Assessing Clinical Effect of HVNI on Patient Ambulation in Acute Care Scenarios: a Feasibility Study
Phase: NA
Conditions: Respiratory Insufficiency, Dyspnea
Sponsor: Vapotherm, Inc.

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 1 of 20                
  
Protocol Title: 
Assessing clinical effect of HVNI on improving patient ambulation in 
acute care scenarios: a feasibility study 
 
Protocol Number: 
 
RP-VTPF2018001Sci  
 
 
Revision: 
 
 
Rev 1.0 – January 30, 2019 
 
 
Principal Investigator: 
Thomas Siler, M.D. 
 
 
 
 
Co-Investigators: 
 
TBD 
 
 
Sponsor: 
 
 
Vapotherm, Inc 
100 Domain Drive 
Exeter, NH  03833 
1 (603) 658-0011 
http://www.vtherm.com 
 
 
 
 
 
 
 
 
 
 
Confidential 
 
Study site should keep protocol, all contents and related information confidential. 
 
 
 
 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 2 of 20                
 
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: 
 
____________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 3 of 20                
 
 
GLOSSARY OF DEFINITIONS AND TERMS .............................................................................................. 4 
I. BACKGROUND AND SIGNIFICANCE ...................................................................................................... 6 
II. OVERALL STUDY OBJECTIVE ............................................................................................................... 9 
III. SUBJECT SELECTION .......................................................................................................................... 10 
IV. STUDY DESIGN ..................................................................................................................................... 10 
V. SUBJECT ENROLLMENT ....................................................................................................................... 11 
VI. STUDY PROCEDURES.......................................................................................................................... 12 
VII. DATA COLLECTION ............................................................................................................................ 16 
VIII. STATISTICAL ANALYSIS .................................................................................................................. 17 
IX. RISKS AND DISCOMFORTS ................................................................................................................ 17 
X. POTENTIAL BENEFITS ......................................................................................................................... 17 
XI. MONITORING AND QUALITY ASSURANCE ...................................................................................... 17 
XII. PROTOCOL DEVIATIONS .................................................................................................................. 18 
XIII. ADVERSE EVENT REPORTING ........................................................................................................ 18 
XIV. CONFIDENTIALITY ........................................................................................................................... 18 
XV. REFERENCES ....................................................................................................................................... 18 
 
 
 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 4 of 20                
 
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): The use of HFNC with specified parameters including flow rates, 
fraction of oxygen, gas temperature and cannula interface dimensions to achieve a defined therapeutic effect. 
 
Non-Invasive Positive Pressure Ventilation (NIPPV): Breathing assist where a mask is strapped tightly to a 
patient’s face and bi-level pressure is administered at an established frequency to support a patient’s minute 
ventilation. 
 
Mechanical Ventilation (MV): Breathing assist that requires intubation and the delivery of forced positive 
pressure breaths at a set frequency. 
 
Respiratory Failure: The inability to maintain sufficient arterial blood oxygen saturation and CO2 levels 
during unassisted spontaneous breathing. 
 
Pulmonary Rehabilitation: Exercise regimen for patients with compromised cardio-pulmonary function. 
 
Vapotherm Transfer Unit (VTU): system composed of a roll stand, power source and gas supply that allows 
the Precision Flow to function independently of wall connections and therefore become mobile, facilitating 
therapy during ambulation. 
 
Ambulatory Oxygen: A portable oxygen cylinder device allowing the patient to carry around their oxygen 
supply so as to breathe during routine mobility & exercises. 
 
Pulse Oximetry Reading (SpO2):  Indirect measure of a patient’s arterial blood oxygen saturation using pulse 
oximetry technology. 
 
Resting SpO2:  SpO2 value the patient demonstrated at rest, while sitting upright and connected to the patient 
monitors prior to the start of the study session.  This value will be patient specific and reflect the patient’s 
clinical status. 
 
Desaturation SpO2: The SpO2 value considered to be the point of desaturation.  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 the sign and symptoms of increased physical exertion, which include airway 
resistance, use of accessory muscles for inspiration or expiration. 
 
Fraction of inspired oxygen (FiO2; %): The percent of the delivered respiratory gas mixture that is oxygen, 
expressed as a fraction. 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 5 of 20                
 
Ventilatory Rate (Respiratory Rate; RR): The number of breaths a subject takes per minute (breaths·min-1). 
 
Blood Pressure (BP): pressure of the blood in the circulatory system.  
 
