Clinical Study of the Vivatmo Pro™ for Fractional Exhaled Nitric Oxide (FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid (ICS) Treatment
Phase: NA
Conditions: Asthma, Asthma in Children
Sponsor: Bosch Healthcare Solutions GmbH

 
CONFIDENTIAL 
 
 
 
 
 
  
 
 
Clinical Study of the Vivatmo proTM for  
Fractional Exhaled Nitric Oxide (FeNO) Monitoring 
in U.S. Asthmatic Patients Responding to Inhaled 
Corticosteroid (ICS) Treatment 
  
 
 
 
 
 
 
Date: September 25, 2020 (Version 2.0) 
 
 
 
 
 
SPONSOR: 
 
Bosch Healthcare Solutions GmbH 
Stuttgarter Strasse 130 
71332 Waiblingen, GERMANY 
PH: +49 711 81158301 
 
 
 
 
 
 
CONFIDENTIALITY NOTICE: 
The information contained in this document is privileged and confidential.  Any distribution, copying, or disclosure 
is strictly prohibited unless such disclosure is required by federal regulations or state law.  Persons to whom the 
information is disclosed must know that it is confidential and that it may not be further disclosed by them. 

 
CONFIDENTIAL 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                    Page   
 
2
Responsibilities and Contact Information 
 
Study Sponsor 
 
Klaus Mueller 
Study Director 
Bosch Healthcare Solutions GmbH 
Stuttgarter Strasse 130 
71332 Waiblingen, GERMANY 
 
PH: +49 160 90816028 
FX: +49 711 811-5119433 
klaush.mueller@de.bosch.com 
www.bosch-healthcare.com/en/ 
 
 
Clinical Study Manager 
 
Neil R. Mucci  
Study Manager 
Global BioClinical (CRO) 
113 Cherry Street, Suite 80042 
Seattle, WA  98104  USA 
 
PH:  1-888-659-1221 
FX:  1-206-299-9895 
neil.mucci@globalbioclinical.com 
www.globalbioclinical.com  
 
Study BioStatistician 
 
Dr. Thomas Keller 
Biostatician 
ACOMED Statistik  
Fockestr. 57 
D 04275 Leipzig, GERMANY 
PH: +49 (0) 341 3910195 
FX: + 49 (0) 32223391141 
t.keller@acomed-statistik.de 
www.acomed-statistik.de 
 
 
 
 
 
 
 

 
CONFIDENTIAL 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
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3
PROTOCOL REVISION HISTORY 
 
Revision 
Effective Date 
Description of Revision 
Version 1.0 
11-May-2020 
Initial Release 
Version 2.0 
25-September-2020 Revisions to modify inclusion and exclusion criteria to enhance enrollment 
of subjects with uncontrolled asthma.  
 
PROTOCOL APPROVAL 
 
 
Name 
Department / 
Affiliation 
Signature 
Date 
Draft / Revision 
Neil Mucci 
GBC (CRO) 
 
 
Reviewer 
Klaus Mueller 
BHCS/PAT 
 
 
Approval 
Carola Doeffinger 
BHCS/QMM 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
CONFIDENTIAL 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                    Page   
 
4
PROTOCOL SIGNATURE PAGE 
 
 
Investigator’s Signature 
 
I have read and approve this protocol. My signature confirms my agreement that the study will 
be conducted in accordance with the protocol and all applicable laws and regulations, including, 
but not limited to, the ICH Guideline for GCP, the CFR, and the ethical principles that have their 
origins in the Declaration of Helsinki.  
 
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care under applicable regulations. 
 
 
 
 
______________________________ 
 
 
____________________ 
 
Name of Investigator  
 
 
 
 
Date 
 
 
 
 

 
CONFIDENTIAL 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
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5
LIST OF ABBREVIATIONS 
 
ACQ 
Asthma Control Questionnaire 
AE 
Adverse Event 
ATS 
American Thoracic Society 
CDC 
Centers for Disease Control 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CLSI 
Clinical Laboratory Standards Institute 
CRF 
Case Report Form  
CRO 
Contract Research Organization 
CV 
Curriculum Vitae 
CV 
Coefficient of Variation (relative standard deviation in %) 
ERS 
European Respiratory Society 
FAS 
Full Analysis Set 
FeNO 
Fractional Exhaled Nitric Oxide 
FDA 
Food and Drug Administration (U.S.) 
GCP 
Good Clinical Practices  
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonization 
ICS 
Inhaled Corticosteroids 
IFU 
Instructions for Use 
IRB/IEC 
Institutional Review Board/Institutional Ethics Committee 
ISF 
Investigational Site File 
µL 
Microliter 
mL 
Milliliter 
NAEPP 
National Asthma Education and Prevention Program 
NHLBI 
National Heart, Lung, and Blood Institute 
NICE 
National Institute for Health and Case Excellence (UK) 
NO 
Nitric Oxide 
OTC 
Over-the-Counter 
PI 
Principal Investigator 
POC 
Point of Care 
PPA 
Positive Percent Agreement 
SAE 
Serious Adverse Event 
SDV 
Source Data Verification 
SIV 
Site Initiation Visit 
TLC 
Total Lung Capacity 
TMF 
Trial Master File 
U.S. 
United States 
USB 
Universal Serial Bus 
 
 
 
 

 
CONFIDENTIAL 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
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6
STUDY SYNOPSIS 
Name of 
Sponsor 
Bosch Healthcare Solutions GmbH 
Name of Device 
Vivatmo proTM  (Bosch Healthcare Solutions GmbH) 
Study Title 
Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring of U.S. Asthmatic Patients Responding to Inhaled 
Corticosteroid (ICS) Treatment 
Study Short 
Title 
Vivatmo proTM US Study 
Study Type 
Multi-center, open label, non-randomized, prospective, single cohort study 
Number of 
Study Sites 
6 clinical sites in the United States 
Target 
Population 
 
120 male and female asthma subjects from 7 to 80 years of age with 
uncontrolled asthma.  Including: 
• ~40 subjects (~30%) from 7 to 17 years of age  
• ~80 subjects (~70%) from 18 to 80 years of age 
 
Study 
Objectives 
 
Primary Objective: 
To measure the impact of inhaled corticosteroid (ICS) treatment on fractional 
exhaled nitric oxide (FeNO) measured with the Vivatmo proTM in adult and 
pediatric subjects with uncontrolled asthma as measured at visits before and 
after treatment. 
 
Secondary Objectives: 
• To compare changes according to the primary objective with those of 
spirometry (lung function), and asthma symptoms before and after 
treatment. 
• To evaluate the precision of repeat measurements made for each subject at 
a single visit. 
• To evaluate the success rate of the subject using the device. 
 
Study General 
Design and 
Duration 
 
This is a multi-center, competitive enrollment, dual-visit, point-of-care study 
to evaluate fractional exhaled nitric oxide (FeNO) measured with the Vivatmo 
proTM, spirometry, and asthma symptoms using an Asthma Control 
Questionnaire (ACQ) in adult and pediatric subjects.  Subjects will be 
screened, enrolled and tested at Study Visit #1 and then prescribed inhaled 
corticosteroid (ICS) treatment as per routine clinical care.  Subjects will return 
for Study Visit #2 in two weeks and repeat fractional exhaled nitric oxide 

 
CONFIDENTIAL 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                    Page   
 
7
(FeNO) measured with the Vivatmo proTM, spirometry, and complete an 
Asthma Control Questionnaire (ACQ).   Results of the fist valid FeNO 
measurement made at each study visit (Visit #1 - pre-treatment and Visit #2 - 
post-treatment) will be analyzed in conjunction with recorded asthma 
symptoms and spirometry results. At least two FeNO measurements will be 
made at each visit allowing assessment of repeatability of the method under 
daily use conditions.  Subject screening, recruitment, initial measurement, 
treatment, and follow up measurement are expected to take 3 months. 
 
Study 
Endpoints 
 
Primary Endpoint: 
The primary analysis variable will be the percent change of the fractional 
exhaled nitric oxide (FeNO) measurement made at Visit #1 compared to Visit 
#2 using the Vivatmo proTM.  The first valid FeNO measurement made at each 
visit will be used for this comparison analysis. 
 
Secondary Outcome Measures:  
• The change in standard outcome measures (asthma symptoms and 
spirometry) between Visit #1 to Visit #2 
• Repeatability as assessed by replicate FeNO measurements (N=2) at one 
or more visits. The first two valid FeNO measurements made for each 
subject at each visit will be used for this repeatability analysis.   
• Success rate (proportion of patients with successful measurement) 
 
Subject 
Inclusion / 
Exclusion 
Criteria 
 
See criteria starting on page 23. 

