
 
Ventilatory Work Effort / Work of Breathing (WOB):  The physical, physiologic muscular demands of 
breathing manifested through signs and symptoms of increased physical exertion, manifested through 
pulmonary changes leading to the use of accessory muscles for inspiration or exhalation. 
 
Fraction of inspired oxygen (FiO2; %): The percent of the delivered respiratory gas mixture that is oxygen, 
expressed as a fraction. 
 
Ventilatory Rate (Respiratory Rate; RR, BPM): The number of breaths a subject takes per minute 
(breaths·min-1). 

            
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Blood Pressure (BP): as measured by systolic and diastolic pressures of the blood contained in the 
circulatory system, measured for this study in mmHg.  
 
Heart Rate (HR): The number of heart beats per minute (beats·min-1). 
 
Modified Borg Scale (Borg): Dyspnea is an important measure of patient respiratory distress & pulmonary 
functional status. The rate of perceived dyspnea (RPD)is determined by patients and clinicians to using 
specific descriptors, on a scale of 0 (no dyspnea) to 10 (unbearable dyspnea). The modified Borg scale is 
additionally used for rating the subjective perceived exertion (RPE) during exercise, while at the same 
workload.  
 
Standard of Care (SOC): Site standard practices for the medical care of patients presenting with specific 
symptoms.  
 
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 site principal investigator at each center will maintain the key.  The CRFs are the property of Vapotherm. 
 
Transcutaneous CO2 (TcPCO2): This non-invasive method of measuring circulating CO2 transdermally, 
indicating trends for arterial carbon dioxide levels using a locally heated electrochemical sensor applied to 
the skin, can be used to assess a patient’s adequate ventilation and oxygenation.  
 
 
 

            
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I. Background and Significance 
  
Hypoxemia and dyspnea are hallmark characteristics of patients with chronic pulmonary disease and can be 
attributed to acute respiratory failure. 1 Oxygen therapy is generally a first stage in addressing dyspnea and 
hypoxia. Often times this therapy is delivered via various devices that provide pressure (mechanical 
ventilation [MV], non-invasive positive pressure ventilation [NIPPV]) and flow-based (high-velocity nasal 
insufflation [HVNI] and high flow nasal cannula [HFNC]) modalities to support oxygenation and ventilation, 
and in many cases, NIPPV & HVNI have been demonstrated to provide comparable support. 2-4 The key 
difference in these modalities can best be described by the alveolar ventilation equation:  alveolar ventilation 
= (Inspired Volume – Dead Space) X Respiratory Rate.  Inspired volume is achieved by adding pressure 
(NIPPV) and Dead Space is eliminated via HVNI; Two separate mechanism of actions that influence alveolar 
ventilation.  HVNI is a therapeutic alternative to NIPPV.2  
 
Vapotherm HVNI therapy, a refined form of HFNC, is premised on the technical ability to create ideally 
conditioned medical grade vapor, which is delivered nasally with an intent to support spontaneous 
ventilation as opposed to simple oxygen therapy. 5,6 Vapotherm technology is unique in its ability to provide 
this conditioned gas through a small-prong nasal cannula resulting in a high velocity without the well-known 
adverse effects related to drying and cooling of the nasal mucosa. 7  The high velocity nasal flow facilitates a 
well described mechanism of improving ventilatory efficiency by way of eliminating carbon dioxide 
traditionally stacked in anatomical dead space of the upper airway. 6  
 
Upper airway purge is important to alveolar gas exchange as the gas that is drawn to the respiratory regions 
of the lungs comes from the dead space or anatomical reservoir created by the flush, in the same way that 
oxygen conservation masks (re-breathers) can incorporate reservoir bags to reduce the bulk flow 
requirements from the oxygen source to achieve the same oxygenation effect. 6,8  Based on mathematical 
modeling, physiologic studies and clinical observations, a flow rate of 4 to 8 L·min-1 through Vapotherm’s 
neonatal cannulae, or 25 to 40 L·min-1 through Vapotherm’s adult cannulae, would purge the anatomical 
reservoir of the upper airway in the window of time between breaths. 9-12  
 
