Nasal High-flow Compared to Non-invasive Ventilation in Treatment of Acute Acidotic Hypercapnic Exacerbation of Chronic Obstructive Pulmonary Disease - a Randomized Controlled Noninferiority Trial
Phase: NA
Conditions: COPD Exacerbation Acute
Sponsor: University of Leipzig

 
 
Confidential 
 
 
 
 
Trial Protocol 
 
Nasal high-flow compared to non-invasive 
ventilation in treatment of acute acidotic 
hypercapnic exacerbation of chronic obstructive 
pulmonary disease – a randomized controlled 
noninferiority trial 
ELVIS 
 
 
 
Coordinating investigators 
Prof. Dr. Hubert Wirtz  
Department of Respiratory Medicine 
University Hospital Leipzig AöR 
Liebigstr. 20 
04103 Leipzig  
PD Dr. Jens Bräunlich 
Clinic Emden 
Hans-Susemihl hospital  
Medical clinic 
Bolardusstraße 20 
26721 Emden 
Biometry 
Dr. rer. nat. habil. David Petroff 
Leipzig University  
Clinical Trial Centre Leipzig 
Härtelstraße 16-18 
04107 Leipzig 
 
 
Responsible Institution 
Leipzig University 
Ritterstr. 26, 04109 Leipzig 
 
 
Date: 16.12.2020 
Version: Final 1.0 
 

 
 
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Table of Contents 
 
 ......................................................................................................................... PAGE 
GENERAL INFORMATION .................................................................................................... 4 
Responsible parties ................................................................................................................ 4 
Summary of the revision history – Amendments ..................................................................... 6 
Synopsis ................................................................................................................................ 7 
Synopse (German version) ..................................................................................................... 9 
Schedule of assessments and procedures ........................................................................... 11 
Flow chart............................................................................................................................. 12 
1 
RATIONALE, MEDICAL BACKGROUND .............................................................. 13 
1.1 
Medical background ................................................................................................ 13 
1.2 
Justification of investigation Design ........................................................................ 14 
1.3 
Risks and benefits .................................................................................................. 16 
2 
OBJECTIVES ......................................................................................................... 17 
2.1 
Hypotheses of the clinical investigation ................................................................... 17 
2.2 
Primary objective .................................................................................................... 17 
2.3 
Secondary objectives .............................................................................................. 17 
3 
TRIAL DESIGN AND DESCRIPTION ..................................................................... 18 
3.1 
Trial design ............................................................................................................. 18 
3.2 
Requirements at the Trial Sites regarding Personnel and Equipment ..................... 18 
3.3 
Trial Sites and Number of Trial Subjects ................................................................. 18 
3.4 
Trial Duration .......................................................................................................... 18 
3.5 
Premature Termination of the Trial ......................................................................... 19 
4 
TRIAL SUBJECTS ................................................................................................. 20 
4.1 
Inclusion criteria ...................................................................................................... 20 
4.2 
Exclusion criteria .................................................................................................... 20 
4.3 
Justification for the Inclusion of vulnerable Populations .......................................... 21 
5 
INVESTIGATIONAL INTERVENTION/PRODUCT ................................................. 21 
5.1 
Non-invasive ventilation (NIV) ................................................................................. 21 
5.2 
Nasal high-flow (NHF) ............................................................................................ 21 
6 
DESCRIPTION OF THE TRIAL/TREATMENT PROCEDURES ............................. 22 
6.1 
Screening ............................................................................................................... 22 
6.2 
Patient Information and Informed Consent .............................................................. 22 
6.3 
Screening Visit ........................................................................................................ 24 
6.4 
Visit 0/Randomization ............................................................................................. 24 
6.5 
Trial procedure(s) during treatment ......................................................................... 25 
6.6 
Dose, mode and scheme of intervention ................................................................. 26 
6.7 
Guidance for switching devices and the need for intubation .................................... 26 
6.8 
Additional treatments .............................................................................................. 27 
6.9 
Follow-up procedures ............................................................................................. 27 
6.10 
Premature termination of the therapy or follow-up for individual patients ................ 28 
6.11 
Counterindicated/Forbidden Concomitant Medication or procedures ...................... 29 
6.12 
Plan for Further Treatment ...................................................................................... 29 
7 
ADVERSE EVENTS (AE/SAE) ............................................................................... 30 
7.1 
Adverse Events and Serious Adverse Events (SAE) ............................................... 30 
7.2 
Device deficiencies and Incidents ........................................................................... 32 

 
 
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7.3 
Concomitant diseases ............................................................................................ 32 
8 
STATISTICAL CONSIDERATIONS ....................................................................... 33 
8.1 
Biometrical Aspects of the Investigation Design ...................................................... 33 
8.2 
End Points .............................................................................................................. 33 
8.3 
Statistical Description of the investigation hypothesis ............................................. 34 
8.4 
Sample Size Discussion ......................................................................................... 34 
8.5 
Statistical Methods .................................................................................................. 35 
8.6 
Statistical Monitoring ............................................................................................... 36 
8.7 
Final Analysis ......................................................................................................... 37 
9 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS ......................................... 38 
9.1 
Submission ............................................................................................................. 38 
9.2 
Protocol Amendments ............................................................................................ 38 
10 
DATA MANAGEMENT AND DATA PROTECTION ............................................... 39 
10.1 
Data protection and professional confidentiality ...................................................... 39 
10.2 
Declaration regarding Data Protection .................................................................... 40 
10.3 
Data protection rights .............................................................................................. 40 
10.4 
Data management/Case Report Forms (CRF) ........................................................ 40 
10.5 
Patient File and Source Data .................................................................................. 41 
10.6 
Data Management .................................................................................................. 41 
10.7 
Archiving ................................................................................................................. 42 
11 
SUPERVISION OF THE CLINICAL TRIAL ............................................................ 43 
11.1 
Access to Source Data ........................................................................................... 43 
11.2 
Monitoring ............................................................................................................... 43 
11.3 
Audits ..................................................................................................................... 43 
11.4 
Independent Supervision of the Trial ...................................................................... 44 
12 
ADMINISTRATIVE AGREEMENTS ....................................................................... 46 
12.1 
Adherence to the protocol ....................................................................................... 46 
12.2 
Funding and Insurance ........................................................................................... 46 
12.3 
Publication Policy and Registration ......................................................................... 46 
12.4 
Data Sharing Statement.......................................................................................... 47 
13 
PROTOCOL SIGNATURES ................................................................................... 48 
14 
PROTOCOL AGREEMENT .................................................................................... 49 
15 
APPENDIX ............................................................................................................. 50 
15.1 
Classification of Adverse Events ............................................................................. 50 
15.2 
Definitions ............................................................................................................... 52 
15.3 
Acronyms ............................................................................................................... 52 
15.4 
Template trial protocol ............................................................................................ 53 
16 
REFERENCES ....................................................................................................... 54 
 

 
 
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GENERAL INFORMATION 
Responsible parties 
Responsible institution 
Leipzig University  
Ritterstr. 26, 04109 Leipzig  
Coordinating investigators 
Prof. Dr. med. Hubert Wirtz  
Department of Respiratory Medicine 
University Hospital Leipzig AöR 
Liebigstr. 20, 04103 Leipzig 
Phone: +49 341 97 12600 
Fax: +49 341 97 12609 
E-Mail: hubert.wirtz@medizin.uni-leipzig.de 
PD Dr. med. Jens Bräunlich 
Clinic Emden 
Hans-Susemihl hospital  
Medical clinic 
Bolardusstraße 20, 26721 Emden 
Phone: +49 21 98 15 98 
Fax: +49 21 98 12 79  
E-Mail: j.braeunlich@klinikum-emden.de  
Project Management 
Nicole Köppe-Bauernfeind, M.Sc. 
Leipzig University  
Clinical Trial Centre Leipzig 
Härtelstraße 16-18, 04107 Leipzig 
Phone: + 49 341 97 16266 
Fax: +49 341 97 16259 
E-Mail: nicole.koeppe-bauernfeind@zks.uni-leipzig.de  
Safety Management 
Madlen Doerschmann 
Leipzig University  
Clinical Trial Centre Leipzig 
Härtelstr. 16-18, 04107 Leipzig 
Phone: +49 341 97 16129 
Fax: +49 341 97 16278 
E-Mail: pharmacovigilance@zks.uni-leipzig.de  
Data Management 
Anke Stolle 
Leipzig University  
Clinical Trial Centre Leipzig 
Härtelstr. 16-18, 04107 Leipzig 
Phone: +49 341 97 16268 
Fax: +49 341 97 16259 
E-Mail: elvis@zks.uni-leipzig.de  
Biometry 
Dr. rer. nat. habil. David Petroff 
Leipzig University  
Clinical Trial Centre Leipzig 
Härtelstr. 16-18, 04107 Leipzig 
Phone: +49 341 97 16354 
Fax: +49 341 97 16189 
E-Mail: david.petroff@zks.uni-leipzig.de 

 
 
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Monitoring 
Nicole Köppe-Bauernfeind, M.Sc. 
Leipzig University  
Clinical Trial Centre Leipzig 
Härtelstr. 16-18, 04107 Leipzig 
Phone: +49 341 97 266 
Fax: +49 341 97 16259 
E-Mail: nicole.koeppe-bauernfeind@zks.uni-leipzig.de 
Funding 
Dr. Laura de la Cruz 
Bundesministerium für Bildung und Forschung (BMBF) 
DLR Projektträger 
Bereich Gesundheit 
Heinrich-Konen-Str. 1, 53227 Bonn 
Phone: +49 30 670557985 
Fax: +49 228 3821 1257 
E-Mail: laura.delacruz@dlr.de 
Data Safety Monitoring Board 
PD Dr. med. Thomas Köhnlein (chairman) 
Internistisches Facharztzentrum Teuchern 
Markt 7, 06682 Teuchern 
Phone: +49 34443 614 0 
Fax: +49 34443 614 16 
E-Mail: thomas.koehnlein@facharztzentrum-teuchern.de  
 
Prof. Dr. med. Christian Witt 
Leiter Forschungsbereich Pneumologie an der Charité – 
Universitätsmedizin Berlin 
Charitéplatz 1, 10117 Berlin 
Phone: +49 30 450 565 021 
E-Mail: christian.witt@charite.de  
 
Jörn Rau 
Medical statistics 
Coordinating Center for Clinical Trials 
Philipps-University of Marburg 
Karl-von-Frisch-Straße 4, 35043 Marburg 
Phone: +49 6421 286 6509 
E-Mail: joern.rau@kks.uni-marburg.de  
 
 
 

 
 
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Summary of the revision history – Amendments  
Number of 
Amendment Contents 
Date of approval 
n.a. 
 