 
CONFIDENTIAL 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                    Page   
 
8
 
Study 
Procedures 
 
• Patients meeting study inclusion/exclusion criteria will be consented and 
will be enrolled in the study. 
• Subjects will be observed during each of two study visits according to 
routine clinical diagnosis and treatment standards for uncontrolled asthma 
patients and will have asthma symptoms recorded using a standardized 
Asthma Control Questionnaire (ACQ). 
• Subjects will have fractional exhaled nitric oxide (FeNO) and spirometry 
measured and documented at each visit.  
• All study subjects will be asked to perform two valid fractional exhaled 
nitric oxide (FeNO) measurements at each study visit using the Vivatmo 
proTM with a limit of 10 total exhalation attempts per subject per visit.  If 
only one valid measurement is taken, it will be used for comparative 
analysis.  No repeatability data will be available for this subject. 
• One operator will guide each subject through the fractional exhaled nitric 
oxide (FeNO) measurements at each visit. 
• At the first visit, after all study assessments (FeNO, Spirometry, ACQ), 
subjects will receive therapy by prescription of inhaled corticosteroid 
(ICS) medication according to routine treatment standards. 
• Subjects will return after 2 weeks (14 days) of treatment for a repeat of 
measurements. 
 
Statistical 
Analysis  
Analysis Population: 
 
The Full Analysis Set (FAS) will be defined as all patients intended to receive 
a FeNO measurement. 
 
The Per Protocol Set will be defined as enrolled subjects without major 
protocol violations, with inhaled corticosteroid (ICS) treatment, and 
successfully completing at least one valid FeNO measurement at both Visit #1 
and Visit #2 will be evaluated for the primary endpoint.   
  
Definition of Measured Value: 
 
For primary endpoint analysis the value of FeNO measurement will be derived 
as the result of the first valid measurement.  
For repeatability, the first and second valid FeNO measurements at each visit 
will be used.  Repeatability will be the pooled result of  pairwise analyses for 
repeatability to demonstrate precision (see below).  
 
Descriptive Statistics: 
Baseline characteristics, such as demographics, as well as analytical clinical 
data by visit will be summarized using descriptive statistical methods. 
Continuous data will be summarized using the mean, the median, standard 

 
CONFIDENTIAL 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                    Page   
 
9
deviation, and range (minimum and maximum value). Categorical values will 
be summarized using frequency counts and percentages. 
 
Analysis of Primary Endpoint: 
The change of FeNO values will be estimated in ANOVA with baseline values 
as the covariable and will be reported as percent change together with the 
95%-confidence interval. In a sensitivity analysis, the first valid single 
measurement is used for the analysis. 
 
Analysis of Secondary Endpoints: 
The relationship between changes in FeNO-values and clinical assessments 
(spirometry, ACQ-questionnaire) will be assessed by Spearman’s rank 
correlation. 
 
Repeatability: 
Repeatability will be estimated together with the 95%-confidence interval as 
pooled standard deviation (mean < 50 ppb) and CV (mean ≥ 50 ppb), 
respectively, using the residual variance component resulting from  a random 
effects ANOVA (as used in CLSI EP05 guideline) with patient and visit as 
random factors. 
 
The resulting pooled repeatabilities are hereby estimated taking into account 
conditions of variability over sites and operators. 
 
Success rates: 
The success rates (proportion of patients with successful measurement within 
FAS) will be reported. The number of attempts necessary to obtain 2 valid 
replicate measurements will be tabulated in contingency tables by visit.  
 
Sample Size: 
Since the effect size of the change (mean change / standard deviation) is on 
the order of 1 (resulting in N=10 and 13 for power = 80% and 90%, 
respectively) and therefore large, the sample size is not determined by the 
primary objective but by the necessity to achieve representative data of FeNO 
measurement data over all age groups, measurement ranges (<, ≥ cut off) and 
sites. Thus, 120 subjects will be recruited. 
 
 
 

 
CONFIDENTIAL 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
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10
TABLE OF CONTENTS 
PROTOCOL REVISION HISTORY ................................................................................................................................. 3 
PROTOCOL APPROVAL................................................................................................................................................... 3 
PROTOCOL SIGNATURE PAGE .................................................................................................................................... 4 
LIST OF ABBREVIATIONS ............................................................................................................................................. 5 
STUDY SYNOPSIS.............................................................................................................................................................. 6 
TABLE OF CONTENTS ..................................................................................................................................................10 
1. 
BACKGROUND AND INVESTIGATIONAL DEVICE ..................................................................................13 
1.1. 
Background .......................................................................................................................................................13 
1.2. 
Description of the Device ................................................................................................................................13 
1.3. 
Intended Use......................................................................................................................................................15 
1.4. 
Special Conditions for Use Statement...........................................................................................................16 
1.5. 
Investigator Requirements .............................................................................................................................16 
2. 
STUDY OBJECTIVES .........................................................................................................................................16 
2.1. 
Primary Objective............................................................................................................................................16 
2.2. 
Secondary Objectives ......................................................................................................................................17 
3. 
STUDY DESIGN...................................................................................................................................................17 
3.1. 
General Design..................................................................................................................................................17 
3.2. 
Study Endpoints ...............................................................................................................................................17 
3.3. 
Number of Subjects..........................................................................................................................................18 
3.4. 
Number of Study Sites .....................................................................................................................................18 
3.5. 
Duration of Study Subject Participation ......................................................................................................18 
3.6. 
Overall Study Duration ...................................................................................................................................19 
4. 
STUDY POPULATION ........................................................................................................................................19 
4.1. 
Asthma Patients who are Candidates for Inhaled Corticosteroid (ICS) Treatment.............................19 
4.2. 
Subject Inclusion Criteria...............................................................................................................................20 
4.3. 
Subject Exclusion Criteria..............................................................................................................................20 
5. 
STUDY INSTRUMENTS AND SUPPLIES ......................................................................................................21 
5.1. 
Investigational Product Receipt, Accountability, and Storage .................................................................21 
5.2. 
Vivatmo proTM Instrument Components, Consumables, and Supplies Provided by Sponsor.............22 
5.3. 
Materials and Space Supplied by Clinical Site............................................................................................22 
5.4. 
Vivatmo proTM General Overview .................................................................................................................22 
5.5. 
Vivatmo proTM Base Station ...........................................................................................................................23 
5.6. 
Vivatmo proTM Handheld ................................................................................................................................23 
5.7. 
Vivatmo proTM Mouthpiece ............................................................................................................................23 
5.8. 
Guidance for Vivatmo proTM Calibration and Routine Quality Control (QC) Testing........................24 

 
CONFIDENTIAL 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                    Page   
 
11
5.9. 
Vivatmo proTM Instrument Support..............................................................................................................24 
6. 
STUDY PROCEDURES.......................................................................................................................................25 
6.1. 
Clinical Site Study Staff Training..................................................................................................................25 
6.2. 
Study Visit #1 Overview..................................................................................................................................25 
6.3. 
Study Visit #2 Overview..................................................................................................................................25 
6.4. 
Patient Screening and Consent ......................................................................................................................25 
6.5. 
Guidance for Preparing and Training Study Subjects on Use of the Vivatmo proTM...........................26 
6.6. 
Guidance for Vivatmo proTM Testing Procedure ........................................................................................26 
6.7. 
Guidance for Vivatmo proTM Test Result Acceptance Criteria and Invalid Results.............................27 
6.8. 
Guidance for Spirometry Testing ..................................................................................................................27 
6.9. 
Guidance for ACQ Data Collection...............................................................................................................27 
7. 
DATA COLLECTION, HANDLING AND RECORD KEEPING ..................................................................27 
7.1. 
Study Management Documentation and Logs ............................................................................................27 
7.2. 
Study Case Report Forms (CRFs).................................................................................................................28 
7.3. 
Vivatmo proTM Instrument Data....................................................................................................................28 
7.4. 
Asthma Control Questionnaire (ACQ) and Spirometry Data ..................................................................29 
7.5. 
Record Retention..............................................................................................................................................29 
7.6. 
Record Access ...................................................................................................................................................29 
7.7. 
Study Training Manual ...................................................................................................................................29 
7.8. 
The Investigational Site File (ISF).................................................................................................................30 
7.9. 
Data Binder .......................................................................................................................................................30 
8. 
DATA ANALYSIS AND STUDY ENDPOINTS................................................................................................30 
8.1. 
Analysis Populations ........................................................................................................................................30 
8.2. 
Descriptive Statistics ........................................................................................................................................31 
8.3. 
Analysis of Primary Endpoint........................................................................................................................31 
8.4. 
Analysis of Secondary Endpoints ..................................................................................................................31 
9. 
COMPLIANCE WITH GOOD CLINICAL PRACTICES (GCP), ETHICAL CONSIDERATIONS, AND 
ADMINISTRATIVE ISSUES ..........................................................................................................................................31 
9.1. 
Adherence to Protocol, Good Clinical Practices (GPC), and Applicable Regulations .........................31 
9.2. 
Institutional Review Board .............................................................................................................................32 
9.3. 
Subject Protections ..........................................................................................................................................32 
9.4. 
Confidentiality ..................................................................................................................................................32 
9.5. 
Monitoring.........................................................................................................................................................33 
9.6. 
Study Deviations...............................................................................................................................................33 
9.7. 
Serious Adverse Event (SAE) Reporting......................................................................................................33 
9.8. 
Risks ...................................................................................................................................................................33 
9.9. 
Potential Benefits..............................................................................................................................................33 