Vapotherm’s humidification system is specifically designed to tolerate a high back pressure in the 
humidification cartridge that is generated by passing these flow rates through small bore cannulae that 
result in the appropriate flow velocities (turbulent energy). 8  Since 2000, Vapotherm HVNI has been used 
extensively and has been well studied and the clinical impact of this ventilation effect using Vapotherm’s 
conventional cannula line is well described 6-8,13,14.6-8,13,14  A multi-center recent randomized clinical trial also 
demonstrated the noninferiority of HVNI to NIPPV in the treatment of undifferentiated respiratory distress 
for patients presenting to the Emergency Department. 2  As Vapotherm leads the innovation of new cannulae 
for the purpose of HVNI, we seek to evaluate the ability of these cannulae to impact ventilatory work effort 
on dyspneic patients.  The goals of the current study are to: (1) evaluate if next generation dual prong 
(Prosoft) cannulae provide comparable dyspneic relief among hypercapnic adults with accompanying 
dyspnea compared to current legacy (control) cannula design, and (2) assess if next generation Solo 
(Unicorn) cannulas at lower flows provide comparable dyspneic relief among hypercapnic adults with 
accompanying dyspnea compared to current legacy to Dual-prong cannula (Prosoft) design.  

            
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II. Overall Study Objective 
 
The overall objective of this study is to evaluate the ability of HVNI next generation Prosoft nasal cannula 
designs to effect ventilation and related physiological responses relative to the conventional legacy cannula 
design, with which there are published clinical outcomes data.  
 
The hypothesis: The next generation nasal cannula designs (Prosoft and Unicorn) will be comparable at 
relieving patient dyspnea while on HVNI, when compared to the conventional legacy cannula.  
 
To test this hypothesis, the study will be conducted with the following specific aims:  
 
Aim #1: Primary Outcome. The primary endpoint is the patient’s targeted relief of dyspnea, as measured by 
the modified Borg scale (rated perceived dyspnea [RPD]) for each cannula design tested. 
 
Aim #2: Secondary Outcomes. The secondary endpoints evaluate the patient vital signs (heart rate [HR], 
respiratory rate [RR], blood pressure [BP]), arterial oxygen saturation (SpO2), and arterial CO2 as measured 
by a transcutaneous CO2 device (TcPCO2).  These measurements will be compiled for each cannula design 
tested. 
 
Aim #3: Tertiary Outcomes. The tertiary endpoints evaluate both patient and clinician perception 
assessment scores. For patient perception/satisfaction these endpoints include: (1) relief of symptoms, and 
(2) comfort/tolerance. For clinician perceptions these endpoints include: (1) technical/clinical difficulties, 
(2) patient comfort & tolerance, (3) ease of use, (4) monitoring & support for therapy, and (5) 
expected/perceived patient outcomes.  
 
These endpoints will establish equivalence of outcomes between the legacy cannula and the new cannula 
designs (both Unicorn and Prosoft) in terms of the ability to relieve dyspnea in adult hypercapnic patients 
experiencing dyspnea.  
 

            
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III. Subject Selection  
Subjects will be identified and recruited by study investigators. The study will take place in an inpatient 
setting sufficient to support patients presenting with hypercapnic respiratory failure. Testing during this 
study will be performed in the presence of health care professionals who will provide appropriate 
supervision and staff training to maintain patient safety. The test will evaluate patient dyspnea, vital signs, 
ventilation, and oxygenation for each cannula design tested. Initial patient contact will be made by study 
investigators. Participants may or may not decide to enroll in the study after being consented.    
 
Inclusion Criteria 
1. Adults, 18 years or older 
2. The cannula prong(s) (Unicorn and Prosoft) will fit the nostril(s) so that the cannula prongs will not 
occlude more than 50% of the available nostril aperture of any single nostril accommodating a 
cannula prong.  
3. Demonstrated dyspnea at baseline, established by patient OR clinician assessment (see below) 
a. Borg Rated Perceived Dyspnea (scale 0-10) of 3 or higher  
4.    Severe patient baseline hypercarbia/hypercapnia of 50 mmHg or higher as measured by TcPCo2 or      
arterial or venous blood gas 
 
Exclusion Criteria 
1. Patient has unstable cardiovascular condition  
2. Significant unilateral or bilateral nasal occlusion  
3. Vigorous physical activity should not be performed within 2 hours of testing  
4. Inability to provide informed consent 
5. Pregnancy  
6. Known contraindication to perform steps of the protocol 
7. Absence of spontaneous respiration or known contraindication to HVNI 
8. Inability to use nasal cannula and HVNI therapy 
9. Agitation or uncooperativeness  
10. Determined by the clinician to be sufficiently unstable or unsuitable for this study  
 
IV. Study Design  
This will be an efficacy study, performed as a prospective, order-randomized crossover design trial to 
evaluate the ability of next generation HVNI nasal cannula designs (Unicorn and Prosoft) to effect ventilation 
and related physiological responses relative to the conventional legacy cannula design. Patients deemed to fit 
the criteria for inclusion will perform the study procedures for both arms of the crossover design. 
Completing both arms will compare the next generation cannula designs to the commonly used legacy design 
for comfort, comparative therapeutic response, and outcomes per the study aims.  Patients are expected to 
complete the study in one session, with appropriate pauses between each nasal cannula design testing 
procedures. After each of the study arms, the clinicians will complete perception score assessments. The 
clinical management will otherwise remain unchanged based on site standard of care practice.  
 