 
 
 
 
 
 
 

 
 
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Synopsis 
Title of the trial 
Nasal high-flow compared to non-invasive ventilation in 
treatment of acute acidotic hypercapnic exacerbation of 
chronic obstructive pulmonary disease – a randomized 
controlled non-inferiority trial 
Acronym 
ELVIS 
Indication 
acute 
acidotic 
hypercapnic 
exacerbation 
of 
chronic 
obstructive pulmonary disease (AECOPD) 
Primary efficacy end point 
Proportion with treatment failure of allocated respiratory 
support within 72 h after start of respiratory support. 
Treatment failure defined as  
a) intubation or  
b) switch to another method of non-invasive ventilation or  
c) death 
Secondary end points 
1. proportions of single components of primary endpoint 
2. proportion intubated within 7 calendar days after 
hospitalisation/randomization 
3. overall survival at day 28 and 90 
4. (invasive) ventilator-free days until day 28  
5. (invasive) ventilator-free hours until assessment of the 
primary endpoint (within the first 72 hours after begin of 
therapy)  
6. ICU/hospital length of stay 
7. sedation required 
Safety endpoints: 
1. (S)AE until discharge/day 28 (whichever comes first) 
2. device related intolerance/complications 
3. complications including severe diseases acquired under 
treatment 
Trial design 
Prospective, randomized, multi-centre open label trial 
following a non-inferiority design 
Trial population 
Inclusion criteria: 
1. Acute hypercapnic exacerbation of chronic obstructive 
pulmonary disease with pH < 7.35 
2. pCO2 > 45mmHg 
3. age ≥ 18 years 
4. written informed consent 
Exclusion criteria: 
1. immediate need for intubation (acc. to intubation criteria 
in this protocol) 
2. pH < 7.15 
3. BMI ≥ 35 kg/m² 
4. established home-NIV or home-CPAP 
5. end-stage disease with DNI/DNR order 
6. diseases that could influence the primary endpoint: e.g. 
acute heart infarction, cardiogenic lung edema, acute 
and massive lung embolism (hypertensive), chronic 

 
 
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dialysis with metabolic acidosis, unstable rib fracture 
influencing ventilation, injury to the face prohibiting use 
of a face mask 
7. acute disease that precludes participation in the trial 
8. tracheotomized patients 
9. psychological/mental or other inabilities to supply 
required informed consent 
10. participation in other interventional trials 
11. suspected lack of compliance 
Sample size 
To be assessed for eligibility: 1500 patients 
To be allocated to trial: 720 patients 
To be analysed: 720 patients (ITT analysis) 
Therapy 
Experimental intervention: Respiratory support with nasal 
high-flow (NHF) 
Control intervention: Respiratory support with non-invasive 
ventilation (NIV) 
Duration of intervention per patient: until randomized device 
no longer needed or discharge (whichever comes first) 
Follow-up per patient: clinical assessment up to discharge, 
for survival: days 28 and 90  
Biometry 
Efficacy: rates per arm and absolute risk reduction (NIV-
NHF) with 95%-confidence intervals (CI) for primary and 
major secondary endpoints; multivariate logistic regression 
analysis to adjust for covariates and/or protocol deviations; 
no interim analysis 
Description of the primary efficacy analysis and population: 
Full Analysis Set based on an intent to treat philosophy 
Safety: all patients according to the treatment received 
Secondary endpoints: Proportions analysed analogously to 
primary endpoint; Cox regression models and Kaplan-Meier 
curves/ results of logrank tests for survival data within both 
full and per-protocol set of patients; ventilator-free 
days/hours by linear regression model including treatment as 
factor and stratification criteria as covariate 
exploratory analysis of patients with switch to another therapy 
to investigate the potential of rescue therapy 
Trial Duration 
Recruitment period (months): 30  
Duration per patient (days): 90 
First patient in to last patient out (months): 33  
Time for data clearance and analysis (months): 8 
Duration of the entire trial (months): 41 
 
 
 

 
 
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Synopse (German version) 
Studientitel 
Nasaler High-Flow im Vergleich zur nicht-invasiver Beatmung bei 
der Behandlung einer akuten azidotischen hyperkapnischen 
Exazerbation einer chronisch obstruktiven Lungenerkrankung 
Akronym 
ELVIS 
Indikation 
akute azidotische hyperkapnische Exazerbation einer chronisch 
obstruktiven Lungenerkrankung (AECOPD) 
Primäres Ziel der Studie/ 
primärer Endpunkt 
Anteil Patienten mit Therapieversagen der zugewiesenen 
Atemunterstützung innerhalb von 72 h nach Beginn der 
Atemunterstützung. Definition des Therapieversagens: 
a) Intubation oder  
b) Wechsel zu anderer nichtinvasiver Beatmungsmethode oder  
c) Tod 
Sekundäre Ziele der 
Studie/ sekundäre 
Endpunkte 
1. Anteile der einzelnen Komponenten des primären Endpunkts 
2. Anteil der intubierten Patienten innerhalb von 7 
Kalendertagen nach Hospitalisierung/Randomisation 
3. Gesamtüberleben an Tag 28 und 90 
4. Beatmungsfreie (invasiv) Tage bis Tag 28 
5. Beatmungsfreie (invasiv) Stunden bis zur Bewertung des 
primären Endpunktes (innerhalb der ersten 72 Stunden nach 
Beginn der Therapie 
6. Intensivstation/Dauer des Krankenhausaufenthaltes 
7. Sedierung erforderlich 
Sicherheits-Endpunkte: 
1. (schwerwiegende) unerwünschte Ereignisse bis zur 
Krankenhausentlassung/Tag 28 (was zuerst eintritt) 
2. Gerätebedingte Intoleranz/Komplikationen 
3. Komplikationen inklusive schwerwiegende Erkrankungen, die 
unter Therapie auftreten  
Studiendesign 
Prospektive, randomisierte, multizentrische, offene Studie nach 
einem Nicht-Unterlegenheits-Design 
Studienpopulation 
Einschlusskriterien: 
1. akute hyperkapnische Exazerbation einer chronisch 
obstruktiven Lungenerkrankung mit pH < 7.35 
2. pCO2 > 45mmHg 
3. Alter ≥ 18 Jahre 
4. unterschriebene Einwilligungserklärung 
Ausschlusskriterien: 
1. unmittelbare Notwendigkeit einer Intubation (gemäß den 
definierten Intubationskriterien) 
2. pH < 7.15 
3. BMI ≥ 35 kg/m² 
4. etablierte Nutzung der NIV oder CPAP zu Hause 
5. Erkrankung im Endstadium mit Kontraindikation/Ablehnung 
einer Beatmung/Reanimation 
6. Erkrankungen, die den primären Endpunkt beeinflussen 
könnten: z.B. akuter Herzinfarkt, kardiogenes Lungenödem, 

 
 
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akute und massive Lungenembolie (hypertonisch), 
chronische Dialyse mit metabolischer Azidose, instabile 
Rippenfraktur, die die Beatmung beeinflusst, 
Gesichtsverletzungen, die das Tragen einer Gesichtsmaske 
verhindern 
7. akute Erkrankung, die eine Teilnahme an der klinischen 
Prüfung ausschließt 
8. tracheotomierte Patienten 
9. psychische/geistige oder sonstige Einschränkungen, um die 
erforderliche Einwilligung nach Aufklärung zu erteilen 
10. Teilnahme an anderen interventionellen Studien 
11. unzureichende Compliance 
Patientenzahl 
gescreent: 1500 Patienten 
randomisert: 720 Patienten 
analysiert: 720 Patienten 
Therapie 
Experimentelle Intervention: Atemunterstützung mit nasalem 
high-flow (NHF) 
Kontroll-Intervention: Atemunterstützung mit nicht-invasiver 
Beatmung (NIV) 
Dauer der Intervention pro Patient: bis das randomisierte 
Beatmungsgerät nicht mehr benötigt wird oder bis zur 
Entlassung (was zuerst eintritt) 
Follow-up pro Patient: Klinische Bewertung bis zur 
Krankenhausentlassung für das Überleben: Tag 28 und Tag 90 
Biometrie 
Konfirmatorische Analyse: Rate pro Arm und absolute 
Risikoreduktion (NIV-NHF) mit 95%-Konfidenzintervallen für 
primaren Endpunkt; ergänzt durch multivariate logistische 
Regression zur Adjustierung bzgl. Kovariaten (z.B. 
Stratifikationskriterien) und/oder Protokollabweichungen; keine 
geplante Interimanalyse 
Analysepopulation: Full Analysis Set gemäß Intent-to-treat 
Prinzip 
Sicherheitsanalysen: alle Patienten gemäß der tatsächlich 
applizierten Methode 
Analysen sekundäre Endpunkte: Raten analog zu primärem 
Endpunkt: Cox regression und Kaplan-Meier curves/ Logrank-
Tests für Survivaldaten in Full analysis und Per-protokoll 
Population; beatmungsfreie days/hours mittels Linearer 
Regression mit Arm/Behandlung als factor und 
Stratifikationskriterien als Kovariaten 
Explorative Analysen zu Wechseln zu einer anderen 
Beatmungsmethode mit dem Ziel, das Potential aller 
eingesetzten Methoden als Rescue-Therapie zu untersuchen 
Zeitplan 
Rekrutierungszeitraum (Monate): 30  
Studiendauer pro Patient (Tage): 90 
Dauer von First patient in bis last patient out (Monate): 33  
Zeit für Datenbereinigung und Analyse (Monate): 8 
Dauer der gesamten Studie (Monate): 50 

 
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Schedule of assessments and procedures  
Examination / Assessment 
 
Treatment 
Follow-up 
 
Screen
-ing 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
 
Visit 4 
Visit 51 
Visit 61 
timepoint 
 
0 h 
1h 
± 30 min 
2h 
± 30 min 
4h 
± 30 min 
6h 
± 30 min 
12h  
± 60 min 
24h  
± 60 min 
36h 
± 90 min 
48h 
± 120 min 
72h 
± 180 min discharge 
day 72 
± 1 day 
day 28 
day 90 
Informed consent 
X3 
 
 
 
 
 
 
 
 
 
 
X4 
 
 
 
Inclusion criteria/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients characteristics (anamnesis, 
comorbidity) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
medication 
X  
 
 
 
 
 
 
X5 
 
X5 
X5  
X 
 
 
 
Clinical 
parameters 
(heart 
rate, 
respiratory 
rate, 
blood 
pressure, 
Borg’s scale) 
X 
 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
 
 
Adverse Events/side-effects 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Glasgow coma scale (GCS) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Blood gas analysis (BGA): pO2, pCO2, 
pH, SpO2, FIO2 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Therapy 
according 
to 
allocated 
device: device parameters  
 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X7 
X6 
X6 
Therapy: oxygen supplement 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X6 
X6 
X6 
infection parameters and biomarkers 
(optional) 
X 
 
 
 
 
 
 
X5 
 
 
X5 
 
 
 
 
                                               
1 Visit 5 and 6 are conducted by telephone  
2 Assessment of intubation; not applicable, if patient is already discharged since no intubation can be stated in this care 
3 Standard (long) version of informed consent OR concise (short) version of informed consent 
4 Standard (long) version of informed consent, if patient is still able to give informed consent  
5 All medications within the last 24h resp. laboratory paramenters any time within the last 24h 
6 A change of device is possible, if switch criteria are fulfiled OR need for intubation criteria are met before 72h  primary endpoint reached 
7 Ongoing treatment, if patient still hospitalized 

 
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Flow chart  
 
 
 
 
 
 
 

 
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1 RATIONALE, MEDICAL BACKGROUND 
1.1 Medical background 
Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable and treatable 
disease that is characterized by persistent respiratory symptoms and airflow limitation due to 
airway and/or alveolar abnormalities usually caused by significant exposure to noxious 
particles or gases. COPD is a leading cause of morbidity and mortality worldwide. Prevalence 
of COPD is much higher in smokers and ex-smokers, in subjects of ≥40 years of age, and in 
men. 384 million people suffered from COPD in 2010, with a global prevalence of 11.7%. 
Globally, around three million deaths occur annually. The occurrence of COPD is expected to 
rise over the next 30 years. Globally, the COPD burden is expected to increase in coming 
decades because of continued exposure to COPD risk factors and aging of the population 1-3.  
The Global Burden of Disease Study reports a prevalence of 251 million cases of COPD 
globally in 2016 1.32. Globally, it is estimated that 3.17 million deaths were caused by the 
disease in 2015 (that is, 5% of all deaths globally in that year). Most patients with COPD 
develop relevant exacerbations of the disease during their lifetime. Some cases were admitted 
to hospital and present respiratory acidosis. Data from the European COPD audit in 13 
countries recruited patients from 422 hospitals Fehler! Verweisquelle konnte nicht 
gefunden werden.. The study period ran from October 25 to December 19, 2010 or from 
January 3 until February 27, 2011 according to the seasonal peak of COPD exacerbations. 
16016 patients were monitored. Of the patients who had blood gases at admission (13069) 
5933 had hypercapnia (45.4%). 2452 of 13041 (18.8%) demonstrated respiratory acidosis. 
Acute exacerbations of COPD are important events in the management of COPD because 
they negatively affect health status, rates of hospitalization/ readmission, and progression. 
AECOPD is characterized by symptoms such as dyspnea, increased sputum purulence and 
volume. Severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD) can 
lead to acute hypercapnia acidotic respiratory failure, a life-threatening condition. 183 out of 
1000 patients die during hypercapnic AECOPD and 341 out of 1000 will be intubated 4.  
In December 2019, we searched the following databases for recent evidence: MEDLINE, 
Cochrane Central, the Cochrane library, clinical trials, DRKS, ICTRP (nasal high flow, COPD; 
no limits), see appendix 2. To date, non-invasive ventilation (NIV) is the standard therapy for 
hypercapnic acidotic respiratory failure in AECOPD according to established national/ 
international guidelines 5. Solid evidence of its effectiveness has been generated for more than 
two decades. RCTs demonstrated a rapid improvement in blood gases and reduction of 
respiratory rate, in reduced rate of intubation, length of hospital stay, and mortality 4-7. Despite 
its beneficial effects, NIV is often poorly tolerated (11-34 % failure rate) 4,8,9. In most cases, the 
adaptation is difficult and time-consuming and may require patient sedation. Nasal high-flow 
(NHF) provides warmed and humidified gas administered through slightly enlarged nasal 
prongs. The almost saturated and warmed gas flow is the basis of very good tolerance even 
at high flow rates. NHF results in only a small increase in airway pressure (further reduced by 
opening the mouth). NHF reduces minute volume, lowers respiratory rate, and decreases the 
work of breathing. Exhaled gas in the upper airways is rapidly washed out, and thus 
physiological dead-space is reduced 10-14. The high flow rates delivered by NHF are sufficient 
to cover even high peak inspiratory flows, thereby avoiding the admixture of ambient air. In a 
recent study, NHF was found to be superior to standard nasal prongs (SNP) and NIV in patients 