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. This scale allows for patients and clinicians to rate dyspneic status by using specific 
descriptors, on a scale of 0 (no dyspnea) to 10 (unbearable dyspnea). The modified Borg scale is also used for 
rating the subjective perceived exertion 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. 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 6 of 20                
 
I. Background and Significance 
Hypoxemia and dyspnea are hallmark characteristics of patients with chronic pulmonary disease 1, and can 
be attributed to acute respiratory failure. Oxygen therapy is the first stage in the treatment and prevention of 
acute respiratory failure. This therapy is delivered through pressure (mechanical ventilation [MV], non-
invasive positive pressure ventilation [NIPPV]) and flow-based (HFNC) modalities to support oxygenation 
and ventilation, and in many cases, NIPPV & HFNC have been demonstrated to provide comparable support 
2-4. The key difference in these modalities lies in a patient’s functional respiratory drive – for the pressure-
based therapies this is not a contraindication. However, oftentimes HFNC can be a stop-gap to & weaning-
step from the invasive and betimes patient-intolerant pressure therapies 2,3,5,6. Many areas of patient care 
commonly use oxygen therapy: intensive care, emergency department, surgical suite, hospice, home-care. 
Further, in many such cases ambulation and early mobility is used in concert with oxygen therapy, as 
exercise is linked to improved patient outcomes 7-9. In fact, early mobility provides profound effects on 
physical health, strength, and mental health. Past studies with ambulatory oxygen evaluated patients with a 
need for oxygenation and ventilatory support during daily activity, including the following: chronic 
obstructive pulmonary disorder (COPD), interstitial lung disease (ARDS), pulmonary hypertension, 
pulmonary fibrosis, post-operative surgery, weaning from mechanical ventilation, and an inability to utilize 
normal lung inspiratory/expiratory mechanics 7-13.  In summary, early mobility and ambulation provides 
hospitals a cost-effective method to improve patient outcomes in a wide range of critical care settings. This 
feasibility study aims to evaluate the effect of high velocity nasal insufflation (HVNI) on patient ambulation 
and to compare HVNI to treatment as usual (TAU).  
 
Ambulatory care oxygen denotes the use of supplemental oxygen during any form of mobility, exercise, and 
daily life activities 7. Use of ambulatory oxygen in patients with respiratory distress has become prevalent as 
patients often desaturate (hypoxemic, <88%) during exercise & mobility assessments 7,8,14. This desaturation, 
especially in patients with resting hypoxemia challenges, has been associated with reduced exercise 
tolerance, reduced FEV1, and in chronic cases even increased patient mortality 10,11,13. It is also used by 
patients on long-term oxygen treatment during any exercise 15. In fact, pulmonary rehabilitation has become 
a standard of care (SOC) for patients with respiratory diseases, with evidence supporting the benefits of 
exercise to improved dyspneic, quality of life (QOL) outcomes, hospital resource allocation, psychosocial 
benefits, and cost-effectiveness 8. The long-term benefits of using oxygen, in conjunction to ambulation, is 
still debated 16-18. Clear episodic improvements have been demonstrated to improve exercise performance 
measures 7,8, reduce exercise dyspnea 1, improve recovery time 8,19, reduce WOB 8, reduce incidence of 
cardiopulmonary complications 20, and in some cases improve patient mental health 8,14. Systematic reviews 
have also highlighted the correlation between longer hospital stays and greater chances for complications 
followed by lengthened rehabilitation due to muscle wasting, which may be ameliorated through early 
ambulation 7,8. A study in COPD patients even suggested that a 4% desaturation during 6-minute-walk-tests 
(6MWT) may predict long-term mortality 11. 
 