Each phase of the study will correspond to a different cannula design. Patients will be enrolled and initially 
entered into the control/baseline phase with the conventional legacy cannula (control), then will be order 
randomized to either of the next generation cannula designs (Test: Unicorn, or Prosoft). 
- 
Phase 1 – Conventional Legacy cannula design (Control)  

            
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- 
Phase 2 – Next generation cannula design (Test#1) (order randomized)  
- 
Phase 3 –Next generation cannula design (Test#2) (order randomized)  
 
 
This study design will focus on four distinct segments for each phase: (1) baseline characterization, (2) 
therapy acclimatization, (3) therapeutic characterization, and (4) VAS for both patient and clinician 
assessment scores. The baseline characterization for Phase 1 will provide patient background, history, and 
initial clinical evaluation. For Phases 2 and 3, baseline characterization will only include the initial clinical 
evaluation, as no further initial evaluation is warranted. The acclimatization period will provide patients 
time to become accustomed to the HVNI therapy and both designs of nasal cannula design. Titration of 
therapy (Flow/FiO2) is only expected during Phase 1 (or in the event the patient decompensates and needs 
adjustment), the legacy cannula, as this study is a comparison of cannula efficacy. For the therapeutic 
characterization, final patient data for the cannula design will be recorded. Following this, the clinician and 
the patient will complete the cannula design’s VAS perception scores. Primary and secondary outcomes will 
be completed upon the conclusion of all study phases. Tertiary outcomes will be completed at the end of each 
individual phase.  
 
This study will be conducted in an inpatient hospital setting where patient testing can be performed with 
appropriate medical supervision and staff training to maintain patient safety.  All respiratory interventions 
will be tracked during the study window for each patient. 
 
V. Subject Enrollment 
 
Subjects will be recruited by investigators and consented prior to participation in this study (Aims 1-3). Once 
consented, the participants and investigators will complete data collection in all Aims during the course of 
the cannula trial period.  
 
Sample Size: 
To provide a sufficiently powered sample dataset, we will enroll up to 32 subjects to complete this study on 
nasal cannula designs, with a calculated sample size of N=26 plus a 20% failure/fallout rate. This will provide 
sufficient data to adequately inform on the study objectives.  
 
This sample size was estimated through use of references that (1) approximated minimal clinical important 
difference of dyspnea (modified Borg scale) and (2) approximated expected standard deviation of prior 
datasets measuring dyspnea.15-17 Estimated minimal clinical important difference of dyspnea was 
determined to be a difference value of 2 in modified Borg for dyspnea.15 In reviewing publications from Roca 
2010 and Schwabbauer 2014, it was estimated that a value of 2 to 3 was suitable for the standard deviation 
of dyspnea for the modified Borg scale. Therefore, for this study, using the paired t-test sample size 
calculation, with an expected difference of 2, and an expected standard deviation of 3, using a desired power 
of 90% with alpha=0.05, the sample size is estimated at 26 to show if the data may or may not have any 
difference.  
 
 

            
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VI. Study Procedures 
This study is non-blinded by necessity, since the difference in cannulas can be perceived by both the clinician 
and patient. Patients may not know the difference between legacy and next generation cannulae, except in 
case of the Unicorn cannula design (as it employs a single-nasal prong). The next generation cannulae will be 
order-randomized after the conventional legacy cannula is used during the control evaluation. The study is a 
crossover design trial that will measure the ventilatory and comfort performance of nasal cannula design, 
specifically the effect on relief of dyspnea as demonstrated by RPD assessment, and measurement by TcPCO2 
device. In addition, patient physiologic outcomes (e.g. HR, RR, BP, SpO2), and patient & clinician assessment 
scores will be assessed and documented. Figure 1 illustrates a flowchart of overall study procedures.  
 
Screening, Enrollment, & Management 
Upon screening, subjects will be asked to participate in this study, and if so, they will provide informed 
consent prior to enrollment. During screening, patient will be evaluated for nostril aperture areas, which will 
accommodate the various cannula designs without occluding greater than 50% of the aperture area of a 
nostril by any cannula design (per inclusion criteria #2). Subjects are instructed that if at any time during the 
study that they wish to discontinue the study, they are free to stop the test and discontinue study 
participation. All study procedures will be explained to the subject.   
 