 
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with severe hypoxemic respiratory failure with regard to intubation rates and mortality 15. The 
reintubation rate in the NHF arm was non-inferior or better compared to either venturi mask, 
SNP or NIV respectively 16,17 in a mixed hypoxemic population. In addition, there is growing 
evidence that NHF results in pCO2 reduction in hypercapnic patients over short periods 18-20. 
In a small pilot trial in patients with stable hypercapnic COPD over 6 weeks of duration NHF 
was found to be not inferior compared to NIV in reducing pCO2 21. Together with CO2 wash-
out studies these results led us to hypothesize that acute hypercapnic COPD patients might 
benefit from NHF as well. A couple of recent smaller trials in the acute setting appear to confirm 
this hypothesis in mixed populations with a subset of hypercapnic COPD patients 22,23. They 
demonstrated significant improvements in blood gases during NHF therapy. In a very recent 
retrospective trial hypercapnic acidotic AECOPD patients were switched to NHF if they did not 
tolerate a prior NIV trial. The authors found comparable improvements to former NIV trials in 
terms of blood gases 24 - observational results arguing in the same direction. 
1.2 Justification of investigation Design 
There is no doubt growing interest in the use of NHF in ventilatory failure. So far most RCT´s 
exploring the use of NHF in acute respiratory failure have excluded hypercapnic patients 15,16,25. 
It is not surprising that in these studies the investigators found only a small decrease of pCO2. 
Most data about efficiency of NHF exists in postextubation respiratory failure. This entitiy 
includes also respiratory acidosis defined as pH<7.35 and paCO2 more than 45 mmHg. 
Interestingly in the two studies by Hernandez et al. a non-significant trend of decreasing 
respiratory acidosis rate during NHF therapy was seen 17,25. These trends were found in 
comparison to conventional oxygen and non-invasive ventilation (NIV). This finding would be 
important because of the prophylactic use of NIV in the postextubation phase have produced 
discordant results. The best domain for NIV in postextubation process was only documented 
in COPD patients 5.  
1.2.1 Evidence from physiological/ preliminary/ retrospective/ observational trials 
An increasing number of studies and case reports with hypercapnic patients have been 
reported 10,13,19,24. Most of the studies investigating the effects of NHF on (relevant) chronic 
hypercapnia were done in COPD patients. The first study was the investigation by Bräunlich 
et al. in 2013 19. This physiological study was the first to describe the complex changes of 
respiratory patterns in healthy volunteers, patients with COPD and lung fibrosis. Here patients 
with stable daytime values of capillary pCO2 using NHF for 8 hours with a flow of 24l/min 
showed a decrease in capillary pCO2 by 0.69 ± 0.2 kPa 14. These changes were found despite 
a decrease in respiratory rate and minute volume. Additionally, significant changes were also 
found in patients with interstitial lung disease (ILD). Another study by the same group published 
in 2016 confirmed these results and documented a decrease of capillary pCO2 in 54 COPD 
patients 20. The main finding was the higher grade of decarboxylation by using higher flow 
rates. The mean decrease in 20l/min was 91 ± 6.7% and in 30l/min 87.4 ± 6.2% after a two 
hours treatment period. Therefore in according to the study by Frizzola et al. decrease in 
hypercapnia was a flow-dependent effect 26. Another interesting study came from a group from 
Milano. Pisani et al. investigated patients with COPD and showed a decrease in arterial pCO2 
at a flow rate of 20 and 30 l/min with closed mouth condition. In 30 l/min but not in 20 l/min 
there was also a decrease in pO2 but with decreasing respiratory rate 27. The retrospective 
clinical study by Jeong et al. revealed the potential decrease in hypercapnia during NHF 

 
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therapy also in a cohort of 46 patients with and without COPD in an emergency department 28. 
Most of the patients in the hypercapnic group had a COPD and acute exacerbation. The 
hypercapnia decreased significantly while increasing paO2. But this observation was only 
found in hypercapnic patients. 
The only study comparing NIV and NHF in a long time setting was conducted in 2015. Ten 
patients without an exacerbation in the last 4 weeks were eligible for participation. These 
patients used NHF in the first 6 weeks with a flow rate of 20l/min. After a study visit a low 
intensity NIV for additional 6 weeks was conducted. In this preliminary study the authors found 
effectiveness in decreasing hypercapnia during NHF therapy.  
Between NIV and NHF no significant differences were found 21. Additionally there exists more 
small studies and case reports. 
Two studies were published in acute AECOPD. The first observational study was conducted 
by Bräunlich et al. 24 Patients with NIV failure were treated with NHF. The authors found an 
increase in pH and a decreasing hypercapnia. These results were confirmed by an Italian 
group 29 . 
In contrast to studies in hypoxemic respiratory failure, most studies investigating the effects in 
decreasing hypercapnia had low numbers of recruited patients. Stability of oxygenation or 
statements about spontaneous reversibility of hypercapnia or time to former hypercapnic 
exacerbations are often lacking. As mentioned all available studies are very different in design 
and patients selection. So a definitive conclusion is premature.  
1.2.2 Evidence from randomized controlled trials 
The TIBICO trial is a cross over study using either NHF or standard NIV in stable hypercapnic 
COPD patients for 6 weeks periods each. The authors found non-inferiority of NHF compared 
to NIV in terms of decreasing hypercapnia and improvement in quality of life. This is the first 
randomized controlled trial which confirmes with a high quality level the beneficial effect of 
NHF in hypercapnic patients 30. 
1.2.3 The need for a trial and justification of design aspects 
Novelty: Preliminary data shows nasal high-flow (NHF) to be comparably effective in improving 
blood gases although only few investigations have been performed. A confirmatory trial 
involving a sufficient number of patients is lacking. NHF is well tolerated and simple to use 20. 
Clinical impact: First: NHF might be an option for those patients who do not tolerate NIV 
therapy. Second, the need of sedation and co-medication may be reduced. Third, NHF is easy 
to use, time-saving in application and well tolerated. Therefore, longer usage times are 
expected. All of these reasons may contribute to the effectiveness of NHF (pCO2 decrease, 
pH normalization, lower respiratory rate, lower intubation rate, possible increase in survival) 
Patient benefits: Patients who do not tolerate NIV are usually treated with oxygen and a large 
fraction of these patients will have to be intubated due to worsening respiratory conditions - 
associated with poorer prognosis. For these patients NHF might be an important and 
potentially life-saving alternative. Improved tolerance of NHF may lead to longer usage periods 
30. In contrast to NIV, patients during NHF are able to eat, drink and speak, resulting in 
improved quality of life.  

 
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Humidification during NHF is superior compared to NIV and improves mucociliary clearance 
31. NHF is not associated with skin rash, bruises, ulceration, or the drying of mucosal surfaces 
as observed with NIV. 
Socioeconomic impact: Intubated and mechanically ventilated patients with AECOPD require 
cost-intensive ICU specific care. If NHF proves to be similarly effective and better tolerated, a 
cost-lowering effect is expected. Due to the high prevalence of AECOPD, this might add up to 
considerable savings. NHF might reduce the use of resources (including staff) even outside 
the ICU-setting. 
In summary, this trial may contribute to extend the treatment of patients with hypercapnic 
acidotic AECOPD. In case of non-inferiority, it might provide a new and resource-efficient 
therapeutic option especially in patients not who do not tolerante NIV. 
1.3 Risks and benefits 
The major risk exists in case of failure of respiratory support by using the NHF device. 
Therefore, we implemented the opportunity to switch the device. This switch can be used as a 
so called “rescue NIV”. This approach has the benefit to avoid intubation in case of device 
failure. The same procedure can be used in case of NIV failure (“rescue NHF”). 
The pronounced benefit is the use of another non-invasive respiratory support device (NHF) 
in case of NIV intolerance. As stated above during optimal study situations 11% of AECOPD 
patients did not tolerate NIV. For these patients only oxygen administration is available (but 
dangerous/ insufficient in case of muscle pump failure). In real life up to 30% of acidotic 
AECOPD patients decline NIV for several reasons. Avoiding intubation could be the most 
relevant benefit in these patients. 
NIV requires trained staff, needs special experience, is time intensive and probably often 
started at ICU. NHF if beneficial is easy to use and preserves ressources. Hence deficient 
respiratory support as documented in the study by Hartl et al. could be avoided 1.32. 
Residual risks associated with the investigational device might be an intolerance of the high 
flow or temperature, nose bleeds, dehydration of the nasal mucous membrane, ingestion of air 
or loud noise resulting from the applicator behind the ear. 
Risks with NIV might be a pressure points on the nose, felling of fullness, drying of the mouth 
and throat area, allergic reactions, sneezing fits, ingestion of air, runny nose, conjunctivitis, 
headache, chest pain and device leakage. 
 

 
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2 OBJECTIVES 
The main objective of the project is to compare nasal high-flow (NHF) with non-invasive 
ventilation (NIV) in cases of acute acidotic hypercapnic exacerbation of chronic obstructive 
pulmonary disease (AECOPD). 
2.1 Hypotheses of the clinical investigation 
Non-inferiority of NHF compared to NIV in acidotic hypercapnic AECOPD. 
2.2 Primary objective 
The primary objective is to analyse treatment failure of allocated respiratory support within 72h 
after start of respiratory support. The precise definition of the corresponding endpoints are 
provided in the section on Biometry. 
2.3 Secondary objectives 
The secondary objectives are to determine and compare the reasons and types of failure, the 
need for ventilation and for sedation. Compliance and acceptance of devices will also be 
investigated. Safety issues of interest are device related intolerance/complications and severe 
diseases acquired under treatment. The corresponding endpoints are defined in the Biometry 
section. 

 
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3 TRIAL DESIGN AND DESCRIPTION 
3.1 Trial design 
ELVIS is a prospective, randomized, multi-centre open label trial following a non-inferiority 
design. 
3.2 Requirements at the Trial Sites regarding Personnel and Equipment 
The co-ordinating Investigator is licenced to practice medicine, is a medical specialist in 
pneumology and/or intensive care medicine and has at least two years of working experience 
in the study specific indication. He/She has theoretical and practical experience in conducting 
clinical trials. 
Investigator and Sub-Investigators are licenced to practice medicine, are medical specialists 
in pneumology and/or intensive care medicine and have at least one year of work experience 
in study specific indication.  
The Investigator is responsible for selecting and assembling the trial team members (especially 
the medical staff) according to the requirements of this trial protocol. The co-ordinating 
investigator/responsible institution will provide these to each trial site. Furthermore, the 
investigator is responsible for training and supervision of the trial team and providing all 
necessary information during the course of the trial. This has to be documented accordingly. 
All study sites must have 
1. In-depth experience in using NIV and NHF 
2. access to intensive/intermediate care units 
3. access to medical emergency units 
4. the general opportunity to recruit patients in this trial. 
 