Multiple studies have demonstrated improved activity, performance, reduced dyspnea, and improved SpO2 
saturation as positive patient outcomes of ambulation during MV and non-invasive ventilation (NIV). In fact, 
early ambulation of patients requiring MV has been communicated as clinically useful as early as 1975 21. 
Previously, NIV has been shown to increase exercise tolerance, reduce exercise desaturation episodes, and 
thereby improve pulmonary rehabilitation 8,22. Menadue et al. specifically explored NIV’s effect on exercise in 
acute hypercapnic exacerbations of respiratory disease, and demonstrated that oxygen by NIV improved the 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 7 of 20                
6MWT performance, reduced patient dyspnea, and improved SpO2 saturations when compared to oxygen 
alone 23. Studies by Jolley et al. 12,16,24, with MV, demonstrated that: (1) in surveys across 47 hospitals in 
Washington State higher activity levels were noted due to SOC practice from available (76%) site mobility 
protocols 24, and (2) adults in acute respiratory failure placed on MV, involved in early physical and 
occupational therapy, were strongly predictive of improved out-of-bed mobility outcomes 12. Accordingly, 
the presence of endotracheal tubing during MV was negatively associated to out-of-bed mobility. A study by 
Nishiyama et al. in IPF patients without resting hypoxemia demonstrated that no benefit existed between air 
& oxygen (4LPM) in terms of exertional dyspnea & performance (6MWT), but noted that mobility 
assessments should be made on an individual basis 20. In fact, mobility during MV is so prevalent and 
effective that Hodgson et al., in a systematic review of literature, developed consensus recommendations on 
safety parameters of ICU mechanically ventilated adults 25. Looking back, these studies and others used 
endpoints from the following pool to assess improved outcomes: exercise performance, recovery time, SpO2 
saturation, clinician perception assessments, perceived dyspnea, perceived exertion, health status 
questionnaires, lung function by spirometry, heart rate, respiratory rate, work of breathing, and mobility 
assessment scoring (BMAT, MMS, mMRC) 7,8,12,26.  
 
As literature has established the importance of ambulation and early mobility during hospital stay, especially 
in patients needing oxygen for daily activity, this study explores the potential benefit of HVNI during patient 
ambulation. Vapotherm’s HVNI therapy is premised on the technical ability to create ideally conditioned 
respiratory gas, which is delivered nasally with an intent to support spontaneous ventilation as opposed to 
simple oxygen therapy 5,27.  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 28.  This high velocity nasal flow facilitates a well described 
mechanism of improving ventilatory efficiency by way of eliminating anatomical dead space of the upper 
airway 5. The purging of the nasal cavity is important to alveolar gas exchange because the gas that is drawn 
to the respiratory regions of the lungs comes from the anatomical reservoir created by the flush, in the same 
way that oxygen conservation masks can incorporate reservoir bags to reduce the bulk flow requirements 
from the oxygen source to achieve the same oxygenation effect 5,29.  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 35 L·min-1 through Vapotherm’s adult cannulae, would purge the anatomical reservoir of 
the upper airway in the window of time between breaths.   
 
Vapotherm’s humidification systems are 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) 29. 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 5,28-31.  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 in the Emergency Department 2.  
 
As Vapotherm Hi-VNI technology becomes more common-place in hospital standard of care & practice, HVNI 
therapy may also have a demonstrable effect on improving patient ambulation and mobility.  Mobility 
represents a key factor in the timely improvement of patient health, and in end-of-life cases it can have a 
mental impact 8. In addition to the patient benefits, ambulation and early ambulation & mobility can also 
reduce the patient hospital resource allocation and reduce the length of stay (LOS). Some hospitals have 
included patient ambulation metrics as a key success factor, and this also can play a role to stepping-down 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 8 of 20                
the patients to less critical care environments. The goal of this study is to establish a low risk model, 
modified from the 6MWT, for patients with dyspnea: (1) evaluate the effect of HVNI on ambulation, and (2) 
assess the impact HVNI use may have on improved outcomes when compared to standard TAU (HVNI).   
 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 9 of 20                
- 
 
II. Overall Study Objective 
 
The overall objective of this study is to evaluate the ability of HVNI to improve patient ambulation relative 
to a treatment as usual (TAU).  
 
The hypothesis is that HVNI therapy, when implemented in conjunction to ambulatory practices, will be 
more effective than TAU to improve patient mobility by reducing the patient’s perceived dyspnea and 
exertion via maintaining oxygenation (reduced desaturation) and supporting ventilation (reduced work of 
breathing [WOB]).  
 
To test this hypothesis, the study will be conducted with the following specific aims:  
 
Aim #1: Primary Outcome. The primary endpoint is exercise performance, defined as the distance and 
duration of patient ambulation.  
 
Aim #2: Secondary Outcomes. The secondary endpoints evaluate the patient recovery interval, defined as 
the recovery time (return time to baseline perceived dyspnea). Other endpoints will include: vital signs 
(heart rate [HR], respiratory rate [RR], blood pressure [BP]), arterial oxygen saturation (SpO2), rated 
perceived exertion (RPE), and rated perceived dyspnea (RPD).  
 
Aim #3: Tertiary Outcomes. The tertiary endpoints evaluate the clinician perception scores. For the 
clinician perceptions this will include: technical/clinical difficulties, patient comfort & tolerance, ease of use, 
monitoring & support for therapy, and expected/perceived patient outcomes.  
 