 
CONFIDENTIAL 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
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12
9.10. 
Compensation ...............................................................................................................................................33 
9.11. 
Quality Assurance Audit ............................................................................................................................34 
9.12. 
Publication Policy ........................................................................................................................................34 
9.13. 
ClinicalTrials.Gov........................................................................................................................................34 
REFERENCES ..................................................................................................................................................................34 
APPENDIX - ASTHMA GUIDANCE AND REFERENCE DOCUMENTS .............................................................35 
 
 
 

 
CONFIDENTIAL 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
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13
1. BACKGROUND AND INVESTIGATIONAL DEVICE 
 
1.1. 
Background 
 
According to the Centers for Disease Control (CDC) asthma has increased 28% in the last 
decade in the Unites States with the number of asthmatic individuals totaling 25 million adults 
(7.9% of the adult US population) and 6.1 million children (8.4% of US children). The National 
Institutes of Health (NIH) guidelines for the diagnosis and management of asthma strongly 
recommend long term anti-inflammatory therapy, such as oral or inhaled corticosteroids to 
reverse airway inflammation in an effort to prevent irreversible airway damage.   The difficulty 
in diagnosing and managing asthma however lies primarily in the lack of available clinical 
technologies capable of assessing airway inflammation, an early and persistent component of 
asthma.  
 
The medical community has expressed the need for objective and noninvasive measures of 
airway inflammation for diagnosing asthma and monitoring the effectiveness of and compliance 
with anti-inflammatory therapies.  Because airway inflammation is a key pathophysiologic 
abnormality in asthma, there has been an emphasis on incorporating inflammatory biomarkers 
into the diagnosis and management of asthma.  
 
Fractional exhaled nitric oxide (FeNO) as a noninvasive surrogate biomarker for airway 
inflammation can play a significant role in supporting asthma treatment and management 
decisions.  Numerous studies have shown that fractional exhaled nitric oxide (FeNO) is well 
correlated with other markers of airway inflammation such as bronchial hyperresponsiveness, 
sputum eosinophils, bronchoalveolar lavage fluid eosinophilia, bronchial biopsy eosinophil 
score, and blood eosinophilia.  Fractional exhaled nitric oxide (FeNO) levels have been shown to 
rise prior to asthma exacerbation and decrease with the use of anti-inflammatory medications in a 
dose dependent manner. Monitoring of fractional exhaled nitric oxide (FeNO) can help clinicians 
and patients with: 
 
• Better self management (1) 
• Better safety (1) 
• Control of adherence (1) 
• Improved asthma control (2) 
• Optimized steroid dosage (3) 
• Reduction of exacerbations (4) 
• Reduction of hospitalization (5) (6) 
• Reduction of costs (5)
 
A new portable device using electrochemical sensors to measure fractional exhaled nitric oxide 
FeNO (Bosch Healthcare Solutions GmbH, Vivatmo proTM) has recently been developed.  The 
aim of this study is to evaluate the performance of this new hand-held device. 
 
1.2. 
Description of the Device 
 
The nitric oxide test system called the Vivatmo pro™ (Bosch Healthcare Solutions GmbH, 
Waiblingen Germany) is a point-of-care (POC) breath gas analyzer that uses solid-state 
electrochemical technology to measure fractional exhaled nitric oxide (FeNO), a biomarker for 
airway inflammation, in human exhaled breath.  Measurement of FeNO is a quantitative and 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
                      Page   
 
15 
non-invasive method to evaluate an asthma patient’s response to anti-inflammatory therapy, as 
well as an adjunct to establishing a clinical assessment of asthma.   The Vivatmo pro™ measures 
expired nitric oxide (NO) in the range of 5 ppb to 300 ppb from a 10 second exhalation. The 
Vivatmo pro™ is suitable for children 7 to 17 years of age and adults 18 to 80 years of age. 
 
Vivatmo pro™ is comprised of two components:  a handheld wireless measurement unit with 
disposable mouthpiece (held and used by the patient) and a base station with touch screen 
interface and AC adapter.  The handheld mouthpiece is a single-patient use, disposable component 
used up to 5 times in a single testing session before being disposed of and replaced.  The device 
keeps track of the number of uses for each mouthpiece. The mouthpiece has an ergonomically 
designed interface for the patient to aid in creating a proper seal during the exhalation maneuver. 
Vivatmo pro™ uses solid state, sensor technology sensitive to NO compounds in parts per 
billion (ppb) in the handheld component with a pneumotachograph display in the base station.  
The solid state sensor in the handheld component is preceded by filters in the disposable 
mouthpiece that: (a) eliminate germs and protect against cross-contamination; (b) eliminate 
potential interfering molecules such as carbon monoxide (CO), ammonia (NH4), and methanol 
(CH4O) by making them inactive; (c) convert breath NO to the NO2 equivalent for measurement; 
and finally (d) dehumidify the breath sample.  Vivatmo pro™ provides visual and audible 
feedback during the FeNO measurement process such that the user can modulate their breath 
speed within the optimal flow parameters as recommended by American Thoracic Society (ATS) 
and European Respiratory Society (ERS) standards.  
 
To use the system the patient empties their lungs, inhales deeply to total lung capacity, and then 
slowly and evenly exhales through the Vivatmo pro™ mouthpiece of the handheld component 
for 10 seconds.  Vivatmo pro™ tests the last three second fraction of a 10 second exhalation in 
order to report the average NO concentration in parts per billion (ppb).  Results are processed 
and stored on the system using dedicated software. In order to verify the device’s performance 
there are control procedures performed on a routine basis.  Vivatmo pro™ also has an optional 
PC application for access and management of electronic testing records. 
 
1.3. 
Intended Use 
 
Vivatmo pro™ Nitric Oxide Test is a portable, non-invasive device to measure fractional 
exhaled nitric oxide (FeNO) in human breath. FeNO is increased in some airway inflammatory 
processes, such as asthma, and often decreases in response to anti-inflammatory treatment. 
Measurement of FeNO by Vivatmo pro™ is a method to measure the decrease in FeNO 
concentration in asthma patients that often occurs after treatment with anti-inflammatory 
pharmacological therapy as an indication of therapeutic effect in patients with elevated FeNO 
levels. FeNO measurements are to be used as an adjunct to established clinical assessments. 
Vivatmo pro™ is suitable for children, approximately 7-17 years, and adults 18 years and older.  
Testing using the Vivatmo pro™ should only be done in a point-of-care healthcare setting under 
professional supervision. Vivatmo pro™ should not be used in critical care, emergency care or in 
anesthesiology.  
  

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
                      Page   
 
16 
1.4. 
Special Conditions for Use Statement 
 
• Vivatmo proTM should only be used as directed in the Vivatmo proTM Instructions for Use 
(IFU).  
• Vivatmo proTM should not be used in critical care, emergency care, or in anesthesiology. 
• Vivatmo proTM results should not be used as a sole parameter for the diagnosis or screening 
of airway diseases. 
• Vivatmo proTM measurement procedure requires patient cooperation and patients must be 
capable of a complete breathing maneuver (exhalation) and cooperating with all necessary 
requirements for test performance. 
• Vivatmo proTM should not be used with infants or by children under 7 years of age.  
• Patients should refrain from eating and drinking for 1 hour before exhaled NO measurement. 
• Recent intake of nitrate rich foods, such as lettuce, spinach, beets, walnuts, peanuts, and 
animal organs, can lead to increased FeNO levels.  
• Alcohol ingestion reduces FeNO levels in patients with asthma and healthy subjects. 
• Patients should not smoke for 1 hour before measurement, and any short-term and long-term 
active and passive smoking history should be recorded.  Smoking reduces FeNO levels. 
• Vivatmo proTM results obtained from patients who smoke should only be considered after 
accounting for the subject's smoking history and the potential impact on FeNO levels.  
• When possible, perform serial FeNO measurements at the same time of the day. 
• Regardless of displayed results clinicians must follow standard clinical care practices for 
symptoms of chest tightness, shortness of breath, and coughing or wheezing for decisions 
relative to treatment, 
• For prescription use only. 
 