Upon enrollment, appropriate study data will be collected (see below under Data Collection), including 
patient demographics (e.g. age, gender, ethnicity, race), anthropometrics (e.g. weight, height, BMI, and 
applicable medical history including a detailed focus on the patient’s current respiratory status (LTOT user, 
positive-airway pressure therapy user, current respiratory therapy). Subjects will be managed by routine 
care while study data is captured as shown in the timeline below (Table 1).  All decision making for patient 
participation will be made per standard practice at the trial site, relying on the judgment of the medical staff. 
Using cards coded to trial patient number, the two next generation test cannulae will be order-randomized 
and that randomization will be determined by the clinician or study staff opening sequential numbered 
opaque envelopes directing such randomization. Time required from screening to the end of the study, is 
estimated to be two hours and fifteen minutes.  
 
 
 

            
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Figure 1. Framework of the clinical study procedures discussed within this protocol. Each Phase is 
designated by a different cannula design, with ‘Test’ symbolizing the order-randomized new cannula 
designs (i.e. Unicorn and Prosoft). 
 
 
Phase 1 – Conventional Legacy cannula design (Control) 
This test session is represented by Phase 1 in Figure 1, where the patient is placed on HVNI therapy with an 
appropriately fitted conventional legacy cannula design. Phase 1 will follow four distinct segments: (1) 
baseline characterization, (2) therapy acclimatization, (3) therapeutic characterization, (4) patient and 
clinician assessment scores. After Phase 1 is completed the next generation cannula test #1 will be able to 
start, as deemed appropriate by the clinician.  
 
Baseline Characterization will be performed just prior to the therapy acclimatization segment of this Phase. 
If there is a reason the clinician does not deem the patient appropriate for the study, per inclusion/exclusion 
criteria, they may stop procedures during baseline characterization. The inpatient may be sitting or lying 
down in a comfortable environment. The patient will be set up and prepared for the cannula testing with 
appropriate data recording devices. While subject is at rest, the following data will be collected (see Table 1): 
RR, HR, BP, SpO2, TcPCO2 and RPD (Modified Borg scale 0-10). For the RPD, the clinician will record patient 
scores. The patient may or may not be on HVNI therapy at this time. The Phase 1, baseline characterization 
will include recording data while the patient is in an uncompromised state (e.g. ON current oxygen therapy, 
if applicable).  
 
Therapy acclimatization (5 – 10 minutes) will be performed immediately after the baseline characterization 
segment is complete, and in accordance with site standard of care practices to maintain patient safety. The 
patient will be fitted with appropriately sized nasal cannula from the conventional legacy design (not to 
exceed 50% occlusion of the nares). Patients will be notified of best practice for the therapy, and clinicians 
will record whether patients prefer to keep their mouths open or closed. The acclimatization segment is the 
interval during which HVNI is to be titrated to provide the patient the appropriate settings for effective HVNI 
therapy. After the final FiO2/Flow settings are implemented and the patient is acclimatized the following 
data will be collected (see Table 1): RR, HR, BP, SpO2, TcPCO2 and RPD (Modified Borg scale 0-10). For the 
RPD, the clinician will record patient scores. Effective flow is recorded. 
 
HVNI will be initiated per the initial settings identified below, after which settings will be titrated per 
standard practice for optimal effect.  When patients are placed, the HVNI initial settings will be the 
following: FiO2 = level approximating the patient’s prior prescription (e.g. if by nasal cannula [NC], 
1LPM NC = 24%, 2LPM NC = 28%, 3LPM NC = 32%, etc.), Flow = 15 L/min, and Temperature = 35 -
37°C. Patients will be fit with a Vapotherm adult nasal cannula that will be applied by a respiratory 
therapist or other clinician skilled in management of HVNI. The flowrate can be decreased or 
increased as rapidly as necessary to alleviate respiratory distress and optimize patient comfort. 
Targets should be to provide relief of perceived dyspnea at an HVNI flow rate between 20 to 35 
L/min (up to 40L/min).  Starting temperature will be between 35 to 37°C; if patients find the gas 
temperature to be uncomfortable, it can be lowered as necessary down to 33 ℃ to enhance tolerance. 
The FiO2 will be set initially to approximate the likely previous dosage (see above) to initially to 
assure adequate oxygenation, but this should be adjusted to maintain a SpO2 > 88%.  
 