These endpoints will establish the effect HVNI therapy may have on improving patient ambulation relative 
to TAU, while potentially demonstrating the effect of HVNI on hospital resource allocation and patient 
comfort. 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 10 of 20                
 
III. Subject Selection  
Subjects will be identified and recruited by study investigators. The feasibility study will take place at a 
clinical setting (e.g. hospital, academic center, out-patient facility), where testing can be performed with 
appropriate supervision and staff training to maintain patient safety. The test model is a modified 6MWT. 
Initial contact will be made by the study investigators, and the participants may or may not decide to enroll.  
Compensation will be provided to participants for enrollment into this study.  
 
Inclusion Criteria 
1. Adults over the age of 18 years 
2. Demonstrated respiratory distress upon mild to moderate exertion (e.g. dyspnea upon standing, 
walking, etc.) 
3. Candidate for clinical ambulation/mobilization  
4. GOLD 4 spirometry or GOLD 3 with significant dyspnea on exertion with or without supplemental 
oxygen 
 
 
Exclusion Criteria 
1. Hypoxemia at resting baseline with SpO2<88% with supplemental oxygen 
2. Inability to provide informed consent 
3. Pregnancy  
4. Known contraindication to perform ambulation, per site SOC practices 
5. Inadequate respiratory drive or any known contraindications to HVNI 
6. Inability to use nasal cannula and HVNI therapy 
7. Agitation or uncooperativeness  
8. Determined by the attending clinician to be sufficiently unstable or unsuitable for this feasibility 
study  
 
IV. Study Design  
The study objective is to evaluate the ability of HVNI to improve patient ambulation relative to TAU by using 
a modified 6MWT model. The hypothesis is that HVNI therapy, when implemented in conjunction to 
ambulatory practices, will be more effective than TAU to improve patient by reducing the patient’s perceived 
dyspnea and exertion via maintaining oxygenation (reduced desaturation) and supporting ventilation 
(reduced WOB). 
 
This will be a feasibility study, performed as a prospective, crossover trial to evaluate the potential patient 
improvement during ambulation while on HVNI relative to TAU. Patients who fit the criteria for inclusion 
will perform ambulation for each study period: the baseline period (TAU) followed by the test period (HVNI). 
The clinical management will otherwise remain unchanged based on the site SOC practices. The patient FiO2 
and flow values will be recorded while on any supplemental oxygen. Subjects will wear appropriate gear and, 
when applicable, have mobile carts to provide supplemental oxygen therapy (e.g. HVNI VTU) during 
ambulation.  
 
This feasibility study design focuses on three distinct phases: (1) baseline characterization, (2) performance 
measures of ambulation, and (3) clinician perceived satisfaction scores. The baseline characterization is to 
provide patient background, history, and initial relevant clinical evaluation from Aim 2. Performance 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 11 of 20                
measures from Aims 1 & 2 will provide physiologic relevant indices before/during/after ambulation session 
and will be used for meaningful comparison between study arms. Lastly, Aim 3 will provide an overall 
assessment from the clinician perceived satisfaction scores. 
 
This feasibility study will involve two study periods:  baseline (TAU) and test (HVNI). Baseline period will be 
administered first, followed by the test period. Patients deemed in need of ambulation (per 
inclusion/exclusion criteria) will be enrolled into the study and will complete both study periods: 
1. Treatment as usual (TAU) of standard practices (control arm) for ambulation at site 
2. Vapotherm HVNI therapy (test arm) administered as described below during ambulation at site 
 
This feasibility study will be conducted in a research facility and where testing can be performed with 
appropriate supervision and staff training to maintain patient safety.  This current study uses a modified 
6MWT ambulation test to evaluate the patient performance. Primary and secondary outcomes will be 
completed upon the completion of each study arm’s ambulation test.  Tertiary outcomes will be completed 
upon study. All respiratory interventions will be tracked during the study window, and disposition and 
mortality will be tracked for each patient.  
 
V. Subject Enrollment 
 
Subjects will be solicited by research staff and consented prior to participation in this feasibility study (Aims 
1-3). Once consented, the participants will complete all Aims during the course of participation in the study, 
per the TAU at each site.  Compensation will be provided to participants for enrollment into this study. 
 
Sample Size: 
To provide a sample data set, we will enroll up to 32 subjects to complete this feasibility assessment, with a 
calculated sample size of N=26 plus a 20% failure rate. This will provide sufficient initial data to inform the 
appropriate sample size of a follow-on randomized study.  
 