1.5. 
Investigator Requirements  
 
The study Principal Investigator (PI) and study staff must read this entire protocol and the 
Vivatmo proTM Instructions for Use before beginning the clinical study.  Site training on the 
study protocol, study subject management, instrument usage, and study data collection will be 
provided by the Sponsor and/or designated Contract Research Organization (CRO) at study 
outset. 
 
2. STUDY OBJECTIVES 
 
The objective of the study is to evaluate fractional exhaled nitric oxide (FeNO) measured with 
Vivatmo proTM, spirometry (lung function), and asthma symptoms in adult and pediatric subjects 
with uncontrolled asthma before and after inhaled corticosteroid (ICS) treatment. 
 
2.1. 
Primary Objective 
 
To measure the impact of inhaled corticosteroid (ICS) treatment on fractional exhaled nitric 
oxide (FeNO) measured with the Vivatmo proTM in adult and pediatric subjects with 
uncontrolled asthma as measured at visits before and after treatment. 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
                      Page   
 
17 
 
2.2. 
Secondary Objectives 
 
• To compare changes according to the primary objective with those of spirometry (lung 
function), and asthma symptoms before and after treatment. 
• To evaluate the precision within a series of repeat measurements made for each subject at a 
single visit. 
• To evaluate the success rate of the subject using the device. 
 
3. STUDY DESIGN 
 
3.1. 
General Design  
 
This is a multi-center, competitive enrollment, dual-visit, non-invasive, point-of-care study 
designed for “treatment monitoring and efficacy” to evaluate fractional exhaled nitric oxide 
(FeNO) measured with Vivatmo proTM, spirometry, and asthma symptoms as assessed by a 
standardized Asthma Control Questionnaire (ACQ) in adult and pediatric subjects with 
uncontrolled asthma.   
 
Subjects will be screened, enrolled and tested at Study Visit #1, undergo fractional exhaled nitric 
oxide (FeNO) measurement with Vivatmo proTM, spirometry, and assessment of asthma 
symptoms using an Asthma Control Questionnaire (ACQ), and will then be prescribed an inhaled 
corticosteroid (ICS) treatment as per the standard of clinical care.  Study subjects will return for 
Study Visit #2 two weeks (14 days) after their initial visit for repeat fractional exhaled nitric 
oxide (FeNO) measurement with Vivatmo proTM, spirometry, and assessment of asthma 
symptoms using an Asthma Control Questionnaire (ACQ).   
 
 
3.2. 
Study Endpoints 
 
Primary Endpoint 
 
The primary analysis variable will be the percent change of the fractional exhaled nitric oxide 
(FeNO) measurement made at Visit #1 compared to Visit #2 using the Vivatmo proTM.  The first 
valid FeNO measurement made at each visit will be used for this comparison analysis. 
 
Secondary Outcome Measures:  
 
• The change in standard outcome measures (asthma symptoms and spirometry) between Visit 
#1 to Visit #2 
• Repeatability as assessed by replicate FeNO measurements (N=2) at one or more visits. The 
first two valid FeNO measurements made for each subject at each visit will be used for this 
repeatability analysis.   
• Success rate (proportion of patients with successful measurement) 
 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
                      Page   
 
18 
3.3. 
Number of Subjects 
 
The study is designed to enroll patients that have clinically diagnosed signs and symptoms of 
uncontrolled asthma and who are candidates for inhaled corticosteroid (ICS) treatment.  The 
study will enroll 120 male and female asthma subjects from 7 to 80 years of age.  This will 
include a target of 40 pediatric subjects (approximately 30% of enrollment) from 7 to 17 years of 
age and a target of 80 adult subjects (approximately 70% of enrollment) from 18 to 80 years of 
age.  This is estimated to be a sample size sufficient to demonstrate device performance in the 
intended use population of pediatric and adult patients.. The Sponsor may extend the overall 
enrollment goal and/or suspend enrollment of adult subjects in order to reach a minimum 
required number of enrolled pediatric subjects. 
 
It is the goal of the study to include moderate to severe asthma patients to the maximum extent 
possible and as per the professional discretion of participating physician investigators.  
Enrollment should optimally include newly diagnosed asthma patients, but may also include 
those patients with a previous history or diagnosis of uncontrolled asthma who have not been 
using corticosteroids for at least 4 weeks prior to study Visit #1.  Patients currently using a short-
acting inhaled bronchodilator medication (also known as a “rescue inhaler”) or leukotriene 
modifiers may be enrolled, but should not participate if they have used these medications within 
one hour of either study Visit #1 or study Visit #2 Vivatmo proTM readings.  Patients using 
inhaled corticosteroids, oral corticosteroids, or who are taking biologic immunotherapy 
medications should not be enrolled. 
 
Measured FeNO levels from the subject population are expected to encompass the full Vivatmo 
proTM measurement range from 5 ppb to 300 ppb.  If a maximum range measurement goal of 270 
ppb is not met by enrollment of 120 subjects then additional subjects may be enrolled until the 
maximum range measurement goal is met. 
 
3.4. 
Number of Study Sites 
 
The study will be conducted at 6 clinical sites in the United States.  This will include specialized 
asthma clinics and practices optimally able to enroll both pediatric and adult subjects.  
 
3.5. 
Duration of Study Subject Participation 
 
Study subject participation will take approximately 50 minutes for visit #1 and 30 minutes for 
visit #2. At the first study visit subjects will be screened, consented, enrolled, assigned a Study 
Subject ID number (~10 minutes).  Subjects will then be instructed on use of the Vivatmo proTM 
(~10 minutes) and then undergo Vivatmo proTM measurement (~10 mins), spirometry (~10 
mins), and ACQ assessment and Case Report Form (CRF) questions (~10 mins). Vivatmo proTM 
measurement, spirometry, ACQ assessment, and CRF questions will be repeated at the second 
study visit. At each study visit subjects will be asked to attempt up to 10 exhalation breaths to 
achieve 2 valid Vivatmo proTM measurements (excluding exhalations for spirometry).  Study 
timing does not include patient counseling for ICS prescription and recommended usage. 
 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
                      Page   
 
19 
3.6. 
Overall Study Duration 
 
Subject screening, recruitment, initial measurements, treatment, follow up measurements, and 
data collection are expected to take 3 months. 
 
4. STUDY POPULATION 
 
4.1. 
Asthma Patients who are Candidates for Study Enrollment and Inhaled 
Corticosteroid (ICS) Treatment 
 
Potential study subjects may be recruited from those already scheduled for clinic visits.  Subjects 
qualified for study participation should (1) have a confirmatory diagnosis of uncontrolled asthma 
made by a physician and (2) have not used inhaled corticosteroids or oral corticosteroids within 4 
weeks prior to enrollment.  Use of a short-acting inhaled bronchodilator, leukotriene modifier, or 
any rescue inhaler will be permitted before the study, but not within one hour of either Vivatmo 
proTM study reading. Subjects may be prescribed or use a rescue inhaler if necessary during the 
study and between study  Visit #1 and study Visit #2. 
 
Eligible study subjects should be diagnosed with uncontrolled asthma and some degree of 
presumed lung inflammation. According to guidelines a diagnosis of uncontrolled asthma is 
established by determining that: 
• Symptoms of recurrent airway obstruction are present, based on patient history and 
examination. 
• Patient has symptoms of cough, recurrent wheezing, recurrent difficulty breathing, or 
recurrent chest tightness are present. 
• Symptoms occur or worsen at night or with exercise, viral infection, exposure to 
allergens and irritants, changes in weather, hard laughing or crying, stress, or other 
factors. 
Long term asthma management is assessed and monitored by: 
 
• Assessing at each visit asthma control, proper medication usage, written asthma action 
plan, patient adherence, and patient concerns.  
• Obtaining lung function measurements by spirometry at least every 1–2 years; more 
frequently for asthma that is not well controlled. 
• Determining if therapy should be adjusted, maintained, stepped-up if needed, stepped-
down, if possible. 
 