Each trial site receives a study-specific NHF device, though other specified devices may also 
be used (see chapter 0). The handling of the devices is carried out according to the 
manufacturer's instructions. 
3.3 Trial Sites and Number of Trial Subjects 
Planned number of participating sites are 35. 
The total number of patients are 720 (see sample size discussion in chapter 8.4) 
3.4 
Trial Duration 
Individual trial duration: 
 
Duration per patient: 90 days 
All patients will remain in the study until the end of the follow-up, which is reached 90 days 
after randomization of the last patient. For an expected recruitment period of 30 months, the 
longest study duration is 33 months.  
 
 

 
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Total duration of the study: 
 
Expected duration of recruitment:  
30 months 
 
Expected time from first patient in to last patient out: 
33 months 
Start of the study is defined as date of the first written informed consent (first patient in - FPI). 
End of study corresponds to last patient out (LPO). 
3.5 Premature Termination of the Trial 
Premature termination of the trial for a single patient is described in chapter 6.10.2. 
3.5.1 Premature termination of the trial at a trial site 
The trial can be aborted at a single site if: 
• the protocol is not adhered to, 
• the quality of data is deficient, 
• there is inadequate recruitment 
The co-ordinating investigator decides whether or not to exclude the site, together with the 
responsible institution and biometrician. 
Investigators and sites no longer participating in the trial must inform the co-ordinating 
investigator immediately and should provide justification for the decision. Further treatment of 
patients still involved in the trial has to be arranged together with the co-ordinating investigator. 
CAUTION: Trial site may be temporarily placed on hold or closed by the co-ordinating 
investigator if no or insufficiently qualified personnel is available.  
3.5.2 Termination of the whole trial or individual arms of the trial  
The trial can be terminated prematurely by the co-ordinating investigator in the event of 
• serious adverse events  
• changes in the risk-benefit considerations, e.g. as a result of unexpected adverse events 
• new insights from other trials 
• an insufficient recruitment rate. 
The responsible ethics committee(s) might also revoke the favourable opinion due to e. g. 
information from other clinical investigations. 
The final decision regarding the premature termination of the trial will be made by the co-
ordinating investigator in consultation with the DSMB. 

 
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4 TRIAL SUBJECTS 
Chronic obstructive pulmonary disease (COPD) is a progressive life-threatening lung disease 
that causes breathlessness (initially with exertion) and predisposes to exacerbations and 
serious illness.  
Most COPD patients have exacerbations 1 or 2 times a year. As mentioned above, in case of 
severe illness a relevant number of these patients were hospitalized. If severe respiratory 
symptoms occur, patients will be hospitalized by entering the emergency room. Acute 
exacerbation of COPD is one of the most reasons for acute presentation. To calculate the 
expected number of patients we requested number of recruitable patients by the centers.  
4.1 Inclusion criteria 
Definition of the trial population 
1. acute hypercapnic exacerbation of chronic obstructive pulmonary disease with 
respiratory acidosis (pH < 7.35) 
2. pCO2 > 45mmHg 
Regulatory requirements 
3. age ≥ 18 years  
4. written informed consent (see chapter 6.2)   
4.2 Exclusion criteria8 
Intervention impossible (due to anatomic/medical reasons) 
1. 
immediate need for intubation (acc. to defining intubation criteria, see chapter 0) 
2. 
pH < 7.15 
3. 
BMI ≥ 35 kg/m² 
4. 
established home-NIV or home-CPAP 
5. 
end-stage disease with DNI/DNR order 
6. 
diseases that could influence the primary endpoint: e.g. acute heart infarction, 
cardiogenic lung edema, acute and massive lung embolism (hypertensive), chronic 
dialysis with metabolic acidosis, unstable rib fracture influencing ventilation, injury to 
the face prohibiting use of a face mask 
7. 
acute disease that precludes participation in the trial 
Contraindications 
8. 
tracheotomized patients  
Regulatory requirements 
9. 
psychological/mental or other inabilities to supply required informed consent  
10. 
participation in other interventional trials 
Others 
11. 
suspected lack of compliance 
                                               
8 In an emergency situation, the examination of the exclusion criteria will be carried out to the best of 
 one’s knowledge at the time of inclusion. 

 
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4.3 Justification for the Inclusion of vulnerable Populations 
This clinical trial will not include vulnerable individuals. 
 
 
5 INVESTIGATIONAL INTERVENTION/PRODUCT 
5.1 Non-invasive ventilation (NIV) 
Use of NIV devices of any manufacturer are allowed that are used routinely. 
5.2 Nasal high-flow (NHF) 
For the nasal high-flow, the device “TNI soft flow” is recommended and will be provided by the 
coordinating investigator before the start of the study. However, other dedicated nasal high-
flow devices can also be used. Such devices must be capable of at least 50 litres per minute 
and sufficient humidification must be ensured. The applicators should also be heated 
sufficiently. Hybrid devices are not allowed. If questions should arise, decisions will be made 
regarding permitted devices after consultation with the coordinating investigator. Before the 
start of the study, the use of the available NHF devices will be checked and documented in the 
qualification documents for the trial centre. 
For more details about the therapy see chapter 6.6. 

 
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6 DESCRIPTION OF THE TRIAL/TREATMENT PROCEDURES 
6.1 Screening 
The participating trial centres will screen all patients with acute acidotic hypercapnic 
exacerbation of chronic obstructive pulmonary disease, as far as the physician can be 
assessed, if the patient coming to the clinic via the emergency room, intensive care unit or 
normal ward. Patients that appear suitable for the trial (see inclusion and exclusion criteria) 
should be informed about the possibility of participation. All screened patients, who refuse to 
participate will be listed in an anonymous screening failure log. This document will include 
information on gender and age. Those willing to participate and giving written informed consent 
will be included into the trial and continue with the trial procedure. 
6.2 Patient Information and Informed Consent 
All patients in this trial are able to give informed consent. Patients who are not able to 
give informed consent will not be included into the study. An authorised trial physician will seek 
the patient’s consent before performing any trial specific medical procedures with the patient.  
Before obtaining informed consent, the potential trial participant will receive information 
regarding the clinical trial. It will be performed by a qualified medical member of the trial group 
authorised by the investigator for this task. 
In accordance with international guidelines, the informed consent of trial participants will be in 
writing (written, dated and signed by the person performing the interview referred to below, 
and by the subject, if possible). 
There are different departments where the patients with acute acidotic hypercapnic 
exacerbation of chronic obstructive pulmonary disease (AECOPD) can be informed about the 
ELVIS trial. A number of patients come to the clinics via emergency room and require rapid 
treatment with a ventilator. If the clinical situation does not permit the standard version (long 
version) of the consent form to be applied right away, a concise version (short version) may 
be used. The standard form will be completed by the patient at the latest before discharge.   
The standard and concise version includes the following items: 
 
the nature, objectives, benefits, implications, risks and potential inconveniences of the 
clinical trial 
 
the expected duration of the subject's participation in the clinical trial 
 
the information that the patient may withdraw his consent to participate at any time 
without giving reasons.  
 
potential treatment alternatives 
 
follow-up measures in case of early termination of the trial for the patient or overall 
 
the applicable damage compensation system in case of damage to a patient 
 
the right on data access, rectification and withdrawal of personal data (short 
information) 
 
The patient gives his/her consent to the study and to data processing in both versions of the 
consent forms (concise and standard version). 

 
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If the patient is not able to sign the short version of informed consent himself, but the patient 
is responsive, it is possible to consent to the study in the presence of witnesses. Witnesses 
must be study-independent persons. 
If the patient's state of health deteriorates and the patient is no longer able to give informed 
consent, the concise version of the informed consent is sufficient. 
 
 
6.2.1 Withdrawal of informed consent  
Patients may withdraw their informed consent in writing or orally at any time without giving 
reasons and without suffering any disadvantage. If patients withdraw their consent, no further 
data will be collected. However, the data processing carried out up to the date of withdrawal 
remains lawful.  
Due to the research character of the study, the rights of the patients regarding data protection 
may be restricted in terms of time and/or content, because otherwise the scientifically correct 
execution of the research project would probably be rendered impossible or seriously impaired 
(Art. 17 (3d) EU-DSGVO) 1.35 and because the processing is carried out for scientific research 
purposes and the interests of the responsible institution in the processing considerably 
outweigh the interests of the person concerned in excluding the processing (Art. 89 EU-
DSGVO in connection with § 27 BDSG). See also chapter 10.1 for further information. 

 
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6.3 Screening Visit 
All patients, who meet the inclusion criteria and none of the exclusion critera are met, will 
continue with the qualifying screening visit, which will be structured as follows: 
 
confirm the patient fulfils inclusion and exclusion criteria 
 
obtaining standard (long) version of informed consent OR concise (short) version of 
informed consent 
 
patients characteristics (anamnesis, comorbidity, concomitant medication) 
 
clinical parameters: heart rate, respiratory rate, blood pressure measurements 
 
Borg’s scale 
 
Glasgow coma scale (GCS) 
 
blood gas analysis (BGA): pO2, pCO2, pH, SpO2, FIO2 
 
therapy according to allocated device: NHF or NIV 
 
optional: infection parameters and biomarker: leucocytes, IL6, CRP, PCT 
6.3.1 Discovery of the Violation of Eligibility Criteria after Inclusion  
In general, the violation of eligibility criteria is not a reason for premature withdrawal of the 
patient from the trial therapy or from the whole trial.  
If a violation of a selection criterion is discovered after randomization of a patient, this has to 
be documented in the eCRF, which will result in an automatic report to the responsible trial 
team members at the ZKS Leipzig.  
After consultation with the co-ordinating investigator, project management of the ZKS Leipzig 
informs the investigator or authorised medical staff immediately regarding the further treatment 
of the patient. The patient’s data will continue to be recorded unless the patient revokes his/her 
informed consent. For procedures after premature trial termination of a single patient see 
chapter 6.9.1 and 6.9.2. 
6.4 Visit 0/Randomization  
Visit 0 is the timepoint after checking the eligibility criteria and patients will be randomized. 
The responsible study personnel have to log on to the secure data base and enter the relevant 
data into the data base to initiate the randomization process. Randomisation will be performed 
centrally, via a secure web-based tool. The allocation to the intervention arm (randomisation 
ratio 1:1) uses computer generated allocation sequences. Randomization will be stratified by 
centre, pH-value ≤/>7.3 and BMI ≤/> 30 kg/m². The randomization result forwarded back 
automatically via email confirmation to the investigator and the Clinical Trial Centre Leipzig 
(email). After the result of the randomization is established, the treatment is started 
immediately (0 hour). The randomization is equal to start of ventilation. 
The device parameters and oxygen supplement have to be documented to this timepoint. 
 