This sample size was calculated through use of references that approximated similar studies 1,32. McCarthy et 
al. found a mean difference of 42.93m with 95CI: 32.64 – 55.21m when evaluating patient ambulation with 
and without adjunctive therapy 32. For this study, using a desired power of 90% with alpha=0.05, the sample 
size is estimated at 26 to show a difference in data between the control and test groups.  

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 12 of 20                
 
VI. Study Procedures 
This feasibility study is non-blinded by necessity, since the provided therapies have different devices. No 
randomization will be incorporated into this feasibility study design. The study arms will be performed as a 
crossover design, baseline performed first followed by the test period. Study model for the ambulation test is 
a modified 6-minute walk test. Figure 1 illustrates an overview of the study procedures.  This feasibility 
study will evaluate the baseline, performance, recovery, and clinical assessment indices to demonstrate the 
effect between TAU and HVNI during ambulatory practice. 
 
Screening, Enrollment, & Management 
Upon screening, subjects will be asked to participate in this study, and if so they will be consented prior to 
enrollment. Subjects are instructed that if at any time during 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, anthropometrics, and applicable history (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 ability to ambulate and 
continue study procedures will be made per standard practice at the site, using the judgment of the research 
team.  
 
 
 
 
 
Figure 1. Framework of the clinical study procedures discussed within this protocol. 
 
 
 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 13 of 20                
Control Session 
The Control session is treatment as usual (TAU), without use of HVNI during any time of this study period.  
 
The Control session will follow three phases (see Figure 1 & Table 1): Baseline Characterization, Ambulation 
Test, and Recovery Interval. After these phases are complete, the next ambulation exercise will be 
determined per standard practice and when deemed appropriate by investigator.  
 
Prior to the Control Session baseline characterization, the subjects should wear comfortable clothing, 
appropriate walking shoes, and usual walking aids (cane, walker, etc.). No vigorous exercise should be 
performed 2 hours prior to the ambulation test 33. 
 
Baseline Characterization Sitting down, the subject will be setup and prepared for the ambulation test with 
appropriate data recording devices and supplemental oxygen (not HVNI). The subject will be allowed to 
acclimate to the supplemental oxygen during this period of time. While subject is at rest, standing up, the 
following data will be collected (see Table 1): RR, HR, BP, SpO2, and RPD (Modified Borg scale 0-10). For the 
RPD & RPE, the coordinator will record patient scores, the FiO2 and flow settings for any supplemental 
oxygen provided to the patient before/during/after this baseline phase. TAU will not include HVNI in this 
study period. The Ambulation Test will be performed after the baseline characterization is. The definition for 
this ambulation test will be to walk until 18 minutes has elapsed or the patient is unable to continue. A timer 
will keep track of the test duration, and the clinician will keep track of the distance traveled during 
ambulation. At test start, test end, & 1-minute intervals the subjects will be asked to rate their RPE (Modified 
Borg scale 0-10). The subject vitals will be monitored during this ambulation test and recorded as follows: 
HR, RR, SpO2. The ambulation test will end if the subject has completed 18 minutes, stops walking for more 
than 10 seconds, has to sit down, has any adverse events, or should the investigator deem necessary. 
 
Recovery Interval will begin immediately following the end of the Ambulation Test. The subject will perform 
this recovery interval while safely seated. The time to return to the subject’s resting-while-standing RPD 
score (Baseline) will be used as recovery time. At the end of the recovery interval, record the subject RR, HR, 
BP, SpO2, and RPD & RPE. Any adverse events will be recorded. Any exacerbations from ambulation walk test 
will be recorded during the recovery interval. Record the recovery end time and date. 
 
After the Recovery Interval is complete, all associated data will be collected including clinician 
perception/satisfaction scores. Then the study will pause until the next ambulation test is scheduled. The 
next ambulation test will be determined per standard practice and when deemed appropriate by the 
investigator.  
 
 
Test Session  
The Test session (with HVNI therapy) will follow three phases (see Figure 1 & Table 1): Baseline 
Characterization, Ambulation Test, and Recovery Interval. After these phases are complete, and all 
associated data is collected (per Table 1), the coordinator will collect all end-of-study data prior to study 
completion.  
 
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 to the test arm, the HVNI start settings will be 
the following: FiO2 = 1.0, Flow = 35 L/min, and Temperature = 35 -37°C.  

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 14 of 20                
- 
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. Initial flow will be set to 35 L/min but can be decreased 
or increased as rapidly as necessary to alleviate respiratory distress and optimize patient comfort. 
Targets should be to lower respiratory rate to the low 20s and with an HVNI flow rate between 20 to 35 
L/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 C to enhance tolerance. The FiO2 will be 1.0 
initially to assure adequate oxygenation, but this should be adjusted promptly to maintain an FiO2 of no 
greater than 0.6 to maintain a PaO2 > 88%.  
  