Therapeutic Characterization will be performed 5-10 minutes after the therapy acclimatization segment is 
completed. This will provide the patient sufficient time to receive clinical effect of the HVNI therapy and 

            
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become sufficiently comfortable with the therapy and cannula. Once the respiratory therapist or other 
clinician skilled in management of HVNI deems that the HVNI settings are having a therapeutic effect, the 
following data will be collected (see Table 1): RR, HR, BP, SpO2, TcPCO2 and RPD (Modified Borg scale 0-10). 
For the RPD, the clinician will record patient scores.  
 
Patient & Clinician Perception Assessments will be performed by the clinician or therapist performing this 
phase’s testing procedures. Immediately following the completion of this phase, as soon as possible, the 
continuous Visual Acuity Scale (VAS) will be completed for each of the five endpoints for clinician 
assessment and the two endpoints for patient assessment. The patient perception/satisfaction assessments 
include: (1) relief of symptoms, and (2) comfort/tolerance. The clinician perception assessments include: (1) 
technical/clinical difficulties, (2) patient comfort & tolerance, (3) ease of use, (4) monitoring & support for 
therapy, and (5) expected/perceived patient outcomes.  
 
Upon completion of this phase, the testing will pause for 15 minutes, until patient has returned to baseline 
dyspnea, prior to proceeding with the next nasal cannula design test. During this pause the patient will not 
perform known to worsen dyspnea. During the pause the patient will resume on their current oxygen 
therapy.  
 
Phase 2 – Test #1 (randomized)  
This test session is represented by Phase 2 in Figure 1, where the patient is placed on HVNI therapy with the 
order-randomized next generation cannula designs. Phase 2 will follow four distinct segments: (1) baseline 
characterization, (2) therapy acclimatization, (3) therapeutic characterization, (4) patient and clinician 
assessment scores.  
 
Baseline Characterization will be performed just prior to the therapy acclimatization segment of this Phase. 
If there is a reason the clinician does not deem the patient appropriate for the study, per inclusion/exclusion 
criteria, they may stop procedures during baseline characterization. Sitting down in a comfortable 
environment, the patient will be setup and prepared for the cannula testing with appropriate data recording 
devices. The patient will be ON current/home oxygen therapy at this time. While subject is at rest, the 
following data will be collected (see Table 1): RR, HR, BP, SpO2, TcPCO2 and RPD (Modified Borg scale 0-10). 
For the RPD, the clinician will record patient scores. 
 
Therapy acclimatization (5 – 10 minutes) will be performed after the baseline characterization segment is 
complete, and in accordance to site SOC to maintain patient safety. The patient will be fitted with 
appropriately sized nasal cannula (not to exceed 50% occlusion of the nares). 
 
 IF order-randomized to the Unicorn cannula, then use the FiO2 & one-half the Flow settings from Phase 1 
as a reference for the Therapeutic Settings.  
o For nostril selection of Unicorn cannula: Ask the patient to state which nostril is easiest to 
breathe through. Use that nostril to place the Solo/Unicorn cannula. 
 IF order-randomized to the Prosoft cannula, then use the FiO2 & the Flow settings from Phase 1 as a 
reference for the Therapeutic Settings.  
 
After the designated FiO2/Flow settings are implemented and the patient is acclimatized, the following data 
will be collected (see Table 1): RR, HR, BP, SpO2, TcPCO2 and RPD (Modified Borg scale 0-10). For the RPD, 
the clinician will record patient scores. Patient perception assessment will also be evaluated at this time.  
 

            
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 NOTE: Should the patient or clinician deem that the therapy is not providing a comparable relief of 
dyspnea, then after recording the data stated above, proceed to increase titration of the flow until relief 
of symptoms, with attention to TcPCO2. At this time, the therapy acclimatization segment should be 
repeated, and data will be appropriately recorded to account for this ‘settings’ adjustment. This is to 
understand any difference in cannula efficacy between legacy design and next generation cannula , 
designs. 
 
Therapeutic Characterization will be performed 5-10 minutes after the therapy acclimatization segment is 
completed. This will provide the patient sufficient time to receive clinical effect of the HVNI therapy and 
become sufficiently comfortable with the therapy and cannula. Once the respiratory therapist or other 
clinician skilled in management of HVNI deems that the HVNI settings are having a therapeutic effect, the 
following data will be collected (see Table 1): RR, HR, BP, SpO2, TcPCO2 and RPD (Modified Borg scale 0-10). 
For the RPD, the clinician will record patient scores.  
 