 

 
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6.5 Trial procedure(s) during treatment 
Visit 1 (V1) includes the first day of treatment. The start of invervention (NIV or NHF) is usually 
the same day like the screening visit. The following examination must be performed one, two, 
four, six (± 30 minutes), twelve and twenty-four hours (± 60 minutes) after the start of 
ventilation:  
 
clinical parameters: heart rate, respiratory rate, blood pressure measurements 
 
Borg’s scale 
 
Glasgow coma scale (GCS) 
 
blood gas analysis (BGA): pO2, pCO2, pH, SpO2, FIO2 
 
documentation of adverse events/side effects 
 
documentation of device parameters and oxygen supplement 
 
therapy according to allocated device: NHF or NIV according to randomization 
 
optional to timepoint 24 hours: infection parameters and biomarker: leucocytes, IL6, 
CRP, PCT 
A change of device during the treatment is possible, if switch criteria are fulfilled OR 
need for intubation criteria are met before 72 hours. For more details see chapter 0. 
Visit 2 (V2) includes the second day after start of ventilation and the following examinations 
must be performed thirty-six (± 90 minutes) and fourty-eight hours (± 120 minutes) after 
the start of ventilation:  
 
clinical parameters: heart rate, respiratory rate, blood pressure measurements 
 
Borg’s scale 
 
Glasgow coma scale (GCS) 
 
blood gas analysis (BGA): pO2, pCO2, pH, SpO2, FIO2 
 
documentation of adverse events/side effects 
 
documentation of device parameters and oxygen supplement 
 
therapy according to allocated device: NHF or NIV according to randomization 
 
optional to timepoint 48 hours: infection parameters and biomarker: Leucocytes, IL6, 
CRP, PCT 
Visit 3 (V3) have to be performed 72 hours (± 180 minutes) after start of ventilation with the 
following assessments: 
 
clinical parameters: heart rate, respiratory rate, blood pressure measurements 
 
Borg’s scale 
 
Glasgow coma scale (GCS) 
 
blood gas analysis (BGA): pO2, pCO2, pH, SpO2, FIO2 
 
documentation of adverse events/side effects 
 
documentation of device parameters and oxygen supplement 
 
therapy according to allocated device: NHF or NIV according to randomization 
The discharge of the patient is individual. Before the patient is discharged from hospital, the 
following examinations/processes must be carried out:  
 
obtaining the standard version of informed consent, if only give informed concent by 
concise version  
 
physical examination: heart rate, respiratory rate, blood pressure measurements 
 
Borg’s scale 

 
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 
Glasgow coma scale (GCS) 
 
blood gas analysis (BGA): pO2, pCO2, pH, SpO2, FIO2 
 
documentation of adverse events/side effects 
 
documentation of device parameters and oxygen supplement 
After discharge treating physician should monitor reversibility of hypercapnia. In case of 
ongoing hypercapnia long-term NIV or NHF should be prescribed. 
6.6 Dose, mode and scheme of intervention  
Patients may be ventilated with NIV/NHF for a short time during transport or prior to 
randomization.  
Following randomization, patients will be treated with the respiratory support device (NIV/NHF) 
according to allocation as medically required or until discharge (whichever comes first).  
In the NIV arm, the physician will begin to apply NIV via facial mask. Pressure support will be 
initiated with 18/4 mbar for adaptation and then increased to achieve effective respiratory 
support with maintained tolerance.  
NHF will start with a flow of 30 l/min at 37 degrees, generally with standard or large sized 
prongs. Later adjustments at a patient level are foreseen. 
With both devices, oxygen should be supplemented to reach O2 saturation of 88-92%.  
The success of the intervention will be monitored by blood gases and outcome parameters. 
Patients should use respiratory support as long as possible, both day and night. The study 
intervention can be initiated on a regular ward or in intermediate or intensive care facilities, as 
well as emergency rooms. 
6.7 Guidance for switching devices and the need for intubation 
6.7.1 Switch from NIV to NHF or vice versa / rescue method in case of worsening of 
respiratory insufficency and in absence of intubation criteria 
It is strongly recommended continuing with the allocated device unless there is clear 
evidence of device failure, defined as any one of the following: 
1. at 1h:  
 an unacceptable decrease in pH (pH change of 0.06),  
 an unacceptable increase in pCO2 (pCO2 change of 10mmHg),  
 an unacceptable decrease in GCS,  
 an unacceptable increase in respiratory rate (RR>20% compare to last 
measurement), 
 insufficient compliance 
2. at 2h 4h, 6h, 12h and every 12h till 72h:  
 unacceptable worsening in pH or pCO2,  
 clinically unstable (beginning at 4h) compared to last status,  
 very poor compliance 
All criteria which lead to the investigator’s decision to switch treatment - including patient’s 
incompliance - will be documented in the patient file and in the CRF so that post-hoc ratings 
are possible (based on the study’s database). 
 

 
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6.7.2 Need for intubation criteria  
Individual decision of the physician in consideration of the clinical evaluation  
Respiratory acidosis pH < 7.15 (strongly recommended, exceptions must be justified) AND 
at least one of the following (recommended) 
1. GCS (Glasgow coma scale) <10 unless medically induced OR 
2. Increasing hypoxemia despite adequate oxygenation (O2 saturation <85% or pcaO2<45 
mmHg/ FiO2 set>50%) OR 
3. A respiratory rate above 40 cycles/min 
Independent from the outcomes regarding device failure and/or intubation, all patients will be 
followed-up until 90d post randomization. 
6.8 Additional treatments 
Standard care follows the local COPD exacerbation protocol:  
 
oral prednisolone 40 mg/day for 5 days; 
 
antibiotics prescribed according to the following criteria:  
o fever (body temperature >38.5°C),  
o elevated C-reactive protein (CRP) >50 mg/L,  
o change in sputum colour, and/or  
o according to the physician's decision of severe illness, and/or 
o FEV1 <30% below of the predicted value 
 
inhaled corticosteroids, beta-agonists and/ or anticholinergics. 
Oxygen will be prescribed in all patients through a standard low flow system in order to 
maintain adequate arterial oxygen saturation (SaO2). Patients will be discharged with regular 
low flow oxygen once they fulfil the criteria for long-term oxygen therapy. 
6.9 Follow-up procedures 
The first follow-up visit (visit 4) will be performed 7days (± 1 day) after the start of 
ventilation.  
The following assessements have to be performed at this follow-up timepoint:  
 
clinical parameters: heart rate, respiratory rate, blood pressure measurements 
 
Borg’s scale 
 
blood gas analysis (BGA): pO2, pCO2, pH, SpO2, FIO2 
  documentation of adverse events/side-effects 
 
documentation of device parameters and oxygen supplement, if necessary 
 
Therapy according to allocated device, if patient still hospitalized on day 7  
 
The second and third follow-up (visit 5 and 6) will be performed 28 and 90 days after the 
start of ventilation by telephone only:  
 
Health status: question of adverse events/side-effects 
 
use of ventilation 
 
For documentation purposes, a worksheet is made available to the trial center in order to 
document the desired parameters and to be able to place them as a source document in the 
patient file. 

 
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6.10 Premature termination of the therapy or follow-up for individual patients 
The primary statistical analysis follows the intention to treat principle as closely as possible. 
For a valid analysis, it is of great importance to minimise the rate of drop-outs. Therefore, in 
patients who do not withdraw their consent, all trial visits shall be performed as scheduled.  
In case of premature termination of therapy, it is necessary to document the date (as exactly 
as possible), the reason of termination and the current condition of the patient. Therefore, the 
eCRF “End of study (ES)” has to be completed for each patient. Data entry to this eCRF page 
will trigger an automatic report to the responsible trial team members at the ZKS Leipzig. 
The “End of study”- eCRF routinely contains the following data: 
 
Date of individual end of trial 
 
Reason for trial termination 
 
Latest patient contact 
6.10.1 Premature termination of therapy for individual patients 
Trial therapy must be terminated prematurely, if the investigator decides/judges that  
 
an adverse event/incidence occurred to a patient and continuation of trial treatment 
would thus be an unaccepptable risk for this particular patient 
 
the worsening of a patient (who is not responding to treatment) contraindicates the 
treatment with trial therapy transiently or permanently  
 
a patient is significantly non-compliant with the requirements of the protocol, thereby 
endangering patient’s safety 
 
any other reason of medical prudence applies 
Trial therapy must also be terminated prematurely  
 
on request of the patient 
With exception of the rules described above, premature termination of therapy should be 
avoided. In case the patient misses the scheduled visits, the investigator may contact the 
patient directly, in order to motivate him/her to continue.  
All further trial visits until day 90 will take place as planned and described in section 6.9.  
Termination of trial therapy does not necessarily mean that the patient is off-trial. 
6.10.2 Premature trial termination for individual patients 
All randomised patients will be followed up until day 90. Premature termination of trial therapy 
does not necessarily lead to individual trial termination. 
The only circumstances in which a premature trial termination (i.e. no further trial visits) in a 
randomised patient is unavoidable are: 
 
a patient is worsening (and not responding to treatment) that contraindicates 
participation in any further trial visits  
 
withdrawal of informed consent, 
 
complete loss of contact to the patient or 
 
death of the patient. 

 
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6.10.3 Premature Termination of the Follow-up for Individual Patients 
Follow-up can be prematurely terminated, if: 
 Informed consent was withdrawn 
 Complete loss of contact to the patient  
 Death of the patient 
6.11 Counterindicated/Forbidden Concomitant Medication or procedures 
The following medication should not be given:  
 
Bicarbonate modifying newly started medication, e.g. bicarbonate modifying newly 
started medication Natriumhydrogenkarbonat (NaHCO)/Bicarnorm   
6.12 Plan for Further Treatment  
After the study patients should be treated to physician’s discretion. The scenario include the 
continued usage or prescription of long-time NIV/NHF. 
 
 

 
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7 ADVERSE EVENTS (AE/SAE) 
Both, the declaration of Helsinki 1.33, as well as the ISO 14155 1.34, chapter 4c and 7.4, prioritize 
subject protection in clinical trials.  
7.1 Adverse Events and Serious Adverse Events (SAE) 
7.1.1 Definitions  
Adverse Events (AE) 
According to ISO 14155, 3.2: Adverse event (AE) is any untoward medical occurrence, 
unintended disease or injury, or untoward clinical signs (including abnormal laboratory 
findings) in subjects, users or other persons, whether or not related to the investigational 
medical device and whether anticipated or unanticipated. 
NOTE 1: This definition includes events related to the investigational medical device or the 
comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3: For users or other persons, this definition is restricted to events related to 
investigational medical devices or comparators. 
Serious Adverse Event (SAE) 
 
According to the ISO 14155: 2020; 3.45: Serious adverse events are adverse events that led 
to any of the following 
a) death,  
b) serious deterioration in the health of the subject, users, or other persons as defined by 
one or more of the following: 
 
a life-threatening illness or injury, or  
 
a permanent impairment of a body structure or a body function including chronic 
diseases, or  
 
in-patient or prolonged hospitalization, or  
 
medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function,  
c) foetal distress, foetal death or a congenital abnormality or birth defect including physical 
or mental impairment 
 
NOTE Planned hospitalization for a pre-existing condition without serious deterioration in 
health, is not considered a serious adverse event.  
Adverse Device Effect (ADE) 
 
According to ISO 14155: 2020; 3.1: an Adverse Device Effect is defined as adverse event 
related to the use of an investigational medical device. 
NOTE 1 This definition includes adverse events resulting from insufficient or inadequate 
 
 
instructions for use, deployment, implantation, installation, or operation, or any 
 
 
malfunction of the investigational medical device. 
NOTE 2  This definition includes any event resulting from use error or from intentional misuse 
 
of the investigational medical device. 
NOTE 3 This includes comparator if the comparator is a medical device. 

 
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Acoordingly, a Serious Adverse Device Effect (SADE) is an ADE fulfilling the criteria for 
seriousness given above. 
7.1.2 Documentation of (Serious) Adverse Events 
All Adverse Events will be documented on special AE-forms from start of ventilation until 
discharge or day 28 (whichever comes first) for each patient.  
Information relevant to AEs will be solicited by the investigator at every patient’s study visit. In 
addition, the patient will be trained to inform the clinical trial site of any health problems arising 
between visits by phone or personal visit. 
Adverse Events are classified by their seriousness, intensity and relationship to the therapeutic 
intervention (see also chapter 15.1). 
There will be no separate SAE-forms in the ELVIS trial. If an AE fulfils any of the criteria for 
a SAE (see chapter 7.1.1 for SAE-definition), the AE has to be marked as “serious” on the 
CRF. This applies to all SAEs, whether or not they are considered to be related to the study 
treatment. 
For both serious and non-serious AEs, documentation should be supported by an entry in the 
patient’s health record.  
Required information includes: the type of AE, seriousness of the event, an estimate of its 
severity, start date, date of resolution, actions required, outcome and an assessment of its 
relationship to trial intervention. 
All abnormal physical and/or laboratory results which are considered to be clinically relevant 
by the investigator should be recorded as (S)AEs. 
The investigator will follow-up the event until the AE has been resolved, resolved with 
sequelae, or was fatal. The investigator should report each AE on according eCRF in a timely 
manner and continuously during the trial.  
Responsibilities of the investigator/recruiting site 
The ELVIS trial follows §23b MPG. Thus, there are no SAE-reporting obligations to the 
competent authority. 
Should SAEs arise, they will be documented on the AE-form of the eCRF and marked as 
“serious” (see above). The criteria for seriousness will also be documented.  
The investigators will be trained to enter data relevant for the safety evaluation of the trial into 
the eCRF without unduly delay. Within the database, a selection of the radio button “serious” 
will trigger an automatic E-mail-announcement of the SAE at ZKS Leipzig. 
If any of the involved ethics committees should require SAE-reports, these will be derived from 
the trial database at the required intervals. 
 