Prior to the Test Session baseline characterization, the subjects will be placed on HVNI, titrated per above 
settings, and subjects will be allowed to acclimate to the supplemental oxygen (HVNI therapy). The subjects 
should wear comfortable clothing, appropriate walking shoes, and usual walking aids (cane, walker, etc.). No 
vigorous exercise should be performed 2 hours prior to the ambulation test 33. Record the start date & time 
of placement on HVNI therapy. 
 
Baseline Characterization will be performed just prior to the next scheduled ambulation test, as deemed 
appropriate for the patient by the investigator. Sitting down, the subject will be setup and prepared for the 
ambulation test with appropriate data recording devices and supplementary oxygen (only HVNI). While 
subject is at rest, standing up, the following data will be collected (see Table 1): RR, HR, BP, SpO2, and RPD 
(Modified Borg scale 0-10). For the RPD & RPE, the coordinator will record patient scores. Record the FiO2 
and flow settings for any supplemental oxygen provided to the patient before/during/after this baseline 
phase.  
 
The Ambulation Test will be performed after the baseline characterization is complete, and in accordance to 
the standard practice of the site and judgment of the investigator to maintain patient safety.  The definition 
for this ambulation test will be to walk until 18 minutes has elapsed or the patient is unable to continue.  A 
timer will keep track of the test duration, and the clinician will keep track of the distance traveled during 
ambulation. At test start, test end, & 1-minute intervals the subjects will be asked to rate their RPD & RPE 
(Modified Borg scale 0-10). The subject vitals will be monitored during this ambulation test and recorded as 
follows: HR, RR, SpO2. The ambulation test will end if, the subject has completed 18 minutes, stops walking 
for more than 10 seconds, has to sit down, has any adverse events, or should the investigator deem 
necessary. 
 
Recovery Interval will begin immediately following the end of the Ambulation Test. The subject will perform 
this recovery interval while safely seated.  The time to return to the subject’s resting-while-standing RPD 
score (Baseline) will be used as recovery time. At the end of the recovery interval, record the subject RR, HR, 
BP, SpO2, and RPD & RPE. Any adverse events will be recorded. Any exacerbations from ambulation walk test 
will be recorded during the recovery interval. Record the recovery end time and date. 
 
After the Recovery Interval is complete, all associated data will be collected (per Table 1). This includes all 
end-of-study data prior to study completion including perception/satisfaction scores.  
 
Other Medical Care 
All other pharmaceutical and medical treatment will remain the purview of the attending physician and will 
be administered per the current standards.  This study is designed to evaluate only intervention of HVNI in 
conjunction with standard (TAU) ambulatory practice, and it is assumed that the ancillary interventions will 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 15 of 20                
follow common clinical practice guidelines and conventions.  All treatments given to the subjects will be 
noted on their CRFs. 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 16 of 20                
 
VII. Data Collection 
 
Table 1. Key study data and collection points. 
  
Baseline 
Characterization 
Ambulation 
Test 
Recovery 
Interval 
 @ Study 
End 
Patient History & Health 
X 
  
  
X 
Treatment: Flow & O2 
X 
X 
X 
X 
Physiologic Parameters 
X 
X 
X 
X 
Performance Parameters 
  
X 
  
  
Recovery Parameters 
  
  
X 
  
Clinician Perception Scores 
 
 
X 
X 
Disposition  
X 
  
  
X 
 
Patient enrollment data collection will include patient history, health, demographics, and interventions. For 
each test session the following data will be recorded for comparison.  
 
Physiologic Parameters 
o SpO2, HR, RR, BP, RPE, RPD  
Performance Parameters 
o Test duration and test distance traveled 
Recovery Parameters  
o Return time to baseline RPD, HR, RR, BP, SpO2, RPD, RPE 
 
Primary Endpoint 
• 
Distance and duration of exercise during ambulation  
 
Secondary Endpoints 
• 
Physiologic parameters – SpO2, HR, RR, BP, RPE, RPD 
• 
Recovery parameters: return time to baseline Rated Perceived Dyspnea score 
• 
Modified Borg scale scores – Rated Perceived Exertion (RPE), Rated Perceived Dyspnea (RPD) 
 