Patient & Clinician Perception Assessment will be performed by the clinician or therapist performing this 
phase’s testing procedures. Immediately following the completion of this phase, as soon as possible, the 
continuous Visual Acuity Scale (VAS) will be completed for each of the five endpoints for clinician 
assessment and the two endpoints for the patient assessment. For the patient perception these include: (1) 
relief of symptoms, and (2) comfort/tolerance. For the clinician perception these include: (1) 
technical/clinical difficulties, (2) patient comfort & tolerance, (3) ease of use, (4) monitoring & support for 
therapy, and (5) expected/perceived patient outcomes. 
 
Upon completion of this phase, the testing will pause for 15 minutes, until patient has returned to baseline 
dyspnea, prior to continuing with the next nasal cannula design test. During this pause the patient will not 
perform known to worsen dyspnea. During the pause the patient will continue with their current oxygen 
therapy.  
 
Phase 3 – Test #2 (randomized)  
 
For Phase 3, go back and repeat all procedures from Phase 2 with the difference 
of testing the second randomized cannula (Prosoft or Unicorn).  
 
Upon completion of this phase, the study testing procedures will be deemed completed, and any final study 
data will be finished at this time. At this time, the patient may resume current/home oxygen therapy. 
 
Other Medical Care 
All other medical treatment will remain the purview of the attending physician and will be administered in 
accordance with clinic standards.  This study is designed to evaluate only the patients’ ventilatory 
performance, oxygenation, and physiologic parameters while on HVNI with current and next generation 
cannula designs. It is assumed that the ancillary interventions will adhere to common clinical practice 
guidelines and conventions.  All treatments given to subjects will be documented on their CRFs. 
 
  
 

            
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VII. Data Collection 
 
Table 1. Key study data and collection points for each Phase of the Study. 
  
Baseline 
Characterization 
Therapy 
Acclimatization 
Therapeutic 
Characterization 
 @ Study 
End 
Patient History & Health 
X 
  
  
 
Treatment: Flow & O2 
X 
X 
X 
 
Physiologic Parameters 
X 
X 
X 
 
Ventilation Parameters 
X  
X 
X  
  
Clinician Perception Scores 
 
  
X 
X 
Patient Perception Scores 
 
 
X 
X 
 
Patient enrollment data collection will include patient history, health, demographics, and current respiratory 
therapies. Only Phase 1 will record the patients’ history and background information.  For each segment of 
each phase, the following data will be recorded for comparison: 
 
Physiologic Parameters 
o SpO2, HR, RR, BP 
Ventilation Parameters 
o RPD, TcPCO2 
 
Primary Endpoint 
• 
Modified Borg scale score(s) –Rated Perceived Dyspnea (RPD) 
 
Secondary Endpoints 
• 
Physiologic parameter(s) – SpO2, HR, RR, BP 
• 
Ventilation parameter(s) –TcPCO2 
 
Tertiary Endpoints – Patient & Clinician Assessments 
• 
Patient Assessment 
o Patient assessment of respiratory response to therapy, ranging from Insufficient to Excellent 
Response, as continuous VAS. 
o Patient assessment of comfort and tolerance of the therapy, ranging from Insufficient to 
Excellent as continuous VAS. 
• 
Clinician Assessment 
o Clinician assessment of patient respiratory response to therapy, ranging from Insufficient to 
Excellent Response, as continuous VAS. 
o Clinician assessment of frequency of rain-out, interface slippage or other technical/clinical 
difficulties applying therapy, ranging from Never to Frequent as continuous VAS. 

            
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o Clinician assessment of patient comfort and tolerance of therapy, ranging from Insufficient to 
Excellent as continuous VAS. 
o Clinician assessment of simplicity of set-up and use, ranging from Complex to Setup and Use 
to Simple to Setup and Use, as continuous VAS. 
o Clinician perception of Monitoring and support of therapy required (adjustments, refilling 
fluids, adjusting interface), ranging from Minimal to Frequent, as continuous VAS. 
 
VIII. Statistical Analysis 
The data analysis will be “per protocol.” Baseline patient demographics and characteristics will be 
summarized, compared, and appropriate statistical testing will be performed for the continuous and 
categorical variables. Assuming a non-normal data distribution for this crossover order-randomized study 
design, the non-parametric Wilcoxon Signed Rank Sum test will be performed with significance interval of 
0.05 on all applicable variables. Parametric analytical analogues (e.g. t-test) will be use if the measurements 
present a normal distribution. Otherwise, for the categorical variables, the Fisher’s Exact test will be 
performed. Data will be compared and graphed accordingly for a visual comparison with accompanied 
statistical notations.  
 
