Study Title: Prospective, Multicenter, Randomized, Controlled Study Comparing Efficacy and Safety of INTELLiVENT-ASV Versus Non-automated Ventilation in Adult ICU Subjects.
Conditions: Acute Respiratory Failure, Coma, Acute Respiratory Distress Syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD), Obesity
Sponsor: Hamilton Medical AG

 
 
 
 
 
 
Cover Page 
Study Title 
EASiVENT 
Prospective, multicenter, randomized, controlled study 
comparing efficacy and safety of INTELLiVENT-ASV 
versus Non-automated Ventilation in adult ICU 
subjects. 
Study NCT number 
NCT04400643 
Document  
Clinical Investigation Plan 
Document version and Date 
2.0 02 October 2020 
 

 
 
 
 
 
 
 
 
 
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Clinical 
Investigation 
Protocol EASiVENT 
   
Prospective, multicenter, randomized, controlled study comparing 
efficacy and safety of INTELLiVENT-ASV versus Non-automated 
Ventilation in adult ICU subjects 

 
 
 
 
 
 
 
 
 
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Study Type: 
Interventional with low risk, Medical Device (MD)  
Study Categorization: 
Pivotal (US), PMCF (EFTA) 
Study Registration: 
ClinicalTrials.gov Identifier: NCT04400643 
Sponsor: 
 
US Sponsor (local): 
Hamilton Medical AG, Via Crusch 8, CH 7402 Bonaduz, 
Switzerland 
Hamilton Medical Inc., 4655 Aircenter Circle Reno NV 89502 
USA 
Principal Investigator: 
Omitted 
Investigational Product: 
INTELLiVENT-ASV 
Protocol Version and Date: 
Version 2.0 – 02 October 2020  
 
 
CONFIDENTIAL 
The information contained in this document is confidential and the property of Hamilton Medical (or 
“sponsor”). The information may not - in full or in part - be transmitted, reproduced, published, or 
disclosed to others than the applicable Competent Ethics Committee(s) and Regulatory Authority(ies) 
without prior written authorisation from the sponsor except to the extent necessary to obtain informed 
consent from those who will participate in the study. 
 
 

 
 
 
 
 
 
 
 
 
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Signature Page(s)  
Clinical Study Document Approval Form 
Study Title 
EASiVENT 
Prospective, multicenter, randomized, controlled study 
comparing efficacy and safety of INTELLiVENT-ASV versus 
Non-automated Ventilation in adult ICU subjects. 
Study number 
NCT04400643 
Document version and Date 
2.0  02 October 2020 
The Sponsor approved the protocol version 2.0 dated 02 October 2020, and confirm hereby to conduct the 
study according to the protocol, current version of the World Medical Association Declaration of Helsinki 
(2013), ICH-GCP guidelines and ISO 14155:2020 standard and the local legally applicable requirements. 
 
 
Author Name: 
Role or Title: 
 
 
 
 
Signature 
Signature Date (DD/MMM/YYYY) 
Author Name: 
Role or Title: 
 
 
 
 
Signature 
Signature Date (DD/MMM/YYYY) 
 
 
Approver Name: 
Role or Title: 
 
 
 
 
Signature 
Signature Date (DD/MMM/YYYY) 

 
 
 
 
 
 
 
 
 
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Principal Investigator  
I have read and understood this trial protocol and agree to conduct the trial as set out in this study 
protocol, the current version of the World Medical Association Declaration of Helsinki (2013), ICH-GCP 
guidelines or ISO 14155: 2020 norm and the local legally applicable requirements. 
The trial will be conducted in accordance with International Conference on Harmonization Good Clinical 
Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), ISO 14155: 2020, and 
applicable local regulations. The Principal Investigator will assure that no deviation from, or changes to 
the protocol will take place without prior agreement from the Investigational Device Exemption (IDE) 
sponsor, funding agency and documented approval from the Institutional Review Board (IRB), 
Independent Competent Ethics Committees (IEC) except where necessary to eliminate an immediate 
hazard(s) to the trial participants. All personnel involved in the conduct of this study maintain current 
Human Subjects Protection and ICH GCP Training certifications.  
The protocol, informed consent form(s), recruitment materials (if applicable), and all participant materials 
will be submitted to the IRB/IEC for review and approval. Approval of both the protocol and the consent 
form must be obtained before any subject is enrolled. Any amendment to the protocol will require review 
and approval by the IRB/IEC before the changes are implemented to the study. All changes to the consent 
form will be IRB/IEC approved; a determination will be made regarding whether a new consent needs to 
be obtained from participants who provided consent, using a previously approved consent form. 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the following: 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46; 
21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 800-898) 
• 
ICH E6; 62 Federal Register 25691 (1997)  
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and applicable US federal regulations and ICH guidelines. 
Site name:  
 
Principal investigator’s name:  
 
 
 
Date (DD/MMM/YYYY) 
 
Signature 
 

 
 
 
 
 
 
 
 
 
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VERSION HISTORY  
 
Version  
Date  
Effective 
Date  
Changes  
1.0 
28 January 2020 
n/a 
Initial version. Part of IDE submission  
1.1 
13 May 2020 
Each site can 
implement as 
soon it is 
approved by 
the required 
central and 
local 
authorities.  
Administrative changes like correction of 
typos, font types and alignments. 
Patient word replaced in the document to 
subject. 
Local US Sponsor added. 
Facility of Coordinating Investigator in 
Europe is updated. 
Section 1.4 Investigational Site(s) added. 
Section 1.7 DSMB section is updated, 
Medical 
Monitor 
function 
and 
responsibility added. 
Section 2.1 updated to facilitate study 
registration in local required databases if 
needed. 
Section 2.6: “If an investigational site is 
suspended or prematurely terminated” 
paragraph added 
3.6 section updated to better reflect the 
device 
distribution 
and 
software 
accessories activation in the study arms. 
Section 5.2 
Secondary endpoint is 
updated with Fio2 level assessment in 
both study arms. 
Section 5.2 VFD section is updated to 
clarify the 28D follow-up and definition of 
NIV is added. 
Clarification added how to calculate VFD 
and when study ventilation will end. 
 Section 5.2 Dropout definition is updated 
and expected number of % is added. 

 
 
 
 
 
 
 
 
 
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Version  
Date  
Effective 
Date  
Changes  
Section 5.2 updated with workload 
collection.  
Section 7.2 INC 5 is updated, subjects 
included in mechanical ventilation studies 
are excluded. 
Section 7.6.1 and 7.7 are added. 
Section 8.1 is added to clarify point of 
enrollment.  
Section E Tracheostomy section updated 
to 
reflect 
that 
these 
are 
only 
recommendations. 
Section 8.4 updated to be aligned with the 
VFD section. 
Section 9 is updated with ISO reference, 
MEDDEV reference, definition of UADE is 
added per 21CFR 812.3. 
Section 9.1.3 Recording and reporting AEs 
is updated.  
Section 9.1.1 Recording and reporting DD 
section added. 
9.2 section update with Adverse Event 
Reporting requirements overview and 
timeline. 
9.2.1 Emergency contact added. 
10. Statistic section updated: 
O’Brien-Fleming-Type method is added 
instead of Wang-Tsiatis. Sample sizes and 
operational characteristics for the trial 
using O’Brien Fleming boundaries for 
futility and efficacy is added. 
Müller and Schäfer method is replaced by 
Following Metha and Pocock (Metha, 
2011). 
Added to use the ITT population as the 
primary analysis population and the mITT 
for additional analyses.  

 
 
 
 
 
 
 
 
 
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Version  
Date  
Effective 
Date  
Changes  
  
Table Values for optimal, acceptable and 
sub-optimal ranges is updated. 
Section 11.2.1 is updated to reflect that 
Memory Box will be used in both study 
arms to record data and it is compatible 
with Hamilton Ventilation devices used in 
both study arms.  
Section 11.3 is updated with potential Site 
qualification visit conduct.  
Section 11.5, 11.6 and 11.7 are added. 
Section 11.8 updated to further describe 
the confidentiality process.  
Section 11.10 is updated to better 
describe the reporting and assessment of 
protocol deviations. 
Section 12 is added. 
Section 15 is updated to indicate the 
applicable law. 
 
2.0 
02 October  2020 
Each site can 
implement as 
soon it is 
approved by 
the required 
central and 
local 
authorities.  
Administrative changes like correction of 
typos, font types and alignments. 
ClinicalTrials.gov 
Identifier: 
NCT04400643has been added throughout 
the document.  
European 
Coordinating 
investigator 
(Marco Maggiorini MD, Pr. deleted and 
added as an author) 
ISO reference data is updated to 2020. 
Abbreviation 
section 
is 
updated/corrected with ADE, AE, ASADE, 
CFR, CRF, CRRT, DD, EC , eCRF, HMV, IDH, 
IMDRF, MDCG, MDR, MEDDEV, SADE, 
UADE, USADE, VCLS and VigOps. 

 
 
 
 
 
 
 
 
 
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Version  
Date  
Effective 
Date  
Changes  
Major changes are listed below:  
Summary of Subject evaluation test 
schedule is update to better reflect the 
order and timing of assessments. 
Furthermore the followings were added: 
Intubation status, Number of recruitment 
movers within the last observation period 
, 
Concomitant 
rescue 
therapies, 
Assessment 
of 
re-intubation 
status, 
Extubation failure, Acute kidney injury, 
Critical illness polyneuro –myopathy 
status, critical illness encephalopathy 
status, tracheostomy status, resusicated 
cardiac arrest status, other,  Other 
imminently life-threatening experience,  
Barotrauma status 
Section 1.4 Blinded word added 
Section 2.6 following is added: If the 
Sponsor agrees to DSMB/ Medical 
Monitor recommendation to terminate 
the Study based on site recorded 
AE(s)/SAE(S) 
Section 3.1: clarification added since 
INTELLiVENT-ASV is a ventilation mode 
and the devices are supplier with it, but 
the clinician will set it as active or non-
active . 
Section 5.2 Secondary safety outcomes 
updated with the followings: In addition 
to better characterize the risk profile of 
the study population the following non-
mechanical ventilation related adverse 
events will be recorded on study day 7 
and 28. 
• 
Sever Acute kidney injury (AKI) in 
need for CRRT/IHD 
• 
Sever 
critical 
illness 
neuro-
myopathy signs of treaplegia 

 
 
 
 
 
 
 
 
 
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Version  
Date  
Effective 
Date  
Changes  
affecting arms shoulder and neck 
with potential implication of 
respiratory muscle. Weakness is 
documented using the following 
score points: score 0 for no visible 
muscle contraction, score 1 for 
visible muscle contraction with no 
or trace movement, score 2 for 
limb movement, but not against 
gravity and score 3 for movement 
against gravity but not resistance. 
• 
Severe 
critical 
illness 
encephalopathy 
leading 
to 
prolongation 
of 
mechanical 
ventilation. The most frequent 
causes being a metabolic or 
electrolyte 
disorder, 
systemic 
inflammation and other causes. 
Hypoxia, 
Stroke, 
intracranial 
bleeding, epilepsy and delirium. 
Encephalopathy is assessed using 
the GCS score and need to be 
reported is < 8 points. 
• 
Withhold of weaning and/or 
withdrawal 
of 
mechanical 
ventilation because of treatment 
limitation related to patient wish 
or treatment futility due to 
irreparable single or multi-organ 
failure 
affect 
mechanical 
ventilation 
strategy, 
weaning 
from mechanical ventilation up to 
withdrawal 
of 
mechanical 
ventilation. 
• 
Extubation failure that is related 
to weaning process by itself or 
associated conditions based on 
the interpretation of the 
investigator. 
• 
Need for tracheostomy that is 
related to a difficult weaning 
process or associated conditions 

 
 
 
 
 
 
 
 
 
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Version  
Date  
Effective 
Date  
Changes  
based on the interpretation of 
the investigator. 
Section 7.3 : exclusion criteria updated 
with the followings: 
EXC #11 updated to have it better 
formulized: 
Decision to withhold or withdraw life 
support. This does not exclude those 
patients committed to full support except 
cardiopulmonary resuscitation. 
EXC # 18, 19 and 20 are added 
Section 7.5 : clarifications added on co-
enrolment guidelines and DSMB role with 
co-enrolment decision.  
Section 7.6 Study Withdrawal updated to 
reflect that the 80% of the ventilation 
time within the allocated randomized 
ventilation mode needs to be recorded. 
Section 8.1: clarifications added on 
screening and baseline assessments.  
Followings added: 
Clarification added how to handle 
shortage of ventilators, limited resource.  
Section 
8.1.2 
Clarification 
added 
regarding point of enrolment: ICF signed 
dated & patient randomized.  
Section 8.2, 8.3, 8.4 and 8.5 updated to 
reflect the changes of the assessment 
schedule. 
Section 8.3.1 updated with the followings 
as well: 
If the subject’s medical condition requires 
medical 
intervention 
(bronchoscopy, 
trancescopy, 
radiology 
or 
OR 
interventions…etc.) and the subject is 

 
 
 
 
 
 
 
 
 
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Version  
Date  
Effective 
Date  
Changes  
allocated to the INTELLiVENT-ASV arm, 
the allocated randomized ventilation 
mode may be switched off for the 
required time period. This needs to be 
documented in the subject’s medical 
chart. 
If the ventilation mode is modified by the 
site personnel by oversight or lack of 
training (deviating from the allocated 
randomization arm) and the subject’s 
medical condition did not require it, the 
ventilation mode should be set back to 
allocated randomization arm. A protocol 
deviation and the event will be recorded 
in the  eCRF accordingly.  
 
Section 9: Adverse Event reporting 
requirements is updated to align with the 
DSMB Chart based on DSMB members 
recommendations. 
Definitions 
added 
which AE/SAEs to be recorded by the site.  
List of AE is created that required to be 
recorded, please see Annex D. 
Definition of Study Specific outcome 
added. 
Adverse Event Review chart is added. 
Table of AE reporting requirements is 
restructured to be more simplified. 
Section 11.5 is updated to reflect that the 
site PI is responsible to determine that the 
study is no longer in the subject’s best 
interest. 
Section 11.6.4: alignment in medical 
reporting requirements in US 
References is update with 2 new 
publications: 

 
 
 
 
 
 
 
 
 
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1 Manufacturer´s State-of-the-Art Documentation, on file  
Version  
Date  
Effective 
Date  
Changes  
1) 
Arnal JM, Saoli M, Garnero A. 
Airway and transpulmonary 
driving pressures and mechanical 
powers selected by INTELLiVENT-
ASV in passive, mechanically 
ventilated ICU patients. Heart 
Lung. 2019 Nov 14:S0147-
9563(19) 30533-3. 
2) 
De Bie AJR, Serpa Neto A, van 
Meenen DM, Bouwman AR, Roos 
AN, Lameijer JR, Korsten EHM, 
Schultz MJ, Bindels AJGH. Fully 
automated postoperative 
ventilation in cardiac surgery 
patients: a randomised clinical 
trial. Br J Anaesth. 2020 Jul 29; 
S0007-0912(20)30497-9. doi: 
10.1016/j.bja.2020.06.037. 
Online ahead of print. 
Annex A  Clinical manifestations and 
medical 
occurrences, 
unintended 
diseases or injuries or clinical signs that 
are attributed to the concurrent illness / 
clinical condition of critically ill subjects in 
an ICU include1:  is updated with the 
followings: 
• 
Congestive Heart failure right 
and left LV 
• 
Atrial flutter/fibrillation 
• 
Acute myocardial infraction 
• 
Abdominal 
hypertension/compartment 
Syndrome 
• 
Stroke 
• 
Intra cerebral bleeding 
Hemodynamic effects: 
PEEP is added 

 
 
 
 
 
 
 
 
 
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Version  
Date  
Effective 
Date  
Changes  
 
Annex D : addition of expected adverse 
event to be recorded by the investigators  

 
 
 
 
 
 
 
 
 
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Abbreviations 
%MinVol 
Minute ventilation expressed in percentage of 
IBW 
∆P 
Driving Pressure 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AKI 
Acute kidney injury 
APRV 
Airway Pressure Release Ventilation 
APV 
Adaptive Pressure Ventilation 
ARDS 
Acute Respiratory Distress Syndrome 
ASADE 
Anticipated Serious Adverse Device Effect 
ASV 
Adaptive Support Ventilation 
ATS 
American Thoracic Society 
CA 
Competent Authority 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRRT 
Continuous Renal Remplacement Therapy  
CO 
Carbon Monoxide 
CO2 
Carbon Dioxide 
COPD 
Chronic Obstructive Pulmonary Disease 
CP 
Conditional Power 
CMV 
Continuous mandatory ventilation 
CPAP 
Continuous Positive Airway Pressure 
DD 
Device Deficiency 

 
 
 
 
 
 
 
 
 
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DSMB 
Data Safety Monitoring Board 
DuoPAP 
Duo Positive Airway Pressure 
EC 
Ethics Committee 
ECCO2R 
Extracorporeal Carbon Dioxide Removal 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
electronic Case Report Form 
FDA 
US Food and Drug Administration 
FiO2 
Fraction of Inspiratory Oxygen 
fSpont 
Spontaneous Breathing Rate 
H2O 
Water 
HFO 
High Frequency Oscillatory Ventilation 
HMV 
Hamilton Medical Vigilance 
IBW 
Ideal Body Weight 
ICU 
Intensive Care Unit 
IHD 
Intermittent haemodialysis 
IMDRF 
International Medical Device Regulation Forum 
IoR 
Investigator of Record 
IRB 
Institutional Review Board 
MDCG 
Medical Device Coordination Group 
MDR 
Medical Device Regulation 
MEDDEV 
Medical Device Vigilance 
MV 
Minute Volume 
NIV 
Non-Invasive Ventilation 

 
 
 
 
 
 
 
 
 
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O2 
Oxygen 
OHRP 
Office for Human Research Protections 
PaO2 
Partial Pressure of Oxygen 
PASV 
Maximum inspiratory pressure limit setting 
PCV 
Pressure Control Ventilation 
PEEP 
Positive End-Expiratory Pressure 
PetCO2 
End-tidal partial pressure of carbon dioxide 
Pmax 
Maximum Pressure 
PPLAT 
Plateau Pressure 
RCexp 
Expiratory time constant 
RR 
Respiratory Rate 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SBT 
Spontaneous Breathing Trial 
SIMV 
Synchronized Intermittent Mandatory Ventilation 
SOFA 
Sequential Organ Failure Assessment 
SpO2 
Oxygen Saturation Measured by Pulse Oximetry 
TRC 
Tube resistance compensation 
T Tube   
Method to perform a weaning trial that consist of 
disconnecting the subject from the ventilator 
UADE 
Unanticipated Adverse Device Effect 
US 
United States 
USADE 
Unanticipated Serious Adverse Device Effect 
VCLS 
Voisin Consulting Life Sciences 

 
 
 
 
 
 
 
 
 
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VFD 
Ventilator Free Day(s) 
VigOps 
Vigilance Operations 
VT 
Tidal Volume 
 

 
 
 
 
 
 
 
 
 
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Table of Content 
Signature Page(s) .......................................................................................................................................... 2 
VERSION HISTORY ................................................................................................................................... 4 
Abbreviations .............................................................................................................................................. 13 
List of Tables ............................................................................................................................................... 22 
List of Figures .............................................................................................................................................. 23 
List of Annexes ............................................................................................................................................ 24 
Clinical Investigation Synopsis .................................................................................................................... 25 
1 
STUDY ADMINISTRATION AND STRUCTURE........................................................................................ 40 
1.1 
Sponsor ....................................................................................................................................... 40 
1.2 
Principal Investigator(s) .............................................................................................................. 40 
1.3 
Investigational Site(s) .................................................................................................................. 40 
1.4 
Statistician ("Biostatistician") ...................................................................................................... 40 
1.5 
Monitoring institution ................................................................................................................. 40 
1.6 
Data Safety Monitoring Board .................................................................................................... 40 
2 
ETHICAL AND REGULATORY ASPECTS ................................................................................................. 42 
2.1 
Study registration ........................................................................................................................ 42 
2.2 
Institutional Review Board (IRB) / Independent Competent Ethics Committee (EC) ................. 42 
2.3 
Competent Authorities (CA) ........................................................................................................ 42 
2.4 
Ethical Conduct of the Study ....................................................................................................... 42 
2.5 
Declaration of interest ................................................................................................................ 42 
2.6 
Suspension or Premature Termination of the Clinical Investigation .......................................... 42 
3 
BACKGROUND AND RATIONALE ......................................................................................................... 44 
3.1 
Investigational device(s) and comparator(s) .............................................................................. 44 
3.2 
Preclinical Evidence ..................................................................................................................... 45 
3.3 
Clinical Evidence to Date ............................................................................................................. 45 
3.4 
Risks and Benefits Statement ..................................................................................................... 46 
4 
STUDY OBJECTIVES .............................................................................................................................. 48 
4.1 
Overall objectives of the study ................................................................................................... 48 
4.2 
Primary Objectives ...................................................................................................................... 48 
4.3 
Secondary Objectives .................................................................................................................. 48 
4.4 
Tertiary Objectives ...................................................................................................................... 48 
5 
STUDY ENDPOINTS .............................................................................................................................. 49 
5.1 
Primary endpoints ....................................................................................................................... 49 
5.2 
Secondary endpoints .................................................................................................................. 49 
5.3 
Tertiary endpoints ....................................................................................................................... 52 

 
 
 
 
 
 
 
 
 
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6 
STUDY DESIGN ..................................................................................................................................... 53 
6.1 
General ........................................................................................................................................ 53 
6.2 
Methods of minimizing bias ........................................................................................................ 53 
 Randomization .......................................................................................................................... 53 
 Blinding ..................................................................................................................................... 53 
6.3 
Justification for the design of the clinical investigation .............................................................. 53 
7 
STUDY POPULATION ............................................................................................................................ 54 
7.1 
Selection of the Study Population............................................................................................... 54 
7.2 
Inclusion Criteria ......................................................................................................................... 54 
7.3 
Exclusion Criteria ......................................................................................................................... 54 
7.4 
Vulnerable Population ................................................................................................................ 55 
7.5 
Co-enrollment Guidelines ........................................................................................................... 55 
7.6 
Study Withdrawal ....................................................................................................................... 55 
 Lost-to-follow-up ...................................................................................................................... 56 
7.7 
Medical care after study exit ...................................................................................................... 56 
7.8 
Informed Consent Process .......................................................................................................... 56 
8 
STUDY PROCEDURES ........................................................................................................................... 58 
8.1 
Screening  and Point of Enrollment process ............................................................................... 58 
 Screening ................................................................................................................................... 58 
 Point of Enrollment and Randomization: ................................................................................. 59 
8.2 
Baseline Assessment (Day 0)....................................................................................................... 59 
8.3 
Intervention Period (Day 1-Day 27): ........................................................................................... 60 
 General management in both groups ....................................................................................... 60 
 Ventilation protocol in non-automated ventilation group ....................................................... 64 
 Ventilation protocol in INTELLiVENT-ASV ventilation group .................................................... 66 
 Measurements .......................................................................................................................... 69 
8.4 
End of study (extubation + 48 hours): ........................................................................................ 69 
8.5 
Study Exit (Day 28): ..................................................................................................................... 70 
8.6 
Supply and Accountability ........................................................................................................... 71 
8.7 
Ancillary Supplies ........................................................................................................................ 71 
9 
SAFETY ................................................................................................................................................. 72 
9.1 
Recording and reporting of AEs .................................................................................................. 72 
 Study-Specific Clinical Outcomes .............................................................................................. 72 
 Adverse Events (AEs) ................................................................................................................. 73 

 
 
 
 
 
 
 
 
 
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 Serious Adverse Event (SAE) ..................................................................................................... 75 
9.2 
Recording and reporting of Device Deficiencies (DDs) ............................................................... 76 
 Device deficiency (ISO 14155)................................................................................................... 76 
 Adverse Device Effect (ADE) (ISO 14155):: ............................................................................... 77 
 Serious Adverse Device Effect (SADE) (ISO 14155): .................................................................. 77 
 Anticipated SADE (ASADE) ........................................................................................................ 77 
 Anticipated Serious Adverse Device Effect from risk management activities of the 
manufacturer: ..................................................................................................................................... 77 
 Unanticipated Adverse Device Effect (UADE): (21 CFR 812.3) ................................................. 77 
 Unanticipated Serious Adverse Device Effect (USADE) (ISO 14155): ....................................... 78 
 Serious Health Threat (ISO 14155) ............................................................................................ 78 
 Incident (MEDDEV 2.12-1) ........................................................................................................ 78 
9.3 
Observation, Categorization, Analysis and Reporting of AEs ..................................................... 80 
 Emergency contact details in case of AEs ................................................................................. 84 
 Analysis of the Benefit/Risk Profile ........................................................................................... 84 
10 STATISTICS ........................................................................................................................................... 85 
10.1 
Statistical Hypothesis .................................................................................................................. 85 
10.2 
Sample Size Determination ......................................................................................................... 85 
10.3 
Adaptive sample size increase .................................................................................................... 87 
10.4 
Statistical Analyses ...................................................................................................................... 88 
 
Definition of populations .................................................................................. 88 
 
Intention-To-Treat (ITT) Population .................................................................. 88 
 
Modified Intention-To-Treat (MITT) Population ............................................... 88 
 
Safety Analysis Population ................................................................................ 88 
 
Analysis of Primary Endpoints ........................................................................... 88 
 
Baseline Descriptive Characteristics .................................................................. 91 
10.5 
Missing Data ................................................................................................................................ 91 
11 QUALITY ASSURANCE AND CONTROL ................................................................................................. 93 
11.1 
Data handling .............................................................................................................................. 93 
 
Case Report Forms ............................................................................................ 93 
 
Specification of source documents ................................................................... 93 
 
Record keeping / archiving ................................................................................ 94 

 
 
 
 
 
 
 
 
 
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11.2 
Data management ...................................................................................................................... 94 
 
Data Management Responsibilities ................................................................... 94 
 
Data Management System ................................................................................ 94 
 
Data Safety ........................................................................................................ 94 
 
Analysis and archiving ....................................................................................... 95 
 