 

 
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7.2 Device deficiencies and Incidents 
7.2.1 Device deficiencies 
‘Device deficiency’ means any inadequacy in the identity, quality, durability, reliability, safety 
or performance of an investigational device, including malfunction, use errors or inadequacy 
in information supplied by the manufacturer including labelling. (ISO 14155: 2020; 3.19) 
If a device deficiency fulfils the criteria of a SAE, the investigator has to follow the procedures 
described in chapter 7.1.2. 
7.2.2 Incidents 
According to Directeive 93/42/EEC, Article 10: ‘Incident’ means: 
a) any malfunction or deterioration in the characteristics and/or performance of a device, as 
 
well as any inadequacy in the labelling or the instructions for usae which might lead to or 
 
might have led to the death of apatient or user or to a serious deterioration in his state of 
 
health.  
b) This also includes any technical or medical reason in relation to the characteristics or 
 
performance of a device for the reasons reffered to in subparagraph a) leading to systematic 
 
recall of devices of the same type by the manufacturer. 
7.2.3 Documentation and Reporting obligations: Investigator 
Documentation and reporting of device deficiencies including serious device deficiencies and 
incidents follows clinical routine according to MPSV §3. Thus, the manufacturer is 
responsible for device deficiencies and reporting of these. Investigator and manufacturer 
colaborate for potential reporting to the competent authority. 
Incidents have to be reported according to clinical routine (MPSV §3) using the „Formblatt 
für die Meldung von Vorkommnissen durch sonstige Inverkehrbringer sowie Betreiber und 
Anwender nach §3 Abs. 2 bis 4 der Medizinprodukte-Sicherheitsplanverordnung“, which is 
available from the website of the BfArM. 
7.3 Concomitant diseases 
If a disease or a condition existed at enrolment and continued unchanged thereafter, this is no 
AE. However, if the disease worsened considerably and/or required additional medical or 
pharmacologic treatment, it has to be reported as AE and SAE, if it fulfils at least one SAE 
criterion as described in section 7.1.1 . 
7.3.1 Therapeutic measures 
If the patient needs treatment due to an adverse event, it must be carried out according to the 
current state of medical research for diagnosis and treatment in order to restore the patient's 
health. 

 
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8 STATISTICAL CONSIDERATIONS 
8.1 Biometrical Aspects of the Investigation Design  
8.1.1 Measures to Prevent Bias 
Randomisation of patients between NHF and NIV is performed centrally via a secure web-
based tool using a modified minimisation procedure with stochastic component according to 
Pocock4 in a 1:1 ratio. The algorithm takes into account the current distribution of patients 
already recruited for the trial in a complex manner which helps ensure allocation concealment.   
Randomisation will be stratified according to the following criteria:  
 
trial site 
 
pH-value ≤/>7.3 and  
 
BMI ≤/> 30 kg/m² 
Patient blinding is not possible due to the nature of interventions.  
The choice to intubate in this open-label trial constitutes a potential bias. Hence we have 
provided specific recommendations regarding the need for intubation see chapter 0. 
8.2 End Points 
8.2.1 Primary Endpoint 
The primary endpoint is the proportion of treatment failure of allocated respiratory support 
within 72h after start of respiratory support. Treatment failure is defined by 
a) intubation or  
b) switch to another method of non-invasive ventilation or  
c) death 
Guidance regarding points (a) and (b) are provided in section 6.7.  
8.2.2 Secondary Endpoints 
1. Proportion of single components identified for the primary endpoint assessment  
2. Proportion of intubation within 7 days after hospitalisation/randomization 
3. Overall survival at 28d and 90d 
4. (Invasive) ventilator-free days until 28d 
5. (Invasive) ventilator-free hours until assessment of the primary endpoint (within the first 
72 hours after begin of therapy) 
6. ICU and hospital lengths of stay 
7. Proportion requiring sedation 
8.2.3 Safety Endpoints 
No specific safety endpoints have been defined, since the efficacy endpoints are closely 
related to the major saftey issues. 

 
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SAE(s) and AE(s) will be listed by treatment received and, as appropriate, those on and off 
device will be distinguished. Device related intolerance will be listed as will complications and 
major diseases acquired under treatment. 
8.3 Statistical Description of the investigation hypothesis 
8.3.1 Statistical Hypotheses/Statistical Estimation Method 
We hypothesized that treatment failure in AECOPD is at most 8 percentage points more 
prevalent for patients with planned NHF compared to planned NIV. 
8.4 Sample Size Discussion 
Two RCT´s have compared NHF and NIV regarding non-inferiority (Doshi et al. 2018; 
Hernández et al. 2016) up to now. Although these studies considered different patients they 
provide rough estimates for the expected difference between the arms and choices of non-
inferioroty margins (15 and 10 percentage points). The reduction of intubation rates from NIV 
studies reported in a recent systematic Cochrane Review (Osadnik et al. 2017) wee 12% vs 
34% (N=1105 of all 17 RCTs) and an absolute risk reduction ARRtotal=-22.1 [-17.3;-26.9] % 
(RR=0.36 [0.28; 0.46]). This review (Osadnik et al. 2017,  see also Plant et al. 2001 and 
Carrera et al. 2009) presented ARR point estimates of -12.7/ -20.7/  -11.9% and corresponding 
lower confidence limits of ARR of -3.4/ -2.0/ -1.6%. Based on these numbers, we defined a 
statistically and medically reasonable non-inferiority margin of Δ=8%. This choice is more 
conservative than in other trials and isfar below the lower confidence limit of ARRtotal as 
requested within statistical guidelines (CHMP/ICH; CHMP/EWP).  
Although our endpoint definition varies to some extent from that in other studies, we based our 
sample size calculations primariily on the reported “need for intubation” rates since intubation 
represents the next step of the therapeutic escalation after NIV therapy and intubation can 
usually be avoided only in a minor proportion of patients by NIV application following NHF. We 
assume that 15% of patients will have treatment failure and that it is equal in both 
randomization arms. 
PASS sample size software (Hintze 2011) was used choosing a non-inferiority test for the 
difference between two groups (by continuity corrected Z-test with pooled variance). To ensure 
an alpha level of 0.025 (1-sided) and a power of ≥0.8, data from a total of N≈680 patients 
should be analysed. The result is expected to be somewhat conservative since the primary 
analysis uses regression methods an thus takes covariates into account. Moreover, continuity 
correction leads to slightly greater sample sizes than without. 
Dropouts and losses to follow up 
Non-compliance and dropout rates are expected to be rather low with regard to the in-hospital 
assessment of the primary endpoint after 72h when its assessment is performed. Therefore, 
the dropout rate is assumed to be <10 %.  
Per arm 360 patients - therefore about 720 patients in total - should be enrolled in the trial to 
ensure sufficiently precise estimations of endpoints after 90d.  
Accordingly, we expect that about 1500 patients will have to be screened for the trial. 

 
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8.5 Statistical Methods 
8.5.1 Analysis Population 
Full analysis set 
The full analysis set (FAS, based on the intention-to-treat (ITT) strategy) is defined to be all 
randomized patients with AECOPD and started on ventilatory support. If, for example, 
pneumonia is detected within 48h (nosocomial), such patients will not be included in the final 
analysis. Patients who test positive for SARS-CoV-2 within 48h will not be included in the full 
analysis set. 
Per protocol set 
The per-protocol (PPS) set is defined by all patients belonging to the FAS without major 
violations of the study protocol.  
The following protocol violations are classified as major: 
 Violation of an eligibility criterion 
 Did not begin use of the allocated device 
 Discontinued use as a result of poor compliance within 72h 
This is not an exclusive list. In the light of protocol violations which actually may occur during 
study conduct, all major protocol violations will be defined, e.g. as part of the statistical analysis 
plan. The completed list will be finalised before database closure and start of the final analysis.  
Safety analysis set 
The safety population is defined to be all randomized patients belonging to the FAS. In safety 
analyses, patients will be classified acoording to the ventilator support applied, irrespective of 
the randomized group allocation. 
8.5.2 Planned Methods for Analysis 
For the confirmatory analysis, linear regression with the stratification variables and the arm as 
covariates will be used and where the dependent variable will be coded as 0, 1. A 95% two-
sided Wald confidence interval for the arm term can then be interpreted in terms of absolute 
risk and the null hypothesis is rejected if it lies entirely to the right of the non-inferiority margin 
of −8 percentage points. As a sensitivity analysis, a two-sided 95%-Wilson confidence interval 
for the difference in proportions will be calculated. Only few missing data regarding all relevant 
endpoints are expected given the rather short period of observation. Nevertheless, 
conservative imputations will be performed independent of treatment arm. Further sensitivity 
analyses are planned to adjust for covariates, possibly imbalanced baseline characteristics 
between groups and/or protocol deviations in multivariable regression models, e.g. for 
(components of) the primary endpoint and/ or in subgroups, which arose from stratification 
criteria. Furthermore, the odds ratios from logistic regression will be computed to have a 
relative risk measure in addition to the absolute one, as recommended by statistical guidelines.  
Absolute risk differences of major secondary endpoints will be analysed in the same way as 
the primary endpoint.  
Kaplan-Meier curves/ results of logrank tests will be presented for 28d- and 90d-mortality. We 
expect the time to death to be (nearly) always available.  

 
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Ventilator-free hours (until 72h assessment) will be analyzed by a linear regression model 
including randomization arm as factor and stratification criteria as covariates. 
Neither imputation of missing values nor adjustments for multiple testing is planned for 
secondary/safety endpoints. No interim analysis is planned.  
The proportion of patients (with 95% confidence limits) who were randomly allocated to NIV 
therapy, but changed to NHF due to insufficient efficacy and avoid an immediate intubation 
and vice versa will be analysed. Both the proportion with and without later intubation will be 
provided. Although these NIV-to-NHF proportions are a form of data exploration, useful 
estimates on the value of NHF as rescue treatment in cases who do not tolerate NIV may be 
derived, especially if compared to usually reported proportions of intubation immediately 
initiated after NIV. 
The proportion of switches to another device before intubation will also be compared to 
investigate potentially existing preferences in favour of NIV, which are assumed by the 
applicants.  
8.6 Statistical Monitoring 
Regular monitoring visits and timely supervision of study documentation including statistical 
monitoring and an established query management will be performed to ensure data quality 
and completeness. 
The trial conduct will be closely supervised by means of central and statistical monitoring 
according to ISO 14155: 2020 chapter 6.7. The objectives are 
 
to detect safety relevant signals as soon as possible 
 
to detect non-compliance and relevant protocol violations and to prevent their future 
occurrence by prompt reaction 
 
to assess potential sources of bias 
 
to prevent missing visits or measurements by prompt reminders  
Therefore, the following issues will be monitored and discussed: 
 
With regard to safety  
o Patients with treatment discontinuation due to adverse events 
o Serious adverse events 
 
With regard to protocol compliance 
o Proportion of patients per site with a switch of device and correct application of the 
criteria for doing so 
o Correct settings for each of the devices 
 
With regard to potential bias 
o Whether or not the patients were ventilated before inclusion in the trial 
o The time lapse between randomization and therapy begin 
o The point in time for switching devices will be compared by device around the 72 
h mark to ensure that patients are not switched with deliberate delay 
o All cases in which intubation is performed without documented fulfillment of the 
guidance criteria 
o All cases in which data suggest that intubation should have been performed, but 
was not 

 
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o Violation of inclusion or exclusion criteria that were discovered after randomization 
– particularly use of NIV or CPAP at home which may not be known when patients 
arrive in an emergency setting. 
 
With regard to missing information 
o Missing visits or visits outside the pre-defined time windows 
o Missing blood gas analysis 
o Missing documentation of the reason for switching devices 
o Missing dates and information on discharge 
o Problems with data when transferring between wards 
Statistical monitoring will be continuously adapted in response to new problems/risks which 
might arise during trial implementation. 
8.7 Final Analysis 
The final analysis will be performed when the data of all enrolled patients have been collected, 
all data management procedures have been finalised and the database has been cleaned for 
analysis. 
In case of a premature termination of the whole trial (due to organisational, financial or other 
reasons) a limited analysis of the data available up to then may be suitable if available sample 
size is sufficient. A power analysis may add information regarding the study results and for 
future trials.  
The decision on the appropriate extent of an analysis will be made jointly between the ZKS 
Leipzig und the coordinating investigator. 
No interim analysis is planned. 
 