IX. Risks and Discomforts 
This study does not present significant risk to patients, as supplemental oxygen is routinely provided to 
patients as a means of standard/routine practice in the study hospitals 18. Use of high flow nasal cannula 
therapy has no known risks and has been used in the clinical setting for approximately 17 years without 
known reports of adverse events related to the administration of high nasal flows when appropriately 
conditioned to near body temperature and fully humidified.  The literature indicates that approximately only 
4 cmH2O of distending pressure may be generated in the upper airway, which is well below any known 
threshold for injury. 19,20  Additionally, it has been demonstrated that delivery of high flows of conditioned 
gas from a nasal cannula has a positive effect on airway mucosal function. 21,22 The patients will be closely 
monitored as part of standard medical practice.  
 
For these reasons, we have determined that this study represents non-significant risk to the subjects. The 
high flow nasal cannula system used has no known risk and has been used in hospitals for about 17 years. 
During both sessions, patients will be closely monitored as part of the normal care. Patients may experience 
mild discomfort from a cannula coming into contact with their nose, face or around their ears; patients may 
also experience runny nose from the humidity contained in the gas flow.  
 
X. Potential Benefits 
Subjects may or may not receive any direct health benefit from participation. Due to the short duration of the 
exposure, it is not likely that the patients enrolled in the HVNI cannula study will themselves benefit from 
participation in this study. The trial may result in scientific knowledge that leads to improvements in the 
quality of patient care, patient experience, and the effect cannula designs have on patient dyspnea relief.  
 

            
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XI. Monitoring and Quality Assurance 
The clinical trial site will be monitored in accordance with policies at Vapotherm and federal regulations that 
pertain to clinical research, namely 21 CFR Parts 50, 54, 56 and 812 and others as applicable.  Monitoring 
will occur at regular frequency by the PI or designee, such as to allow ongoing review of data collected, site 
qualifications and compliance with the protocol.  All investigators will be appropriately trained to ensure 
compliance with the protocol. Audits of the study CRF’s will be regularly conducted by the Sponsor.  
 
XII. Protocol Deviations 
Any deviations from the Data Collection plan identified during monitoring or through other means will be 
documented on case report forms. These include, but are not limited to items such as the following:  
• 
Deviation from the procedural sequencing, per the protocol 
• 
Failure to complete the Baseline characterization  
• 
Failure to complete all sections of the Study Phases 
• 
Failure to capture time and place in trial of any device failure 
• 
Failure to capture/record data included in the protocol 
• 
Subject inability to complete both the control and test study arms 
If the study site demonstrates a pattern of consistent and frequent deviations, the sponsor will undertake 
appropriate activities (e.g. re-training) to attempt to bring the site into compliance with the protocol. A 
pattern of repeated serious deviations from the protocol may result in site termination from the study. 
 
XIII. Adverse Event Reporting 
During the course of the subjects’ participation in the study, the investigator will determine whether any 
adverse events have occurred.  For the purposes of this protocol, an adverse event is defined as any 
undesirable event experienced by a subject, that is or is not attributed to the device or procedure required by 
this protocol.  If any adverse event occurs, whether anticipated or unanticipated, the investigators will 
immediately contact the sponsor representative (site monitor) indicated on page 1. 
 
XIV. Confidentiality 
Rigorous procedures will be followed to maintain confidentiality of subject identification and test-related 
information and to adhere to government regulations concerning privacy.  Methods to protect the privacy of 
subjects and clinical information are employed and built into the trial.  A unique identification number 
designed to protect the identity of subjects will be used to identify the subject on case report forms, 
recruitment logs, data forms or other reports. 
 
This unique identification number will not be linked to identifiable data; no personal or identifiable patient 
data will be collected.  The Vapotherm clinical research staff member managing 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.  The linked data will be maintained by the site study staff and stored at the study site 
for two years from the end of the study.  
 

            
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Confidentiality will be protected and maintained to the extent allowed by law. 
                                                                                                                                                                                                                                         