Electronic and central data validation............................................................... 95 
11.3 
Monitoring Plan .......................................................................................................................... 95 
11.4 
Quality Assurance, audits and inspections ................................................................................. 96 
11.5 
Study management ..................................................................................................................... 96 
11.6 
Records and reports .................................................................................................................... 96 
 
Study Investigator records ................................................................................ 96 
 
Investigator reporting responsibilities .............................................................. 97 
 
Hamilton Medical records ................................................................................. 99 
 
Hamilton Medical reporting requirements in US ............................................ 100 
 
Hamilton Medical reporting requirements in US /EU ..................................... 101 
11.7 
Subject compensation and indemnification ............................................................................. 101 
11.8 
Confidentiality, Data Protection ............................................................................................... 101 
11.9 
Amendments to the CIP ............................................................................................................ 102 
11.10 Deviations from the Clinical Investigation Plan ........................................................................ 102 
 
Request for approval of study deviations ....................................................... 102 
 
Reporting requirements for study deviations ................................................. 103 
12 Study device/product traceability ..................................................................................................... 104 
12.1 
Supply of investigational devices/products .............................................................................. 104 
12.2 
Storage and handling of investigational devices/products ....................................................... 104 
12.3 
Device return procedures ......................................................................................................... 104 
13 PUBLICATION POLICY ........................................................................................................................ 105 
14 FUNDING AND SUPPORT ................................................................................................................... 107 
15 INSURANCE ........................................................................................................................................ 108 
REFERENCES .............................................................................................................................................. 109 
Annex A: Identification of Risks and AE´s for the intended subject population, the clinical background and 
the device in question identified from clinical experience for INTELLiVENT-ASV .................................... 113 
Anticipated device deficiencies from search for AE´s from clinical experience for data pertinent to 
INTELLiVENT-ASV  ................................................................................................................................. 118 

 
 
 
 
 
 
 
 
 
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Anticipated device deficiencies from search for AE´s from Vigilance databases and complaints for 
INTELLiVENT-ASV .................................................................................................................................. 122 
Anticipated device deficiencies from risk management activities of the manufacturer: ..................... 123 
Annex B: Summary of clinical studies using INTELLiVENT-ASV ................................................................. 124 
Annex C: INTELLiVENT-ASV Investigational Device Study Training Concept ............................................ 128 
Annex D: List of Adverse Event ................................................................................................................. 131 
 
 
 

 
 
 
 
 
 
 
 
 
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List of Tables 
Table 1: Summary of subject evaluation tests: schedule of assessments for both Study Arms. ................ 37 
Table 2: Management of pH and PaCO2: ................................................................................................... 65 
Table 3: Management of pH and PaCO2: .................................................................................................... 67 
Table 4: Adverse Event Reporting Requirements ....................................................................................... 84 
Table 5: Sample sizes and operational characteristics for the trial using O’Brien Fleming boundaries for 
futility and efficacy. ............................................................................................................................. 86 
Table 6: Values for optimal, acceptable and sub-optimal ranges............................................................... 90 
Table 7: Investigator Reporting Responsibilities ......................................................................................... 97 
Table 8: Hamilton Medical Reporting Requirements in Us ...................................................................... 100 
Table 9: Root causes for Mechanical Ventilation [] .................................................................................. 113 
Table 10: Characteristics and outcome for ventilated ICU subjects [] ...................................................... 114 
Table 11: Baseline demographics and comorbidities for Invasive Mechanical Ventilation ) [5] ............... 115 
Table 12: Responses from authors/seniors authors against the “mainstatement” ................................. 118 
Table 13: published studies on IV-ASV...................................................................................................... 124 
 

 
 
 
 
 
 
 
 
 
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List of Figures 
Figure 1: Adverse Events Categorisation Chart........................................................................................... 79 
Figure 2: Device Deficiency Categorisation Chart ....................................................................................... 80 
Figure 3: Adverse Event Review Chart ........................................................................................................ 82 
 

 
 
 
 
 
 
 
 
 
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List of Annexes  
Annex A: Identification of Risks and AE´s for the intended subject population, the clinical background 
and the device in question identified from clinical experience for INTELLiVENT-ASV ...................... 113 
Annex B: Summary of clinical studies using INTELLiVENT-ASV ................................................................. 124 
Annex C: INTELLiVENT-ASV Investigational Device Study Training Concept ............................................ 128 
Annex D: List of Reportable Adverse Event .............................................................................................. 131 
 

 
 
 
 
 
 
 
 
 
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Clinical Investigation Synopsis 
Sponsor:  
Hamilton Medical AG, Via Crusch 8, CH 7402 Bonaduz, Switzerland 
US Sponsor: 
Hamilton Medical Inc., 4655 Aircenter Circle 4655 Reno NV 89502 USA 
Study Title: 
Prospective, multicenter, randomized, controlled study comparing efficacy 
and safety of INTELLiVENT-ASV versus Non-automated Ventilation in adult 
ICU subjects. 
Short Title / Study ID: 
EASiVENT 
Protocol Version and 
Date: 
Protocol Version 2.0  dated 02 October 2020 
Trial registration: 
ClinicalTrials.gov Identifier: NCT04400643 
 
Study category and 
Rationale 
IDE Study / PMCF in EFTA  
Results will serve as the primary basis for the determination of reasonable 
assurance of safety and efficacy of INTELLiVENT-ASV of a pre-market 
approval application (PMA) and the FDA’s overall benefit-risk 
determination. 
Clinical Phase: 
Pivotal 

 
 
 
 
 
 
 
 
 
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Background 
and 
Rationale: 
INTELLiVENT-ASV is a software accessory that automatically adjusts 
ventilation and oxygenation variables to keep the subject within clinician-
set target ranges, from intubation until extubation. 
The INTELLiVENT-ASV is a closed-loop ventilation mode and is intended as 
an accessory for currently marketed Hamilton Medical ventilators.  
INTELLiVENT-ASV includes the following features:  
1. Ventilation controller (% MinVol)  
2. Oxygenation controller (FiO2 & PEEP)  
3. Quick Wean  
With INTELLiVENT-ASV, the clinician sets subject targets for PetCO2 and 
SpO2 and selects the subject’s initial respiratory condition (normal lung, 
Acute Respiratory Distress Syndrome (ARDS), chronic hypercapnia or brain 
injury). The system automates the controls for CO2 elimination (%MinVol) 
and oxygenation (PEEP and FiO2) based on these targets and on the 
monitoring input from the subject (PetCO2 and SpO2). INTELLiVENT-ASV 
continuously monitors subject conditions and safely adjusts parameters to 
keep the subject within the predefined target ranges, with minimal clinician 
interaction, from intubation until extubation. 
Primary Objective(s): 
Efficacy: To assess the efficacy of INTELLiVENT-ASV in adult ICU subjects up 
to 7 days after enrollment. 
Safety: To assess the safety of INTELLiVENT-ASV in adult ICU subjects up to 
7 days after enrollment. 

 
 
 
 
 
 
 
 
 
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Primary endpoints 
Efficacy 
The primary efficacy endpoint will be to assess the ability to keep 
ventilation and oxygenation variables in optimal target ranges.  
This endpoint will be determined by the percentage of time spent with six 
(6) variables in the optimal range during the 7 days after enrollment: 
1) Tidal volume (VT)  
2) Maximum pressure (Pmax) 
3) Oxygen saturation measured by pulse oximetry (SpO2) 
4) End-tidal partial pressure of carbon dioxide (PetCO2)  
5) Respiratory rate (RR) for spontaneous breathing subjects 
6) Pmax-PEEP for passive ARDS subjects 
The optimal and sub-optimal ranges are defined by pertinent guidelines for 
different clinical conditions including normal lungs, brain injury, ARDS, and 
chronic hypercapnia.  
 
Safety: 
The primary safety endpoint will be determined by percentage of time 
spent with at least one variable in the sub-optimal range during the 7 days 
after enrollment.  

 
 
 
 
 
 
 
 
 
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Secondary endpoints 
Secondary endpoints will be measured continuously up to 28 days after 
enrollment.  
The secondary endpoints will assess ventilation safety and efficacy by 
measuring physiological variables, clinical outcomes, and associated 
interventions continuously up to 28 days after enrolment.  
Efficacy 
Physiologic parameters:  
1) Respiratory mechanics (Compliance, resistance, expiratory time 
constant) will be assessed automatically breath-by-breath  
2) Oxygenation (PaO2/FiO2, FiO2, PEEP) 
3) Ventilation (VT, RR, mechanical power will be assessed 
automatically breath-by-breath, ΔP, PPLAT, will be assessed twice a 
day). 
4) FiO2 levels to be assessed in both study arms 
Outcomes:  
1) Duration of invasive mechanical ventilation: time between 
intubation and last extubation or death. When a subject is re-
intubated within 48 hours after extubation, the period between 
extubation and re-intubation is considered as invasive ventilation 
days. 
2) Duration of non-invasive mechanical ventilation: noninvasive 
ventilation (NIV) refers to Continuous Positive Airway Pressure 
(CPAP) or pressure support NIV delivered before intubation or after 
extubation. High flow therapy is not considered in this calculation. 
3) Total duration of mechanical ventilation: sum of duration of 
invasive and noninvasive mechanical ventilation. 
4) Time from intubation to first successful Spontaneous Breathing 
Trial (SBT) 
5) Passive ventilation duration: passive ventilation is defined when 
the percentage of subject’s triggered breath is lower than 25% of 
total respiratory rate.  
6) Weaning duration: time between the first sedation cessation to the 
last extubation or the last disconnection from the ventilator for 
tracheostomized subjects. Subjects reintubated within 48h after 
extubation will be kept in the study. Subject that are re-intubated 
beyond 48h will be considered as weaned from the ventilation. 
 

 
 
 
 
 
 
 
 
 
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7) Ventilator free days (VFD) up to day 28:  
VFD to day 28 are defined as: the number of days from the time of 
initiating unassisted breathing to day 28 after start of ventilation, 
assuming survival for at least 48 hours and no re-intubation within 
48 hours after initiating unassisted breathing and continued 
unassisted breathing to day 28.  
 
NIV will be considered as assisted breathing. CPAP will not be 
considered as assisted breathing. Ventilator free days will be 
calculated separately for invasive ventilation support and any other 
ventilation support (invasive and noninvasive). 
 
If a subject returns to assisted breathing (re-intubated within 48 
hours) and subsequently achieves unassisted breathing to day 28, 
VFDs will be counted from the end of the last period of assisted 
breathing to day 28.  
 
A period of assisted breathing lasting less than 24 hours and for the 
purpose of a surgical procedure will not count against the VFD 
calculation.  
 
If a subject was receiving assisted invasive breathing on day 27 or 
dies prior to day 28, VFDs will be -1. 
 
For subjects transferred to another hospital or other health care 
facility,  study data collection will be stopped but subject will be 
contacted via a phone call on day 28 post enrollment to assess VFD 
endpoint if possible: 
• 
ICU and hospital length of stay (discharge). 
• 
ICU mortality (if the subjects is hospitalized in another 
hospital than the investigational site) 
• 
Non-intensive ventilation (NIV) duration 
• 
28 days mortality 
• 
Ventilation duration for study period (if reintubated 
beyond 48h) 
• 
Tracheostomy 
 
 
 

 
 
 
 
 
 
 
 
 
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Associated interventions: 
1) Duration and doses of sedative infusion 
2) Duration and doses of analgesic infusion 
3) Duration and doses of vasopressors 
4) Duration and doses of myorelaxant 
5) Number of recruitment maneuvers  
6) Time spent in prone position 
7) Time spent with nitric oxide 
Workload: 
1) Number of manual adjustment will be collected in both ventilation 
arms until considered as weaned from the ventilation. 
Safety 
The secondary safety endpoint will be determined by evaluating the 
number of Serious Adverse Events (all SAEs included) within 28 days of the 
enrollment and the rescue therapy requirement (APRV, high frequency 
ventilation, ECCO2R and ECMO). 
In addition to better characterise the risk profile of the study population the 
following non-mechanical ventilation related adverse events will be 
recorded on study day 7 and 28. 
• 
Severe Acute kidney injury (AKI) in need for Complete Renal 
Replacement Theray (CRRT)/intermittent haemodialysis (IHD) 
• 
Severe critical illness neuro-myopathy signs of tetraplegia affecting 
arms shoulder and neck with potential implication of respiratory 
muscle. Weakness is documented using the following score points: 
score 0 for no visible muscle contraction, score 1 for visible muscle 
contraction with no or trace movement, score 2 for limb 
movement, but not against gravity and score 3 for movement 
against gravity but not resistance. 
• 
Severe critical illness encephalopathy leading to prolongation of 
mechanical ventilation. The most frequent causes being a 
metabolic or electrolyte disorder, systemic inflammation and other 
causes. Hypoxia, Stroke, intracranial bleeding, epilepsy and 
delirium. Encephalopathy is assessed using the GCS score and need 
to be reported is < 8 points. 
• 
Withhold of weaning and/or withdrawal of mechanical ventilation 
because of treatment limitation related to patient wish or 
treatment futility due to irreparable single or multi-organ failure 

 
 
 
 
 
 
 
 
 
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affect mechanical ventilation strategy, weaning from mechanical 
ventilation up to withdrawal of mechanical ventilation. 
 
 
• 
Extubation failure that is related to weaning process by itself or 
associated conditions based on the interpretation of the 
investigator. 
• 
Need for tracheostomy that is related to a difficult weaning 
process or associated conditions based on the interpretation of 
the investigator. 
 
Tertiary endpoints 
Tertiary endpoints will be measured continuously during ventilation period 
from day 8 up to day 28 after enrollment.  
Efficacy 
Efficacy of the investigational device by assessing the ability to keep 
ventilation and oxygenation variables in optimal target ranges. 
This endpoint will be determined by the percentage of time spent with six 
(6) variables in the optimal range during day 8 through day 28:  
1) 
Tidal volume (VT)  
2) 
Maximum pressure (Pmax) 
3) 
Oxygen saturation measured by pulse oximetry (SpO2) 
4) 
End-tidal partial pressure of carbon dioxide (PetCO2)  
5) 
Respiratory rate (RR) for spontaneous breathing subjects 
6) 
Pmax-PEEP for passive ARDS subjects 
The optimal and sub-optimal ranges are defined by pertinent guidelines for 
different clinical conditions including normal lungs, brain injury, ARDS, and 
chronic hypercapnia.  
Tertiary endpoints will be measured continuously during ventilation period 
from day 8 up to day 28 after enrollment.  
Safety: 
The tertiary safety endpoint will be determined by percentage of time spent 
with at least one variable in the sub-optimal range from day 8 up to day 28 
after enrollment. 
 

 
 
 
 
 
 
 
 
 
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Study design: 
Prospective, Multicenter, Randomized (1:1), Controlled Study. This study is 
single-blind because only the subject will be unaware of the ventilation 
modality administered. The reference treatment used for comparison is a 
combination of controlled modes for passive subjects (volume control or 
pressure control) and assisted/spontaneous modes for active subjects 
(synchronized intermittent mechanical ventilation or pressure support) 
Study Population: 
Eligible subjects are adult ICU subjects requiring invasive mechanical 
ventilation, 21 years and older and fulfilling the inclusion and exclusion 
criteria. 
Inclusion / Exclusion 
criteria: 
Inclusion Criteria 
Adults must fulfill all of the following inclusion criteria to be eligible for 
enrollment into this study: 
1. Age ≥ 21 years old  
2. Weight > 40 kilograms 
3. Under invasive ventilation for less than 24 hours  
4. Expected to be mechanically ventilated for at least 24 hours after 
enrollment 
5. Agrees to not participate in other interventional research studies 
involving  mechanical ventilation  for the duration of study 
participation, unless approved by the DSMB  
6. Signature of the informed consent by the subject or his/her next-
of-kin according to country or state regulation 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
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Exclusion Criteria 
Adults who meet any of the following criteria are not eligible for enrollment 
into this study: 
1. Fulfilling weaning criteria according to the weaning procedure of 
the ICU  
2. Need for “rescue therapy” (ECMO, ECCO2R, HFO))  
3. Brain death status 
4. Respiratory drive disorder (Cheyne-Stokes breathing)  
5. Arterial hypoxia due to a non-pulmonary condition (right-to-left 
shunting due to congenital disease, hepato-pulmonary syndrome, ) 
6. Broncho-pleural fistula 
7. Chronic or acute dyshemoglobinemia: acute CO poisoning, meth-
hemoglobin, sickle cell disease. 
8. Chronic respiratory failure requiring long term invasive ventilation;  
9. Moribund subject: death expected within 24 hours 
10. Positive pregnancy test at screening  for childbearing age women 
11. Decision to withhold or withdraw life support. This does not 
exclude those patients committed to full support except 
cardiopulmonary resuscitation. 
12. Subject under guardianship  
13. Subject deprived of liberties  
14. Subject included in another interventional research study involving 
mechanical ventilation under consent. 
15. Any other condition, that in the opinion of the IoR/designee, would 
preclude informed consent (by the spouse/next of kin), make study 
participation unsafe, complicate interpretation of study outcome 
data, or otherwise interfere with achieving the study objectives 
16. Low quality index on the SpO2 measurement using finger and ear 
sensor for > 3 hours  
17. Subjects already enrolled in the present study in a previous episode 
of acute respiratory failure 
18. High PaCO2 – ETCO2 gap (> 2.6 kPa or 19.5 mmHg) for > 3 hours 
19. Patient tracheostomized at the time of inclusion 
20. Patient ventilated with helium 
 

 
 
 
 
 
 
 
 
 
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Measurements 
and 
procedures: 
Efficacy and Safety are measured by assessing the ability to keep ventilation 
and oxygenation variables in optimal target ranges: 
1) Tidal volume (VT)  
2) Maximum pressure (Pmax) 
3) Oxygen saturation measured by pulse oximetry (SpO2) 
4) End-tidal partial pressure of carbon dioxide (PetCO2)  
5) Respiratory rate (RR) for spontaneous breathing subjects 
6) Pmax-PEEP for passive ARDS subjects 
The optimal and sub-optimal ranges are defined by pertinent 
guidelines for different clinical conditions including normal lungs, 
brain injury, ARDS, and chronic hypercapnia.  
• 
Physiologic parameters 
• 
Outcomes 
• 
Associated interventions 
• 
Number of Serious Adverse Events 
 
Study Product / 
Intervention:  
INTELLiVENT-ASV, utilizing a Hamilton-Medical ventilator. 
 
 
 
 
 
 
Control Intervention 
(if applicable): 
Non automated Ventilation (administered according to the ICU protocols), 
utilizing Hamilton Medical ventilator. 
Number of 
Participants with 
Rationale: 
Minimum of 254 and a maximum of 508 subjects. 
An adaptive sample size reassessment is foreseen at the second interim 
analysis. The method used is the 'promising zone' approach. Following 
Mehta and Pocock (Mehta, 2011), sample sizes will only be increased in 
case the interim results are promising, in which case the overall type-I error 
is not inflated by use of the conventional Wald statistic. 

 
 
 
 
 
 
 
 
 
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Participant Duration: 
Each enrolled subject will be followed for a maximum of 28 days. 
The Study Completion should be completed at the time when a subject 
completes the study in the Case Report Form (CRF). A subject will be 
considered to have completed the study for the following reasons: 
• Subject completes the follow-up visits the protocol as planned until 
Day 28.  
• Subject dies. 
• Subject or legally authorized representative requests to be withdrawn 
from the study. 
• Investigator requests that the subject is withdrawn from the study to 
protect the welfare of the subject. This is a decision based on site’s 
Principal Investigator’s judgement.  
 
Dropout could occur when subjects are ventilated for less than 24 hours 
after inclusion because of unexpected death, transfer to another ICU or 
withdrawal of informed consent. A maximum dropout rate of 5% of these 
cases is expected.  
Study Duration: 
Accrual is expected to be completed in approximately 24 months. 
Study Schedule: 
Month Year of First-Participant-In (planned): Q4 2020 
Month Year of Last-Participant-Out (planned): Q4 2022 
Sponsor: 
Hamilton Medical AG, Via Crusch 8, CH 7402 Bonaduz, Switzerland 
US Sponsor : 
Hamilton Medical Inc., 4655 Aircenter Circle 4655 Reno NV 89502 USA 
US Principal 
Investigator: 
Omitted 
Study Centre(s): 
Approximately twenty (20) sites with ICU capability in United States and 
European countries 
Statistical 
Considerations: 
EASiVENT hypothesizes that INTELLiVENT-ASV will outperform “Non 
automated Ventilation” on the Hamilton Medical Ventilators, in terms of 
efficacy and safety.  
GCP Statement: 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki 2013, the ICH-GCP or ISO 14155: 2020 
(as far as applicable) as well as all national legal and regulatory 
requirements.  

 
 
 
 
 
 
 
 
 
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Data oversight 
A Data Safety Monitoring Committee (DSMB) will be established to 
independently evaluate subject health status, device performance, and 
identify any safety concerns regarding subjects’ well-being. Contact details 
of the committee will be available in the investigational site file. 
 
 
 

 
 
 
 
 
 
 
 
 
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Table 1: Summary of subject evaluation tests: schedule of assessments for both Study Arms.  
The following clinical and research tests will be conducted with the following sequence during the study to assess eligibility, efficacy and safety 
Study Period 
Screening 
Baseline 
Intervention Period  
End of 
Study 
Study Exit 
Time 
Day 0 
Day 0 
Day 0 
Day 0 
Day 1 
Day 1 
Day 
2-3 
Day 4 
Day 4 
Day 5-6 
Day 7 
Day 7 
Day 8-
27 
Day XX 
Day 28 
Time specifications 
T0 
T0+1h 
T0+6h 
(only if T0 
before 12 
a.m.) 
morning 
visit time 
+ at leat 
6h 
mornig 
visit time 
+ at least 
6h 
morning 
visit 
time + 
at least 
6h 
Visit # 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 
7-
10 
Visit 
11 
Visit 12 
Visit 13-
16 
Visit 
17 
Visit 18 
Visit 
19-59 
Visit 60 
Visit 61 
Inclusion/exclusion criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy Test 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed Consent  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Randomization  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographic Data  
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Intubation/reintubation status 
X 
X 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Acute Pulmonary Condition  
X 
  
  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X** 
Medical  history & comorbidity factors 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Current INTELLIVENT-ASV  settings 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
INTELLIVENT-ASV randomisation violation status 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Vital Signs  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Ventilatory parameters manual assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
24h Recording of ventilation parameters *(Memory 
Box) 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Blood gas analysis (If available visit ± 2h) 
X 
X# 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
ICU severity Scores (SAPS II, APACHE II) 
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
SOFA score 
  
  
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
Concomitant sedation, analgesia and myorelaxants 
use 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Concomitant vasopressors and inotropics use 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  

 
 
 
 
 
 
 
 
 
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Study Period 
Screening 
Baseline 
Intervention Period  
End of 
Study 
Study Exit 
Time 
Day 0 
Day 0 
Day 0 
Day 0 
Day 1 
Day 1 
Day 
2-3 
Day 4 
Day 4 
Day 5-6 
Day 7 
Day 7 
Day 8-
27 
Day XX 
Day 28 
Time specifications 
T0 
T0+1h 
T0+6h 
(only if T0 
before 12 
a.m.) 
morning 
visit time 
+ at leat 
6h 
mornig 
visit time 
+ at least 
6h 
morning 
visit 
time + 
at least 
6h 
Visit # 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 
7-
10 
Visit 
11 
Visit 12 
Visit 13-
16 
Visit 
17 
Visit 18 
Visit 
19-59 
Visit 60 
Visit 61 
Number of recruitment maneuvers within the last 
observation period 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Concomitant rescue therapies (proning, Nitric 
oxyde, ...) 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Weaning information  NIV, CPAP, High Flow.) 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Screening of readiness to extubate criteria (SBT) 
  
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Assessment of re-intubation status 
  
  
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
  
Extubation failure (yes/no) 
  
  
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Acute Kidney Injury (AKI) status and need vor RRT 
(yes/no) 
X 
X 
  
  
  
  
  
X 
  
Xƒ 
X 
  
Xƒ 
X 
X 
Criticall illess polyneuro- myopathy status (yes/no) 
X 
X 
  
  
  
  
  
X 
  
Xƒ 
X 
  
Xƒ 
X 
X 
Critcial illess encepahlopathy status (yes/no) 
X 
X 
  
  
  
  
  
X 
  
Xƒ 
X 
  
Xƒ 
X 
X 
Tracheostomy status (yes/no) 
  
  
  
  
  
  
  
  
  
  
X 
  
Xƒ 
X 
X 
Resuscitted cardiac arrest status (yes/no) 
  
  
  
  
  
  
  
X 
  
  
X 
  
  
X 
  
Other imminently life-threatening experience  
  
  
  
  
  
  
  
X 
  
  
X 
  
  
X 
  
Barotrauma status (yes/no) 
  
  
  
  
  
  
  
X 
  
  
X 
  
  
X 
  
Rescue therapy requirement (APRV, HFO, ECCO2R 
and ECMO). 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Patient status incl. Withhold of weaning and/or 
withdrawald of MV 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X** 
Ventilation duration for study period (if reintubated 
beyond 48h) 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
ICU and hospital length of stay 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X** 
ICU/Hospital death 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X** 

 
 
 
 
 
 
 
 
 
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Study Period 
Screening 
Baseline 
Intervention Period  
End of 
Study 
Study Exit 
Time 
Day 0 
Day 0 
Day 0 
Day 0 
Day 1 
Day 1 
Day 
2-3 
Day 4 
Day 4 
Day 5-6 
Day 7 
Day 7 
Day 8-
27 
Day XX 
Day 28 
Time specifications 
T0 
T0+1h 
T0+6h 
(only if T0 
before 12 
a.m.) 
morning 
visit time 
+ at leat 
6h 
mornig 
visit time 
+ at least 
6h 
morning 
visit 
time + 
at least 
6h 
Visit # 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 
7-
10 
Visit 
11 
Visit 12 
Visit 13-
16 
Visit 
17 
Visit 18 
Visit 
19-59 
Visit 60 
Visit 61 
Adverse Event collection  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X** 
Legend 
* 24H recording of ventilation parameters include: Ventilator settings, Alarm settings and Breath-by-breath monitoring of: Tidal volume (VT), total Respiratory rate 
(RR), spontaneous RR, inspiratory time, expiratory time, Maximum pressure (Pmax), Oxygen saturation measured by pulse oximetry (SpO2), End-tidal partial pressure 
of carbon dioxide (PetCO2), PEEP, inspiratory flow, expiratory flow, static compliance for passive subjects, inspiratory resistance for passive subjects, expiratory time 
constant.    
ƒ to be assesst only in the morning visit.  
# if ventilator settings have changed since visit 1 
 

 
 
 
 
 
 
 
 
 
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1 
STUDY ADMINISTRATION AND STRUCTURE  
1.1 
Sponsor  
Hamilton Medical AG, Via Crusch 8, CH 7402 Bonaduz, Switzerland 
US Sponsor: Hamilton Medical Inc., 4655 Aircenter Circle Reno NV 89502 USA  
 
1.2 
Principal Investigator(s)  
Omitted 
 
1.3 
Investigational Site(s)  
Investigational sites will be located both in Europe and in US.  
The list of sites with contact details of the study team and principal investigators is maintained in the Trial 
Master File and provided to the investigators.  
 