 

 
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9 ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS  
All persons participating in the conduct of the trial (responsible institution, co-ordinating 
investigator, investigators, etc.) commit themselves to observe the Declaration of Helsinki of 
the WMA (in its current version), as well as all pertinent national laws and the ISO 14155) 
(where appropriate and applicable). 
9.1 Submission  
According to the professional code of conduct for doctors (§ 15) the clinical trial will be 
submitted to the ethics committee responsible for the co-ordinating investigator, as well as the 
ethics committees responsible for further participating trial sites. The latter also receive the 
primary statement issued by the ethics committee of the co-ordinating investigator. 
9.2 Protocol Amendments  
Changes made to the protocol that was appraised positively by the ethics committee must be 
positively reappraised and approved if the changes 
 
are such that they may affect the subjects' safety, e.g. fundamental changes to the 
therapeutic procedures 
 
result in further data collection that necessitates changes to the patient information 
and/or informed consent form, 
 
affect the interpretation of the scientific documents upon which the trial is based or the 
significance of the results of the trial, 
 
significantly affect the leadership or conduct of the trial, 
 
concern the quality or the innocuousness of the investigational device. 
These changes have to be approved by co-ordinating investigators, if applicable in agreement 
with the biometrician and/or DSMB. 
After the approval/favourable opinion of the changes was obtained, all trial sites will be 
informed of the changes and supplied with changed documents (if applicable). 

 
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10 DATA MANAGEMENT AND DATA PROTECTION 
10.1 Data protection and professional confidentiality  
Leipzig University responsible institution, together with ZKS Leipzig and the trial sites, is 
responsible for the implementation and data processing in accordance with Article 4(7) of the 
General Data Protection Regulation 2016/679 in this trial. The ZKS Leipzig is responsible for 
implementation of procedures for data collection, storage, protection, retention and 
destruction. The data stored in the trial database is secured against unauthorized access. The 
database are located at the ZKS Leipzig at Härtelstr. 16-18, 04107 Leipzig in access-protected 
server rooms. The ZKS Leipzig is responsible for the security of the stored data and has a 
corresponding IT security and data protection concept according to the requirements of the 
German Federal Office for Information Security (www.bsi.bund.de). 
All data will be initially collected by investigators in the recruiting trial sites. Together with 
information on the trial, eligible patients will be informed about data capture, transmission, 
analysis processes and their rights according to the General Data Protection Regulation 
(GDPR). Once a patient is eligible and has given his/her informed consent (concise version) 
to trial participation and data collection, the investigator will assign the patient a unique patient 
identification code. Patient identification code lists will be generated in advance by ZKS Leipzig 
and forwarded to the recruiting sites. These lists are part of the investigator site file and remain 
at the recruiting site. These lists are the only documents that allow for re-identification of the 
patients.  
All clinical data entered by the investigators (or their designated staff) into eCRFs will be 
recorded in a pseudonymized form (i.e. without reference to the patient’s name and date of 
birth) exclusively using the patient’s identification code. 
Clinical monitors appointed by ZKS Leipzig will regularly visit the recruiting sites and verify the 
informed consent forms. This serves to verify that the patient has unambiguously given his or 
her consent for trial participation as well as for data capture, transmission and analysis. The 
patients are informed of this fact and agree to the procedure with the patient 
information/informed consent.  
Patients may withdraw their informed consent in writing or orally at any time without giving 
reasons and without suffering any disadvantage. If patients withdraw their consent, no further 
data will be collected. However, the data processing carried out up to the date of withdrawal 
remains lawful.  
If the informed consent is withdrawn, the patient has the right of data deletion according to the 
GDPR. Information as to when and why a patient was randomised and when he withdrew 
consent must be retained in the documentation.  
According to GDPR, the responsible institution conducting the study is generally obliged to 
delete its data from the study database after withdrawal of consent. Within the framework of 
this study, the coordinating investigator would like to limit this right to deletion, as is permitted 
in Article 17 paragraph 3 point of the GDPR, and continue to process and not delete the 
security-relevant data that has been collected until the withdrawal of consent. In this study, 
safety-relevant data is all information about possible side effects of the NIV or NHF devices.  

 
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10.2 Declaration regarding Data Protection 
We hereby confirm that all clinical trial information will be recorded, processed, handled and 
stored by ZKS Leipzig, Härtelstr. 16-18, 04107 Leipzig, Germany on behalf of the responsible 
institution.  
Data captured by the investigators will be processed in such a way that it can be accurately 
reported, interpreted and verified while the confidentiality of records and the personal data of 
the subjects remain protected. Data capture and processing will be in accordance with the 
applicable law on personal data protection and with the GDPR (EC) 2016/679 of the European 
parliament and of the council. 
Access to the data is strictly limited to authorised persons. Data are protected against 
unauthorised access. 
10.3 Data protection rights 
According to the basic data protection regulation, the study participants have the following 
rights regarding their personal data: 
The right to be informed about their personal data that are collected, processed or, if 
applicable, transferred to third parties in the course of the clinical trial. (if necessary, handing 
out a copy free of charge). 
Right to have incorrect personal data corrected.  
Right to have their personal data deleted, with the exception of the security data described 
above. 
Right to limit processing (in exceptional cases). The right to limit processing must be requested 
from the investigator or the data protection officer of the trial site.  
Right to data transfer of personal data collected about the study participant. This data shall be 
transmitted either to the trial participant himself or, if technically possible, to another body 
designated by the trial participant. 
Right to refuse (conditionally) the use of the data (see also right to cancellation) 
 
The data protection officer of the responsible institution is:  
Datenschutzbeauftragter Medizinischen Fakultät der Universität Leipzig 
Philipp-Rosenthal-Straße 27 
04103 Leipzig 
Telefon:  
+49 (0)341 / 97-16105 
E-Mail:  
dsbmf@medizin.uni-leipzig.de  
10.4 Data management/Case Report Forms (CRF) 
In the context of a database for electronic data capture only, the Case Report Form (CRF) will 
be designed by the ZKS Leipzig in cooperation with the Co-ordinating investigator and 
provided as electronic form (eCRF). In order to facilitate the documentation as per protocol in 
case of malfunction of the electronic system or any of its components, a paper version of the 

 
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CRF (interim CRF) will be provided in the ISF (investigator site file). The data on this paper 
version will be transferred to the eCRF as soon as the electronic system is available again. 
Special CRF forms will be provided as paper CRF: 
 Patient dairy since these will be filled in by the patient directly 
 Randomization for randomization by fax, if the online tool does not work 
An eCRF will be provided for each patient. The patient will be identified as per patient-ID only. 
The eCRF must be completed shortly after each trial visit according to ISO 14155:2020 chapter 
7.8.1 and to enable central monitoring of the trial data. 
Access to the data base will be limited to authorised staff only. Authorisation is granted by the 
site’s investigator using the trial specific staff signature and delegation log. Based on the staff 
signature and delegation log access to the eCRF will be granted by the responsible staff at the 
ZKS Leipzig.  
Authorised staff members on site will be able to enter and update data as well as finalise data 
by electronic signature during the conduct of the trial according to a trial specific concept for 
documentation. This concept is based on the internal Standard Operating Procedures 
implemented by the ZKS Leipzig and follows the ISO 14155: 2020. All entries and data 
changes will be tracked automatically including date, time and person who entered/changed 
information (audit trail). Major correction(s) or major missing data have to be explained. 
10.5 Patient File and Source Data 
All information required by the protocol and therefore collected during the clinical trial must be 
recorded by the Investigator or an authorised member of the trial team as source data in the 
source documentation for the trial (e.g. patient file).  
Source data according to ISO 14155: 2020 chapter 3.47 are defined as any information in 
original records and/or certified copies of original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Source data are contained in source documents. 
The Source Data Agreement is defining source data and their location for respective CRF 
entries. It will be filled in at the initiation visit, signed by the investigator and filed in the trial 
master file.  
In order to confirm the completeness, accuracy and consistency of the data with the data in 
the source documents the principal investigator has to electronically sign each patient’s CRF 
after the individual end of trial participation. 
10.6 Data Management  
For creation of the trial database a clinical data management system will be used. The trial 
database will be validated according to the Standard Operating Procedures (SOPs) of the ZKS 
Leipzig prior to data capture. 
Data management will be done according to the SOPs of the ZKS Leipzig. 
During the whole course of the trial, a backup of the data is made on a daily basis according 
to the backup policies of the IT-Network IMISE/ZKS Leipzig. Unauthorised access to 
pseudonomyzed patient data is prevented by the access concept of the trial database, which 

 
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is based on a strict hierarchy and role concept. Any change of data (e.g. when data is changed 
in the database during query management) is recorded automatically via audit trail within the 
database. 
At the end of the trial, once the data entry has been declared complete, the database will be 
locked. Thereafter, any changes to the database are possible only by joint written agreement 
between responsible institution/co-ordinating investigator, biometrician and data manager. 
10.7 Archiving  
All relevant trial documentation (Trial Master File), the electronically stored data, the original 
CRFs and the final report will be stored for at least 10 years at the university archive Leipzig 
after the regular or premature end of the trial.  
At the investigating sites, the investigators’ files, patient identification lists, signed written 
consent forms, copies of all CRFs and the patients’ files will be stored for at least 10 years 
after the regular or premature end of the trial.  
10.7.1 Anonymization of Data after the end of Archiving  
After the end of the archiving period, all clinical data present at the ZKS Leipzig will be stored 
in an anonymous form. 
All data will be subject to an anonymization process removing personalised data as far as 
possible, i.e. without endangering the possibility to answer scientific questions related to the 
trial. Anonymised data will be relocated to a separate, access restricted, file location and 
secondary data sources will be deleted. The data protection officer of the co-ordinating 
investigator will be contacted before anonymization to ensure a correct and actual 
implementation of this process. 

 
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11 SUPERVISION OF THE CLINICAL TRIAL 
11.1 Access to Source Data 
According to ISO 14155: 2020 chapter 6.7, the principal investigator must permit all authorized 
third parties access to the trial site and the medical records of the trial subjects (source data). 
These include the clinical trial monitors, auditors and other authorized employees of the 
sponsor, as well as members of the local or federal authorities. All these persons are sworn to 
secrecy. 
11.2 Monitoring 
The ZKS Leipzig will be responsible for trial monitoring. Initiation, regular and close-out visits 
will be performed in all trial sites. A risk-based monitoring strategy will be implemented, as 
required by ISO 14155: 2020 chapter 6.7. 
During trial conduct, central and statistical monitoring procedures will be combined with on-
site monitoring visits in order to achieve high protocol compliance and data quality, as well as 
to ensure patients’ safety and rights. The choosen monitoring strategy depends on the results 
of the risk analysis done during the protocol development and will described in the trial specific 
monitoring plan.  
In general, a first monitoring visit at a trial site will be scheduled after the inclusion of the site’s 
first three patients, checking protocol compliance and preventing further systematic errors due 
to misunderstandings. All trial sites will then be visited regularly. The frequency of further on-
site monitoring visits will depend on the trial site’s recruitment rate and on whether problems 
have been detected with the site, either by prior on-site visits or by central monitoring.  
Prior to every scheduled on-site visit, the monitor will be provided patient synopses 
summarising the data already available in the database, and indicating possible protocol 
deviations or inconsistencies. If deemed necessary (e. g. in case of a high number of data 
inconsistencies/queries), queries rised by vigilance and/or from the statistical monitoring will 
be communicated to the site in due time before the on site visit, to enable a timely processing. 
During the visits the monitor will: 
 
check informed consent forms of all patients enrolled  
 
perform source data verification of the key data (selected baseline parameters, therapy 
delivery, serious adverse events, follow-up) in a random sample of the site’s patients 
 
perform targeted source data verification for patients with possible deviations 
 
discuss open queries raised by data management or drug safety personnel 
 
check essential parts of the investigator site file (see monitoring plan) 
 
check source data for AEs or SAEs, which have not been properly reported in the eCRF 
 
check for major violation of the respective guidelines and laws and/or protocol violations 
according to the trial specific monitoring plan. 
11.3 Audits 
The responsible institution might conduct site audits in order to guarantee that the conduct of 
the trial is in accordance with the DoH, DIN ISO 14155 and the trial protocol.  
The investigator agrees to provide access to the auditor for all relevant documents.  