To these general diagnostic procedures Vivatmo proTM FeNO measurement will be added after 
taking full account of the uncontrolled asthma diagnosis and guidelines described above.  
Vivatmo proTM FeNO results will not be used for diagnostic decisions or to confirm the presence 
of asthma. 
 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
                      Page   
 
20 
Since asthma has varying severity that may impact Vivatmo proTM results, sites should enroll 
subjects meeting study criteria in a sequential manner that does not introduce bias into the study 
design or results.  Sites should avoid enrollment of subjects diagnosed with asthma who will not 
be prescribed inhaled corticosteroid (ICS) treatment, who are not able to fill their ICS 
prescription, or who may not comply with recommended ICS usage. 
 
 
4.2. 
Subject Inclusion Criteria  
 
Patients meeting the following criteria may be included: 
 
1. Subject is 7 to 80 years of age.* 
 
2. Subject is  newly diagnosed or has a confirmed past diagnosis of uncontrolled asthma 
determined by a physician and as defined below: 
(a) Symptoms of cough, recurrent wheezing, recurrent difficulty breathing, or recurrent 
chest tightness are present. 
(b) Symptoms occur or worsen at night or with exercise, exposure to allergens and 
irritants, changes in weather, hard laughing or crying, stress, or other factors. 
 
3. Has been identified as a candidate for inhaled corticosteroid (ICS) treatment and is willing 
and able to comply with the recommended ICS treatment plan. 
 
4. Is willing and able to perform Vivatmo proTM testing at initial and follow-up study visits. 
 
5. Subject or legal guardian is willing and able to provide informed consent. 
 
 
4.3. 
Subject Exclusion Criteria 
 
Patients meeting the following criteria should be excluded: 
 
1. Subject has used inhaled corticosteroids or oral corticosteroids within 4 weeks prior to 
enrollment; or subject has taken biologic immunotherapy medications.**  
 
2. Subject has other current serious medical conditions (other than asthma) that may impair 
study participation and measurements unless deemed acceptable by the study site investigator 
including, but not limited to: 
(a) respiratory diseases,   
(b) cardiovascular diseases,  
(c) neuromuscular diseases, or 
(d) chest wall or spinal column deformities. 
 
3. Subject is suffering from acute upper or lower respiratory infection including: 
(a) common cold, 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
                      Page   
 
21 
(b) influenza, or 
(c) pneumonia. 
 
4. Subject is pregnant. 
 
5. Subject is currently participating in another interventional pharmaceutical study or 
undergoing another asthma therapy. 
 
6. Subject has engaged in any of the following within one hour prior to fractional exhaled nitric 
oxide (FeNO) measurement: 
(a) food and beverage (other than water) intake,  
(b) caffeine (coffee, tea, etc.) intake, 
(c) nicotine (including cigarettes, cigars, pipe, nicotine chewing gum, nicotine patch, 
snuff, vapor e-cigarettes, etc.) intake,  
(d) strenuous exercise, or 
(e) use of a short-acting inhaled bronchodilator, leukotriene modifier, or any rescue 
inhaler. 
 
7. Subject has a history of prior or excessive alcohol use*** or drug abuse within last 12 
months. 
 
8. Subject has a familial or close relationship with study personnel (device instructors of 
administrators). 
 
9. Subject is unwilling or unable to perform Vivatmo proTM and spirometry testing (pulmonary 
function test) at initial and follow-up study visits and to comply with treatment plan. 
 
10. Subject or legal guardian is unwilling or unable to provide informed consent. 
 
Inclusion/Exclusion Notes:  
(*)  
Including 30% pediatric cases (age 7 to 17) and 70% adult cases (age 18 to 80) 
 
(**)  
Subjects undergoing a corticosteroid “wash-out” are not allowed. 
  
Subjects on leukotriene modifiers (such as Singulair) prior to or during the study are 
allowed. 
Antihistamine usage prior to and during the study is allowed. 
 
(***)  Excessive alcohol use defined as more than 2 alcoholic drinks per day (14 per week) 
for adult males and more than 1 alcoholic drink per day (7 per week) for adult 
females. 
 
5. STUDY INSTRUMENTS AND SUPPLIES 
 
5.1. 
Investigational Product Receipt, Accountability, and Storage 
 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
                      Page   
 
22 
The investigational product in this study is the Vivatmo proTM instrument. To ensure that the 
investigational product will not be used for any purpose other than what is stated in this protocol, 
the Principal Investigator (PI), or responsible party designated by the PI, will maintain an 
inventory record of all investigational products and consumables received, used, returned, or 
discarded.  At the start of the study, material accountability (inventory) forms will be provided 
by Sponsor with detailed instructions.  Material delivery dates, quantities used, and 
lot/batch/serial numbers will be tracked throughout the study.   
 
5.2. 
Vivatmo proTM Instrument Components, Consumables, and Supplies Provided by 
Sponsor 
 
The following Vivatmo proTM instrument components and consumables will be provided by the 
Sponsor to each participating clinical site: 
 
• Vivatmo proTM base station with AC power adapter 
• Vivatmo proTM handheld unit 
• Vivatmo proTM Oxycap Mouthpiece (“blue” on outside) for standard study 
measurements  
• Vivatmo proTM Level 0 Mouthpiece (“opaque/white” outside and “blue” inside) for 
instrument quality control measurements. 
• Vivatmo proTM owner´s manual 
• Vivatmo proTM software (for attached PC computer) 
• USB printer (black and white) 
 
5.3. 
Materials and Space Supplied by Clinical Site 
 
Each participating clinical site will agree to provide the following: 
 
• Designated space for Vivatmo proTM set-up and conducting study subject testing 
• Designated space for storage of Vivatmo proTM consumables 
• Spirometry test equipment (ATS/ERS compliant) 
• PC computer (connected to internet and the Vivatmo proTM for delivery of electronic 
measurement results and study data) 
• Inhaled corticosteroid (ICS) prescription (covered under standard of clinical care and not 
reimbursed as part of the study) 
• Secure storage for study records and study related documents 
 
5.4. 
Vivatmo proTM General Overview 
 
Vivatmo proTM device will be delivered to each participating clinic, set up, and calibrated by the 
Sponsor, or designated CRO, prior to or at the time of the study site initiation visit (SIV).  
Vivatmo proTM instrument should be used at temperatures of 59°F to 81°F (15°C to 27°C) and 15% 
to 60% relative air humidity.  Vivatmo proTM device should be stored in conditions not to fall below 
or exceed 41°F to 104°F (5°C to 40°C) and 10% to 85% relative air humidity.  Surfaces of the 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
                      Page   
 
23 
Vivatmo proTM base station and handheld unit should be wiped down regularly with 30% ethanol 
or disinfecting wipes containing up to 30 % alcohol.  Protect all openings from ingress of moisture 
or liquid. Do not spray anything directly onto the device. 
 
5.5. 
Vivatmo proTM Base Station 
 
The device base station will be set up for secure access by two or more administrators designated at 
each study site.  The device hardware, firmware, and software version will be recorded at the time 
of set-up.  The device will be connected to a USB printer and will also be connected to a PC 
computer with internet access (via USB cable, ethernet cable, or wifi) running the dedicated 
Vivatmo proTM software application and which will be used for delivery of electronic study 
records.  The USB printer may alternately be connected to the PC computer.  The Vivatmo proTM 
software will not be connected to any patient electronic medical record system for the study.   
 
The Vivatmo proTM base station has a 7 inch color touchscreen with 1024 x 600 pixels, weighs 3 
lbs (1,350 g) and is 6.3 in x 8.4 in x 10.4 in (16.0 cm x 21.3 cm x 26.5 cm).  It has the ability to store 
up to 15,000 patient measurements, print measurement results using a USB printer, and export 
electronic measurement data files (see study data management section below).   
 
5.6. 
Vivatmo proTM Handheld 
 
Vivatmo proTM cordless handheld component contains a lithium-ion battery that is recharged by 
placement on the base station.  It is capable for 5,000 measurement attempts and synchronizes 
data to the base station. The cordless handheld stores 1,000 measurements.  It performs 
measurements over an exhalation time of 10 seconds with FeNO measurements in the range 5 
ppb to 300 ppb.  The Vivatmo proTM handheld has a startup time of 60 sec, a time-to-result of 5 
sec, and a regeneration-time of 90 sec.  
 
5.7. 
Vivatmo proTM Mouthpiece 
 
The study will use the disposable Vivatmo proTM Oxycap Mouthpiece (“blue” on outside) for 
standard study measurements.  The study will use the disposable Vivatmo proTM Level 0 
Mouthpiece (“opaque/white” outside and “blue” inside) for instrument quality control (QC) 
measurements. 
 