1.4 
Statistician ("Biostatistician")  
An independent blinded statistician from IDDI will be in charge of optimizing the study design and 
performing the statistical analysis.  
 
1.5 
Monitoring institution 
VCLS will be in charge of monitoring activities at sites.  
Voisin Consulting Life Sciences  
64, avenue Pierre Grenier 
92100 Boulogne Billancourt 
France 
 
1.6 
Data Safety Monitoring Board  
A Data Safety Monitoring Board (DSMB) will be settled by the sponsor and will be composed experts in 
mechanical ventilation independent from the study coordinators and investigators.  
The responsibility of the DSMB is to evaluate safety data during the course of the trial and to advise 
Hamilton Medical about the continuing safety of the Study. 
 
Listings of recorded Adverse Events/Serious Adverse Events and Device Deficiencies will be provided by 
VCLS VigOps to the Independent Medical Monitor to evaluate safety of the study device. All events, 

 
 
 
 
 
 
 
 
 
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including any device related events will be reviewed on a case by case base by the Independent Blinded 
Medical Monitor. A safety concern raised by the Independent Medical Monitor triggers a DSMB meeting.  
Trial data will be reviewed on a periodic basis as defined in the DSMB Charter. 
 
Based on the available safety data, the DSMB may recommend that Hamilton Medical modify or terminate 
the trial. DSMB composition, duties, procedures, deliberation rules are detailed and documented in the 
DSMB Charter. 

 
 
 
 
 
 
 
 
 
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2 
ETHICAL AND REGULATORY ASPECTS  
2.1 
Study registration  
Study is registered at ClinicalTrials.gov, ClinicalTrials.gov Identifier: NCT04400643. 
Study registration in any other databases that might be required per local requirements/regulations will 
be done by the sponsor or designee.  
 
2.2 
Institutional Review Board (IRB) / Independent Competent Ethics Committee (EC) 
It is the responsibility of the investigator and of Hamilton Medical to have prospective approval of the 
study protocol, protocol amendments, informed consent forms, and other relevant documents, e.g., 
recruitment advertisements, if applicable, from the IRB/EC. All correspondence with the IRB/EC should be 
retained in the Investigator Site File. Copies of IRB/EC approvals should be forwarded to Hamilton Medical.  
 
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is where the 
change is necessary to eliminate apparent hazards to the subjects. In that event, the investigator must 
notify the IRB/EC and Hamilton Medical in writing immediately after the implementation.  
 
2.3 
Competent Authorities (CA)  
Competent authorities will be notified prospectively by Hamilton Medical as need be.  The sponsor, 
Hamilton Medical, will be ultimately responsible for ensuring that competent authorities’ approvals are 
approved in target countries.  
 
2.4 
Ethical Conduct of the Study  
The study will be carried out in accordance to the protocol and with principles enunciated in the current 
version of the Declaration of Helsinki (2013), the guidelines of Good Clinical Practice (GCP) issued by ICH 
and in accordance to local regulation law. 
 
2.5 
Declaration of interest 
Site investigator will complete financial disclosure form (Form 3455), 21 CFR Part 54. 
 
2.6 
Suspension or Premature Termination of the Clinical Investigation 
This study may be discontinued at any time by Hamilton Medical, the US FDA, OHRP, other government 
or regulatory authorities, or site IRB(s)/EC(s). 
The Sponsor may decide to stop the study early or close a site in the following situations:  

 
 
 
 
 
 
 
 
 
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• 
If the Sponsor received information about the Investigational device which is liable to change the 
benefit/risk balance;  
• 
In the event of inadequate recruitment within the predetermined time on the site, 
• 
If the Investigator received information about the investigational device or resources that may 
jeopardize the conduct the study;  
• 
If the Sponsor considers that the results of the Clinical Study are not scientifically convincing;  
• 
If the objective of the study is no longer relevant or of interest;  
• 
If the Investigator fails to meet of his/her fundamental obligations through the terms of this 
agreement, and particularly a breach of the Clinical Study Protocol, a breach of the current laws and 
regulations or a breach of Good Clinical practices requirements;  
• 
If the total number of subjects recruited is achieved earlier than planned; 
• 
If it is a regulatory decision; 
• 
If the Sponsor agrees with DSMB/ Medical Monitor’s recommendation to terminate the Study based 
on site recorded AE(s)/SAE(S). 
 
In all situations, the Sponsor will inform the Investigator of its decision in writing.  
If an investigational site is suspended or prematurely terminated: 
• 
The investigator shall then promptly inform enrolled subjects 
• 
The investigator agreement will be terminated 
• 
The investigator will inform the institution  
• 
Sponsor will inform the Regulatory Authority(ies) (where required by applicable regulatory 
requirements) 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of definite 
outcomes, investigators must assess whether to continue, modify or immediately stop the clinical study 
in the respective investigation site and immediately inform the sponsor and IEC/IRB, if applicable. 
 

 
 
 
 
 
 
 
 
 
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3 
BACKGROUND AND RATIONALE  
Mechanical ventilation is the first line supportive treatment of acute respiratory failure in ICU subjects 
and ensures the replacement of gas exchange during respiratory failure in ICU subjects (2). Ventilation 
support should be adapted to cellular metabolism in order to provide necessary oxygen (oxygenation) and 
to eliminate carbon dioxide (ventilation).  
In conventional ventilation modes, clinicians adjust and modify the oxygenation and ventilation 
parameters manually. Subjects in an ICU evolve continually, and parameters may not be optimal with 
manual adjustments (3). These manual adjustments represent a substantial workload for clinicians during 
subject care (4), as conventional ventilation modes compel them to adjust all parameters and modify 
adjustments when the physiological status of the subject changes.  
Some ventilation modalities adjust ventilation automatically according to physiological parameters 
measured on the subject (5, 6). They have been proven beneficial with regards to ventilation optimization 
as adapted in real time to subject clinical condition, decreased care workload and ventilation duration (7, 
8, and 9). Unnecessary high FiO2 leading to hyperoxemia is detrimental. The ability to adjust FiO2 to subject 
needs is likely beneficial for subjects and reduce costs. Currently, no automated oxygenation control is 
available on marketed ventilators for adult subjects in the US.  
Adaptive Support Ventilation mode (ASV) has been used for 21 years in Europe and INTELLiVENT-ASV 
software accessory received CE marking in 2010 in Europe. It is a software accessory that fully automates 
Hamilton Medical's ASV mode, automatically adjusting both oxygenation and ventilation settings (10). The 
oxygenation parameters, FiO2 and PEEP, are adjusted according to oxygen saturation measured by pulse 
oximetry (SpO2). Ventilation is adjusted according to end-tidal partial pressure of carbon dioxide 
measurement (PetCO2) in passive subjects (without spontaneous ventilation) and according to respiratory 
rate (RR) and PetCO2 in active subjects (with spontaneous ventilation). The system can stabilize the subject 
in these optimal zones with maximum safety. 
When target MV is determined, tidal volume (VT) and RR are determined according to the principle of the 
least respiratory work and force of breathing (11, 12). Clinicians choose target ranges for SpO2 and PetCO2 
in addition to the limits for FiO2, PEEP, and inspiratory pressure.  
INTELLiVENT-ASV safety and efficacy have been demonstrated in post-cardiac surgery (13) and in ICU 
subjects over periods of time up to 48 hours (10, 14). A randomized, cross-over, pilot study comparing 
INTELLiVENT-ASV mode to ASV in fifty (50) passive ICU subjects in Europe demonstrated better efficacy of 
ventilation, by delivering less volumes and pressures without alteration of gas exchange (10). The 
automatically selected parameters remained within the defined safety limits. The present study will assess 
safety and efficacy of INTELLiVENT-ASV in ICU subjects up to 7 days after enrollment. 
 
3.1 
Investigational device(s) and comparator(s) 
Non automated ventilation arm: 
Non automated ventilation mode (administered according to the ICU protocols), utilizing Hamilton 
Medical ventilator.  

 
 
 
 
 
 
 
 
 
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For those ventilators used for treating the subjects in the non-automated ventilation mode INTELLiVENT-
ASV ventilation mode will not be selected.  
It will be evaluated on a site by site cases if Hamilton Medical ventilators will be supplied by the Sponsor 
to be used for this study in the non-automated ventilation arm. 
If there is a need to have the ventilators provided by the Sponsor upon completion of evaluation, Sponsor 
will supply the devices. 
Automated ventilation arm: 
INTELLiVENT-ASV ventilation mode, utilizing a Hamilton-Medical ventilator. 
For those subjects in the automated arm the INTELLiVENT-ASV ventilation mode will be selected. 
Sponsor will supply ventilation system, to be used for this study, if needed.  
 
All subjects will be ventilated with a Hamilton ventilator equipped with SpO2 and PetCO2 sensors in order 
to assess the main endpoints. 
INTELLiVENT-ASV is a software accessory that automatically adjusts ventilation and oxygenation 
parameters to keep the subject within clinician-set target ranges, from intubation until extubation. 
It is a closed-loop ventilation mode and is intended as an accessory for currently marketed Hamilton 
Medical ventilators.  
INTELLiVENT-ASV includes the following features:  
1. Ventilation controller (% MinVol)  
2. Oxygenation controller (FiO2 & PEEP)  
3. Quick Wean  
The investigator brochure provides details on physiological inputs and sensor management.  
Please refer to the Investigator Brochure for more details 
 
3.2 
Preclinical Evidence  
Preclinical evidence is included in the Investigator Brochure.  
 
3.3 
Clinical Evidence to Date  
Please refer to Annex B 
 
 

 
 
 
 
 
 
 
 
 
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3.4 
Risks and Benefits Statement 
Risks 
Subjects suffering from critical illness and requiring invasive mechanical ventilation are exposed to 
numerous risks. First, critical illness in and of itself can cause numerous complications and mechanical 
ventilation may not always prevent a fatal outcome related to the underlying disease. Second, invasive 
mechanical ventilation is an invasive, potentially prolonged procedure that exposes the subject to specific 
risks of complications related to: Airway management (tracheal tube intubation), need of analgesia and 
sedation, infection, critical-illness neuromyopathy and thrombosis. Even in situations where mechanical 
ventilation can help improve gas exchange, inappropriate ventilator settings can lead to: ventilator-
induced lung injury, lung barotrauma (pneumothorax) and iatrogenic alterations in O2 and CO2 arterial 
blood content. There is mounting evidence that not only low O2 and high CO2, but also low CO2 and high 
O2 can be deleterious to the critically ill subject. In short, the risks of invasive mechanical ventilation should 
be lower than the risks of the critical illness. Clinicians involved in the management of critically ill subjects 
continuously try to minimize these risks by periodical arterial blood gas sampling leading to regular 
iterative adjustments of the settings of the ventilator. In some instances, a continuous monitoring of 
PetCO2 and SpO2 is performed. Strategies aiming at limiting sedation and detecting as soon as possible the 
ability of the subject to be liberated from the ventilator are also systematically implemented, to minimize 
the time spent under invasive mechanical ventilation.  
Both groups will be exposed to the risks inherent to invasive mechanical ventilation, such as ventilator 
malfunction and error in arterial blood gas measurements. Each ICU has specific strategies and policies to 
prevent and handle such problems. 
Conceivably, risks specific to INTELLiVENT-ASV include erroneously setting respiratory condition or ideal 
body weight and sensor malfunction. To minimize the risk of erroneous setting, a specific training will be 
provided to all healthcare workers handling subjects included in the study (refer to Annex C). Regarding 
sensor malfunction, INTELLiVENT-ASV per design handles such occurrence by interrupting the close-loop 
automatic adaptations, keeping the ongoing setting and alarming the ICU team to the condition. They will 
then have the choice either to correct the sensor failure (a typical example would be a dislodged SpO2 
sensor due to subject’s movement) or to enter new settings manually as in the control group. 
Furthermore, the attending physician has at any time the possibility to switch to conventional ventilation 
if she/he deems it necessary. 
Although the above-mentioned situations are theoretically possible, preliminary studies have shown that 
among different groups of subjects, there is a safer ventilation with INTELLiVENT-ASV compared to 
conventional ventilation in volume (13). 
Subjects are monitored as any ICU subject, with particular attention to ventilation parameters. The 
attending physician in the ICU always has the possibility to fall back to conventional ventilation for 
whatever reason.   
The risk level is estimated to be moderate. The INTELLiVENT-ASV system was the subject of a risk analysis, 
and preliminary studies have not reported any adverse events related to INTELLIVENT-ASV during more 
than 200 hours of cumulative ventilation with INTELLiVENT-ASV (10, 13).   

 
 
 
 
 
 
 
 
 
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Benefits 
The common health field benefit is to make available to this subject population, a ventilator that 
continuously adapts the delivered ventilation and oxygenation in real time to the needs of mechanically 
ventilated ICU subjects. These automations are a real progress in relation to the current procedures and 
above all may increase the safety of mechanically ventilated subjects. 
The individual risk faced is therefore limited, and alarm settings can alert the physician in order to 
immediately correct as needed any ventilation or oxygenation anomaly. The potential overall benefit is 
high for ICU subjects. The benefit / risk balance does justify the study conduct as there is no additional 
risk anticipated for subjects – there may be the possibility to detect additional clinical benefits as outlined 
before.  

 
 
 
 
 
 
 
 
 
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4 
STUDY OBJECTIVES  
4.1 
Overall objectives of the study 
The study is designed to assess safety and efficacy of INTELLiVENT-ASV, a software accessory integrated 
in Hamilton ventilators that is designed to fully and automatically adjust both oxygenation and ventilation 
settings. 
Efficacy and safety are primarily assessed to keep ventilation and oxygenation variables in optimal target 
ranges according to pertinent guidelines for Invasive Mechanical Ventilation. 
 
4.2 
Primary Objectives 
Efficacy: To assess the efficacy of INTELLiVENT-ASV in adult ICU subjects up to 7 days after enrollment. 
Safety: To assess the safety of INTELLiVENT-ASV in adult ICU subjects up to 7 days after enrollment. 
 
4.3 
Secondary Objectives 
The secondary objective is the assessment of ventilation safety and effectiveness by measuring 
physiologic parameters, clinical outcomes associated interventions and typical clinical complications up 
to day 28 after enrollment.  
 
4.4 
Tertiary Objectives 
Efficacy: To assess the efficacy of INTELLiVENT-ASV in adult ICU subjects from day 8 up to day 28 after 
enrollment. 
Safety: To assess the safety of INTELLiVENT-ASV in adult ICU subjects from day 8 up to day 28 after 
enrollment. 
 
 

 
 
 
 
 
 
 
 
 
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5 
STUDY ENDPOINTS  
5.1 
Primary endpoints 
Primary endpoints will be measured continuously during ventilation period up to 7 days after enrollment.  
 
Efficacy 
Efficacy of the investigational device by assessing the ability to keep ventilation and oxygenation variables 
in optimal target ranges. 
This endpoint will be determined by the percentage of time spent with six (6) variables in the optimal 
range:  
1) Tidal volume (VT)  
2) Maximum pressure (Pmax) 
3) Oxygen saturation measured by pulse oximetry (SpO2) 
4) End-tidal partial pressure of carbon dioxide (PetCO2)  
5) Respiratory rate (RR) for spontaneous breathing subjects 
6) Pmax-PEEP for passive ARDS subjects 
The optimal and sub-optimal ranges are defined by pertinent guidelines for different clinical conditions 
including normal lungs, brain injury, ARDS, and chronic hypercapnia.  
Safety: 
The primary safety endpoint will be determined by percentage of time spent with at least one variable in 
the sub-optimal range during the first seven (7) days of enrollment.  
For the invasive mechanical ventilation ranges, please refer to section 10.4.5 Analysis of Primary 
Endpoints. 
 
5.2 
Secondary endpoints 
Secondary endpoints will be recorded continuously until the end of intervention period (up to 28 days 
after enrollment).  
 
Efficacy 
Physiologic parameters:  
1. Respiratory mechanics (Compliance, resistance, expiratory time constant) will be 
assessed automatically breath-by-breath  
2. Oxygenation (PaO2/FiO2, FiO2, PEEP) 
3. Ventilation (VT, RR, mechanical power will be assessed automatically breath-by-breath, 
ΔP, PPLAT, will be assessed twice a day). 

 
 
 
 
 
 
 
 
 
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4. FiO2 levels to be assessed in both study arms 
Outcomes:  
1. Duration of invasive mechanical ventilation: time between intubation and last extubation 
or death. When a subject is re-intubated within 48 hours after extubation, the period 
between extubation and re-intubation is considered as invasive ventilation days. 
2. Duration of non-invasive mechanical ventilation: noninvasive ventilation refers to CPAP 
or pressure support NIV delivered before intubation or after extubation. High flow 
therapy is not considered in this calculation. 
3. Total duration of mechanical ventilation: sum of duration of invasive and noninvasive 
mechanical ventilation. 
4. Time from intubation to first successful SBT 
5. Passive ventilation duration: passive ventilation is defined when the percentage of 
subject’s triggered breath is lower than 25% of total respiratory rate.  
6. Weaning duration: time between the first sedation cessation to the last extubation or the 
last disconnection from the ventilator for tracheostomized subjects. Subjects reintubated 
within 48h after extubation will be kept in the study. Subject re-intubated beyond 48h 
will be considered as weaned from the ventilation. 
7. VFD to day 28 are defined as: the number of days from the time of initiating unassisted 
breathing to day 28 after start of ventilation, assuming survival for at least 48 hours and 
no re-intubation within 48 hours after initiating unassisted breathing and continued 
unassisted breathing to day 28.  
 
NIV will be considered as assisted breathing. CPAP will not be considered as assisted 
breathing. Ventilator free days will be calculated separately for invasive ventilation 
support and any other ventilation support (invasive and noninvasive). 
 
If a subject returns to assisted breathing (re-intubated within 48 hours) and subsequently 
achieves unassisted breathing to day 28, VFDs will be counted from the end of the last 
period of assisted breathing to day 28.  
 
A period of assisted breathing lasting less than 24 hours and for the purpose of a surgical 
procedure will not count against the VFD calculation.  
 
If a subject was receiving assisted invasive breathing on day 27 or dies prior to day 28, 
VFDs will be - 1. 
 
For subjects transferred to another hospital or other health care facility, study data 
collection will be stopped but subject will be contacted via a phone call on day 28 post 
enrollment to assess VFD endpoint if possible: 
o ICU and hospital length of stay (discharge). 

 
 
 
 
 
 
 
 
 
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o ICU mortality (if the subjects is hospitalized in another hospital than the 
investigational site) 
o Non-intensive ventilation (NIV) duration 
o 28 days mortality 
o Ventilation duration for study period (if reintubated beyond 48h) 
Dropout could occur when patients are ventilated for less than 24 hours after inclusion 
because of unexpected death, transfer to another ICU, or withdrawal of informed 
consent. A maximum dropout rate of 5% of these cases is expected.  
 
Associated interventions: 
1. Duration and doses of sedative infusion 
2. Duration and doses of analgesic infusion 
3. Duration and doses of vasopressors 
4. Duration and doses of myorelaxant 
5. Number of recruitment maneuvers  
6. Time spent in prone position 
7. Time spent with nitric oxide 
Workload: 
1. Number of manual adjustment will be collected in both ventilation arms until considered 
as weaned from the ventilation. 
Safety: 
The secondary safety endpoint will be determined by evaluating the number of Serious Adverse Events 
(all SAEs included) within 28 days of the enrollment and the rescue therapy requirement (APRV, high 
frequency ventilation, ECCO2R and ECMO). 
In addition to better characterise the risk profile of the study population the following non-mechanical 
ventilation related adverse events will be recorded on study day 7 and 28. 
• 
Severe Acute kidney injury (AKI) in need for CRRT/IHD 
• 
Severe critical illness neuro-myopathy signs of tetraplegia affecting arms shoulder and neck with 
potential implication of respiratory muscle. Weakness is documented using the following score 
points: score 0 for no visible muscle contraction, score 1 for visible muscle contraction with no or 
trace movement, score 2 for limb movement, but not against gravity and score 3 for movement 
against gravity but not resistance. 
• 
Severe critical illness encephalopathy leading to prolongation of mechanical ventilation. The most 
frequent causes being a metabolic or electrolyte disorder, systemic inflammation and other 
causes. Hypoxia, Stroke, intracranial bleeding, epilepsy and delirium. Encephalopathy is assessed 
using the GCS score and need to be reported is < 8 points. 
• 
Withhold of weaning and/or withdrawal of mechanical ventilation because of treatment 
limitation related to patient wish or treatment futility due to irreparable single or multi-organ 

 
 
 
 
 
 
 
 
 
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failure affect mechanical ventilation strategy, weaning from mechanical ventilation up to 
withdrawal of mechanical ventilation. 
• 
Extubation failure that is related to weaning process by itself or associated conditions based on 
the interpretation of the investigator. 
• 
Need for tracheostomy that is related to a difficult weaning process or associated conditions 
based on the interpretation of the investigator. 
5.3 
Tertiary endpoints 
Tertiary endpoints will be measured continuously during ventilation period from day 8 up to day 28 after 
enrollment. 
 
Efficacy 
Efficacy of the investigational device by assessing the ability to keep ventilation and oxygenation variables 
in optimal target ranges. 
This endpoint will be determined by the percentage of time spent with six (6) variables in the optimal 
range:  
1) Tidal volume (VT)  
2) Maximum pressure (Pmax) 
3) Oxygen saturation measured by pulse oximetry (SpO2) 
4) End-tidal partial pressure of carbon dioxide (PetCO2)  
5) Respiratory rate (RR) for spontaneous breathing subjects 
6) Pmax-PEEP for passive ARDS subjects 
The optimal and sub-optimal ranges are defined by pertinent guidelines for different clinical conditions 
including normal lungs, brain injury, ARDS, and chronic hypercapnia.  
Tertiary endpoints will be measured continuously during ventilation period from day 8 up to day 28 after 
enrollment.  
 
Safety: 
The tertiary safety endpoint will be determined by percentage of time spent with at least one variable in 
the sub-optimal range from day 8 up to day 28 after enrollment. 

 
 
 
 
 
 
 
 
 
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6 
STUDY DESIGN 
6.1 
General 
EASiVENT is a Pivotal, two-arm, controlled, single-blind, multicenter, randomized trial of INTELLiVENT-ASV 
versus non automated Ventilation in adult ICU subjects. 
 
6.2 
Methods of minimizing bias  
 Randomization 
The subjects will be randomized to either INTELLiVENT-ASV or Non automated Ventilation using in a 1:1 
ratio by a computerized central randomization system.  
The two study arms will be stratified by subject condition at inclusion (normal lungs, ARDS, chronic 
hypercapnia, or brain injury) and by site to ensure balanced assignment for interventions at each site. The 
randomization scheme will be generated and maintained by the randomization module part of the 
electronic case report form (eCRF).  
 
 Blinding 
Study subjects will be blinded to the random intervention assignment. Therefore, this study is considered 
single blind since study staff will know each subject’s intervention assignment. 
 
6.3 
Justification for the design of the clinical investigation 
The reference treatment used for comparison is a combination of controlled modes for passive subjects 
(volume control or pressure control) and assisted/spontaneous modes for active subjects (synchronized 
intermittent mechanical ventilation or pressure support). 
Sample size has been adjusted with an adaptive design to be able to fulfill the targeted endpoints (see 
section 10.2) 

 
 
 
 
 
 
 
 
 
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7 
STUDY POPULATION  
7.1 
Selection of the Study Population 
Eligible patients are adult ICU subjects, 21 years and older, requiring invasive mechanical ventilation and 
fulfilling the inclusion and exclusion criteria. 
ICU patients will be selected from sites in Europe and in US. Recruitment will be competitive.  
 
7.2 
Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for enrollment into this study: 
1. Age ≥ 21 years old  
2. Weight > 40 kilograms 
3. Under invasive ventilation for less than 24 hours  
4. Expected to be mechanically ventilated for at least 24 hours after enrollment 
5. Agrees to not participate in other interventional research studies involving  mechanical ventilation  
for the duration of study participation, unless approved by the DSMB 
6. Signature of the informed consent by the subject or his/her next-of-kin according to country or 
state regulation 
 
7.3 
Exclusion Criteria 
Subjects who meet any of the following criteria are not eligible for enrollment into this study: 
1. Fulfilling weaning criteria according to the weaning procedure of the ICU  
2. Need for “rescue therapy” (ECMO, ECCO2R, HFO))  
3. Brain death status 
4. Respiratory drive disorder (Cheyne-Stokes breathing)  
5. Arterial hypoxia due to a non-pulmonary condition (right-to-left shunting due to congenital 
disease, hepato-pulmonary syndrome, ) 
6. Broncho-pleural fistula 
7. Chronic or acute dyshemoglobinemia: acute CO poisoning, meth-hemoglobin, sickle cell disease. 
8. Chronic respiratory failure requiring long term invasive ventilation;  
9. Moribund subject: death expected within 24 hours 
10. Positive pregnancy test at screening  for childbearing age women 
11. Decision to withhold or withdraw life support. This does not exclude those patients committed to 
full support except cardiopulmonary resuscitation. 
12. Subject under guardianship  
13. Subject deprived of liberties  
14. Subject included in another interventional research study involving mechanical ventilation under 
consent. 