XV. References 
1. 
Ejiofor SI, Bayliss S, Gassamma A, Turner AM. Ambulatory Oxygen for Exercise-Induced 
Desaturation and Dyspnea in Chronic Obstructive Pulmonary Disease (COPD): Systematic Review and 
Meta-Analysis. Chronic Obstr Pulm Dis. 2016;3(1):419-434. 
2. 
Doshi P, Whittle JS, Bublewicz M, et al. High-Velocity Nasal Insufflation in the Treatment of 
Respiratory Failure: A Randomized Clinical Trial. Ann Emerg Med. 2018;72(1):73-83 e75. 
3. 
Hernández G, Roca O, Colinas L. High-flow nasal cannula support therapy: new insights and. Critical 
care. 2017;21(1):1-11. 
4. 
Lavizzari A, Colnaghi M, Ciuffini F, et al. Heated, Humidified High-Flow Nasal Cannula vs Nasal 
Continuous Positive Airway Pressure for Respiratory Distress Syndrome of Prematurity: A 
Randomized Clinical Noninferiority Trial. JAMA Pediatr. 2016. 
5. 
Waugh JB, Granger WM. An evaluation of 2 new devices for nasal high-flow gas therapy. Respiratory 
care. 2004;49(8):902-906. 
6. 
Dysart K, Miller TL, Wolfson MR, Shaffer TH. Research in high flow therapy: mechanisms of action. 
Respiratory medicine. 2009;103(10):1400-1405. 
7. 
Woodhead DD, Lambert DK, Clark JM, Christensen RD. Comparing two methods of delivering high-
flow gas therapy by nasal cannula following endotracheal extubation: a prospective, randomized, 
masked, crossover trial. Journal of perinatology : official journal of the California Perinatal 
Association. 2006;26(8):481-485. 
8. 
Frizzola M, Miller TL, Rodriguez ME, et al. High-flow nasal cannula: impact on oxygenation and 
ventilation in an acute lung injury model. Pediatric pulmonology. 2011;46(1):67-74. 
9. 
Doshi P, Whittle JS, Bublewicz M, et al. High-Velocity Nasal Insufflation in the Treatment of 
Respiratory Failure: A Randomized Clinical Trial. Ann Emerg Med. 2018. 
10. 
Weiler T, Kamerkar A, Hotz J, Ross PA, Newth CJL, Khemani RG. The Relationship between High Flow 
Nasal Cannula Flow Rate and Effort of Breathing in Children. The Journal of pediatrics. 2017;189:66-
71. 
11. 
Yoder BA, Manley B, Collins CL, et al. Consensus approach to nasal high-flow therapy in neonates. 
Journal of Perinatology. 2017;Advanced Online Publication. 
12. 
Miller TL, Saberi B, Saberi S. Computational Fluid Dynamics Modeling of Extrathoracic Airway Flush: 
Evaluation of High Flow Nasal Cannula Design Elements. Journal of Pulmonary & Respiratory Medicine. 
2016;6(5):376. 
13. 
Greenspan JS, Wolfson MR, Shaffer TH. Airway responsiveness to low inspired gas temperature in 
preterm neonates. The Journal of pediatrics. 1991;118(3):443-445. 
14. 
Shepard JW, Jr., Burger CD. Nasal and oral flow-volume loops in normal subjects and patients with 
obstructive sleep apnea. Am Rev Respir Dis. 1990;142(6 Pt 1):1288-1293. 
15. 
Crisafulli E, Clini EM. Measures of dyspnea in pulmonary rehabilitation. Multidiscip Respir Med. 
2010;5(3):202-210. 
16. 
Schwabbauer N, Berg B, Blumenstock G, Haap M, Hetzel J, Riessen R. Nasal high-flow oxygen therapy 
in patients with hypoxic respiratory failure: effect on functional and subjective respiratory 

            
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HVNI Cannula Efficacy in Relieving Dyspnea 
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parameters compared to conventional oxygen therapy and non-invasive ventilation (NIV). BMC 
Anesthesiol. 2014;14:66. 
17. 
Roca O, Riera J, Torres F, Masclans JR. High-flow oxygen therapy in acute respiratory failure. 
Respiratory care. 2010;55(4):408-413. 
18. 
Laboratories ATSCoPSfCPF. ATS statement: guidelines for the six-minute walk test. Am J Respir 
Crit Care Med. 2002;166(1):111-117. 
19. 
McGinley BM, Patil SP, Kirkness JP, Smith PL, Schwartz AR, Schneider H. A nasal cannula can be used 
to treat obstructive sleep apnea. Am J Respir Crit Care Med. 2007;176(2):194-200. 
20. 
Parke R, McGuinness S, Eccleston M. Nasal high-flow therapy delivers low level positive airway 
pressure. British journal of anaesthesia. 2009;103(6):886-890. 
21. 
Hasani A, Chapman TH, McCool D, Smith RE, Dilworth JP, Agnew JE. Domiciliary humidification 
improves lung mucociliary clearance in patients with bronchiectasis. Chron Respir Dis. 2008;5(2):81-
86. 
22. 
Williams R, Rankin N, Smith T, Galler D, Seakins P. Relationship between the humidity and 
temperature of inspired gas and the function of the airway mucosa. Crit Care Med. 1996;24(11):1920-
1929.