The design of the mouthpiece allows the subject to close their lips around it in a relaxed and 
natural way resembling the mouthpiece of a flute. This supports velum closure and accurate 
device measurement.  When using Vivatmo proTM mouthpieces instrument operators should 
ensure the following: 
 
• Check that disposable Vivatmo proTM mouthpieces have not expired (expiration dates are 
printed on the packaging). 
• Vivatmo proTM mouthpieces should be unpackaged immediately prior to use and used 
within 15 minutes of opening. 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
                      Page   
 
24 
• Each Vivatmo proTM mouthpiece may be used for one patient performing a maximum of 
5 exhalations.  Replace the mouthpiece after every 5 exhalation attempts. 
• Ensure that the Vivatmo proTM mouthpiece fits on the handheld unit properly to avoid 
leakage of air around the edge of the disposable fitting, which may lead to a lower 
measurement result. 
• Do not attempt to clean the disposable mouthpiece.  
• Dispose of used mouthpieces in the waste for contaminated patient material. 
 
5.8. 
Guidance for Vivatmo proTM Calibration and Routine Quality Control (QC) Testing 
 
Each Vivatmo proTM device will be pre-calibrated prior to initial use for the study and no additional 
calibration will be needed during the study.   
 
Quality Control (QC) testing should be performed by the designated device administrator (QC 
tester) on a routine basis and is recommended to be performed weekly or after every 50 
measurements. The identity of the individual designated and performing QC testing is recorded 
within the device software and they must meet the following criteria: 
 
• Be over 18 years of age; 
• Be a non-smoker 
• Have no ongoing cold or known airway disease 
• Be expected to have stable FeNO values between 10 ppb and 40 ppb 
• Preferably have no allergies or asthma  
 
Quality Control (QC) testing is performed by: 
 
• Making 4 measurements in 7 days using the Vivatmo proTM, with 1 measurement per day 
• Confirming that the QC mean value from measurements on the first 3 days is between 5 
ppb to 50 ppb, and 
• Confirming that the QC measurement on the 4th day is within ±10 ppb from mean value 
 
If the QC tester does not perform a QC test in 30 days, the qualification is suspended and the QC 
tester needs to re-qualify within the instrument software. 
 
5.9. 
Vivatmo proTM Instrument Support 
 
Each site will be provided with a Vivatmo proTM device and the necessary consumables to 
conduct the planned number of measurements.  In the event that an instrument requires 
troubleshooting, the designated local study coordinator may contact the Study Manager, who will 
coordinate technical assessment and provide either verbal or written instructions.  
 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
                      Page   
 
25 
6. STUDY PROCEDURES 
 
6.1. 
Clinical Site Study Staff Training 
 
At the initiation of the study the Sponsor, and/or designee, will visit each study site. The Sponsor 
will ensure that study staff are informed and understand the study requirements.  
The Principal Investigator (PI) and designated study staff at each participating site will attend a 
training session conducted at a site initiation visit (SIV) or other appropriate training session. 
Training will include, but will not be limited to, procedures to select, prepare, and manage 
patients for the study; review of the study protocol, visit plan, and testing plan; review of device 
training and operation; and completion of the study Case Report Forms (CRFs). 
Designated study staff should familiarize themselves with the Vivatmo proTM user manual.  All 
trained study personnel will sign a training log. No study staff will perform any study-related 
procedures prior to being trained and signing a training log. 
6.2. 
Study Visit #1 Overview 
 
Study Visit #1 will include patient screening, consent, enrollment, assignment of a Study Subject 
ID number, subject training on use of the Vivatmo proTM, Vivatmo proTM measurement, 
spirometry, ACQ assessment, and Case Report Form (CRF) completion.  
 
6.3. 
Study Visit #2 Overview 
 
Study Visit #2 will be conducted at 14 days from study Visit #1 (14 to 21 days is the acceptable 
range).  Study Visit #2 will include a subject training refresher (if necessary) on use of the 
Vivatmo proTM, Vivatmo proTM measurement, spirometry, ACQ assessment, and Case Report 
Form (CRF) completion.  
 
Study patients should be instructed to withhold (not take) their prescribed ICS (except rescue 
inhalers) the day that they come in for Study Visit #2. 
 
6.4. 
Patient Screening and Consent 
 
Subjects will optimally be selected from those already scheduled for clinic visits. Prior to study 
participation and the collection of any study data the PI, and designated study coordinator, will 
obtain informed consent from each subject who meets inclusion/exclusion criteria.  The date of 
informed consent and confirmation of compliance with study inclusion/exclusion criteria will be 
recorded on the designated study CRF.  Upon completion of consent subjects will be enrolled 
into the study and this will optimally occur after confirmation of a clinical diagnosis of asthma 
and prior to prescription of inhaled corticosteroid (ICS) treatment.  Diagnosis of asthma may 
require spirometry measurement. 
 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
                      Page   
 
26 
6.5. 
Guidance for Preparing and Training Study Subjects on Use of the Vivatmo proTM  
 
Study Coordinators, designated testers, and study subjects should wash their hands prior to using 
the Vivatmo proTM device for testing.  The study coordinator should explain the test to the 
subject and demonstrate appropriate techniques.  It is recommended that study coordinators train 
subjects (especially children) on proper grasping technique and exhalation technique prior to 
performing the first Vivatmo proTM measurement.  Training may involve practice with holding 
and positioning the handheld component and practicing a controlled exhalation using a “Flow 
Be” floating ball toy (where constant exhalation flow/rate causes a toy ball to be suspended in 
air), using a musical instrument, or other equivalent simulation.  The test assumes a full 
inhalation before beginning. 
 
The subject may need to be prompted or encouraged to ‘‘blow” the air from their lungs.  
Enthusiastic coaching of the subject using appropriate body language and phrases, such as ‘‘keep 
going’’, may be required.   Encouragement, detailed but simple instructions, lack of intimidation, 
and visual feedback from the instrument are important in helping children to perform the test.  
 
It is helpful to observe the subject to check for distress and to observe the Vivatmo proTM base 
station display during the test to help ensure correct effort.   If the patient feels ‘‘dizzy’’ testing 
should be stopped.  Well-fitting false teeth should not be routinely removed, since they preserve 
oropharyngeal geometry and results may generally be better with them in place.  Correct patient 
performance (exhalation flow rate) is required for the measurement to be considered valid. 
 
6.6. 
Guidance for Vivatmo proTM Testing Procedure 
 
Fractional exhaled nitric oxide (FeNO) measurements should be performed according to the 
American Thoracic Society (ATS) and European Respiratory Society (ERS) Guidelines.  Study 
subjects should be tested while in the seated position, preferably using a chair with arms and 
without wheels, and without using a nose clip.  Subjects should maintain good posture with head 
slightly elevated. Vivatmo proTM measurements should be made prior to spirometry 
measurements. When possible perform serial Vivatmo proTM measurements at the same time of 
the day. 
 
Subjects should inhale to total lung capacity and then exhale into the mouthpiece of the Vivatmo 
proTM handheld unit at a constant pressure and stable flow rate for 10 seconds guided by visual 
cues and auditory cues on the display of the Vivatmo proTM   base station.  Results are processed 
using dedicated software and in approximately 5 seconds, the NO concentration is displayed on 
the device in parts per billion (ppb).  
 
The exhalation may be repeated after a brief rest period until 2 acceptable measurements are 
obtained.  A total of up to 10 exhalations may be performed in order to achieve 2 acceptable 
measurements.  The Vivatmo proTM mouthpiece should be changed after every 5 exhalation 
attempts and recorded appropriately on Study Case Report Form (CRF). 
 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
                      Page   
 
27 
The Vivatmo proTM measurements, spirometry measurements, and asthma control questionnaire 
information collection may be performed in any sequence at a given patient visit so long as they 
are all performed on the same day. 
 
6.7. 
Guidance for Vivatmo proTM Test Result Acceptance Criteria and Invalid Results 
 
Vivatmo proTM will indicate if each measurement is valid and acceptable or if it is invalid.   
If the first 2 exhalation measurements at a given study visit are valid then no additional 
measurements need be performed at that visit.  A subject must produce each valid measurement 
within no more than 5 exhalation measurement attempts at a given study visit.  If an exhalation 
measurement is invalid at a given study visit then exhalation measurement should be repeated at 
the visit with the subject performing up to a maximum of 10 exhalation measurements total  (2 x 
5) at the visit or until a total of 2 valid measurements are obtained.  The Vivatmo proTM 
mouthpiece should be changed after every 5 exhalation attempts 
 
6.8. 
Guidance for Spirometry Testing 
 
Electronic peak air flow spirometry testing will be performed at each study visit in accordance 
with ATS guidelines.  Only ATS/ERS compliant electronic spirometers should be used and the 
same spirometer should be used on each study patient at each study visit.  Participating clinical 
sites will use spirometers routinely used for clinical care.  Spirometers will not be provided by 
the Sponsor to clinical sites participating in the study.  Spirometry results at each study visit 
including fractional exhaled volume (FEV1%), number of exhalations measured, make and 
model of spirometer, and spirometer reference standard used will be recorded in the designated 
study CRF. 
 