 
 
 
 
 
 
 
 
 
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15. Any other condition, that in the opinion of the IoR/designee, would preclude informed consent 
(by the spouse/next of kin), make study participation unsafe, complicate interpretation of study 
outcome data, or otherwise interfere with achieving the study objectives. 
16. Low quality index on the SpO2 measurement using finger and ear sensor for > 3 hours 
17. Subjects already enrolled in the present study in a previous episode of acute respiratory failure 
18. High PaCO2 – ETCO2 gap (> 2.6 kPa or 19.5 mmHg) for > 3 hours 
19. Patient tracheostomized at the time of inclusion 
20. Patient ventilated with helium 
 
7.4 
Vulnerable Population 
Pregnant Women 
Any female with childbearing potential that tests positive for pregnancy at screening is not eligible to 
participate in this study. 
Subject under guardianship/ Subject deprived of liberties  
Any subject who is under guardianship or deprived of liberties is not eligible to participate in this study.  
Children 
This study will not enroll persons under the age of 21 years.  
 
7.5 
Co-enrollment Guidelines 
As indicated in Sections 7.2 and 7.3 above, subjects are not permitted to take part in other research 
studies involving mechanical ventilation  for the duration of study participation while taking part in 
EASiVENT, unless approved by the DSMB. Should any participant (or friend, family member, etc.) report 
concurrent participant in another research study after enrollment into EASiVENT not previously approved 
by the DSMB, the IoR/designee must consult the DSMB regarding ongoing participation and potential 
safety considerations associated with co-enrollment.  
 
7.6 
Study Withdrawal 
Participants (or spouse/next of kin or legally authorized representative) may voluntarily withdraw from 
this study for any reason at any time, regardless of the participant retention strategies utilized. 
Additionally, the IoR may also withdraw participants from the study in order to protect their safety and/or 
if they are unwilling or unable to comply with required study procedures after consultation with primary 
investigator and Hamilton Medical. Participants may be withdrawn from the study if the study sponsor, 
government or regulatory authorities (including Office for Human Research Protections [OHRP] and the 
FDA) or site IRBs/ECs terminate the study prior to its planned end. Every reasonable effort will be made 
to complete a final evaluation of participants who withdrawal/terminate early from the study, and study 

 
 
 
 
 
 
 
 
 
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staff will record the reason(s) for all withdrawals in the participants’ study records. In addition, subject 
withdrawal will be documented in the eCRF on the End of Study forms.  
If subjects are transferred after seven (7) days of start of ventilation, primary endpoints will be assessed 
and study ventilation protocol ended. However, the ventilation duration and mortality will be captured 
on Day 28 after enrollment via a phone call as described in VFD section. 
 
Dropout could occur when patients are ventilated for less than 24 hours after inclusion because of 
unexpected death, transfer to another ICU, or withdrawal of informed consent. We expect a maximum of 
5% of these cases.  
Note a maximum of 5% of subjects are anticipated for which not 80% of mechanical ventilation time, 
within the allocated randomized ventilation mode, could be recorded due to documented technical 
reason. 
 
Please refer to: Section 10.5 “Missing Data” 
 Lost-to-follow-up  
A subject is to be considered lost to follow-up once the investigator and/or research staff has made three 
documented attempts to contact the subject in case of Day 28 data collection and the subject is not 
reachable. The third attempt should be made by certified mail to the subject. 
In case the required data of Day 28 is available in the national/site database there is no need to send out 
a certified mail to the subject.   
 
 
7.7 
Medical care after study exit 
After the subjects exit the study (Day 28 data collection completed), the subject will be followed as per 
routine standard of care. No long-term follow-up is planned per the protocol. 
 
7.8 
Informed Consent Process 
Written informed consent will be obtained from each study participant, spouse/next of kin or a legally 
authorized representative. As the protocol is dealing with ICU subjects, it is anticipated that most of 
subjects are in a life-threatening situation and it is not feasible to obtain their informed consent as a result 
of their medical condition. In that case, a legally authorized representative or a family member of the 
subject will be asked to provide consent and that he or she may discontinue the subject's participation at 
any time without penalty or loss of benefits to which the subject is otherwise entitled. If a legally 
authorized representative or family member is told about the clinical investigation and the subject's 
condition improves, the subject is also to be informed as soon as feasible. 

 
 
 
 
 
 
 
 
 
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Each study site will have their site specific study informed consent form(s) for local use that describes the 
purpose of the study, randomization and the importance of participation in both study interventions to 
the success of the study, the procedures to be followed, the risks and benefits of participation, the distinct 
between research and clinical care, and the right to withdraw from the study at any time, in accordance 
with all applicable regulations. If applicable, the study site is also responsible for translating the template 
form into the local language, and verifying the accuracy of the translation by performing an independent 
back-translation.  
All USA sites will cover the elements required per Office for Human Research Protections (OHRP) CFR 
§46.116 - Informed Consent Checklist - Basic and Additional Elements in their local consent forms. 
Each participant (or spouse/next of kin or a legally authorized representative) will document his/her 
provision of informed consent by signing his/her informed consent form.  
Each signed and dated consent must be maintained by the clinical investigator and a copy of the informed 
consent must be provided to the subject.  
 
 

 
 
 
 
 
 
 
 
 
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8 
STUDY PROCEDURES 
8.1 
Screening  and Point of Enrollment process  
 Screening 
Patient’s eligibility will be determined by the investigator or designee based upon the followings: 
1. The availability of Hamilton’s ventilators designated for the study.  
a. If subject’s participation will be waived due to lack of device availability it will be 
documented on the study Pre-Screened subjects log. 
b. If the number of eligible patient is greater than the number of the available ventilators 
that are designated for the study, the chronological order to ICU admission (date & time) 
must be respected.   
 
2. Site personnel workload assessment: 
If subject’s participation will be waived due to resource limitation of the study team, the 
chronological order to ICU admission (date & time) must be respected and the reason will be 
documented on the study Pre-Screened subjects log. 
 
3. Pregnancy test (for female subjects of childbearing potential). Test must be completed per 
institutional standard of care at the time of screening. Results must be negative. 
 
4. Investigators or designee will assess if the potential patient is expected to be on invasive 
mechanical ventilation for more than 24 hours based upon review of their medical history and 
disease progress for inclusion in the trial.  
If the patient appears to meet the eligibility criteria, and is expected to be ventilated for more 
than 24 hours: 
a. Then the investigator will discuss the study with the patient or next-of-kind or a legally 
authorized representative and provide information relating to the potential risks and 
benefits, and required follow-up procedures per the informed consent process, and 
b. The investigator will check that the patient did not express his/her right to object to 
participate in the study in any identifiable manner, including obtaining clear oral 
information from any available relative(s) on the patient’s will. 
 
After the patient or next-of-kind or a legally authorized representative has voluntarily signed and 
dated the Informed Consent Form (ICF), the patient will be considered as a study candidate. 
If a the patient and or the next-of –kind or a legally authorized representative does not sign the 
ICF or the patient expressed his/her right to object to participate in the study in any identifiable 
manner, then no further study specific screening procedures can occur.  
 
The consenting process has to be documented in the subject source data.  
 

 
 
 
 
 
 
 
 
 
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 Point of Enrollment and Randomization: 
Subjects or next-of-kind or a legally authorized representative who sign and date the ICF and meet all of 
the study eligibility criteria will be eligible for inclusion into the EASiVENT Study.  
Two different scenarios might occur: 
1. The patient is already under invasive ventilation (intubated) for less than 24 hours, the next-of-
kind or a legally authorized representative will sign and date the ICF.  
2. The patient is able to sign and date the ICF before intubation. 
 
The subject will only be considered enrolled when the ICF signed and dated and the subject will be 
randomly assigned (1:1) to automate ventilation with INTELLiVENT-ASV or to the non-automated 
ventilation.   
Randomization will be stratified according to the clinical condition at inclusion (normal lungs, ARDS, 
chronic hypercapnia, brain injury). According to randomization allocation, the subject’s attending 
physician will adjust the ventilator settings and recording will start.  
Recording of ventilation data will start as randomization is completed and allocated randomization mode 
is selected. 
Enrolled subjects will be documented on the Screening and Enrolment Log. 
The investigator will maintain a log of all subjects screened and enrolled in the clinical study, assigning an 
identification code linked to their names, alternative subject identification or contact information. 
Patients who do not qualify for enrollment will be documented as ineligible on the Screening and 
Enrollment log. 
Adverse Event collection will be started after point of enrollment.  
 
8.2 
Baseline Assessment (Day 0)  
Collection of baseline information will take place only after the subject or next-of-kind or a legally 
authorized representative has given voluntary, documented informed consent and will include the 
following: 
 
• 
Intubation status 
• 
Demographic data : gender, age, height (measured at entry time), actual weight; 
• 
Vital signs: blood pressure, pulse rate and temperature  
• 
Subject comorbidity & medical history (including pulmonary and cardiovascular medical history) 
and acute pulmonary condition;  
• 
Ventilator parameters manual assessment 
• 
24h Recording of ventilation parameters (Memory Box) 

 
 
 
 
 
 
 
 
 
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• 
Concomitant rescue therapies (proning, Nitric oxyde, ...) 
• 
Acute Kidney Injury (AKI) status and need for RRT (yes/no) 
• 
Critical illness encephalopathy status (yes/no) 
• 
Blood gas analysis 
• 
Criticall illess polyneuro- myopathy status (yes/no) 
• 
Adverse Event collection 
 
All concomitant medications including sedation, analgesic, myorelaxants, concomitant vasopressors, 
inotropics use and the drugs used to treat chronic diseases. 
 
Ventilation start date/time as well as ventilation parameters will be recorded in the eCRF.  
In addition, main ventilation variables used for analysis will be recorded breath by breath:  
• 
Tidal volume (VT);  
• 
Respiratory rate (RR);  
• 
Maximum pressure (Pmax);  
• 
Oxygen saturation measured by pulse oximetry (SpO2);  
• 
End-tidal partial pressure of carbon dioxide (PetCO2).  
Plateau pressure and total PEEP will be measured by inspiratory and expiratory occlusions respectively at 
regular intervals and recorded in the electronic Case Report Form (eCRF) twice a day during the passive 
ventilation period.  
 
8.3 
Intervention Period (Day 1-Day 27):  
 General management in both groups 
From inclusion up to day of extubation (and not reintubated within 48h after extubation), ventilation 
settings will be adjusted by the attending physician or respiratory therapist. Subject condition, sedation, 
analgesic and vasopressor use, and one blood gas analysis will be collected twice a day if blood gas analysis 
is done routinely by the ICU department, otherwise ventilation parameters will only be collected.  
Subjects will be monitored by the attending physicians and all ventilation variables will be continuously 
recorded from inclusion to extubation or death. Except for ventilation, all other procedures and care 
(sedation, hemodynamics, glycemic control, etc.) will be conducted according to the protocols of the site 
by the subject’s attending physicians.  
Data listed below will be captured in the eCRF: 
• 
Intubation/reintubation status 
• 
INTELLIVENT-ASV randomization violation status 
• 
Vitals signs: Blood pressure, pulse rate and temperature;  
• 
Acute pulmonary condition; 
• 
24h Recording of ventilation parameters (Memory Box) 

 
 
 
 
 
 
 
 
 
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• 
Ventilation settings 
• 
All concomitant medications including sedation;  
• 
SOFA will be repeated at day 3 and 7, in order to follow the evolution of organ failure. 
• 
Memory Box recording 
• 
Blood gas analysis 
• 
Severity scores based on the most abnormal values in oxygenation and laboratory results in the 
last 24h period (day 0):  
o Simplified Acute Physiology Score (SAPS II) 
o Acute Physiology and Chronic Health Evaluation (APACHE II) 
o SOFA score  
• 
Concomitant sedation, analgesia and myorelaxants use 
• 
Concomitant vasopressors and inotropics use 
• 
Number of recruitment movers within the last observation period 
• 
Concomitant rescue therapies (proning, Nitric oxyde, ...) 
• 
Weaning information associated interventions (Patient Passive/Active but still on MV, NIV, CPAP, 
High Flow.) 
• 
Advers Event collection 
 
Recorded data has to be 24 hours at minimum and 80% of the invasive ventilation duration within the 
allocated randomized ventilation mode have to be recorded in the in Memory Box. 
If the subject’s medical condition requires  medical intervention (bronchoscopy, trancescopy, radiology or 
OR interventions…etc) and the subject is allocated to the INTELLiVENT-ASV arm, the allocated randomized 
ventilation mode may be switched off for the required time period. This needs to be documented in the 
subject’s medical chart. 
Dropout could occur when patients are ventilated for less than 24 hours after inclusion because of 
unexpected death, transfer to another ICU, or withdrawal of informed consent. We expect a maximum of 
5% of these cases. Note a maximum of 5% of subjects are anticipated for which not 80% of mechanical 
ventilation time could be recorded within the allocated randomized ventilation mode due to documented 
technical reason. The recorded data will be used (with 'percent spent' calculated per the recorded time) 
for the primary analysis of the co-primary endpoints. As a sensitivity analysis, these values will be treated 
as missing data.  
If the ventilation mode is modified by the site personnel by oversight or lack of training (deviating from 
the allocated randomization arm) and the subject’s medical condition did not require it, the ventilation 
mode should be set back to allocated randomization arm. A protocol deviation and the event will be 
recorded in the  eCRF accordingly.  
If the site’s principal investigator determines that the study is no longer in the subject’s best interest 
(including the randomized ventilation mode) the subject’s ventilation and study data collection ends. 
The site needs to complete an AE and the End of Study eCRF. 

 
 
 
 
 
 
 
 
 
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A. Gas exchanges targets: 
SpO2 will be kept in the ranges: 
- 94 - 98% for normal lung, mild and moderate ARDS, and brain injured subjects 
- 90-96% for moderate ARDS 
- 88 - 95% for severe ARDS 
- 90 - 94% for COPD without chronic hypoxemia or hypercapnia 
- 88 - 92% for chronic hypercapnic subjects or subjects on long term oxygen 
  PaCO2 will be kept in the range: 
- 35 - 40 mm Hg for brain injury 
- 35 - 50 mm Hg for normal lung, mild and moderate ARDS, COPD subjects without chronic hypercapnia 
- ≥ 50 mm Hg in severe ARDS, severe COPD, and subjects with chronic hypercapnia if pH > 7.25 
 
B. Passive subjects: 
i. 
Ventilator settings: 
Tidal volume will be kept in the range: 
- 6-10 mL/Kg IBW for normal lung subjects, brain injury, and COPD subjects 
- 4-8 mL/Kg IBW for ARDS 
 
ii.Lung protection monitoring: 
Plateau pressure will be measured at least twice a day and kept below 30 cmH2O. Driving pressure will 
be measured at least four times a day and kept below 15 cmH2O in all subjects. 
In ARDS subjects, Plateau pressure between 30 and 35 cmH2O will be accepted if driving pressure 
remains below 15 cmH2O.  
If plateau pressure exceeds 35 cmH2O or driving pressure exceeds 15 cmH2O, tidal volume will be 
decreased by 1 mL/Kg IBW keeping it above 4 mL/Kg or inspiratory pressure will be decreased by 2 
cmH2O. 
 
iii. 
Additional and rescue procedures: 
Continuous myorelaxant infusion, repeated recruitment maneuvers, nitric oxide, and prone position 
will be considered as additional procedures at the clinician’s discretion.  
If PaO2 ≥ 55 mmHg or SpO2 ≥ 88% with FIO2 of 1.0 cannot be maintained, clinicians may employ rescue 
procedures. APRV, high frequency ventilation, ECCO2R and ECMO will be considered as a rescue 
therapies. The subjects will continue to be followed and included in the analysis on an intention-to-
treat basis. Failure of the protocol and subsequent need for rescue therapy will constitute a secondary 
outcome. Control group subjects will not be allowed to cross-over to the INTELLiVENT-ASV group. 
 
C. Spontaneous breathing subjects: 
i. Ventilator settings: 
Ventilation support will be adjusted to keep tidal volume in the range: 
- 6-10 mL/Kg IBW for normal lung subjects, brain injury, and COPD subjects 

 
 
 
 
 
 
 
 
 
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- 4-8 mL/Kg IBW for ARDS 
Ventilation support will be adjusted to keep respiratory rate ≤ 35 Breaths/min. 
Inspiratory trigger settings will be set between 1 and 5 L/min or 0.5 and 2 cmH2O or activate 
Intellisync+. 
Expiratory trigger setting will be set between 10 and 80% of the maximal inspiratory flow or activate 
Intellisync+. 
Pressure rise time will be set between 0 and 400 ms. 
Automated tube compensation if appropriate. 
 
 
D. Weaning: 
The INTELLiVENT-ASV or control arm ventilator protocols will be continued until subjects are able to 
breathe unassisted for 48 hours, death, ICU discharge, study withdrawal, if the site’s principal 
investigator  determines that the study is no longer in the subject’s best interest or day 28, whichever 
comes first.  
i. 
Screening of readiness to wean criteria 
A screening of readiness to wean criteria will be performed twice a day between 6h00 and 18h00 for 
all subjects mechanically ventilated for more than 24h.  
ii. 
Extubation 
After a successful weaning trial, extubation criteria will be assessed: 
- 
Coma Glasgow Score > 8 
- 
Ability to cough 
- 
Ability to swallow 
- 
Absence of severe upper airway obstruction 
- 
Successful cuff leak test 
If all these criteria are fulfilled, subject will be extubated within 12 hours after the successful weaning 
trial. 
iii. 
Ventilation management after extubation 
High flow nasal treatment, CPAP, and NIV can be used after extubation. 
 
iv. 
Definition of unsuccessful extubation 
If reintubation occurs within 48-hours of extubation, this event will be noted as a reintubation. 
v. 
Completion of ventilator procedures. 
Subjects will be considered to have completed the study ventilator procedures if any of the following 
conditions occur: 
1. Death 
2. ICU discharge 
3. Subject or proxy withdraws consent 

 
 
 
 
 
 
 
 
 
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4. Principal investigator of site determines that the trial is no longer in the subject’s best interest 
5. Completed a period of 48 hours of unassisted breathing. 
If a subject requires positive pressure ventilation after a period of unassisted breathing, these will be 
at the discretion of the team caring for the subject. 
E. Tracheostomy 
The following recommendations to be consider for Tracheostomy.  
 
Tracheostomy will only be performed on strict indications and preferably not earlier than 10 days after 
intubation. 
Indications for tracheostomy will be: 
- 
Failure to intubate 
- 
Expected duration of mechanical ventilation > 14 days 
- 
Glasgow Coma Score < 7 and/or inadequate swallow or cough reflex with sputum retention 
- 
Severe ICU-acquired weakness 
- 
Prolonged or unsuccessful weaning 
- 
Repeated respiratory failure after extubation 
 
Readiness to wean criteria will be the same as intubated subjects. The weaning schedule for unassisted 
ventilation with a tracheostomy will follow the local protocol of the participating centers. 
F. Sedation 
Sedation will be prescribed with a sedation target using RASS or RAMSAY scale re-assessed at least 
once a day. Sedation will be monitored at least 2 times a day. 
A daily cessation of sedation will be performed if there is no contraindication. 
The subject’s study follow up ends after 28 days after enrollment, even if subject remains on 
mechanical ventilation. During this 28 days period, for subjects reintubated within 48h after 
extubation, VFD will not be counted and ventilator protocols will be continued. Subject re-intubated 
beyond 48h will be considered as weaned for ventilator and ventilator procedures will not be 
continued. 
 Ventilation protocol in non-automated ventilation group 
In order to standardize the non-automated ventilation process, Investigators will aim to keep the control 
arm (conventional non-automated ventilator) as close to the standard of care of the participating sites as 
possible.   
General approach: The overall goals for the control arm ventilation protocol will be similar to those in the 
INTELLiVENT-ASV group including all recommendation available regarding gas exchanges targets, 
ventilator settings, protective ventilation targets, and weaning management (16, 32). 
 
A. Passive subjects: 
i. 
Ventilation mode 

 
 
 
 
 
 
 
 
 
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Any controlled mode will be possible such as volume control (CMV), pressure control (P-CMV), dual 
mode (APVcmv and APVsimv), DuoPAP, SIMV, and P-SIMV. APRV will not be accepted. Tube resistance 
compensation (TRC) can be added. 
 
 
ii. 
Ventilator settings 
Respiratory rate will be adjusted according to PaCO2 with a maximum of 35 Breaths/min. 
Table 2: Management of pH and PaCO2:  
pH < 7.15 
pH= 7.15 – 
7.29 
pH= 7.29 – 
7.45 
pH > 7.45 
Increase Respiratory 
rate up to 35 b/min 
and keep PaCO2 > 25 
mm Hg 
Increase 
Respiratory 
rate up to 35 
b/min 
and 
keep PaCO2 > 
25 mm Hg 
Maintain VT 
around 
6 
mL/kg IBW in 
ARDS 
subjects and 
between 6 – 
8 mL/Kg IBW 
for 
other 
subjects and 
maintain 
respiratory 
rate below 35 
b/min. 
Decrease 
respiratory 
rate but not 
below 6 /min 
Consider NaHCO3 
Consider 
NaHCO3 
 
 
If needed increase VT 
by 1 ml/Kg IBW or 
increase PINSP by 2 
cmH2O 
with 
a 
maximum VT at 8 
mL/Kg IBW for ARDS 
subjects 
and 
10 
mL/Kg IBW for other 
subjects. PPLAT can be 
higher 
than 
35 
cmH2O in case of 
extreme acidosis. 
If 
needed 
increase 
VT 
by 1 ml/Kg 
IBW 
or 
increase PINSP 
by 2 cmH2O 
with 
a 
maximum VT 
at 8 mL/Kg 
IBW for ARDS 
subjects and 
10 
mL/Kg 
IBW for other 
subjects. 
Keep PPLAT ≤ 
35 cmH2O. 
 
If 
needed 
decrease VT 
by 1 ml/Kg 
IBW 
or 
decrease PINSP 
by 2 cmH2O 
with 
a 
minimum VT 
at 4 mL/Kg 
IBW for ARDS 
subjects and 
5 mL/Kg IBW 
for 
other 
subjects. 

 
 
 
 
 
 
 
 
 
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PEEP will be set using PEEP/FiO2 table, PEEP trial or transpulmonary pressure (based on the local hospital 
protocol). 
PEEP will be kept in the range: 
- 5-10 cmH2O for normal lung subjects and COPD 
- 5-25 cmH2O for ARDS subjects 
- 5-15 cmH2O for obese subjects 
FiO2 will be adjusted to the lowest to achieve SpO2 target. 
 
B. Spontaneous breathing subjects: 
i. 
Ventilation mode: 
Any assisted and spontaneous mode will be possible such as pressure support (SPONT), volume support 
(VS), SIMV, P-SIMV, and DuoPAP. APRV will not be accepted. 
 
ii. Ventilator settings: 
Ventilation support will be adjusted to keep tidal volume in the range: 
- 6-10 mL/Kg IBW for normal lung subjects, brain injury, and COPD subjects 
- 4-8 mL/Kg IBW for ARDS 
Ventilation support will be adjusted to keep respiratory rate ≤ 35 Breaths/min. 
PEEP will be kept in the range: 
- 5-10 cmH2O for normal lung subjects and COPD 
- 5-15 cmH2O for ARDS and obese subjects 
 
C. Weaning 
The INTELLiVENT-ASV or control arm ventilator protocols will be continued until subjects are able to 
breathe unassisted for 48 hours, death, ICU discharge, study withdrawal, the  Principal investigator of 
the site determines that the study is no longer in the subject’s best interest or day 28, whichever comes 
first.  
i. 
Weaning trial 
When the readiness to wean criteria will be fulfilled, a weaning trial will be performed on the same day 
for a duration of 30 min by any method with PEEP ≤ 5 cmH2O and PS ≤ 7 cmH2O: CPAP, tube 
compensation, minimal pressure support, T tube, or tracheostomy mask. 
 
 Ventilation protocol in INTELLiVENT-ASV ventilation group 
Subject allocated to INTELLiVENT-ASV group will be ventilated with this mode from inclusion to the end 
of the study. Tube resistance compensation (TRC) can be added. 
 
A. Passive subjects: 
i. 
Ventilator settings: 

 
 
 
 
 
 
 
 
 
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Clinician will set the IBW, subject condition, PetCO2 and SpO2 targets, PEEP ranges, and alarms and 
activate the controllers. The minimal FiO2 will be set at 0.21. An arterial blood gas will be performed 30-
60 min later in order to adjust the PetCO2 target. 
 
Table 3: Management of pH and PaCO2:  
pH < 7.15 
pH= 7.15 – 
7.29 
pH= 7.29 – 
7.45 
pH > 7.45 
Decrease 
PetCO2 
targets by 5 mm Hg 
and keep PaCO2 > 25 
mm Hg 
Decrease 
PetCO2 
targets by 5 
mm Hg and 
keep PaCO2 > 
25 mm Hg 
No change 
Increase 
PetCO2 
targets by 5 
mm Hg 
Consider NaHCO3 
Consider 
NaHCO3 
 
 
 
 
ii. Controller deactivation 
PEEP and FiO2 controller will be transiently deactivated if it is not possible to get a good SpO2 signal with 
both finger and ear sensors. SpO2 signal quality will then be re-assessed every 6h in order to restart 
oxygenation controller as soon as possible. 
PEEP controller is by design deactivated when brain injury and chronic hypercapnia conditions are 
selected. PEEP will be set manually as in the non-automated ventilation group. 
PEEP controller will not be deactivated in normal and ARDS conditions. Clinician can adjust PEEP ranges 
and use very narrow ranges if it is clinically needed. 
Ventilation controller will be de-activated only if the clinical condition needs a %MV below 70% or above 
200%.  
Reasons and duration of controllers de-activation will be recorded in the eCRF. 
 