Tertiary Endpoints   
• 
Clinician perception of patient respiratory response to therapy, ranging from NO Response to 
Excellent Response, as continuous VAS. 
• 
Clinician perception of frequency of rain-out, interface slippage or other technical/clinical difficulties 
applying therapy, ranging from Never to Frequent as continuous VAS. 
• 
Clinician perception of patient comfort and tolerance of therapy, ranging from Very Poorly Tolerated 
to Very Well Tolerated as continuous VAS. 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 17 of 20                
• 
Clinician perception of Simplicity of set-up and use, ranging from Complex to Setup and Use to Simple 
to Setup and Use, as continuous VAS. 
• 
Clinician perception of Monitoring and support of therapy required (adjustments, refilling fluids, 
adjusting interface), ranging from Almost Constantly to Almost Never, as continuous VAS. 
VIII. Statistical Analysis   
The data analysis will be “per protocol.” Baseline patient demographics and characteristics will be 
summarized, and appropriate statistical testing will be performed for the continuous and categorical 
variables. Assuming a non-normal data distribution for this crossover study design, the non-parametric 
Wilcoxon Signed Rank Sum test will be performed with significance interval of 0.05 on all applicable 
variables. 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 pilot study does not present significant risk to patients, as supplemental oxygen is routinely provided to 
patients and the 6MWT is a standard/routine practice 33. The Treatment-as-Usual at the study sites involves 
the application of simple supplemental oxygen during mobilization. Use of the high flow nasal cannula 
therapy has no known risks and has been used in the clinical setting for approximately seventeen 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 34,35 which is well 
below any known threshold for injury.  In addition, it has been demonstrated that delivery of high flows of 
conditioned gas from a nasal cannula has a positive effect on airway mucosal function 36,37. The patients will 
be closely monitored as part of standard medical practice. Ambulation is implemented as part of the 
standard care practice for the patients included in this study.  
 
For these reasons, we have determined that this study represents non-significant risk to the subjects, beyond 
the discomfort related to routine ambulation therapy.  
 
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 ambulation pilot study will themselves benefit 
from participation in this study. The trial may result in knowledge that leads to improvements in the quality 
of care, patient experience and ultimately cost of care associated with the care for patients with respiratory 
distress and/or failure. Compensation will be provided to participants for enrollment into this study.  
 
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 clinical research, namely 21 CFR Parts 50, 54, 56 and 812 and others as applicable 
and GCP/ICH guidelines.  Monitoring will occur at regular frequency by the sponsor, such as to allow ongoing 
review of data collected, site qualifications and compliance with the protocol.  All investigators  and study 
staff will be appropriately trained to ensure compliance with the protocol. 
 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 18 of 20                
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:  
• 
Failure to compete the Baseline characterization  
• 
Failure to capture time and place 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 subject’s participation in the study, the investigator will determine whether any 
adverse events have occurred.  For the purposes of this protocol, an adverse event is any undesirable 
clinical/medical occurrence in a subject that is or is not attributed to the device or procedure required by 
this protocol.  If any adverse event occurs, either anticipated or unanticipated, the investigators will 
immediately contact the sponsor’s 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.  The privacy rules and 
requirements according to governing regulations will be adhered to.  Methods to protect the privacy of 
subjects and clinical information will be used.  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 clinical research site will maintain the linking log behind locked door. All 
Vapotherm representatives involved in this study will only have access to the patients’ unique identification 
number.  The linked data will be stored within the study binder at the clinical research site for two years 
from the end of the study.  
 