 
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11.4 Independent Supervision of the Trial 
An Independent Data Safety Monitoring Board (DSMB) will meet periodically to perform a 
review and an evaluation of the accumulated study data regarding: 
 safety of the trial intervention  
 integrity and validity of the data 
 appropriate study conduct 
 study progress 
to guarantee the subject’s safety. 
The DSMB will consist of three individual experts who are not involved in the ELVIS clinical 
trial activities and who have no conflict of interest (financial, proprietary, professional or other) 
with any of the participating organisations. 
These core members have sufficient combined expertise in the medical disciplines at hand: 
 the clinical aspects of the underlying disease (AECOPD) 
 complications associated with the treatment of AECOPD 
 biostatistics 
 clinical trial conduct and methodology 
Other ad hoc specialists may be invited as a non-voting member of the DSMB whenever 
additional expertise is required. 
In addition, the DSMB will advise the co-ordinating investigator concerning further trial 
implementation 
(unchanged 
continuation, 
continuation 
with 
changes, 
interruption, 
termination).  
A DSMB-charter will further specify the tasks of the DSMB. 
In order to allow the DSMB to fulfil its responsibilities, the DSMB will receive safety reports on 
a regular basis by the ZKS Leipzig. While reviewing, the DSMB will consider the study-specific 
data as well as any relevant background knowledge of AECOPD treatment, the therapeutic 
procedures and the information provided about the patient population in the study.  
The DSMB will specifically review: 
 the quality, completeness, accuracy and timeliness of the collected data 
 the collected data that may provide evidence of study-related adverse effects so far 
 the performance of the individual clinical centres that are involved in the study 
 the overall compliance with the study protocol and the goals for recruitment and retention  
 all factors internal or external to the study that may affect the study outcome, compromise 
the confidentiality or the ethics of the study or impact patient safety (protocol violations, 
newly available scientific or therapeutic developments…) 
The DSMB will meet at regular intervals (twice a year, preferably by telephone, but in person 
if needed) in open sessions. The DSMB will maintain the data confidentiality during all phases 
of the reviews and deliberations.  

 
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Following DSMB meetings, the DSMB will provide written recommendations to the co-
ordinating investigators on the continuation, modification or termination of the clinical trial. 
Such recommendations can be based on the detection of emerging negative data trends or 
prospects of ethical or safety guidelines not being met. The DSMB may also request contacts 
between itself and the co-ordinating investigator by telephone or in person. 
The ZKS Leipzig will support the DSMB by providing updated data in appropriate format for 
analyses. 

 
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12 ADMINISTRATIVE AGREEMENTS 
12.1 Adherence to the protocol 
The study will be conducted in accordance with the protocol and DIN ISO 14155 as well as 
applicable regulatory requirements. 
Protocol violations are all deviations from the procedures outlined in this document, e.g.  
- 
examinations that are missed or that take place at the wrong time  
- 
non-compliance 
- 
intake of prohibited medication 
After a patient has been enrolled, it is the investigator's responsibility to avoid protocol 
violations in order to obtain unbiased data for the trial. 
Those protocol violations deemed to be major are defined by the risk analysis performed before 
and during trial implementation and will be further detailed in separate documents belonging 
to the risk assessment/monitoring plan. This list can be augmented in the course of the trial. 
Major protocol violations will be reported to the ZKS Leipzig, which will inform the co-ordinating 
investigator.  
All protocol violations will be documented and discussed with the responsible biometrician 
before closing the data base and carrying out the statistical analysis.  
The investigator must ensure that the recorded data are documented as per protocol. Minor 
variations are inevitable in clinical routine, but must be documented together with a justification. 
12.2 Funding and Insurance 
The trial is funded by the Bundesministerium für Bildung und Forschung (Förderkennzeichen: 
01KG2002).  
All trial participants will be insured during trial participation by a volunteers' trial insurance to 
the medical faculty of the Leipzig University: 
Policy number: 
28 138971 03764 
Policy holder: 
HDI Global SE, Eisenbahnstr. 1-3, 04315 Leipzig 
Maximum sum insured: 
500.000 € 
A copy of the insurance policy and the insurance conditions will be filed in the investigator site 
file and the second will be handed to the subject on their request. 
12.3 Publication Policy and Registration 
The results of this trial will be submitted for publication in a peer-reviewed, international 
English-language journal of appropriate aim and scope. Accordingly, the clinical trial will be 
registered at clinicaltrials.gov before recruitment starts. According to the results of main and 
concomitant studies, the results may be submitted in separate or combined manuscripts; 
decisions about the form and scope of individual manuscripts will be discussed among all 
persons participating in the design, conduct and analysis of the trial who qualify for authorship. 
The co-ordinating investigator together with the biometrician(s) is responsible for drafting and 

 
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circulating manuscripts and for discussing and handling requests by co-authors and co-
ordinating investigator to edit the text. 
The authorship will follow the criteria for authorship developed by the International Committee 
of Medical Journal Editors (ICMJE), including those that distinguish authors from other 
contributors. 
The ICMJE recommends that authorship be based on the following 4 criteria: 
 
Substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work; AND 
 
Drafting the work or revising it critically for important intellectual content; AND 
 
Final approval of the version to be published; AND 
 
Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved. 
All those designated as authors should meet all four criteria for authorship, and all who meet 
the four criteria should be identified as authors. Those who do not meet all four criteria will be 
acknowledged in the manuscript.  
The scientific use of data resulting from this trial by local trial sites is ruled by the site contracts 
between the co-ordinating investigator/responsible institution and the local trial sites. 
Generally, sites might use data for own scientific questions (independent from the questions 
discussed in this trial protocol) and publication after consultation with the co-ordinating 
investigator. 
12.4 Data Sharing Statement  
According to the recommendations on data sharing by the International Committee of Medical 
Journal Editors (ICMJE) data resulting from the ELVIS trial will be made available to the 
scientific community as follows: 
After publication of the major results and upon reasonable request from researchers 
performing an individual patient data meta-analysis, individual patient data that underlie 
published results will be shared after de-identification. This requires approval by the local 
ethics committee of the researcher requesting the data along with public registration of the 
meta-analysis. The coordinating investigator will contact the data protection officer before de-
identification to ensure a correct and actual implementation of this process. 
Summary statistics that go beyond the scope of published material will be made available to 
researchers for meta-analysis upon reasonable request and if the necessary data analysis is 
not unduly time-consuming. Together with publication of the main results, the trial protocol in 
full will be made publically available as well as the statistical analysis plan. 
 
 
 
 

 
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14 PROTOCOL AGREEMENT  
 
Herewith I declare that I have read and understood the present protocol and agree to honour 
each part of it. I will ensure that all the patients enrolled in the trial by my site will be treated, 
observed and documented in accordance with this protocol. I will ensure that all persons 
assisting with the trial under my supervision are adequately informed about the protocol, the 
investigational product and their duties.  
I further declare that I do not have any financial and other competing interests in this trial. 
 
Centre-ID 
ELVIS -    
Address trial site (stamp) 
 
 
 
 
 
 
 
 
 
 
Date 
 
Signature Investigator  
 
 
 
 

 
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15 APPENDIX 
15.1 Classification of Adverse Events 
15.1.1 Degree of severity 
The degree of severity of an Adverse Event will be determined in accordance with the 
definitions in 7.1.1. 
15.1.2 Assessment of intensity  
The assessment of the intensity accords with CTCAE V5.0 
 
Mild Adverse 
Event 
 
asymptomatic or mild symptoms;  
 
clinical or diagnostic observations only;  
 
intervention not indicated. 
Moderate 
Adverse Event 
 
minimal, local or noninvasive intervention indicated;  
 
limiting age-appropriate instrumental ADL*9. 
Severe Adverse 
Event 
 
medically significant but not immediately life-threatening;  
 
hospitalization or prolongation of hospitalization indicated; 
 
disabling; 
 
limiting self care ADL** 
Life-threatening 
Adverse Event 
 
Life-threatening consequences; 
 
urgent intervention indicated  
Death related to 
Adverse Event 
 
15.1.3 Determining the causal relationship  
The investigator must assess whether or not the Adverse Event is causally related to the 
investigational device. The following classification is to be used.  
 
Reasonable possibility 
 
No reasonable possibility 
A reasonable possibility exists, if one of the following WHO-UMC criteria is met: 
 
occurring in a plausible time relationship to drug administration, and which cannot be 
explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should be clinically plausible. The event must be 
                                               
9 Activities of Daily Living (ADL):  
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 

 
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definitive pharmacologically or phenomenologically, using a satisfactory rechallenge 
procedure if necessary.  
 
with a reasonable time sequence to administration of the drug, unlikely to be attributed 
to concurrent disease or other drugs or chemicals, and which follows a clinically 
reasonable response on withdrawal (dechallenge). Rechallenge information is not 
required to fulfil this definition.  
 
with a reasonable time sequence to administration of the drug, but which could also be 
explained by concurrent disease or other drugs or chemicals. Information on drug 
withdrawal may be lacking or unclear.  
 
more data is essential for a proper assessment or the additional data are under 
examination 
 
cannot be judged because information is insufficient or contradictory, and which cannot 
be supplemented or verified 
No reasonable possibility exists, if the following WHO-UMC criterion is met: 
 
 with a temporal relationship to drug administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease provide 
plausible explanations. 
15.1.4 Expected/Unexpected 
Adverse Events are unexpected if they do not occur in the manner or with the intensity 
described in the reference document for the medical device (see investigator’s files).  
15.1.5 Outcome of an Adverse Event 
The outcome of an Adverse Event is classified as follows: 
 
recovered/resolved 
 
recovering/resolving 
 
not recovered/not resolved 
 
recovered/resolved with sequelae 
 
fatal* 
 
unknown  
*Note: A patient’s death is not in itself an event, but the consequence of one. The event that 
led to the patient’s death must be documented completely and reported even if death occurs 
four weeks after stopping medication and independent of whether or not there is a relation to 
the therapy or not. 

 
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15.2 Definitions 
15.2.1 Borg Scale  
 
 
 
15.3 Acronyms  
ADL 
activities of daily living 
ADE 
adverse device effect 
AE 
adverse event 
AECOPD 
acute exacerbation of chronic obstructive pulmonary disease 
BGA 
Blood gas analysis  
BMI 
Body-Mass-Index 
COPD 
Chronic obstructive pulmonary disease 
CPAP 
continuous positive airway pressure 
CRP 
C-reactive protein 
DNI 
Do Not Intubate 
DNR 
Do Not Resuscitate 
DoH 
Declaration of Helsinki 
DSGVO 
Datenschutzgrundverordnung 
DSMB 
data safety monitoring board 
EC 
ethics committee 
eCRF 
electronic case report form 
FAS 
full analysis set  

 
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FPI 
First patient in 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale 
GDPR 
General Data Protection Regulation 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ICU 
Intensive care unit 
IL6 
Interleukin-6 
IMISE 
Institute for Medical Informatics, Statistics and Epidemiology 
ISF 
Investigator Site File 
ITT 
intention-to-treat 
LPO 
Last patient out 
MPG  
Medizinproduktegesetz 
MPSV 
Medizinprodukte-Sicherheitsplanverordnung 
NHF 
nasal high-flow 
NIV 
non-invasive ventilation 
PCT 
Procalcitonine 
PPS 
per protocol set 
RCT 
randomized controlled trial 
SADE  
serious adverse device effect 
SAE 
serious adverse event 
TMF 
Trial Master File 
VFD 
ventilator-free days 
ZKS Leipzig  
Zentrum für Klinische Studien Leipzig 
 
15.4 Template trial protocol 
This trial protocol was written based on a template by the ZKS Leipzig based on the SOPs of 
the ZKS Leipzig. 
The used template version is: Draft 1.1 from 26.06.2020 
 
 

 
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