B. Spontaneous breathing subjects: 
i. 
Ventilator settings: 
Clinician will set the IBW, subject condition, PetCO2 and SpO2 targets, PEEP ranges, and alarms and 
activate the controllers. The minimal FiO2 will be set at 0.21. An arterial blood gas will be performed 30-
60 min later in order to adjust the PetCO2 target. 
PEEP will be kept in the range: 
- 5-10 cmH2O for normal lung subjects and COPD 
- 5-15 cmH2O for ARDS and obese subjects 
 
 

 
 
 
 
 
 
 
 
 
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C. Weaning: 
Weaning in the INTELLiVENT-ASV group will use quick wean function.   
i. 
Quick wean activation 
Quick wean will be activated when subject is stabilized with absence or minimum doses of sedation and 
vasopressor. 
If subject has a coma Glasgow score above 8, quick wean function will be activated with SBT. 
If subject has a coma Glasgow score below or equal to 8, quick wean function will be activated without 
SBT initially and SBT will be activated when the coma Glasgow score is above 8. 
 
ii. Quick wean settings 
Observation time will be set at 30 min before starting SBT. 
Period between 2 SBT will be adjusted by the clinician according to the clinical needs. 
Default settings to start SBT will be used: 
PEEP ≤ 8 cmH2O 
FiO2 ≤ 40% 
Tolerance time: 180 s 
RR ≤ 35 b/min 
Minimum VT ≥ 5 mL/kg IBW 
Rapid Schallow Breathing index ≤ 105 
PS between 5 and 12 cmH2O 
 
iii. 
Weaning trial 
Weaning trial will use the automatic SBT of the quick wean option with a PEEP of 5 cmH2O, a %MV at 
25%, and a duration of 30 min. 
Criteria to abort SBT will be: 
- 
PEEP > 8 cmH2O for the duration of tolerance time 
- 
FiO2 > 50% for the duration of tolerance time 
- 
Tolerance time: 180 s 
- 
RR > 35 b/min for the duration of tolerance time 
- 
Minimum VT  < 5 mL/kg IBW for the duration of tolerance time 
- 
Rapid Schallow Breathing index  > 105 for the duration of tolerance time 
- 
PS > 12 cmH2O  
- 
RR increase > 50% 
- 
PetCO2 increase > 8 mm Hg 
- 
Apnea defined by a spontaneous RR below the target RR determined by ASV controller  
- 
SpO2 sensor failure 
 
iv. 
Extubation 
After a failed SBT, the clinician may decide to repeat it the same day or to stop SBT for some time, 
keeping the quick wean function active. 

 
 
 
 
 
 
 
 
 
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After a successful SBT, clinician will check the extubation criteria. If all criteria are fulfilled, extubation 
will be performed within 12 h. 
 
 Measurements 
Breath-by-breath ventilation variable will be recorded during the full duration of study period. 
On top of that, ΔP, Pplat, total PEEP, and blood gas results (if performed) will be measured twice a day 
and reported on the eCRF. 
Information of acute pulmonary condition will be recorded in the eCRF.  
Information about controllers de-activation and weaning process will be reported on a daily basis on the 
eCRF. 
All concomitant medications will be recorded in the eCRF including sedation.  
 
8.4 
End of study (extubation + 48 hours): 
The end of study visit should be completed at the time a subject completes the study ventilation protocol. 
It means that the subject is extubated and there is no need for re-intubation within 48 hours.  
Subject reintubated within 48h after extubation will continue to be ventilated per the allocated 
randomized ventilation mode. 
Subject re-intubated beyond 48h will be considered as weaned for the ventilation procedure. They remain 
in the study but only a phone call will be done on Day 28.  
Following data point to be collected and recorded: 
• 
Intubation/ re-intubation status 
• 
Acute Pulmonary Condition  
• 
Vital Signs  
• 
Ventilator parameters manual assessment 
• 
24h Recording of ventilation parameters (Memory Box) 
• 
Blood gas analysis (If available visit ± 2h) 
• 
SOFA score 
• 
Concomitant sedation, analgesia and myorelaxants use 
• 
Concomitant vasopressors and inotropics use 
• 
Number of recruitment maneuvers within the last observation period 
• 
Concomitant rescue therapies (proning, Nitric oxyde, ...) 
• 
Weaning information associated interventions (Patient Passive/Active but still on MV, NIV, CPAP, 
High Flow.) 
• 
Screening of readiness to extubate criteria (SBT) 
• 
Assessment of re-intubation status 

 
 
 
 
 
 
 
 
 
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• 
Extubation failure  
• 
Acute Kidney Injury (AKI) status and need for RRT  
• 
Critical illness polyneuro- myopathy status  
• 
Critical illness encephalopathy status  
• 
Tracheostomy status  
• 
Resuscitated cardiac arrest status  
• 
Other imminently life-threatening experience  
• 
Barotrauma status  
• 
Rescue therapy requirement (APRV, high frequency ventilation, ECCO2R and ECMO). 
• 
Withhold of weaning and/or withdrawal of mechanical ventilation status 
• 
Ventilation duration for study period (if reintubated beyond 48h) 
• 
ICU and hospital length of stay 
• 
ICU mortality (if subjects hospitalized somewhere else) or 28 Days mortality 
• 
Adverse Event collection 
 
8.5 
Study Exit (Day 28): 
Prior to completion of study close out, all subject data must be captured and monitored in the eCRF.    
A subject will be considered to have completed the study for the following reasons: 
• 
Subject completes follow-ups (Day 28) required per investigational plan. 
• 
Subject dies. 
• 
Subject or legally authorized representative requests to be withdrawn from the study. 
• 
Investigator requests to be withdrawn from the study to protect the welfare of the 
subject. (In that case, it is at the site’s principal investigator’s discretion to determine that 
the study is no longer in the subject’s best interest.) 
 
In case of sponsor’s decision to stop the study, the site will be notified by the sponsor in written of the 
intention to close the study. Study close out visits are then to be performed. During these visits, the 
monitors will ensure that the investigator’s regulatory files are up to date and complete and that any 
outstanding issues from previous visits have been resolved. The site will be informed that all requirements 
have been met with a study closure letter.  
Following data point to be collected and recorded: 
• 
Intubation status 
• 
Acute Pulmonary condition 
• 
Extubation failure - with SBT 
• 
Acute Kidney Injury (AKI) status and need for RRT 
 
  

 
 
 
 
 
 
 
 
 
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• 
Critical illness polyneuro- myopathy status  
• 
Critical illness encephalopathy status  
• 
Tracheostomy status  
• 
Ventilation duration for study period (if reintubated beyond 48h) 
• 
ICU and hospital length of stay 
• 
ICU mortality  
• 
Adverse Event collection 
8.6 
Supply and Accountability 
Ventilation system serial number utilized for each subject will be documented and placed in the subject’s 
study file. 
 
8.7 
Ancillary Supplies 
Additional equipment or consumables such as heated humidifier, ventilator circuit, flow sensor, SPO2 
sensor and CO2 sensor cupula will be supplied by Hamilton Medical, if needed. The ancillary supplies have 
all market authorization in US and European country sites. 
 

 
 
 
 
 
 
 
 
 
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9 
SAFETY 
Please refer to: 
Annex A 
Identification of Risks and Adverse Events (AE´s) for the intended subject population, the clinical 
background and the device in question identified from clinical experience for INTELLiVENT-ASV 
Annex D: List of Adverse Event 
List of reportable Adverse Event  
9.1 
Recording and reporting of AEs 
 
• 
Recording: Entry of an event into the clinical database by site staff as they “become aware” 
(Soladis System) or into the safety database by the safety team (VigOps). . 
• 
Reporting: Sending a report to the National Competent Authority, EC/IRB.  Sites are responsible 
for submitting reports to their IRB or EC in most countries.  
The EASiVENT study includes a general ICU patient population in need of mechanical ventilation for at 
least 24 hours. This population includes critically ill patients spanning a variety of primary and secondary 
medical conditions that can cause AEs including severe disability and death irrespective of study 
participation. The expected mortality in EASiVENT Study patient population is around 30%.  
Given the high acuity of diseases and morbidity related to ICU patient populations, not all AEs will be 
reported in the EASiVENT Study. 
AE information will be collected throughout the study and reported to Hamilton Medical on the Adverse 
Event collected in the eCRF. The investigator is responsible for detecting, documenting and reporting AEs 
to Hamilton Medical through the eCRF or via a paper form if the eCRF is not available. 
For AEs that require immediate reporting (see Table 4: Adverse Event Reporting Requirements), initial 
reporting may be done using the Events Form via email to VCLS VigOps (contact details will be provided 
in the investigational site file), or in the Serious Adverse Events form in the eCRF with as much information 
as is available. In case the investigator requires information from the Sponsor in an emergency situation, 
the contact details for emergency situations are given in the investigational site file. 
Investigators in the US should submit Unanticipated Device Effects (UADEs) to their IRBs at the same time 
as notifying VCLS VigOps. 
 
 Study-Specific Clinical Outcomes 
A list of anticipated AEs (AAEs) that are expected from underlying disease states are listed in Annex A 
of protocol– ” Clinical manifestations and medical occurrences, unintended diseases or injuries or 
clinical signs that are attributed to the concurrent illness / clinical condition of critically ill subjects in 
an ICU include”.  

 
 
 
 
 
 
 
 
 
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All AEs that are listed under the above mentioned section of Annex A will be classified as “study-specific 
clinical outcomes”, as these AE(s) are by their nature, incidence, severity, and outcome previously 
identified in the risk analysis report and the State-of-the-Art analysis.  
Study-specific clinical outcomes of patients in need of mechanical ventilation will be recorded in eCRF as 
secondary outcomes and will not be recorded as AEs unless the investigator deems the AE to be possibly, 
probably or definitely (causal) related to the mechanical ventilation itself (or lead to permanent 
discontinuation of study interventions (except death events that are considered as study specific clinical 
outcomes)), in which case such events would be recorded as (AEs). 
The following AE(s) will be considered study-specific clinical outcomes: 
1. Death related to the underlying illness or associated conditions based on the interpretation of the 
investigator. 
2. Significant hemodynamic instability, defined as (a) norepinephrine-equivalent vasopressor dose 
initiation or increase from any dose that is both double and at least 0.15 mcg/kg/min increased over 
≤  60 minutes to maintain blood pressure target OR (b) dobutamine-equivalent inotropic dose 
initiation or increase from any dose that is both double and at least 5 mcg/kg/min over ≤ 60 minutes 
to maintain cardiac output target in case of left or right ventricular dysfunction/failure) that is 
related to the underlying illness or associated conditions based on the interpretation of the 
investigator 
3. Progression of respiratory failure as demonstrated by new post-enrollment use of respiratory rescue 
therapy (e.g. ECMO, ECCO2R, inhaled vasodilators, prone positioning), that is related to progression 
of the underling illness or associated conditions based on the interpretation of the investigator. 
4. Anoxic brain injury that is related to the underling illness or associated conditions based on the 
interpretation of the investigator 
5. Extubation failure that is related to progression of the underling illness or associated conditions 
based on the interpretation of the investigator. 
6. Need for tracheostomy that is related to progression of the underling illness or associated 
conditions based on the interpretation of the investigator. 
 
 Adverse Events (AEs) 
ISO 14155 / MDR 2017/745 Definition (regulatory definition): 
An AE is any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, 
(including an abnormal laboratory finding,) in subjects, users or other persons, in the context of a clinica 
investigation, whether or not related to the investigational medical device. and whether anticipated or 
unanticipated. 
NOTE 1 to entry: This definition includes events related to the investigational medical device or the 
comparator. 
NOTE 2 to entry: This definition includes events related to the procedures involved. 

 
 
 
 
 
 
 
 
 
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NOTE 3 to entry: For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
 
Specificities to EASiVENT: 
The following Adverse Events (AEs) will be recorded during the EASiVENT Study Days 0 through 28: 
1. Serious Adverse Events (SAEs) other than those listed as study-specific outcomes 
2. Non-serious AEs that are considered by the investigator to be possibly, probably, or definitely 
(causally) related to mechanical ventilation as a supportive measure for acute respiratory 
failure.  
For details please refer to EASiVENT Study list of Adverse Event, Annex D 
3.  AEs that lead to permanent discontinuation of INTELLiVENT-ASV-Management. 
 
Investigators will be instructed to record their assessment of the potential relatedness of each Adverse 
Event (AE) to protocol procedures and mechanical ventilation. Potential relatedness of an event to 
mechanical ventilation will be determined by evaluating the temporal relationship and if the event is 
unanticipated or unexplained given the patient’s clinical course, care, and previous medical conditions. 
The degree of certainty the investigator has regarding relatedness of the event to mechanical ventilation 
will be recorded as not related, possibly related, probably related, or definitely (causal) related. If 
patient's INTELLiVENT-ASV-Management is discontinued as a result of an AE, study site personnel will 
clearly record in the eCRF of the Study the circumstances and data leading to discontinuation of 
INTELLiVENT-ASV as ventilation mode. 
By the nature of this patient population a myriad of non-serious Adverse Events (AEs) will occur during 
the Study. Due to the complexity of critical illness, it may be difficult for the investigators to classify 
whether an Adverse Event (AE) is related or not to the underlying condition or the sequelae of it or to 
mechanical ventilator support. 
Therefore, investigators will be instructed that events such as: 
a. transitory hypertension or  
b. hypotension, tachy- or bradycardia,  
c. arrhythmias (such as atrial fibrillation, heart block, ventricular tachycardia, or ventricular 
fibrillation),  
d. transitory hypoxemia or 
e. hypercapnia, 
f. impaired cognitive function due to sedation/analgesia or delirium (see AE list attached),  
 
Are not considered study population specific clinical outcomes and should be recorded as adverse 
events only if they are serious events or are considered to be related to mechanical ventilation or lead 
to discontinuation of INTELLiVENT-ASV mode. 
The blinded medical monitor and DSMB will evaluate investigator-reported SAEs and AEs and 
independently assess potential relatedness to study procedures and, where indicated, make 
recommendations for safety modifications to the protocol, temporary suspension, or even termination 
of the study. 

 
 
 
 
 
 
 
 
 
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 Serious Adverse Event (SAE) 
ISO 14155 / MDR 2017/745 Definition (regulatory definition):  
An SAE is any adverse event that led to any of the following: 
a) led to a death 
b) led to a serious deterioration in health of the subject, users or other persons as defined by one 
or more ofthat resulted in any 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-subject hHospitalization or prolongation of existing patient hospitalization, or 
- in medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to a body structure or a body function, 
- Chronic disease, 
- led to foetal distress, foetal death or a congenital abnormality or birth defect including 
physical or mental impairment physical or mental impairment or birth defect. 
Specificities to EASiVENT: 
SAE recording begins after the patient has signed informed consent and has received INTELLiVENT-ASV or 
standard of care mechanical ventilation (point of enrollment). If a patient experiences a SAE after signing 
informed consent, but prior to receiving the study intervention, the event will not be recorded unless the 
investigator feels the event may have been caused by a study procedure. 
SAEs will be collected Day 0 through Day 28 of the  study period or until extubation, whichever occurs 
first. Thereafter, SAEs are not required to be recorded unless the investigator feels the events were 
possibly, probably, or definitely (causal) related to study procedures. 
An SAE is any Adverse Event (AE) that results in one of the following events and is not classified as a 
study-specific clinical outcome using the definitions enumerated above: 
1. Death that is not related to the underlying illness or associated condition or death that is possibly, 
probably, or definitely (causal) related to study procedures 
2. Resuscitated cardiac arrest that is not related to the underlying illness or associated condition, or 
that is possibly, probably, or definitely (causal) related to study procedures 
3. Significant hemodynamic instability defined as (a) norepinephrine-equivalent vasopressor dose 
initiation or increase from any dose that is both double and at least 0.15 mcg/kg/min increased over 
> 60 minutes to maintain blood pressure target OR (b) dobutamin-equivalent inotropic dose 
initiation or increase from any dose that is both double and at least 5 mcg/kg/min over > 60 minutes 
to maintain cardiac output target in case of right ventricular dysfunction/failure,  that is not related 
to the underlying illness or associated condition or that is possibly, probably, or definitely (causal) 
related to study procedures 

 
 
 
 
 
 
 
 
 
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4. Gross barotrauma (pneumothorax, pneumomediastinum, or subcutaneous emphysema) requiring 
chest tube or other surgical intervention, where the apparent barotrauma is not related to a 
procedural complication (e.g., a central venous catheter insertion causing pleural injury) 
5. Significant hypercapnic acidemia (PaCO2 > 60 mm Hg and pH < 7.20 with Vt > 8 ml/kg PBW and RR > 
30 b/min) for at least two consecutive arterial blood gas measurments 60 min apart  
6. Significant hypocapnic alkalemia (PaCO2 < 30 mm Hg with pH > 7.50) for at least two consecutive 
arterial blood gas 60 min apart  
7. Significant hypoxemia (oxygen saturation < 85% or PaO2 < 55 mm Hg with FiO2 1.0) sustained for at 
least 30 minutes for at least two consecutive arterial blood gas measurments 60 min apart 
8. Progression of respiratory failure as demonstrated by new post-enrollment use of respiratory rescue 
therapy (e.g. ECMO and ECCO2R), if it is considered as related (possibly, probably, definitely (causal)) 
to the ventilation mode and neither to the underlying illness nor associated conditions based on the 
interpretation of the investigator.   
9. Hypoxic brain injury, which must be documented with a confirmatory neuroimaging and other 
clinical evaluations as per local routine practice as applicable , a documented significant hypoxemia 
event (defined above) during study participation, that is not related to the underlying illness or 
associated condition 
10. Other imminently life-threatening event that is not related to the underlying illness or associated 
condition or that is possibly, probably, or definitely (causal) related to study procedures 
11. Site investigator decides to change the allocated ventilation mode because if it is considered as 
related (possibly, probably, definitely (causal)) to the ventilation mode and neither to the underlying 
illness nor associated conditions based on the interpretation of the investigator.  
 
9.2 
Recording and reporting of Device Deficiencies (DDs) 
DD information will be collected throughout the study and reported to Hamilton Medical. DDs should be 
recorded in on the Serious Adverse Event Form in the eCRF. In case the eCRF is not available the Event 
form needs to be completed manually and must be sent to VCLS VigOps team. Contact details are given 
in the investigational site file. The investigator is responsible for reporting all DDs to the Sponsor. 
 
See the Serious Adverse Event eCRF for the information to be reported for each DD. 
DDs that did not lead to an AE but could have led to a SAE: 
a) If either suitable action had not been taken, 
b) If intervention had not been made, or 
c) If circumstances had been less fortunate, 
Require immediate reporting (see Table 4: Adverse Event Reporting Requirements). Initial reporting may 
be done by eCRF, or using the Event Form via email to VCLS VigOps, with as much information as available. 
In case the AE/DD is related to an investigational Hamilton Medical device used during the study the VCLS 
VigOps team will ensure prompt review, and appropriate reporting. 
 Device deficiency (ISO 14155) 
Inadequacy of an medical device related to its identity, quality, durability, reliability, usability, safety 
or performanc 

 
 
 
 
 
 
 
 
 
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 Adverse Device Effect (ADE) (ISO 14155):: 
Adverse event related to the use of an investigational medical device. 
NOTE 1: This includes any adverse event resulting from insufficiencies or inadequacies in the 
instructions for use, the deployment, the implantation, the installation, the operation, or any 
malfunction of the investigational medical device. 
NOTE 2: This also includes any event that is a result of a use error or intentional abnormal use of the 
investigational medical device. 
Note 3 to entry: this includes ‘comparator’ if the comparator is a medical device.  
 Serious Adverse Device Effect (SADE) (ISO 14155): 
Adverse device effect that has resulted in any of the consequences characteristic of a serious adverse 
event. 
 Anticipated SADE (ASADE)  
ISO 14155 Definition (Regulatory definition) 
Effect which by its nature, incidence, severity or outcome has been previously identified in the risk 
analysis report. 
Specificities to EASiVENT: 
The INTELLIVENT-ASV ventilation mode was launched in the year 2010. Since then 3576 INTELLiVENT-ASV 
software accessories have been sold worldwide. 
Today, there has been no reported problems, events, serious adverse events or recalls due to the 
INTELLiVENT-ASV accessory software on HAMILTON ventilators. The vigilance database searches for 
Bfarm (the German database and the largest European database for medical device adverse event 
reporting) did not yield any events, reported problems, serious adverse events due to or related to 
INTELLiVENT-ASV. 
 Anticipated Serious Adverse Device Effect from risk management activities of the 
manufacturer:  
Anticipated Serious adverse device effect which by its nature, incidence, severity or outcome has been 
identified in the current version of the risk analysis report are the following, please refer to Annex A 
 Unanticipated Adverse Device Effect (UADE): (21 CFR 812.3) 
Any serious adverse effect on health or safety or any life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or application, or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of subjects. 

 
 
 
 
 
 
 
 
 
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 Unanticipated Serious Adverse Device Effect (USADE) (ISO 14155): 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. 
AEs, SAEs, ADEs, SADEs and USADEs are included in the “incident” definition for post-market vigilance. 
NOTE 1 to entry: Planned hospitalization for pre-existing condition, or a procedure required by the Clinical 
Investigation Plan, without a serious deterioration in health, is not considered a serious adverse event. 
 Serious Health Threat (ISO 14155) 
A signal from any adverse event or device deficiency that indicates an imminent risk of death or a 
serious deterioration in the health in subjects, users or other persons, and that requires prompt 
remedial action for other subjects, users or other persons  
Note 1 to entry: This would include events that are of significant and unexpected nature such that they 
become alarming as a potential serious health hazard or possibility of multiple deaths occurring at 
short intervals. 
 Incident (MEDDEV 2.12-1) 
Any malfunction or deterioration in the characteristics and/or performance of a device, as well as any 
inadequacy in the labeling or the instructions for use which, directly or indirectly, might lead to or 
might have led to the death of a subject, or user or of other persons or to a serious deterioration in 
their state of health. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
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Figure 1: Adverse Events Categorisation Chart 
 
 
 

 
 
 
 
 
 
 
 
 
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Figure 2: Device Deficiency Categorisation Chart 
 
9.3 
Observation, Categorization, Analysis and Reporting of AEs 
AEs and DDs will be screened twice a day by VCLS VigOps and assessed during the clinical investigation by 
VCLS VigOps, the medical monitor as well as by a DSMB and classified in-line with the definitions of MDR, 
ISO 14155, IMDRF, MDCG and US specific definitions according to 21 CFR part 812. 
All recorded and reported AEs and DDs will be reviewed by VCLS VigOps, Study Management and/ or 
designee. This review will include the determination whether the AE/DD meets regulatory reporting 
requirements (see Table 4: Adverse Event Reporting Requirements). The sponsor will ensure timely AE/DD 
reporting to meet global and country specific regulatory requirements. 
A list of anticipated AEs that are expected in nature is included in Annex A of protocol–” Clinical 
manifestations and medical occurrences, unintended diseases or injuries or clinical signs that are 
attributed to the concurrent illness / clinical condition of critically ill subjects in an ICU include”.  
In case the AE/DD is related to a Hamilton Medical market released device, other than the devices under 
study, used during the study, Hamilton Medical Study Management and/or designee will immediately 
report this device related AE/DD to the Hamilton Medical Vigilance (HMV) group. The HMV group will 
ensure prompt review, and appropriate reporting. 
Hamilton will determine with the support of the Medical Monitor and DSMB members, on an ongoing 
basis if the risk assessment is to be updated and assess whether corrective or preventive action is 
required. 
All AE´s that are contained in the Annex A of protocol– ” Clinical manifestations and medical occurrences, 
unintended diseases or injuries or clinical signs that are attributed to the concurrent illness / clinical 
condition of critically ill subjects in an ICU include” can be classified as “anticipated”, as these effects are 
Device deficiency categorisation chart
Device deficiency
Could it have led 
to a SADE?
Device deficienty 
with SADE potential
AE
Yes
No

 
 
 
 
 
 
 
 
 
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by their nature, incidence, severity and outcome previously identified in the risk assessment and the State-
of-the-Art analysis. These events are common for the subject population intended and these events 
represent part of the natural outcome of this population with regard to the underlying diseases and the 
expected medical condition. 
Attention will be paid for risks and AEs for the intended subject population (critically ill subjects requiring 
invasive mechanical ventilation) and the clinical background for the device in question identified from 
clinical experience for INTELLiVENT-ASV. Special attention will be paid to any potentially INTELLIVENT-ASV 
specific software issues, those events that can be attributed to the subject population on an ICU, but also 
can possibly be a typical, ventilation-related AE.

 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 3: Adverse Event Review Chart 

 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 4: Adverse Event Reporting Requirements 
SAEs, ADEs, SADEs, UADEs, USADEs and Device Deficiency with SADE potential: 
Investigator submit to: 
Hamilton Medical 
As soon as possible, but in no case later than three (3) calendar days after the clinical site study team 
first learns of the event or of new information in relation with an already reported event. 
EC/IRB 
Reporting timeframe as per local EC/IRB requirement. 
Sponsor submit to: 
 
Regulatory 
Authorities 
Reporting timeframe as per local requirement. 
 
All other AEs 
Investigator submit to: 
 
Hamilton Medical 
Submit in a timely manner after the clinical site study team first learns of the event. 
All other Device Deficiencies 
Investigator submit to: 
 
Hamilton Medical 
Submit in a timely manner after the clinical site study team first learns of the deficiency. 
 
 Emergency contact details in case of AEs 
In case of an immediately reportable AE the investigators can contact the Hamilton Medical Study 
Manager. Contact details of Hamilton Medical Study Management are given in the Investigational Site 
File. 
 
In case the investigator requires information in a medical emergency situation the investigator can contact 
the Medical Expert. Contact details of Medical Experts are given in the Investigational Site File. 
 
 Analysis of the Benefit/Risk Profile 
There will be periodically review and evaluation of the accumulated study data for safety, study conduct, 
progress and efficacy by Hamilton Medical and with the input of the Medical Monitor and DSMB. 
Analysis of the Benefit/Risk Profile considers study specific data as well as relevant background knowledge 
about critically ill subjects, their medical diagnosis, treatment and prognosis and the investigational 
device. 
It will be analyzed, if all risks and hazards are duly mitigated by risk management control procedures, and 
if additional information will be necessary to contribute to the benefit risk profile of the device. 