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. Annals of emergency medicine. 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. 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 19 of 20                
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. 
Dysart K, Miller TL, Wolfson MR, Shaffer TH. Research in high flow therapy: mechanisms of action. Respir Med. 
2009;103(10):1400-1405. 
6. 
Miller SM, Dowd SA. High-flow nasal cannula and extubation success in the premature infant: a comparison of 
two modalities. Journal of perinatology : official journal of the California Perinatal Association. 2010;30(12):805-
808. 
7. 
Ameer F, Carson KV, Usmani ZA, Smith BJ. Ambulatory oxygen for people with chronic obstructive pulmonary 
disease who are not hypoxaemic at rest. Cochrane Database Syst Rev. 2014(6):CD000238. 
8. 
Ries AL, Bauldoff GS, Carlin BW, et al. Pulmonary Rehabilitation: Joint ACCP/AACVPR Evidence-Based Clinical 
Practice Guidelines. Chest. 2007;131(5 Suppl):4S-42S. 
9. 
Zomorodi M, Topley D, McAnaw M. Developing a mobility protocol for early mobilization of patients in a 
surgical/trauma ICU. Crit Care Res Pract. 2012;2012:964547. 
10. 
Andrianopoulos V, Franssen FM, Peeters JP, et al. Exercise-induced oxygen desaturation in COPD patients 
without resting hypoxemia. Respir Physiol Neurobiol. 2014;190:40-46. 
11. 
Casanova C, Cote C, Marin JM, et al. Distance and oxygen desaturation during the 6-min walk test as predictors 
of long-term mortality in patients with COPD. Chest. 2008;134(4):746-752. 
12. 
Jolley SE, Moss M, Needham DM, et al. Point Prevalence Study of Mobilization Practices for Acute Respiratory 
Failure Patients in the United States. Crit Care Med. 2017;45(2):205-215. 
13. 
Vainshelboim B, Kramer MR, Izhakian S, Lima RM, Oliveira J. Physical Activity and Exertional Desaturation Are 
Associated with Mortality in Idiopathic Pulmonary Fibrosis. J Clin Med. 2016;5(8). 
14. 
Walker ML, Austin AG, Banke GM, et al. Reference group data for the functional gait assessment. Phys Ther. 
2007;87(11):1468-1477. 
15. 
Suntharalingam J, Hippolyte S, Knowles V, Freeman D, Patel I, Hardinge M. When should I be considering home 
oxygen for my patients? NPJ Prim Care Respir Med. 2016;26:15074. 
16. 
Jolly EC, Di Boscio V, Aguirre L, Luna CM, Berensztein S, Gene RJ. Effects of supplemental oxygen during activity 
in patients with advanced COPD without severe resting hypoxemia. Chest. 2001;120(2):437-443. 
17. 
Long-Term Oxygen Treatment Trial Research G, Albert RK, Au DH, et al. A Randomized Trial of Long-Term 
Oxygen for COPD with Moderate Desaturation. N Engl J Med. 2016;375(17):1617-1627. 
18. 
Sandland CJ, Morgan MD, Singh SJ. Detecting oxygen desaturation in patients with COPD: incremental versus 
endurance shuttle walking. Respir Med. 2008;102(8):1148-1152. 
19. 
Combes A, Costa MA, Trouillet JL, et al. Morbidity, mortality, and quality-of-life outcomes of patients requiring 
>or=14 days of mechanical ventilation. Crit Care Med. 2003;31(5):1373-1381. 
20. 
Nishiyama O, Miyajima H, Fukai Y, et al. Effect of ambulatory oxygen on exertional dyspnea in IPF patients 
without resting hypoxemia. Respir Med. 2013;107(8):1241-1246. 
21. 
Burns JR. Early Ambulation of Patients Requiring Ventilatory Assistance. Chest. 1975;68(4):608. 
22. 
Dyer F, Flude L, Bazari F, et al. Non-invasive ventilation (NIV) as an aid to rehabilitation in acute respiratory 
disease. BMC Pulm Med. 2011;11:58. 
23. 
Menadue C, Alison JA, Piper AJ, Flunt D, Ellis ER. Bilevel ventilation during exercise in acute on chronic 
respiratory failure: a preliminary study. Respir Med. 2010;104(2):219-227. 
24. 
Jolley SE, Dale CR, Hough CL. Hospital-level factors associated with report of physical activity in patients on 
mechanical ventilation across Washington State. Ann Am Thorac Soc. 2015;12(2):209-215. 
25. 
Hodgson CL, Stiller K, Needham DM, et al. Expert consensus and recommendations on safety criteria for active 
mobilization of mechanically ventilated critically ill adults. Crit Care. 2014;18(6):658. 
26. 
Spruit MA, Watkins ML, Edwards LD, et al. Determinants of poor 6-min walking distance in patients with COPD: 
the ECLIPSE cohort. Respir Med. 2010;104(6):849-857. 
27. 
Waugh JB, Granger WM. An evaluation of 2 new devices for nasal high-flow gas therapy. Respiratory care. 
2004;49(8):902-906. 

            
           Vapotherm, Inc 
HVNI Ambulation Feasibility Study 
Confidential 
                                         
 
Rev 1.0 – Updated January 30, 2019 
                   Confidential 
                              Page 20 of 20                
28. 
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. 
29. 
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. 
30. 
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. 
31. 
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. 
32. 
McCarthy B, Casey D, Devane D, Murphy K, Murphy E, Lacasse Y. Pulmonary rehabilitation for chronic 
obstructive pulmonary disease. Cochrane Database Syst Rev. 2015(2):CD003793. 
33. 
Laboratories ATSCoPSfCPF. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 
2002;166(1):111-117. 
34. 
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. 
35. 
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. 
36. 
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. 
37. 
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.