6.9. 
Guidance for ACQ Data Collection 
 
Subject responses to questions on the standardized Asthma Control Questionnaire (ACQ) will be 
obtained at any time during the study visit.  This information will frequently be available prior to 
Vivatmo proTM testing at the time of confirmation of a clinical diagnosis of asthma.  ACQ 
responses will be recorded at each of the 2 study visits.  ACQ responses will be recorded in the 
designated study case report form (CRF).   
 
7. DATA COLLECTION, HANDLING AND RECORD KEEPING 
 
7.1. 
Study Management Documentation and Logs 
 
Participating clinical sites will maintain a Patient Screening Log and a Subject Enrollment Log.  
The Patient Screening Log should contain a nonconfidential (coded) listing of potential study 
patients screened at the clinic for study participation and identify those that were included in the 
study, those that were not included in the study, and the reasons why patients were not included 
(excluded).  The Subject Enrollment log should identify enrolled study subjects and their 
assigned Study Subject ID. 
 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
                      Page   
 
28 
7.2. 
Study Case Report Forms (CRFs) 
 
In addition to instrument electronic report data, study Case Report Forms (CRFs) will be the 
primary data collection tool for the study and will constitute the original study record.  The 
following study information will be collected using eCRFs/CRFs for each study subject: 
 
CRF 1 - Consent and Demographics 
CRF 2 - Current Asthma Prescription and Asthma History 
CRF 3 - Other Medical Conditions and Medications 
CRF 4 - Visit #1 - ACQ and Spirometry Results 
CRF 5 - Visit #1 - Vivatmo proTM Results 
CRF 6 - Visit #2 - ACQ and Spirometry Results 
CRF 7 - Visit #2 - Vivatmo proTM Results 
 
Data may be delivered via completion of electronic case report forms (eCRFS) directly into the 
online study database or by completion and delivery of PDF scans of completed hardcopy case 
report forms (CRFs). The PI, or designee, at each site must verify the accuracy and completeness 
of all recorded data by signing and dating all case report forms (eCRFs/CRFs) prior to 
submitting them.  If a manual entry requires change, the correction will be made as follows: 
 
• Draw a single line through the incorrect entry. 
• Enter changed/corrected data (“white-out”, erasure, or any form of obliteration of data is not 
permitted under any circumstances). 
Neither the Sponsor nor its designee can interpret a blank answer as “none” or “N/A”; therefore, 
all fields must be completed.  If data are not available, a straight line should be drawn through all 
applicable fields manually completed forms and unused pages, and dated and initialed to indicate 
there was no omission. 
All supportive documentation must be clearly identified with the Study Subject ID number.  Any 
personal information, including subject name, address, phone number, medical record number, or 
social security number must be removed or rendered illegible to preserve study subject 
confidentiality. 
All records (e.g., regulatory documents, CRFs, study logs, data sheets) will be sent to the clinical 
monitor when requested.  Unless otherwise instructed, original documents completed at the study 
site will remain in the Investigational Site File (ISF) while copies will be sent to sponsor, or 
designee, for the study Trial Master File (TMF).   
The PI ensures the accuracy, completeness, legibility, and timeliness of the data reported to 
Sponsor as well as storage and security of the study files.  Study ISF binders and CRF template 
forms will be provided by the sponsor. 
 
7.3. 
Vivatmo proTM Instrument Data 
 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
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The following instrument testing data will be reported to the sponsor or designee: 
 
• Study Visit #1 - Vivatmo proTM Test Results 
• Study Visit #2 - Vivatmo proTM Test Results 
 
Instrument test results for each patient visit will be printed at the time of the visit (or 
immediately after) and stored in study data binder.  Electronic exports of Vivatmo proTM study 
results files will be emailed to the study sponsor or designee for uploading into study database. 
 
Reports for the following will also be printed and stored in the study data binder and delivered 
electronically to the study Sponsor or designee. 
 
• Vivatmo proTM Initial Set-Up and Installation Information (as needed) 
• Vivatmo proTM QC results 
 
7.4. 
Asthma Control Questionnaire (ACQ) and Spirometry Data 
 
Asthma Control Questionnaire (ACQ) and Spirometry data for each patient visit will be recorded 
in the designated CRF.  These CRFs will include: 
 
• Study Visit #1 - ACQ Responses and Spirometry Testing Result 
• Study Visit #2 - ACQ Responses and Spirometry Testing Result 
 
7.5. 
Record Retention 
 
All records pertaining to this study must be maintained by the PI in a condition suitable for 
inspection for whichever is the longer of: 
• Two (2) years following FDA clearance to market of the investigational product; 
• Two (2) years following termination or discontinuance of the entire clinical investigation; 
or   
• Record retention policy of the investigational site and/or IRB/IEC. 
 
7.6. 
Record Access 
 
The PI and institution will permit study-related monitoring, audits, IRB/IEC review, and 
regulatory inspection (FDA or other regulatory authority) by providing direct access to study 
documents. 
 
7.7. 
Study Training Manual 
 
The study training manual will contain the following: 
 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
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• Table of Contents 
• Study Protocol 
• Study Informed Consent Template 
• Study Case Report Form Templates (CRFs) 
• Screening Log Template 
• Enrollment Log Template 
• Study Material Accountability Log Template  
• Study Deviation Report Template 
 
7.8. 
The Investigational Site File (ISF)  
 
The Investigational Site File (ISF) a.k.a. “Regulatory Binder” will contain the following: 
 
• IRB approval of Study Protocol 
• IRB approved Patient Informed Consent Template  
• Completed and Signed Investigator Statement 
• Completed and Signed Financial Disclosure Form 3454 or 3455  
• Signed Clinical Site Agreement (Clinical Trial Agreement) 
• All relevant and significant communications between sponsor, site and IRB, including all 
electronic and paper communications (e.g., emails, letters) 
• Investigator notifications of protocol amendments and addenda 
• IRB updates 
• PI CV and Licenses 
• PI GCP Certifications 
• Site Staff Study Training Documentation 
 
7.9. 
Data Binder 
 
The study data binder will contain the following: 
 
• Original completed Case Report Forms (CRFs) 
• Printouts of the Vivatmo proTM Test Result Data  
• Printouts of Vivatmo proTM Initial Set-Up and Installation Information  
• Printouts of Vivatmo proTM QC results 
 
8. DATA ANALYSIS AND STUDY ENDPOINTS 
 
8.1. 
Analysis Populations 
 
The Full Analysis Set (FAS) will be defined as all patients intended to receive a FeNO 
measurement. 
 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
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The Per Protocol Set will be defined as enrolled subjects without major protocol violations, with 
inhaled corticosteroid (ICS) treatment, and successfully completing at least one valid FeNO 
measurement at both Visit #1 and Visit #2 will be evaluated for the primary endpoint.   
 
8.2. 
Descriptive Statistics 
 
Baseline characteristics, such as demographic, as well as analytical clinical data by visit will be 
summarized using descriptive statistical methods. Continuous data will be summarized using the 
mean, the median, standard deviation, and range (minimum and maximum value). Categorical 
values will be summarized using frequency counts and percentages. 
 
8.3. 
Analysis of Primary Endpoint 
 
The change of FeNO values will be estimated in ANOVA with baseline values as the covariable 
and will be reported as percent change together with the 95%-confidence interval. 
 
8.4. 
Analysis of Secondary Endpoints 
 
The relationship between changes of FeNO-values and clinical assessments (spirometry, ACQ-
questionnaire) will be assessed by Spearman’s rank correlation. 
 
Repeatability will be estimated together with the 95%-confidence interval as pooled standard 
deviation (mean of measurement pair < 50 ppb) and CV (mean of measurement pair ≥ 50 ppb), 
respectively, using the residual variance component resulting from a random effects ANOVA (as 
used in CLSI EP05 guideline) with patient and visit as random factors. . Technically, the CV is 
estimated as 100 x standard deviation applying the random effects ANOVA on ln-transformed 
values. The resulting pooled repeatability is hereby estimated taking in account conditions of 
variability over sites and operators. 
 
The success rates (proportion of patients with successful measurement within FAS) will be 
reported. The number of attempts necessary to obtain 2 valid replicate measurements will be 
tabulated in contingency tables by visit. 
 