 
 
 
 
 
 
 
 
 
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10 STATISTICS 
10.1 Statistical Hypothesis 
EASiVENT hypothesizes that INTELLiVENT-ASV will outperform non-automated Ventilation on the 
Hamilton Medical Ventilators, in terms of efficacy and safety.  
The hypothesis for the primary endpoint regarding effectiveness is that when all six variables are in the 
optimal target ranges, mechanical ventilation is optimized with a minimum risk of ventilation induced lung 
injury. 
The hypothesis for the primary endpoint regarding safety is that that when one of these variables is in 
sub-optimal range, there is a risk of clinical complication, either ventilation induced lung injuries, or 
systemic complication. 
 
10.2 Sample Size Determination 
A minimum of 254 and maximum of 508 subjects will be included in this study, based on adaptive sample 
size assessments at scheduled interim analyses. Subjects will be selected for this study according to 
Section 7 of this protocol. Requirements related to participant withdrawal from the study are described 
in Section 7.6. All sites will have a minimum number of enrollment targets in order to meet overall cross-
site enrollment and protocol goals. 
Inclusion will be halted at sites that reach the 30% inclusion cap of total enrollment. 
 
Sample sizes for a group sequential design with 2 interim analyses 
The planned sample size is a minimum of 254 and a maximum of 508 subjects. 
The sample sizes for this trial are calculated using the following assumptions: 
• 
significance level equal to 0.025 (1-sided) 
• 
power of 0.8 (at final analysis) 
• 
allocation ratio of 1:1 
• 
Two interim analyses at half and three-quarter information time (i.e. when half and three-quarter 
of the subjects are evaluable for response), spending functions with O’Brien-Fleming-Type 
boundaries for efficacy and futility. Efficacy endpoint (%All in optimal, more is better) on logit-
scale: 
o Mean conventional = -1.86 
o Mean INTELLiVENT-ASV = -1.28 
o Sd = 1.5 for both devices 
• 
Safety endpoint (%Any in sub-optimal, less is better) on logit-scale: 
o Mean conventional = -0.09 
o Mean INTELLiVENT-ASV = -0.74 
o Sd = 1.6 for both devices 

 
 
 
 
 
 
 
 
 
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• 
Correlation between endpoints = -0.85 
• 
Dropout could occur when subjects are ventilated for less than 24 hours after inclusion because 
of unexpected death, transfer to another ICU or withdrawal of informed consent. A maximum 
dropout rate of 5% of these cases is expected. Given that the large uncertainty on the assumed 
performance differences and the inclusion of a sample size reassessment, the initial sample size 
is not increased to deal with this dropout rate. At the second interim the sample size will be re-
estimated, taking this observed dropout rate into account. 
The table below shows the sample sizes and characteristics of a study with two (2) interim analyses, with 
O’Brien-Flemming boundaries for efficacy and futility. The final sample size for this group sequential 
design is 254. 254 stands for the number of subjects with evaluable endpoints and means more subjects 
might have to be enrolled to reach this number. The p-values for significance are increasing at each 
analysis while the p-value to stop for futility decreases from the first interim analysis to the final analysis. 
The study has a high probability to stop at the first interim analysis if both ventilation modes have an equal 
performance. 
Table 5: Sample sizes and operational characteristics for the trial using O’Brien Fleming boundaries for 
futility and efficacy. 
Analysis 
SS 
Z 
Efficacy 
Nominal p 
Efficacy 
α Spend 
Power 
(Prob stop HA) 
1   (IA1) 
128 
2.96 
0.0015 
0.0015 
0.25 
2   (IA2) 
192 
2.36 
0.0093 
0.0097 
0.43 
3 (final) 
254 
2.02 
0.0220 
0.0250 
0.19 
 
 
 
Analysis 
SS 
Z 
Futility 
Nominal p 
Futility 
Prob Futility Stop  
(Prob stop under H0) 
1   (IA1) 
128 
0.44 
0.3315 
0.67 
2   (IA2) 
192 
1.34 
0.0904 
0.25 
3 (final) 
254 
2.02 
0.0220 
0.06 

 
 
 
 
 
 
 
 
 
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Recorded data has to be 24 h at minimum, and 80% of the invasive ventilation duration within the 
allocated randomized ventilation mode have to be recorded in the Memory box.  
 
10.3 Adaptive sample size increase 
An adaptive sample size reassessment is foreseen at the second interim analysis. In case promising results 
are obtained at this interim analysis, additional resources will be committed to the trial. Following Metha 
and Pocock (1), sample sizes will only be increased in case the interim results are promising, in which case 
the overall type-I error is not inflated by use of the conventional Wald Statistic. The maximum number of 
additional subjects will be capped at 254 (above the pre-planned 254 subjects) or a maximal total sample 
size of 508. In addition, following Chen, DeMets and Lan (33) and Gao, Ware and Mehta (34), sample sizes 
will only be increased in case the interim results are promising, in which case the type-I error is not inflated 
by use of the conventional Wald statistic. More specifically, this ‘promising zone’ is defined in terms of 
the conditional probability of rejecting the null-hypothesis at final analysis, given the estimated 
performance difference at interim (‘conditional power’) and assuming that this estimated performance 
difference is the true underlying difference. Depending on the conditional power (CP) for each of the two 
endpoints at the second interim analysis, we consider three different zones and anticipated actions: 
1) Unfavorable zone: At least one endpoint with CP <0.33. 
The interim results are so disappointing that it is not worth to increase the sample size to retrieve CP and 
the original sample size is retained. Following (34), this zone is defined as 0 to 0.33, for a sample size 
reassessment at 0.75 information fraction and a maximal increase in sample size of 50%. If the CP for 
either of endpoints is below 0.33, this is considered unfavorable and no sample size increase will be 
performed. 
2) Promising zone: Both endpoints with CP >0.33, at least one endpoint with CP <0.80 
If the CP is above 0.33 but below the originally planned 0.80 for at least one endpoint, the sample size will 
be increased by just the right amount to recover the targeted power of 0.80, while not exceeding the pre-
specified maximal sample size of 508 subjects. As stated above, both endpoints would need to have a CP 
above 0.33 and one endpoint a CP below 0.80 to embark on a sample size increase. The sample size 
increase will be set to the higher of two recalculated sample sizes if both endpoints have a CP between 
0.33 and 0.80. 
3) Favorable zone: Both endpoints CP >0.80 
The conditional power at second interim analysis is 0.80 or larger for both endpoints. In this zone, the 
interim results are sufficiently favorable that the trial continues to the original sample size without the 
need to adaptively increase the trial size.  
 

 
 
 
 
 
 
 
 
 
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10.4 Statistical Analyses 
 Definition of populations 
The following populations will be used: 
 Intention-To-Treat (ITT) Population 
The Intention-To-Treat population (ITT) will consist of all randomized subjects, whether they receive 
invasive (mechanical or non-mechanical) ventilation. Subjects who receive the wrong ventilation support 
will be analysed in the arm to which they were randomized. The ITT population will be used for primary 
efficacy analyses. 
 
Modified Intention-To-Treat (MITT) Population 
The MITT population consists of all ITT subjects whose recorded data are at least 24h and at least 80% of 
the invasive ventilation duration within the allocated randomized ventilation mode is recorded in the eCRF 
The sensitivity analyses for efficacy endpoints will be conducted using the MITT population. Subjects will 
be analyzed in the group to which they were randomized. 
 Safety Analysis Population  
The Safety population will include all subjects who once received invasive (mechanical or non-mechanical) 
ventilation. Subjects will be analyzed according to the treatment that they actually received. The safety 
population will be used for safety analyses.  
 
 Analysis of Primary Endpoints 
The objective of this study is to compare the efficacy and the safety of the investigational automated 
ventilation (INTELLiVENT-ASV) with a control ventilation group (conventional non-automated ventilation) 
in ICU subjects.  
The hypothesis is that INTELLiVENT-ASV is better than conventional non-automated ventilation in terms 
of efficacy and safety.  
 
Efficacy and safety endpoints are composite endpoints and are based on six variables that will be 
continuously recorded during the study period:  
1) Tidal volume (VT)  
2) Maximum pressure (Pmax) 
3) Oxygen saturation measured by pulse oximetry (SpO2) 
4) End-tidal partial pressure of carbon dioxide (PetCO2)  
5) Respiratory rate (RR) for spontaneous breathing subjects 
6) Pmax-PEEP for passive ARDS subjects 
Endpoints will be measured up to seven (7) days after randomization  

 
 
 
 
 
 
 
 
 
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Values for optimal, acceptable and sub-optimal ranges have been defined according to previously 
published studies (13, 14) and current recommendations. These ranges are adapted to the subject clinical 
condition and may be different for passive and spontaneous breathing ventilation periods. 
 
 

 
 
 
 
 
 
 
 
 
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Table 6: Values for optimal, acceptable and sub-optimal ranges 
Variable 
Ref. 
Subject 
condition 
Subject activity 
Sub-optimal 
low 
Acceptable 
low 
Optimal 
Acceptable 
high 
Sub-optimal 
high 
SpO2 (%) 
20 
None 
Passive or active 
< 90 
≥90 and <94 
≥94 and ≤98   Or > 98 if FiO2= 21% 
> 98 
NA 
SpO2 (%) 
 
ARDS 
Passive or active 
< 85 
≥85 and <88 
≥88 and ≤96 or > 96 if FiO2= 21% 
>96 
NA 
SpO2 (%) 
20 
Brain injury 
Passive or active 
< 90 
≥90 and <94 
≥94 and ≤98 Or > 98 if FiO2= 21% 
> 98 
NA 
SpO2 (%) 
20 
Chronic 
hypercapnia 
Passive or active 
< 85 
≥85 and <88 
≥88 and ≤92 or > 92 if FiO2= 21% 
>92 and ≤98 
> 98 
 
 
 
 
 
 
 
 
 
PetCO2 (mm Hg) 
 
None 
Passive 
< 25 
≥ 25 and < 34 
≥ 34 and ≤ 44 
> 44 and ≤49 
> 49 
PetCO2 (mm Hg) 
19 
ARDS 
Passive 
< 25 
≥ 25 and < 32 
≥ 32 and ≤ 42 
> 42 and ≤ 52 
> 52 
PetCO2 (mm Hg) 
 
None or ARDS 
Active 
NA 
< 25 
≥ 25 and ≤45 
> 45 and ≤55 
> 55 
PetCO2 (mm Hg) 
 
Brain injury 
Passive or active 
< 29 
≥ 29 and < 34 
≥ 34 and ≤ 39 
> 39 and ≤ 44 
> 44 
PetCO2 (mm Hg) 
 
Chronic 
hypercapnia 
Passive or active 
< 25 
≥ 25 and < 35 
≥ 35 and ≤ 55 
> 55 and ≤ 60 
> 60 
 
 
 
 
 
 
 
 
 
VT (mL/Kg IBW) 
21 
None 
Passive 
< 4 
≥ 4 and < 5 
≥ 5 and ≤ 8 
> 8 and ≤ 10 
> 10 
VT (mL/Kg IBW) 
15, 27, 35 
ARDS 
Passive 
< 4 
 
≥ 4 and ≤ 8 
> 8 and ≤ 10 
> 10 
VT (mL/Kg IBW) 
 
None,ARDS, or 
brain injury 
Active 
< 4 
≥ 4 and < 5 
≥ 5 and ≤ 10 
> 10 and ≤ 12 
> 12 
VT (mL/Kg IBW) 
 
Brain injury 
Passive 
< 4 
≥ 4 and < 5 
≥ 5 and ≤ 8 
> 8 and ≤ 10 
> 10 
VT (mL/Kg IBW) 
 
Chronic 
hypercapnia 
Passive or active 
< 4 
≥ 4 and < 5 
≥ 5 and ≤ 10 
> 10 and ≤ 12 
> 12 
 
 
 
 
 
 
 
 
 
Pmax (cm H2O) 
 
None 
Passive 
NA 
< 10 
≥ 10 and ≤ 25 
> 25 and ≤ 30 
> 30 
Pmax (cm H2O) 
15, 27, 35 
ARDS 
Passive 
NA 
< 10 
≥ 10 and ≤ 30 
> 30 and ≤ 35 
> 35 
Pmax (cm H2O) 
 
None or ARDS 
Active 
NA 
< 10 
≥ 10 and ≤ 25 
> 25 and ≤ 30 
> 30 
Pmax (cm H2O) 
 
Brain injury 
Passive or active 
NA 
< 10 
≥ 10 and ≤ 25 
> 25 and ≤ 30 
> 30 
Pmax (cm H2O) 
 
Chronic 
hypercapnia 
Passive or active 
NA 
< 10 
≥ 10 and ≤ 30 
> 30 and ≤ 35 
> 35 
Pmax-PEEP 
(cm 
H2O) 
4, 
ARDS 
Passive 
NA 
NA 
<15 
≥15 and <18 
≥ 18 
 
 
 
 
 
 
 
 
 
RR (b/min) 
 
None  
Active 
< 10 
≥ 10 and < 12 
≥ 12 and ≤ 30 
> 30 and ≤ 35 
> 35 
RR (b/min) 
 
Brain injury or 
ARDS 
Active 
< 10 
≥ 10 and < 12 
≥ 12 and ≤ 35 
> 35 and ≤ 40 
> 40 
RR (b/min) 
 
Chronic 
hypercapnia 
Active 
< 8 
≥ 8 and < 10 
≥ 10 and ≤ 35 
> 35 and ≤ 40 
> 40 
Efficacy and safety endpoints are co-primary endpoints:  
Efficacy will be calculated as the percentage of time spent with all variables in the optimal target ranges.  
Safety will be calculated as the percentage of time spent with at least one variable in the sub-optimal target ranges.  

 
 
 
 
 
 
 
 
 
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 Baseline Descriptive Characteristics 
All subjects’ characteristics at baseline will be described overall and by treatment group:  
- 
Age,  
- 
Height and weight,  
- 
Comorbidities and medical history,  
- 
Treatment concomitant, 
- 
Reason for hospitalization  
- 
Smoking status  
- 
Ethnicity, if possible   
10.5 Missing Data 
Please refer to section 7.2 "Inclusion Criteria” and 8.4 "End of study”. 
Subject will be considered to have completed the study for the following reasons: 
• 
Subject completes follow-ups (Day 28) required per investigational plan. 
• 
Subject dies.  
• 
Subject or legally authorized representative requests to be withdrawn from the study. 
• 
Investigator requests to be withdrawn from the study to protect the welfare of the 
subject. (In that case, it is at the site’s principal investigator’s discretion to determine that 
the study is no longer in the subject’s best interest). 
The sponsor deems a dataset “complete” if both of the following conditions are achieved: 
1. Minimum of 24h of recorded data available 
2. Minimum of 80% of the total invasive ventilation within the allocated randomized ventilation 
mode time has been recorded. 
An incomplete dataset leading to a dropout in the study is a dataset that misses at least one of the above 
mentioned variables.  
The reason for an incomplete dataset can be: 
• 
Early termination of recording caused by a transfer to another ICU 
• 
Subject or legally authorized representative requests to be withdrawn from the study. 
• 
Site’s Principal Investigator’s decides to stop the inclusion for any reason. 
• 
Technical failure in recording. 
• 
Less than 80% the invasive ventilation within the allocated randomized ventilation mode duration 
have been recorded in the Memory Box. 
• 
Recorded data is less than 24h. 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
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Dropout could occur when patients are ventilated for less than 24 hours after inclusion because of: 
unexpected death, transfer to another ICU, or withdrawal of informed consent. We expect a maximum of 
5% of these cases.  
Note a maximum of 5% of subjects are anticipated for which not 80% of mechanical ventilation time within 
the allocated randomized ventilation mode could be recorded due to documented technical reason. The 
recorded data will be used (with 'percent spent' calculated per the recorded time) for the primary analysis 
of the co-primary endpoints. As a sensitivity analysis, these values will be treated as missing data.  
 
Because technical failure in recording may not be detected on time by the investigators, a continued 
enrollment is planned. 
Technical issue in capturing the necessary data, the dropout probability is assumed to be equal for all 
subjects, regardless of their condition and ventilation modalities. Therefore, replacing subjects without 
collected data is not expected to cause any bias. 
It is assumed the study will enroll subjects until the required number of subjects with evaluable endpoints 
has been reached.  
 

 
 
 
 
 
 
 
 
 
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11 QUALITY ASSURANCE AND CONTROL 
11.1 Data handling  
 Case Report Forms  
As used in the protocol, the term Case Report Form (CRF) should be understood to refer to an electronic 
data record.  
A CRF is required and should be completed for each enrolled subject. The completed original CRF is the 
sole property of Hamilton Medical and should not be made available in any form to third parties, except 
for authorized representatives of Hamilton Medical or appropriate regulatory authorities, without written 
permission from Hamilton Medical.  
The investigator has the ultimate responsibility for the collection and reporting of all data entered in the 
CRF and ensuring that they are accurate, authentic, attributable, complete, consistent, legible, timely 
(contemporaneous), enduring and available when required.  
The CRF should be electronically signed by the investigator or by an authorized staff member to attest 
that the data contained on the CRFs are true. Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (as necessary) and should not obscure the initial data.  
 
 Specification of source documents  
Source Documents and Access to Source Data/Documents: 
All sites must maintain source data/documents in accordance with ISO 14155:2020. Each site will 
maintain, and store securely, complete, accurate and current study records throughout the study. The 
sites will maintain all study documentation for a minimum of two years following the date of marketing 
approval for the device being tested for the indication in which it was studied. If no marketing application 
is filed, or if the application is not approved, the records must be retained for two year after the 
investigation is discontinued and the US FDA is notified. These documents should be retained for a longer 
period, however, if required by the applicable regulatory requirements or by an agreement with the 
sponsor.  
Source documents are the hospitals or the physician’s subject chart and data collected automatically from 
the ventilator. Data collected automatically from the ventilator will not be monitored. They will be 
extracted from the ventilator and directly integrated to the database.  
In some cases the CRF, or part of the CRF, may also serve as source document. In these cases, a document 
should be available at the investigator’s site as well as at Hamilton Medical to clearly identify those data 
recorded in the CRF and for which the CRF will stand as source document.  
 
 

 
 
 
 
 
 
 
 
 
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 Record keeping / archiving  
Study records must be maintained on site for the entire period of study implementation. Instructions for 
record storage will be provided by Hamilton Medical. The records should be retained by the investigator 
according to ICH, ISO14155:2020 and local regulations or as specified in the clinical study agreement, 
whichever is longer.  
No study records may be moved to an off-site location or destroyed prior to receiving approval from 
Hamilton Medical. If the investigator becomes unable for any reason to continue to retain study records 
for the required period (e.g. retirement, relocation) Hamilton Medical should be prospectively notified. 
The study records must be transferred to a designee acceptable to Hamilton Medical such as another 
investigator, another institution, or to an independent third party arranged by Hamilton Medical. The 
investigator must obtain Hamilton Medical written permission before disposing of any records, even if 
retention requirements have been met.  
 
11.2 Data management  
 Data Management Responsibilities 
Study CRFs will be developed by the data manager and statistician in conjunction with Hamilton Medical. 
Quality control reports and queries will be routinely generated and distributed automatically by the eCRF 
to the study sites for verification and resolution. As part of the study activation process, the study site 
must identify all CRFs or part of the CRFs to be used as source documents. 
Subject’s ventilation data in both arms are directly recorded from the ventilators via a serial port using a 
Memory Box. The Memory Boxes are compatible with all Hamilton Medical ventilators. 
This memory box contains a memory card and is solely for investigational use and is just basically saving 
output data from the ventilators. These data will not be cleaned due to the automated nature of the 
subject recordings.  
 
 Data Management System  
The Data Management System is an electronic system hosted by the CRO, Soladis.  
 
 Data Safety 
Data Management activities are managed by a CRO, Soladis.  
The Data Entry application (EDC) is created by the Soladis developer’s team. The outputs are validated 
and reviewed by the Soladis Data Manager. 
 

 
 
 
 
 
 
 
 
 
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 Analysis and archiving 
At the end of the project, the data entered in the EDC (audit trial included) of each site are transmitted to 
the latter as PDF prints of the CRF (archival copies) stored by subject on CD-ROM/DVD-Rom.  
The eCRFs data (PDF file), appendices, documents and study specific quality records which constitute the 
Data Management part of the Trial Master File are filed in binders, labelled and transmitted to Hamilton 
Medical according to the instructions. Remaining copies are destroyed. Once the statistical analysis is 
completed, or before on Hamilton Medical’s demand, the database is archived on CD-Rom/DVD-Rom and 
removed from Soladis database.  
 Electronic and central data validation  
Proper data recording will be monitored by dedicated study CRAs. Monitoring activities and checks to be 
performed before the transfer to central database are defined in the monitoring plan.  
Ventilation parameters recorded by breath and by subject will be recorded on a SD card inserted in the 
Memory box. Data saved on the SD card will be transferred from participating sites in an anonymized 
form, and then stored on secure servers within Soladis. Any subject related documents will not be 
transferred to any unauthorized party and are will not be processed and/or transferred other than in 
accordance with the subjects’ consent.  
All baseline, follow up data will be entered on an eCRF. Information on the eCRF will, where relevant, be 
accepted as source data and transferred, in part, and as appropriate, to a database, password protected 
to defined users and with an audit trial managed from Soladis.  
 
11.3 Monitoring Plan 
A site qualification visit may be conducted by Sponsor (or designees) to review the clinical investigational 
plan, regulatory and study requirements with the investigator and study personnel. 
A site initiation visit will be performed once regulatory approvals are obtained and the site’s requirements 
for study participation are met. Sites will be considered as active once training phase is completed for US 
sites.  
Source data review will be carried out by a Clinical Research Associate (CRA), a representative of the 
Sponsor who will conduct on-site visits to check the CRF data against the original documents and confirm 
that these are complete and clear.  
The CRA will ensure that the study is conducted in accordance with the protocol and with regulatory 
requirements by frequent communications (by letter, telephone or fax) and that subjects’ rights are 
respected.  
The study closure visit will be performed by the monitor at the end of the study. 
A monitoring plan is detailing all monitoring procedures.  

 
 
 
 
 
 
 
 
 
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11.4 Quality Assurance, audits and inspections  
The monitoring and audit procedures written by Hamilton Medical will be set up in order to be consistent 
with Good Clinical Practice and ISO 14155:2020. Direct on‐site access to the site’s documentation and 
medical records must be permitted. 
In order to guarantee that the clinical study protocol complies with Good Clinical Practice, ISO 14155: 
2020 and current regulatory requirements, the investigator must allow audits to be performed by, or at 
the request of Hamilton Medical or by people instructed by Hamilton Medical, and inspections to be 
carried out by the Competent Authorities. 
The investigator undertakes to grant the auditors/inspectors direct access to examine the study records 
in knowledge of the fact that these people are subject to professional secrecy and that as such they must 
not reveal either the identity of people or their medical information. 
The investigator undertakes to assist in the correct conduct of audits and inspections as well as possible, 
enabling access to all of the premises, data and documents required. The medical file and any other study 
documents may be photocopied during an audit or inspection provided that the names of the subjects 
are blanked out on the copies in order to guarantee confidentiality. 
As soon as the investigator is informed of a forthcoming inspection by the authorities, he/she will inform 
Hamilton Medical and allow Hamilton Medical to take part in this inspection. 
During these inspections, the confidentiality of the data checked and subject protection must be 
observed. 
The investigator will communicate all of the results and all of the information resulting from the 
inspections carried out by the regulatory authorities to Hamilton Medical as soon as possible. 
The investigator will take the appropriate measures as instructed by Hamilton Medical to rectify any 
problems identified during the audit or during the inspections. A site visit log will be maintained at study 
site to document all visits. 
11.5 Study management 
The study is sponsored by Hamilton Medical.   
Study team contact details will be provided in the investigational site file as part of the Trial Master File. 
11.6 Records and reports 
 Study Investigator records 
An Investigator Site File will be maintained up to date by the investigator.  
At a minimum, the following records must be kept up to date by the study site:  
• 
Clinical Investigation Plan and, if applicable, any amendments with signed page  
• 
IRB/EC correspondence, including approvals 
• 
Instructions for Use 
• 
IRB/EC approved Informed Consent form 

 
 
 
 
 
 
 
 
 
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• 
Regulatory Authority approval or notification 
• 
Fully signed Clinical Investigation Agreement and confidentiality agreement (if not 
included in the Clinical Investigation Agreement) 
• 
Financial disclosures 
• 
Completed Delegation of Authority Form and Curriculum Vitae of all investigation site 
personnel 
• 
Training documentation of all investigation site personnel 
• 
Relevant communications from sponsor, monitor  
• 
Subject screening log and/or subject identification log  
• 
Signed, dated and fully executed Informed Consent forms 
• 
Fully executed CRFs and corrections 
• 
Reports of Adverse Events and Device Deficiencies 
• 
Device accountability records, if required 
 Investigator reporting responsibilities 
 
Table 7: Investigator Reporting Responsibilities  
Report 
Submitted to 
Description 
Unanticipated Adverse 
Device Effect  
EC/IRB and Sponsor   
Refer to Table for Adverse Event Reporting 
Requirements (above) 
Adverse Events 
Sponsor 
Refer to Table for  Adverse Event Reporting 
Requirements (above) 
Withdrawal of EC/IRB 
approval 
Sponsor 
US:  
An investigator shall report to the sponsor, 
within five (5) working days, a withdrawal of 
approval by the reviewing IRB of the 
investigator's part of an investigation. (21 CFR 
812.150(a)(2)). 
 
Europe:  
As required and in compliance with local 
regulatory requirements. 

 
 
 
 
 
 
 
 
 
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Report 
Submitted to 
Description 
Progress 
Sponsor, the monitor, and 
the EC/IRB 
US: 
An investigator shall submit progress reports 
on the investigation at regular intervals, but in 
no event less often than yearly. (21 CFR 
812.150(a)(3)). 
 
Europe:  
As required and in compliance with local 
regulatory requirements. 
Study deviations 
Sponsor and EC/IRB 
US: 
Notice of deviations from the CIP to protect 
the life or physical well-being of a subject in 
an emergency shall be given as soon as 
possible, but no later than 5 working days 
after the emergency occurred. (21 CFR 
812.150(a)(4)). 
 
Europe:  
As required and in compliance with local 
regulatory requirements. 
Failure to obtain 
Informed Consent 
prior to investigational 
device use 
Sponsor and EC/IRB 
US: 
If an investigator uses an investigational 
device without obtaining informed consent, 
the investigator shall report such use within 5 
working days after device use. (21 CFR 
812.150(a)(5)). 
 
Europe:  
As required and in compliance with local 
regulatory requirements. 
Final Clinical study 
report 
Sponsor, EC/IRBs and 
Relevant Authorities 
US: 
This report must be submitted within 3 
months of study completion or termination of 
the investigation or the investigator’s part of 
the investigation. (21 CFR 812.150(a)(6)). 
 
Europe: 
As required and in compliance with local 
regulatory requirements. 

 
 
 
 
 
 
 
 
 
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Report 
Submitted to 
Description 
Other  
EC/IRB and FDA  
US: 
An investigator shall, upon request by a 
reviewing EC/IRB, FDA or any other regulatory 
agency, provide accurate, complete, and 
current information about any aspect of the 
investigation. (21 CFR 12.150(a)(7)). 
 
Europe: 
As required and in compliance with local 
regulatory requirements. 
 Hamilton Medical records 
At a minimum, the sponsor will keep the following records in the Trial Master File: 
• 
All essential study documents and correspondence that pertains to the clinical study 
• 
CIP and, if applicable, any amendments 
• 
Instructions for Use 
• 
Sample of labeling attached to the investigational device 
• 
Curriculum Vitae of investigators and investigation site personnel 
• 
Delegation of Authority Form and training records of investigators and investigation site 
personnel 
• 
EC/IRB approvals/notifications and regulatory approvals/notifications 
• 
Signed Clinical Investigation Agreements and signed agreements with third parties 
• 
Shipping records for investigational devices and clinical-investigation related documents 
and materials, if required 
• 
EC/IRB approved Informed Consent Forms 
• 
Site selection reports, site initiation reports and monitoring visit reports  
• 
Adverse event and Device Deficiency reports 
• 
Financial disclosure information 
• 
Fully executed CRFs and corrections 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
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 Hamilton Medical reporting requirements in US  
 
Table 8: Hamilton Medical Reporting Requirements in Us  
Report 
Submit to 
Description 
Adverse Events  
IRB, Investigators, FDA 
and relevant 
authorities, where 
applicable 
Sponsor will report adverse events as required and in 
compliance with local regulatory requirements, as 
applicable and described in Study Medical Device 
Vigilance and Project Specific Procedure Plan 
Unanticipated Adverse 
Device Effect (UADE) 
Investigators, IRB, FDA, 
and relevant authorities 
Notification within ten (10) working days after the 
sponsor first receives notice of the effect. (21 CFR 
812.150(b)(1)). 
 
Withdrawal of IRB 
approval 
Investigators, IRB, FDA, 
and relevant authorities 
Notification within five (5) working days after receipt of 
the withdrawal of approval. (21 CFR 812.150(b)(2)). 
 
Withdrawal of FDA 
approval 
Investigators, IRB, and 
relevant authorities 
Notification within five (5) working days after receipt of 
notice of the withdrawal of approval. (21 CFR 
812.150(b)(3)). 
 
Current Investigator List 
FDA 
Submit at 6-month intervals, a current list of the names 
and addresses of all investigators participating in the 
investigation. (21 CFR 812.150(b)(4)). 
 
Progress Reports 
IRB and FDA 
At regular intervals, but not less than yearly, a sponsor 
shall submit progress reports to all reviewing IRB's and 
EC’s. In the case of a significant risk device, a sponsor 
shall also submit progress reports to FDA. A sponsor of a 
treatment IDE shall submit semi-annual progress reports 
to all reviewing IRB's and FDA in accordance with § 
812.36(f) and annual reports in accordance with this 
section. 
 
Recall and device 
disposition 
IRB relevant authorities, 
and FDA 
Notification within 30 working days after the request is 
made and will include the reasons for any request that an 
investigator return, repair, or otherwise dispose of any 
devices. (21 CFR 812.150(b)(6)). 
 
Failure to obtain 
Informed Consent 
FDA 
Investigator’s report will be submitted to FDA within five 
(5) working days of notification. (21 CFR 812.150(b)(8)). 

 
 
 
 
 
 
 
 
 
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Report 
Submit to 
Description 
Other 
 IRB/FDA 
Sponsor shall, upon request by a reviewing IRB or FDA, 
provide accurate, complete, and current information 
about any aspect of the investigation. (21 CFR 
812.150(b)(10)). 
 
 Hamilton Medical reporting requirements in US /EU 
 
Report 
Submit to 
Description 
Adverse Events, Device 
Deficiencies  
EC, Investigators, and 
relevant authorities, 
where applicable 
Sponsor will report adverse events as required and in 
compliance with local regulatory requirements, as 
applicable and described in Study Medical Device 
Vigilance and Project Specific Procedure Plan 
Premature termination or 
suspension of study 
Investigators,EC/ IRB, 
and Relevant authorities 
Provide prompt notification of termination or suspension 
and reason(s). (ISO 14155: 2020), (MHLW Ordinance 36, 
Article 32). 
Final Report 
Investigators, EC IRB, 
and regulatory 
authorities, where 
applicable and FDA 
Sponsor will notify EC/IRB and FDA within 30 working 
days of the completion or termination of the 
investigation.  
A final report will be submitted to the FDA, investigators, 
and EC/IRBs within six (6) months after completion or 
termination of this study. (21 CFR 812.150(b)(7)). 
 
In Europe – per the local laws and regulations. 
Study Deviations 
Investigators 
Ensure that all deviations from the CIP are reviewed with 
the appropriate clinical investigator(s), are reported on 
the case report forms and the final report of the clinical 
investigation and reported per local laws and regulations. 
 
11.7 Subject compensation and indemnification 
Subjects will not receive any compensation for their participation in this study. 
 
11.8 Confidentiality, Data Protection  
Any confidential information relating to INTELLIVENT-ASV or the study, including any data and results 
from the study will be the exclusive property of Hamilton Medical. The investigator and any other persons 
involved in the study will protect the confidentiality of the proprietary information belonging to Hamilton 
Medical. 

 
 
 
 
 
 
 
 
 
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Subject confidentiality will be maintained throughout the clinical study to the extent permitted by law. 
That is, every attempt will be made to remove subject identifiers from clinical study documents. For this 
purpose, a unique subject identification code (site number and subject number) will be assigned and used 
to allow identification of all data reported for each subject. This will also ensure that the information can 
be tracked back to the source data. 
 
Study data may be made available to third parties, e.g., in the case of an audit performed by regulatory 
authorities, provided the data are treated confidentially and that the subject’s privacy is guaranteed. The 
identity of a subject will never be disclosed in the event that study data are published. 
 
11.9 Amendments to the CIP 
Any change to this protocol will be documented in a protocol amendment, issued by Hamilton Medical, 
and agreed upon by the principal investigator prior to its implementation. Protocol Amendments and 
documents updated as a result of the Protocol Amendment must not be implemented until all approvals 
(EC/IRB and RAs, if applicable) have been obtained. 
Changes to the protocol to eliminate immediate hazard(s) to study subjects may be implemented prior to 
EC(s)/IRB(s) and RA approval. 
 
11.10 Deviations from the Clinical Investigation Plan 
A protocol deviation is defined as an event where the clinical investigator or site personnel did not conduct 
the study according to the clinical investigational plan, applicable laws or regulations, or the Investigator 
Agreement.  
 
Under working conditions, deviations from the protocol may occur. Every attempt must be made to avoid 
deviations. All deviations will be recorded for the study. 
United States regulations (21 CFR 812.140) require that investigators maintain accurate, complete, and 
current records relating to the clinical study. This includes documents showing the dates and reasons for 
each deviation from the clinical investigational plan.  
If deviations from the protocol are reported, the investigator informs the monitor, and the implications 
of the deviation needs be escalated to Hamilton Medical.  
All protocol deviations must be reported to the EC/IRB policies and/or local laws, as applicable. All 
deviations will be summarized and reported in regular progress reports to the FDA. Deviation reports and 
supporting documentation will be kept in the investigator site file and the study master file.  
 
 Request for approval of study deviations 
In case of study deviations that can affect the subject’s rights, safety and well-being or the scientific 
integrity of the clinical study, approval from the EC/IRB and Regulatory Authority must also be obtained 

 
 
 
 
 
 
 
 
 
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before implementation. The investigator shall timely contact the monitor and Hamilton Medical for 
review of the proposed change/deviation. 
In any emergency situation the investigator shall exercise his/her judgment to safeguard the subject’s 
interest. The investigator shall report the deviation as soon as possible to Hamilton Medical and the 
reviewing EC/IRB, if applicable. Hamilton Medical will inform the Regulatory Authorities, if required. 
 
 Reporting requirements for study deviations 
The investigator shall adhere to EC/IRB requirements and procedures for reporting study deviations. 
Hamilton Medical is responsible for analyzing deviations, assessing their significance, and identifying any 
additional corrective and/or preventive actions (e.g. amend the protocol, additional training, terminate 
the study, etc.). Repetitive or serious investigator compliance issues may result in the need to initiate a 
corrective action plan, and in some cases freeze enrolment or ultimately terminate the investigator’s 
participation in the clinical study: 
• 
Non-compliance to obtain subject’s informed consent 
• 
Non-compliance to the inclusion/exclusion criteria 
• 
Failure to follow subjects per scheduled follow-ups 
• 
Failure to submit data in a timely manner 
• 
Failure to follow-up with findings on monitoring reports 
• 
EC/IRB approval expiration 
• 
EC/IRB suspension of the center 
If a site is terminated or suspended, no additional enrollments will be allowed at the center.  
Hamilton Medical will provide investigation site-specific reports to the investigators on a periodic basis 
summarizing information on deviations that occurred at the investigation site.  

 
 
 
 
 
 
 
 
 
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12 Study device/product traceability 
12.1 Supply of investigational devices/products 
Hamilton Medical investigational devices/products will be ordered and shipped to the site prior site 
activation as applicable. All devices are supplied with INTELLIVENT-ASV Software accessory.  
However, the activation of the INTELLiVENT-ASV software accessory can be done only with a key code 
provided by the sponsor.  
US only: The investigational device (INTELLiVENT-ASV accessory is activated), the instructions for use, or 
the packaging, or the ventilator will indicate that the investigational device is exclusively for use in a 
clinical investigation. 
12.2 Storage and handling of investigational devices/products 
US only: Investigational devices/products must be stored in a secured area if they are not used to treat 
study patients. The method of storage shall prevent the use of investigational devices/products for other 
applications than mentioned in this clinical investigation plan. In addition, all information for the use, 
storage, and handling of the investigational device/product as indicated in the Instructions for Use must 
be taken into account. 
12.3 Device return procedures 
All non-functioning devices/products should be returned to Hamilton Medical for analysis.  
 
The final disposition of the device must be recorded on the device disposition log, if the device is 
Hamilton’s property. Relevant information should also be recorded on associated eCRF. Detailed 
instructions for the return of non-functioning devices will be provided in the investigational site file. 
 

 
 
 
 
 
 
 
 
 
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13 PUBLICATION POLICY 
It is understood that this study is part of a multi-center study and a publication of data/results from all 
sites is expected.  Hamilton Medical certifies that it intends to submit the multicenter study results for 
publication in a peer-reviewed medical journal and/or to submit such results for disclosure in a publicly 
accessible website within twelve (12) months after the study conclusion. If the study results are under 
review by peer-reviewed medical journals that prohibit pre-publication disclosure at the 12-month 
timeframe, Hamilton Medical agrees that disclosure will be posted on publicly accessible websites at the 
time of publication. The study results will be disclosed as soon as possible if there are any significant safety 
findings. Hamilton Medical further certifies that the multicenter study results will be published/disclosed 
regardless of whether they support the hypothesis being tested or are contrary to the predicated 
outcome.  At such time as the results are submitted for publication or posted on publicly accessible 
websites at the time of publication, notification that a submission of the multi-center results is not 
planned, or eighteen (18) months after the study conclusion, whichever shall first occur, Hamilton Medical 
shall make study results available to the investigators for individual publication analysis and public 
disclosure.  Investigators shall be free to publish the data/results from the study in accordance with this 
section.  Investigators shall be free to publish the data/results of the Study subjects agreed in the contract 
with Hamilton Medical.   
The Institution shall require the investigators to furnish Hamilton Medical with a copy of any proposed 
publication prior to submission for publication, at least sixty (60) days prior to submission for manuscripts 
and at least twenty-one (21) days prior to submission for abstracts.  Hamilton Medical shall be entitled to 
review such proposed publications solely for the purpose of identifying Hamilton Medical’s confidential 
information, which shall be removed from the publication upon Hamilton Medical’s request to the extent 
such deletion does not preclude the complete and accurate presentation and interpretation of the study 
results; and to identify any patentable inventions, which shall be addressed as described below; and to 
provide any other comments Hamilton Medical desires to provide, provided that investigators shall have 
no obligation to address any such additional comments.   
At the expiration of such sixty (60) day or twenty-one (21) day period, investigators may proceed with 
submission for publication provided that any identified Hamilton Medical’s Proprietary Information has 
been removed; and provided further that upon notice by Hamilton Medical that Hamilton Medical 
reasonably believes a patent application claiming an Invention should be filed prior to such publication, 
in Institution’s discretion such submission shall be delayed for up to an additional sixty (60) days or until 
any patent application or applications have been filed, whichever shall first occur.  In no event shall the 
submission of such publication of results be delayed for more than one hundred and twenty (120) days 
for manuscripts and for more than sixty-seven (67) days for abstracts from the date such proposed 
publication was provided to Hamilton Medical; at the end of said one hundred and twenty (120) or sixty-
seven (67) days, investigators shall be free to publish such results as proposed. 
If an investigator is or becomes the multi-site coordinating principal investigator or overall Study chair, 
he/she shall have access to data from all Study sites for analyses for publication.  If an investigator is or 
becomes an author or if the investigator’s activities warrant authorship on any multi-center Study 
publication, or if the investigator is or becomes a member of any Study publication and analysis 

 
 
 
 
 
 
 
 
 
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committee, the investigator shall have access to data from all Study sites for analyses for publication.  
Hamilton Medical shall also provide the Investigator in any of these events with a copy of the abstract and 
manuscript for any multi-center Study publication and with an adequate opportunity to review and have 
input into such abstract and manuscript prior to submission for publication.  The investigator shall, in all 
cases, at his/her sole discretion, have the right to decline to be an author and to have his/her name 
removed as an author from any multi-center Study publication.   
If Hamilton Medical chooses to provide publication support for any multicenter publication that includes 
the investigator as an author, such support shall be governed by an Agreement between the investigator 
and Hamilton Medical, including but not limited to its publication provisions.  For the purpose of clarity, 
any such publication support is a transfer of value between Hamilton Medical and Institution and not to 
the investigator for purposes of reporting under The Physician’s Payment Sunshine Act.   
If no multi-center Study publication occurs within twelve (12) months after the Study Conclusion, 
Hamilton Medical shall at that time provide access to data from all Study sites to the Study academic 
coordinating site, or if Hamilton Medical elects not to provide access to data from all Study sites to the 
Study academic coordinating site, then upon request it will provide access to data from all Study sites to 
Institution or to at least one other academic medical center participating in the Study for purposes of 
publication of the Study results. 
 
 
 

 
 
 
 
 
 
 
 
 
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14 FUNDING AND SUPPORT 
This study is funded and supported by Hamilton Medical AG and local sponsor Hamilton Medical Inc. 
 
 

 
 
 
 
 
 
 
 
 
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15 INSURANCE 
The sponsor will cover the study by a subject-insurance.  
Hamilton Medical Inc. is a wholly owned subsidiary of Hamilton Medical AG., which as the parent company 
of such entity maintains appropriate clinical study liability insurance coverage as required under 
applicable laws and regulations and will comply with applicable law and custom concerning specific 
insurance coverage. If required, a Clinical Trial Insurance statement/certificate will be provided to the 
EC/IRB. 
 
 
 
 

 
 
 
 
 
 
 
 
 
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Dojat M, Harf A, Touchard D, Lemaire F, Brochard L. Clinical evaluation of a computer-controlled 
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Arnal JM, Wysocki M, Nafati C, Donati S, Granier I, Corno G et al. Automatic selection of breathing 
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Kirakli C, Naz I, Ediboglu O, Tatar D, Budak A, Tellioglu E. A Randomized Controlled Trial Comparing 
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Kirakli C, Ozdemir I, Ucar Z, Cimen P, Kepil S, Ozkan S. Adaptive Support Ventilation for Faster 
Weaning in COPD: A Randomized Controlled Trial. Eur Respir J 2011;38:774-80 
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Arnal JM, Wysocki M, Novotni D, Demory D, Lopez R, Donati SY, Granier I, Corno G, Durand-
Gasselin J. Safety and efficacy of a fully closed-loop control ventilation (IntelliVent-ASV) in sedated 
ICU patients with acute respiratory failure: a prospective randomized crossover study. Intensive 
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Bialais E, Wittebole X, Vignaux L, Roeseler J, Wysocki M, Meyer J, Reychler G, Novotni D, Sottiaux 
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Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA 
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Fan E, Del Sorbo L, Goligher E, Hodgson C, Munshi L, Walkey A, Adhikari N, Amato M, Branson R, 
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Ranieri M, Ribenfeld G, Rubin E, Seckel M, Slutsky A, Talmor D, Thompson T, Wunsch A, Uleryk E, 
Brochard L.  An Official American Thoracic Society/European Society of Intensive Care 
Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in 
Adult Patients with Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med 2017; 195: 
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practice in the prehospital setting and on the Neuro-ICU. Curr Opin Anaesthesiol. 2015;28(5):517-
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Farhoumand PD, Siemieniuk JLK, Satia I, Irusen EM, Refaat MM, Mikita JS, Smith M, Cohen DN, 
Vandvik PO, Agoritsas T, Lytvyn L, Guyatt GH. Oxygen therapy for acutely ill medical patients: a 
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Davidson AC, Banham S, Elliott M, Kennedy D, Gelder C, Glossop A, Church AC, Creagh-Brown B, 
Dodd JW, Felton T, Mansfield L, McDonnell L, Parker R, Patterson CM, Sovani M, Thomas L; BTS 
Standards of Care Committee Member, British Thoracic Society/Intensive Care Society Acute 
Hypercapnic Respiratory Failure Guideline Development Group, On behalf of the British Thoracic 
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hypercapnic respiratory failure in adults. Thorax. 2016;71 Suppl 2:ii1-35.  
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Barnes T, Zochios V, Parhar K. Re-examining Permissive Hypercapnia in ARDS: A Narrative Review. 
Chest. 2018;154(1):185-195.  
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O'Driscoll BR, Howard LS, Earis J, Mak V; British Thoracic Society Emergency Oxygen Guideline 
Group; BTS Emergency Oxygen Guideline Development Group. BTS guideline for oxygen use in 
adults in healthcare and emergency settings. Thorax. 2017;72(Suppl 1):ii1-ii90.  
24) 
Lellouche F, Lipes J. Prophylactic protective ventilation: lower tidal volumes for all critically ill 
patients? Intensive Care Med. 2013;39(1):6-15.  
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McConville JF, Kress JP. Weaning patients from the ventilator. N Engl J Med. 2013;368(11):1068-
9.  
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Boles JM, Bion J, Connors A, Herridge M, Marsh B, Melot C, Pearl R, Silverman H, Stanchina M, 
Vieillard-Baron A, Welte T.Weaning from mechanical ventilation. Eur Respir J. 2007;29(5):1033-
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The Spanish Lung Failure Collaborative Group. Esteban A, Alía I, Gordo F, Fernández R, Solsona JF, 
Vallverdú I, Macías S, Allegue JM, Blanco J, Carriedo D, León M, de la Cal MA, Taboada F, Gonzalez 
de Velasco J, Palazón E, Carrizosa F, Tomás R, Suarez J, Goldwasser RS. Extubation outcome after 
spontaneous breathing trials with T-tube or pressure support ventilation. Am J Respir Crit Care 
Med. 1997;156(2 Pt 1):459-65. 
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Spanish Lung Failure Collaborative Group. Esteban A, Alía I, Tobin MJ, Gil A, Gordo F, Vallverdú I, 
Blanch L, Bonet A, Vázquez A, de Pablo R, Torres A, de La Cal MA, Macías S. Effect of spontaneous 

 
 
 
 
 
 
 
 
 
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breathing trial duration on outcome of attempts to discontinue mechanical ventilation. Am J 
Respir Crit Care Med. 1999;159(2):512-8. 
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Thompson BT, Chambers RC, Liu KD. Acute Respiratory Distress Syndrome. N Engl J Med. 
2017;377(19):1904-1905.  
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Claesson J, Freundlich M, Gunnarsson I, Laake JH, Vandvik PO, Varpula T, Aasmundstad TA; 
Scandinavian Society of Anaesthesiology and Intensive Care Medicine.Scandinavian clinical 
practice guideline on mechanical ventilation in adults with the acute respiratory distress 
syndrome. Acta Anaesthesiol Scand. 2015 ;59(3):286-97.  
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 Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung 
CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, 
Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo 
JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, 
Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, 
Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, 
Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, 
Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: International Guidelines 
for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017;45(3):486-552.  
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Amato MB, Meade MO, Slutsky AS, Brochard L, Costa EL, Schoenfeld DA, Stewart TE, Briel M, 
Talmor D, Mercat A, Richard JC, Carvalho CR, Brower RG.Driving pressure and survival in the acute 
respiratory distress syndrome. N Engl J Med. 2015;372(8):747-55.  
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Schönhofer B, Geiseler J, Dellweg D, Moerer O, Barchfeld T, Fuchs H, Karg O, Rosseau S, Sitter H, 
Weber-Carstens S, Westhoff M, Windisch W.S2k-Guideline "Prolonged Weaning". Pneumologie. 
2015;69(10):595-607.  
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Schmidt GA, Girard TD, Kress JP, Morris PE, Ouellette DR, Alhazzani W, Burns SM, Epstein SK, 
Esteban A, Fan E, Ferrer M, Fraser GL, Gong MN, Hough CL, Mehta S, Nanchal R, Patel S, Pawlik 
AJ, Schweickert WD, Sessler CN, Strøm T, Wilson KC, Truwit JD.Liberation From Mechanical 
Ventilation in Critically Ill Adults: Executive Summary of an Official American College of Chest 
Physicians/American Thoracic Society Clinical Practice Guideline. Chest. 2017;151(1):160-165.  
35) 
Chen YH, DeMets DL, Lan KK. Increasing the sample size when the unblinded interim result is 
promising. Statistics in Medicine 2004; 23:1023-1038  
36) 
Gao P, Ware JH, Mehta C. Sample size re-estimation for adaptive sequential design in clinical trials. 
Journal of Biopharmaceutical Statistics 2008; 18:1184-1196 
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Narendra DK, Hess DR, Sessler CN, Belete HM, Guntupalli KK, Khusid F, Carpati CM, Astiz ME, Raoof 
S. Update in Management of Severe Hypoxemic Respiratory Failure. Chest. 2017;152(4):867-879.  
38) 
The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as 
compared with traditional tidal volumes for acute lung injury and the acute respiratory distress 
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39) 
The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as 
compared with traditional tidal volumes for acute lung injury and the acute respiratory distress 
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40) 
The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as 
compared with traditional tidal volumes for acute lung injury and the acute respiratory distress 
syndrome. N Engl J Med 2000;342(18):1301–1308 
41) 
Arnal JM, Saoli M, Garnero A. Airway and transpulmonary driving pressures and mechanical 
powers selected by INTELLiVENT-ASV in passive, mechanically ventilated ICU patients. Heart 
Lung. 2019 Nov 14:S0147-9563(19) 30533-3. 
42) 
De Bie AJR, Serpa Neto A, van Meenen DM, Bouwman AR, Roos AN, Lameijer JR, Korsten EHM, 
Schultz MJ, Bindels AJGH. Fully automated postoperative ventilation in cardiac surgery patients: 
a randomised clinical trial. Br J Anaesth. 2020 Jul 29; S0007-0912(20)30497-9. doi: 
10.1016/j.bja.2020.06.037. Online ahead of print. 
 

 
 
 
 
 
 
 
 
 
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Annex A: Identification of Risks and AE´s for the intended subject population, the clinical 
background and the device in question identified from clinical experience for INTELLiVENT-ASV  
State of the Art: Adverse Events for mechanical ventilation and critically ill ICU population 
A sound review of documentation for the medical fields of mechanical ventilation has been conducted. 
Applicable medical standards and guidance documents (published by medical associations) describe the 
natural course of critically ill subjects and the consequences of mechanical ventilation.  
As the more common indications for invasive mechanical ventilation are inability to protect the airway, 
inadequate oxygenation and inadequate ventilation, Risks and Adverse events for Mechanical Ventilation 
overlap with conditions of the underlying disease that were reasons for the admission to an ICU.  
In a population-based study of 8,309,344 US cases of non-surgical episodes of invasive mechanical 
ventilation, hospital mortality was strongly influenced by the underlying medical diagnosis. In 2009, 
hospital mortality amounted to 34.2% for pneumonia, 18.5% for COPD and 32.7% for heart failure subjects 
requiring invasive mechanical ventilation [2].  
 
Root causes for mechanical ventilation of critically ill subjects in an ICU (industrialized countries) are:  
Table 9: Root causes for Mechanical Ventilation [3] 
Root causes for Mechanical Ventilation 
Occurence 
COPD 
5% 
Asthma 
1% 
Other chronic lung diseases 
2% 
Coma 
19% 
Neuromuscolar diseases 
1% 
Acute respiratory failure 
 
Postoperative 
21% 
 
2 A B Mehta, SN Syeda, RS Wiener, AJ Walkey Epidemiological Trends in Invasive Mechanical Ventilation in the United States: A Population-Based 
Study J Crit Care. 2015 Dec; 30(6): 1217–1221. 
3 Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, Ranieri M, 
Rubenfeld G, Thompson BT, Wrigge H, Slutsky AS, Pesenti A; LUNG SAFE Investigators; ESICM Trials Group. Epidemiology, 
Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. 
JAMA. 2016 Feb 23;315(8):788-800.  
 