9. COMPLIANCE WITH GOOD CLINICAL PRACTICES (GCP), ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
 
9.1. 
Adherence to Protocol, Good Clinical Practices (GPC), and Applicable Regulations 
 
The study shall be conducted as described in this protocol, according to good clinical practices 
(GCP), in compliance with the principles set forth in the Declaration of Helsinki, and according 
to applicable U.S. Federal Regulations.   
The PI shall ensure that all work and services described herein shall be conducted in accordance 
with the highest standards of medical and clinical research practice. The PI will provide copies of 
the protocol to all co-Investigators or other staff responsible for study conduct.  

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
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9.2. 
Institutional Review Board  
 
The protocol, as well as the Informed Consent template, will be approved by a central IRB 
(WIRB - Western IRB, Puyallup, WA) prior to the start of the study. 
 
The Institutional Review Board (IRB) will review and approve enrollment of subjects into this 
study.   The PI shall obtain written confirmation from the IRB that the protocol and other 
applicable documents have been approved.  The study cannot begin until approval is received. 
If the study continues beyond the time period specified by the IRB, the PI would request a 
renewal of the study.  The renewal application will include any applicable documents required 
for the duration of the study. The PI will obtain written confirmation from the IRB that the study 
has been renewed.  The PI will inform the IRB when the study has been terminated and obtain 
written confirmation from the IRB/IEC of the study closure. 
9.3. 
Subject Protections 
 
It is the responsibility of the PI to assure that informed consent is obtained from each subject or 
legal guardian in accordance with current regulations. The content of the informed consent will 
conform to current ICH and FDA guidelines for the protection of human subjects, and/or to the 
specific IRB requirements. The informed consent form must be in English, signed and dated by 
the subject, or legal guardian, and Investigator, or designee.  
Each subject will be given verbal and written information describing the nature and duration of 
the study.  This will take place under conditions where the subject, and/or legal guardian, has 
adequate time to consider the potential risks associated with his/her participation in the study. All 
subjects’ questions must be answered adequately to ensure that they have the information they 
require to make an informed decision about participation in the study.  The signed informed 
consent form will be filed in a study Investigational Site File (ISF) along with all other Case 
Report Forms (CRFs). 
No subject names, medical record numbers, or other personally identifying information will be 
used as part of the study or transmitted to the sponsor or designee.  Case Report Forms (CRFs) 
will not contain any confidential information linking the date or outcome result to a subject.  
Only the study site will have the information that links a subject to his/her identifying 
information.  Subjects will only be referred to by using their unique Subject ID number. 
9.4. 
Confidentiality 
 
This study protocol, study, documentation, and all other information generated, will be held in 
strict confidence by the PI and their representatives. No information concerning the study or the 
data will be released to any unauthorized third party without prior written approval by the 
Sponsor. 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
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9.5. 
Monitoring 
 
The Study Manager and Clinical Monitor, as representatives of the Sponsor, have the obligation 
to follow this study closely.  The Study Manager and/or Clinical Monitor will visit the study 
facility/site as needed, in addition to maintaining necessary contact by telephone, tele/video-
conference, e-mail, facsimile, and/or letter communication.  Monitoring of this study will entail 
review of the required study documents, such as Case Report Forms (CRFs), investigational 
testing results, quality control test results, staff training records, and other activities as deemed 
necessary during monitoring visits.  
9.6. 
Study Deviations 
 
All effort must be made to avoid deviations from the protocol, regulations, or GCPs.  If a 
deviation occurs, it must be reported to the study Sponsor, or designee, and recorded by site 
personnel in a deviation report describing the deviation and corrective/preventative actions; 
which is kept with the ISF and a copy provided to the sponsor, or designee, for the TMF. The 
study manager will determine whether the site’s IRB/IEC must be informed 
9.7. 
Serious Adverse Event (SAE) Reporting 
 
A significant adverse event (SAE) is one that has a serious adverse effect on the health or safety 
of a study subject, or causes any medical problem, life-threatening problem, or death of the study 
subject.  
All SAEs should be recorded by the PI and reported by the PI to the Sponsor, or designee, and to 
the IRB within 24 hours after the PI becomes aware of the SAE.  The Sponsor will collect 
adverse event information and may report serious and unanticipated adverse events to the FDA.  
9.8. 
Risks 
 
There are no known direct risks to patient health.  
9.9. 
Potential Benefits 
 
There is no guaranteed of benefit to a subject for participation in this study. Subjects are to be 
treated for their asthma per their physician’s standard of care.    
 
9.10. Compensation 
 
Subjects may be offered a gift card, (worth no more than $25 per visit) for study participation.   
Sites may be compensated for time and effort completing study tasks.  
 
All study instruments and supplies will be provided to the participating sites at no charge. 
Subject medications will not be covered by the Study Sponsor.  

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
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9.11. Quality Assurance Audit 
 
In the event that PI is contacted by a Regulatory Agency in relation to this study, the PI will 
notify the Sponsor immediately.  The PI or designee must be available to respond to reasonable 
requests and audit queries made during an audit process. The PI must provide the Sponsor with 
copies of all correspondence that may affect the review of the current study (e.g., Form FDA 
483, Inspectional Observations, and warning letters).  
 
9.12. Publication Policy 
 
The data and results from this study are the sole property of the Sponsor.  The Sponsor will have 
the right to access and use all data and results generated during the clinical study. The PI will not 
use the study related data without the written consent of the Sponsor for any purpose other than 
for study completion or for generation of publication material. The Sponsor must approve all 
material for publication prior to submission. 
 
9.13. ClinicalTrials.Gov 
 
This study will be posted on clinicaltrials.gov (www.clinicaltrials.gov). 
 
 
 
REFERENCES 
1. Systematic meta-review of supported self-management for asthma: a healthcare perspective. Pinnock, 
Hilary, et al. 2017, BMC Medicine, Vol. 15, p. 64. 
 
2. Current evidence and future research needs for FeNO measurement in respiratory diseases. Bjermer, 
Leif, et al. s.l. : Elsevier, February 2014, Respiratory Medicine, Vol. 108, pp. 830-841. 
 
3. Internet-based tapering of oral corticosteroids in severe asthma: a pragmatic randomised controlled 
trial. Hashimoto, Simone, et al. 6, June 2011, Thorax, Vol. 66, pp. 514-520. 
 
4. Exhaled nitric oxide to predict corticosteroid responsiveness and reduce asthma exacerbation rates. 
Donohue, James F and Jain, Neal. 7, July 2013, Respiratory Medicine, Vol. 107, pp. 943-52. 
 
5. Symptom- and fraction of exhaled nitric oxide–driven strategies for asthma control: A cluster-
randomized trial in primary care. Honkoop, Persijn J, et al. 3, March 2015, The Journal of Allergy and 
Clinical Immunology, Vol. 135, pp. 682-88. 
 
6. Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a 
double-blind, randomised controlled trial. Powell, Heather, et al. 9795, September 2011, The Lancet, 
Vol. 378, pp. 983-990. 
 
 
 

CONFIDENTIAL 
 
 
PROTOCOL:  Clinical Study of the Vivatmo proTM for Fractional Exhaled Nitric Oxide 
(FeNO) Monitoring in U.S. Asthmatic Patients Responding to Inhaled Corticosteroid 
(ICS) Treatment (VER 2.0 – 25-Sept-2020) 
 
                                 
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APPENDIX - Asthma Guidance and Reference Documents 
 
1. ACQ - Asthma Control Questionnaire 
https://www.thoracic.org/members/assemblies/assemblies/srn/questionaires/acq.php 
 
2. ATS / ERS Guidelines - Standardization of Lung Function Testing - American Thoracic 
Society / European Respiratory Society Task Force 
https://www.thoracic.org/statements/resources/pfet/PFT2.pdf 
 
3. NEAPP Guidelines - National Asthma Education and Prevention Program Guidelines  
(2002) 
https://www.nhlbi.nih.gov/files/docs/guidelines/asthmafullrpt_archive.pdf 
 
4. NICE Asthma Guidelines - National Institute for Health and Care Excellence (UK) 
 
a. Diagnosis and Monitoring of Asthma in Adults, Children and Young People,  
NICE Guideline, No. 80.1  
https://www.ncbi.nlm.nih.gov/books/NBK469773/ 
 
b. Chronic Asthma: Management, NICE Guideline, No. 80 
https://www.ncbi.nlm.nih.gov/books/NBK469772/ 
 
5. NHLBI Guidelines - Guidelines for the Diagnosis and Management of Asthma (EPR-3) 
National Heart, Lung, and Blood Institute 
https://www.nhlbi.nih.gov/health-topics/guidelines-for-diagnosis-management-of-asthma