 
 
 
 
 
 
 
 
 
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Pneumonia 
11% 
Sepsis 
9% 
ARDS 
3% 
Congestive Heart failure 
6% 
Cardiac Arrest 
5% 
Trauma 
6% 
Aspiration 
3% 
Other 
9% 
 
 
 
Characteristics and outcome for ventilated ICU subjects (industrialized countries) 
Table 10: Characteristics and outcome for ventilated ICU subjects [4] 
Endpoint 
Occurrence in % 
Death of ventilated ARDS subjects 
27-45% 
Barotrauma (and pneumothorax) of ventilated 
ARDS subjects 
10% 
ICU Mortality 
29-32% 
Days of mechanical ventilation 
2-8 
Incidence of subjects with ARDS 
 
at ICU admission 
10% 
all ventilated subjects 
24% 
 
 
 
4 Esteban A, Ferguson ND, Meade MO, Frutos-Vivar F, Apezteguia C, Brochard L, Raymondos K, Nin N, Hurtado J, Tomicic V, 
González M, Elizalde J, Nightingale P, Abroug F, Pelosi P, Arabi Y, Moreno R, Jibaja M, D'Empaire G, Sandi F, Matamis D, 
Montañez AM, Anzueto A; VENTILA Group. Evolution of mechanical ventilation in response to clinical research. Am J Respir Crit 
Care Med. 2008; 177(2):170-7. 
 

 
 
 
 
 
 
 
 
 
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Mehta and al. [2] identified 8,309,344 cases of invasive mechanical ventilation from 1993-2009. Utilization 
of invasive mechanical ventilation for non-surgical indications increased from 178.9/100,000 in 1993 to 
310.9/100,000 US adults in 2009. Pneumonia cases requiring invasive mechanical ventilation showed the 
largest increase (103.6%), whereas COPD cases remained relatively stable (2.5% increase) and HF cases 
decreased by 55.4%. Similar demographic and clinical changes were observed for pneumonia, COPD, and 
HF, with cases of invasive mechanical ventilation becoming younger, more ethnically diverse, and more 
frequently insured by Medicaid. Outcome trends for patients differed based on diagnosis. Adjusted 
hospital mortality decreased over time for cases of pneumonia (OR per 5 years=0.89, 95% CI 0.88-0.90) 
and COPD (OR per 5 years=0.97, 95% CI 0.97-0.98) but increased for HF (OR per 5 years=1.10, 95% CI 1.09-
1.12). 
 
Table 11: Baseline demographics and comorbidities for Invasive Mechanical Ventilation ) [5] 
Baseline 
demographics 
and 
comorbidities for 3 representative years* 
1993 
(n=341,164 
001 
(n=431,144) 
2009 
(n=723,310) 
p-
value** 
Age: Mean (SD) 
65.2 (17.4) 
64.2 (17.7) 
61.6 (17.7) 
<0.0001 
Male 
51.4 
50.9 
53.2 
<0.0001 
Race 
 
 
 
<0.0001 
White 
60.1 
54.7 
56.8  
 
Black 
11.5 
11.6 
14.0  
 
Hispanic 
5.5 
6.4 
7.9  
 
Other† 
22.9 
27.2 
21.3 
 
Primary Payer 
 
 
 
<0.0001 
Medicare 
61.5 
58.4 
54.4  
 
Medicaid 
10.1 
11.6 
14.3  
 
Private Insurance 
19.1 
21.5 
20.7  
 
Other† 
9.4 
8.5 
10.6 
 
Comorbidities 
 
 
 
<0.0001 
No comorbidities 
12.8 
7.0 
4.7  
 
1-2 comorbidities 
55.1 
44.2 
34.6  
 
>2 comorbidities 
32.2 
48.9 
60.7 
 
Chronic HF 
27.7 
27.3 
22.3 
<0.0001 
Chronic Lung Disease 
26.7 
31.7 
28.4 
<0.0001 
Valvular Heart Disease 
7.1 
7.8 
4.0 
<0.0001 
Peripheral Vascular Disease 
3.1 
4.1 
5.0 
<0.0001 
Hypertension 
20.5 
34.4 
42.6 
<0.0001 
Paralysis 
3.2 
4.4 
6.3 
<0.0001 
Other Neurologic Disorders 
9.2 
12.3 
12.8 
<0.0001 
Diabetes w/o chronic complications 
10.6 
17.1 
20.1 
<0.0001 
Renal Failure 
4.2 
8.2 
15.5 
<0.0001 
Liver Disease 
2.3 
4.1 
4.2 
<0.0001 
Metastatic Cancer 
2.7 
3.3 
3.2 
<0.0001 
Obesity 
1.5 
3.4 
7.4 
<0.0001 
Weight Loss 
3.9 
6.5 
15.3 
<0.0001 
Alcohol Abuse 
6.1 
8.5 
8.8 
<0.0001 
Drug Abuse 
2.6 
4.5 
5.7 
<0.0001 
* First year (1993), middle year (2001), final year of study (2008) to convey representative temporal changes in patient characteristics. 

 
 
 
 
 
 
 
 
 
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** All statistical testes represent trends over the 17 year study sample. 
† Includes individuals for whom data was missing. 
Clinical manifestations and medical occurrences, unintended diseases or injuries or clinical signs that 
are attributed to the concurrent illness / clinical condition of critically ill subjects in an ICU include5:  
• 
Death  
• 
Barotrauma /Volutrauma (and pneumothorax) from manual or mechanical ventilation during 
emergency therapies etc. 
• 
Pneumonia 
• 
Sepsis / Infections 
• 
ARDS 
• 
Congestive Heart failure right and left LV 
• 
Atrial flutter/fibrillation 
• 
Acute myocardial infraction 
• 
Cardiac Arrest 
• 
Trauma / iatrogenic trauma caused by emergency therapies 
• 
Aspiration 
• 
Bleeding 
• 
Gastrointestinal bleeding  
• 
Abdominal hypertension/compartment Syndrome 
• 
Thrombosis 
• 
Embolism 
• 
Allergies 
• 
Nutrition deficiencies 
• 
Renal failure 
• 
Liver failure 
• 
Critical illness neuro-myopathy 
• 
Stroke 
• 
Intra cerebral bleeding 
• 
Other single- and multi-organ failure 
 
Complications of Mechanical Ventilation include5:  
 
Complications during Endotracheal intubation  
• 
Trauma of the upper airways (especially with tracheostomy) 
• 
Bleedings 
• 
Gastric Aspiration 
 
 
5 Manufacturer´s State-of-the-Art Documentation, on file  

 
 
 
 
 
 
 
 
 
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Hemodynamic Effects  
• 
High plateau pressures  and PEEP can negatively impact right-ventricular preload and afterload 
• 
Pulmonary hypertension and PEEP can result into right-to-left shunting across a patent foramen 
ovale and worsen hypoxemia 
 
Oxygen Toxicity  
• 
Reabsorption atelectasis 
• 
Increased mortality with high FiO2 
 
Complications of Sedation  
• 
negative inotropy 
• 
vasodilation 
• 
negative and toxic cerebral effects  
 
Effects on Respiratory Muscles and Respiratory Infections 
• 
Disuse atrophy of the diaphragm 
• 
Limb muscle weakness 
• 
Diaphragm dysfunction 
• 
Ventilation-acquired pneumonia 
• 
Microaspiration 
 
Ventilator-Induced Lung Injury  
• 
Severe inflammatory response 
• 
Barotrauma / Volutrauma 
 
Long-term Consequences  
• 
Impairment of physical, cognitive, and mental health  
• 
Cognitive impairment  
• 
Depressive symptoms 
 

 
 
 
 
 
 
 
 
 
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Anticipated device deficiencies from search for AE´s from clinical experience for data pertinent 
to INTELLiVENT-ASV 6 
The INTELLiVENT-ASV is a ventilation mode which can currently be installed on the following Hamilton 
Medical ventilators: HAMILTON-C1 (K181216), HAMILTON-C3 (K161450), HAMILTON-G5/S1 (K103803) 
and HAMILTON-C6 (510(k) submission under preparation). As this ventilation mode can only be used with 
the parent ventilators, the safety outcomes of INTELLiVENT-ASV may be reported as “ventilator related” 
in the publications. To answer this question, we contacted the corresponding authors/ senior authors of 
the publications (List of the publications in the Appendix-1 of Q18153), to ascertain the followings: 
• 
If there was any INTELLiVENT-ASV, related safety issues during the study. 
The responses from the corresponding authors/ senior authors were matched against the “main-
statement” of the publication and presented in the Table-below. 
Table 12: Responses from authors/seniors authors against the “mainstatement” 
No. 
Title  
Design 
and 
Methods 
Safety 
Cumulative 
duration 
of 
ventilation 
with 
INTELLiVENT-
ASV mode 
1 
Feasibility study on full closed-
loop 
control 
ventilation 
(IntelliVent-ASV) in ICU s with 
acute 
respiratory 
failure: 
a 
prospective 
observational 
comparative study. 
Arnal, JM., Garnero, A., Novonti, 
D. et al.  
 
Crit 
Care 
(2013) 
17: 
R196. 
https://doi.org/10.1186/cc12890 
 
Prospective, 
Observational 
Main 
statement: 
No 
safety issue occurred. 
Safety issues not-related 
to ventilation are as 
below: 
 
Event 
No. 
Pneumothorax 1 
Re-intubation 
2 
Deactivation 
of PEEP setting 
1 
Deactivation 
of FiO2 control 
1 
9408 hours 
2 
Safety and efficacy of a fully 
closed-loop control ventilation 
(IntelliVent-ASV®) in sedated ICU 
patients with acute respiratory 
failure: a prospective randomized 
crossover study 
Prospective, 
Randomized 
controlled trial 
Main statement: There 
were no safety issues 
requiring 
premature 
interruption 
of 
INTELLiVENT-ASV: 
 
100 hours 
 
6 Manufacturers Clinical Evaluation report including PMS, on file 

 
 
 
 
 
 
 
 
 
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No. 
Title  
Design 
and 
Methods 
Safety 
Cumulative 
duration 
of 
ventilation 
with 
INTELLiVENT-
ASV mode 
 
Arnal, JM., Wysocki, M., Novotni, 
D. et al.  
 
Intensive Care Med (2012) 38: 
781. 
https://doi.org/10.1007/s00134-
012-2548-6 
 
No events related to 
INTELLIVENT-ASV 
 
3 
Closed loop ventilation mode in 
intensive care unit: a randomized 
controlled clinical trial comparing 
the numbers of manual ventilator 
setting changes. 
Arnal JM, Garnero A, Novotni D,et 
al. 
 
Minerva 
Anestesiol. 
2018 
Jan;84(1):58-67.  
 
doi: 
10.23736/S0375-
9393.17.11963-2. 
Randomized 
controlled trial 
Main statement: There 
were no safety issues 
requiring 
premature 
interruption 
of 
INTELLiVENT-ASV group: 
 
No events related to 
INTELLIVENT-ASV 
 
In the control group, the 
following safety events 
occurred: 
 
Event 
No 
Hypercapnia 1 
Hypoxemia 
1 
4320 hours 
4 
Evaluation of fully automated 
ventilation: 
a 
randomized 
controlled study in post-cardiac 
surgery patients 
Lellouche F, Bouchard PA, Simard 
S, L'Her E, Wysocki M. 
 
doi: 10.1007/s00134-012-2799-2. 
Randomized 
controlled trial 
Main 
statement: 
No 
safety issue occurred. 
 
Event not related to 
ventilation: 
Event 
No 
Massive 
bleeding due 
to surgery 
1 
156 hours 
5 
Prospective 
Randomized 
Crossover Study of a New Closed-
Randomized 
controlled trial 
Main 
statement: 
No 
safety issue occurred. 
334 hours 

 
 
 
 
 
 
 
 
 
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No. 
Title  
Design 
and 
Methods 
Safety 
Cumulative 
duration 
of 
ventilation 
with 
INTELLiVENT-
ASV mode 
loop 
Control 
System 
Versus 
Pressure Support during weaning 
from Mechanical Ventilation 
 
Clavieras N, Wysocki M, Coisel Y, 
et al 
 
Anesthesiology. 
2013 
Sep;119(3):631-41.  
doi: 
10.1097/ALN.0b013e3182952608. 
No detailed info. 
 
6 
Closed-loop 
ventilation 
mode 
(lntelliVent-ASV) in intensive care 
unit: 
a 
randomized 
trial 
of 
ventilation delivered. 
 
Bialais E, Wittebole X, Vignaux L, et 
al, 
Minerva 
Anestesiol. 
2016 
Jun;82(6):657-68. 
Randomized 
controlled trial 
Main 
statement: 
No 
safety issue occurred. 
No detailed info 
5544 hours 
7 
Automated 
Weaning 
from 
Mechanical Ventilation after Off-
Pump Coronary Artery Bypass 
Grafting 
 
Fot EV, Izotova NN, Yudina AS, et 
al  
Front Med (Lausanne). 2017 Mar 
21;4:31. 
 doi: 
10.3389/fmed.2017.00031. 
eCollection 2017. 
Randomized 
controlled trial 
Main 
statement: 
No 
safety issue occurred. 
 
No events related to 
INTELLIVENT-ASV 
 
58 hours 
8 
A prospective comparison of the 
efficacy and safety of fully closed-
loop 
control 
ventilation 
(INTELLiVENT-ASV) 
with 
conventional 
ASV 
and 
SIMV 
modes 
Prospective, 
cross over 
Main 
statement: 
No 
safety issue occurred. 
 
The 
corresponding 
author confirmed that 
40 hours 

 
 
 
 
 
 
 
 
 
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No. 
Title  
Design 
and 
Methods 
Safety 
Cumulative 
duration 
of 
ventilation 
with 
INTELLiVENT-
ASV mode 
 
A Abutbul, S Sviri, V Zbedat, DM 
Linton, PV van Heerden 
 
Southern African Journal of Critical 
Care 2014;30(1):28-32. 
 
 DOI:10.7196/SAJCC.197 
there were no ventilator 
related safety issues. 
9 
Fully 
automated 
closed-loop 
ventilation is safe and effective in 
post-cardiac surgery patients 
(Letter to the Editor) 
Beijers, A.J.R., Roos, A.N. & 
Bindels, A.J.G.H.  
 
Intensive Care Med (2014) 40: 
752. 
https://doi.org/10.1007/s00134-
014-3234-7 
Prospective, 
Non-inferiority  
Main 
statement: 
No 
safety issue occurred. 
 
The 
corresponding 
author confirmed that 
there were no ventilator 
related safety issues. 
10,330 hours 
10 
Airway 
and 
trans-pulmonary 
driving pressures and mechanical 
powers selected by INTELLiVENT-
ASV in passive, mechanically 
ventilated ICU patients. 
Submitted in 2019 
Observational 
Main 
statement: 
No 
safety issue occurred. 
 
The 
corresponding 
author confirmed that 
there were no ventilator 
related safety issues. 
255 hours 
11 
A randomized controlled trial 
comparing 
full 
closed 
loop 
controlled ventilation (IntelliVent- 
ASV™) 
with 
conventional 
ventilation in intubated COPD 
subjects (interim analysis results) 
 
38th International Symposium on 
Intensive care and Emergency 
medicine (ISICEM) 
Randomized 
controlled trial 
Main 
statement: 
No 
safety issue occurred. 
 
The 
corresponding 
author confirmed that 
there were no ventilator 
related safety issues. 
 
Event not related to 
ventilation: 
2709 hours 

 
 
 
 
 
 
 
 
 
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No. 
Title  
Design 
and 
Methods 
Safety 
Cumulative 
duration 
of 
ventilation 
with 
INTELLiVENT-
ASV mode 
Event 
No 
Hypotension(due 
to hypovolemia) 
4 
Re-intubation 
8 
 
In the identified literature, there was no occurrence of adverse events, which were associated with the 
device in question (INTELLiVENT-ASV).  
 
This also corresponds with the state of the art for mechanical ventilation: The subject population for which 
the device is intended, is a critically ill population and adverse events expected are mostly associated to 
the underlying disease. Their occurrence is high and ventilator-specific adverse events overlap with the 
expected underlying diseases and adverse events during the ICU-stay. 
Anticipated device deficiencies from search for AE´s from Vigilance databases and complaints 
for INTELLiVENT-ASV 
The INTELLIVENT-ASV ventilation mode was launched in the year 2010. Since then more than 4000 
INTELLiVENT-ASV software accessories have been sold worldwide. 
 
The table below has all INTELLIVENT-ASV sold as a software accessory worldwide.  
Region 
INTELLiVENT-ASV software accessory 
Asia-Pacific 
577 
Europe 
2190 
Indian Subcontinent 
24 
Latin America 
267 
The Middle East and Africa (MEA) 
518 
Total 
3576 
 
Until now, there has been no reported problems, events, serious adverse events or recalls due to the 
INTELLiVENT-ASV accessory software on HAMILTON ventilators. The vigilance database searches for 
Bfarm (the German database and the largest European database for medical device adverse event 

 
 
 
 
 
 
 
 
 
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reporting) did not yield any events, reported problems, serious adverse events due to or related to 
INTELLiVENT-ASV. 
 
Anticipated device deficiencies from risk management activities of the manufacturer:  
Anticipated Serious adverse device effect which by its nature, incidence, severity or outcome has been 
identified in the current version of the risk analysis report 
• 
User errors such as false settings, wrong subject’s conditions and offset setting 
• 
Delayed detection of the change of the status of the subject 
• 
Incorrect SpO2 measurement 
• 
Incorrect CO2 measurement 
• 
Too low signal quality 
• 
Wrong sensor values 
• 
Subject ventilated with the wrong target range 
• 
PEEP too high 
• 
Controller dysfunction 
• 
Target shifts for SpO2 or FiO2  
• 
Too early extubation based on only ventilatory parameters 
• 
User thinks he is in automatic mode but is in manual mode 
• 
controller dysfunction 
• 
Trigger too sensitive leading to false (auto) triggering 

 
 
 
 
 
 
 
 
 
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Annex B: Summary of clinical studies using INTELLiVENT-ASV 
 
Table 13: published studies on IV-ASV. 
Study 
Study 
Design  
Compa-
rator  
Clinical 
and 
respiratory 
condition 
# 
of 
subjects1 
Time-
frame 
Cummulative 
Time (h)1 
Outcome 
measure 
Safety 
Efficacy 
Workload, 
user 
interface 
Outcome 
Arnal, 
2012 
RCT, 
Cross-
Over 
ASV 
mixed subjects 
sedated, 
passive 
(60% 
ARDS) 
50 
2 x 2 hours 
100 
safety, 
efficacy 
Need 
to 
interrupt 
IV-
ASV2 
Ventilatory 
automatic 
setting 
required 
to 
reach 
the 
targets 
- 
IV-ASV was safe 
and able set less 
pressure, 
volume 
and FiO2 
Clavieras, 
2013 
RCT, 
Cross-
Over 
PS 
mixed subjects 
spontaneous 
"weaning"  
14 
2 
x 
24 
hours 
336 
efficacy, 
respiratory 
variability, 
safety 
Time-spent in 
“acceptable” 
ventilation: RR 
12-35 
breaths/min, 
VT 5-12 ml/kg 
of 
PBW, 
PetCO2<55 
mmHg 
Oxygenation: 
PaO2/FiO2; 
ventilatory 
variability 
Sedation 
scores, 
number of 
automatic 
and manual 
setting 
changes 
IV-ASV 
improved 
PaO2/FiO2 
with 
more 
setting 
changes 
Arnal, 
2013  
Prospe-
ctive, 
observa-
tional 
- 
mixed subjects, 
45 normal, 16 
ARDS, 19 COPD 
100 
<24h 
intubation 
until 
extubation 
9400 
safety 
Need 
to 
interrupt 
IV-
ASV3 
- 
- 
IV-ASV was safe. 
Settings 
were 
different according 
to 
the 
lung 
condition 
Lellouche, 
2013 
RCT, 
Parallel 
Groups 
CMV, 
then PS 
postoperative 
(cardiac 
surgery under 
CPB) 
30 
Post-
operative 
until “fast-
track” 
extubation 
100 
safety, 
efficacy 
Time-spent in 
“Not 
acceptable” 
range4 
Time-spent in 
“Optimal” 
zone3 
Number of 
manual 
ventilatory 
setting 
changes 
IV-ASV maintained 
a predefined target 
range of optimal 
ventilation 
and 
reduced 
the 
number 
of 
interventions 

 
 
 
 
 
 
 
 
 
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Bialais, 
2016 
RCT, 
Parallel 
Groups 
PACV, 
then PS 
mixed subjects, 
22 normal, 11 
ARDS, 1 COPD, 
5 brain injury 
42 
2 
x 
48 
hours 
2016 
safety, 
efficacy and 
workload 
Time-spent in 
“Non-optimal” 
zone according 
to 
clinical 
condition5 
Time-spent in 
“Optimal” 
zone 
according to 
clinical 
condition5 
Number of 
manual 
ventilatory 
setting 
changes 
and ABG 
IV-ASV 
provided 
more often optimal 
parameters 
and 
reduced 
the 
workload 
Fot, 2017 
RCT, 
Parallel 
Groups 
SIMV, 
then PS 
postoperative 
(off-pump 
cardiac 
surgery) 
18 
postop 
until “fast-
track” 
extubation 
60 
duration of 
MV, 
safety 
and 
workload 
Time-spent in 
“Safety” zone: 
RR 
10-30 
breaths/min, 
VT 6-10 ml/kg 
of 
PBW, 
PetCO2 25-45 
mmHg, 
SpO2>90%, 
Ppeak<35 
cmH2O 
Absence 
of 
respiratory 
complications 
Duration 
of 
postoperative 
ventilation 
Number of 
manual 
ventilatory 
setting 
changes 
IV-ASV provided a 
protective 
mechanical 
ventilation 
and 
reduces 
the 
workload without 
prolonging 
the 
duration 
of 
mechanical 
ventilation 
Anan'ev, 
2017 
RCT, 
Cross-
Over 
P-CMV 
TBI 
under 
controlled 
ventilation 
12 
2 
x 
12 
hours 
72 
PaCO2 
range, safety 
Similar to 2 
PaCO2 range 
Number of 
manual 
ventilatory 
setting 
changes 
IV-ASV 
may 
be 
more effective in 
maintaining 
a 
PaCO2 target with 
fewer 
manual 
adjustment 
of 
ventilation 
parameters  
Arnal, 
2018 
RCT, 
Parallel 
Groups 
ACV, 
then PS 
mixed subjects, 
9 
normal, 
8 
ARDS, 3 COPD 
30 
<24h 
intubation 
until 
extubation 
3168 
workload, 
acceptance 
- 
- 
Manual 
ventilatory 
settings, 
ABG, 
sedation 
dose 
and 
user 
acceptance 
IV-ASV reduced the 
number of manual 
and was easier to 
use 
for 
the 
caregivers 

 
 
 
 
 
 
 
 
 
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Arnal, 
2019  
Prospe-
ctive, 
observa-
tional 
 
mixed subjects, 
98 normal, 129 
ARDS, 28 COPD 
255 
<48h 
intubation  
- 
Driving 
pressure, 
mechanical 
power (DP, 
MP) 
 
 
 
IV-ASV 
selected 
safe ranges of DP et 
MP. 
In 
ARDS 
subjects, lung DP 
and MP were also 
safe 
De 
Bie, 
2020 
RCT, 
Parallel 
Groups 
P-CMV, 
then PS 
postoperative 
(uncomplicated 
cardiac surgery 
220 
3h 
330h 
Time spent 
(and 
# 
of 
breaths) 
in 
“optimal” 
and 
“acceptable” 
safety zones.  
Time spent in 
“critical” zone, 
re-intubation, 
postoperative 
pulmonary 
complications 
Time 
to 
spontaneous 
breathing, 
duration 
of 
mechanical 
ventilation 
- 
IV-ASV 
optimised 
lung 
protective 
ventilation during 
postoperative 
ventilation, 
with 
fewer episodes of 
severe hypoxaemia 
and an accelerated 
resumption 
of 
spontaneous 
breathing 
 
 
 
 
 
 
 
 
 
 
 
 
Notes of Table 1: 
RCT: randomized controlled trial, ASV: Adaptive Support Ventilation, PSV: Pressure Support Ventilation, CMV: Continuous Mandatory Ventilation, PACV: Pressure 
Assist-Control Ventilation, SIMV: Synchronized Intermittent Mandatory Ventilation, P-CMV: Pressure (controlled)-Continuous Mandatory Ventilation, ACV: 
Assist-Control Ventilation, CPB: cardio-pulmonary bypass, ARDS: Acute Respiratory Distress Syndrome, COPD: Chronic Obstructive Pulmonary Disease, TBI: 
traumatic brain injury. 
1: receiving IntelliVent-ASV ventilation. 
 
2: “Need to interrupt IV-ASV if one of the conditions below present for > 120 seconds:  
 SpO2 <85 % for if VT > 12 mL/kg PBW. 
 
3: “Need to interrupt IV-ASV if one of the conditions below present for > 30 seconds: 
• 
Pplat > 35 cmH2O,  
• 
Vt > 10 mL/kg (12 mL/Kg for COPD),  
• 
RR > 35 breath/min (passive subjects) or RR > 40 breath/min (active subjects).  
• 
The oxygenation controller was deactivated if SpO2 was below 85% for more than 1 minute. Severe respiratory acidosis with pHa < 7.20. 
 

 
 
 
 
 
 
 
 
 
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4: “Not acceptable” or “Acceptable” (i.e., not “Optimal”) if lasting more than 30 s 
 
 
Optimal 
Acceptable 
Not acceptable 
Vt (ml/kg PBW) 
6-10 
>10-12 
>12 
PetCO2 (mmHg) 
30-45 
<30-25 or >45-50 
<25 or >51 
Pplat (cmH2O) 
<30 
31-35 
>35 
SpO2 (%) 
94-98 (>94 if FiO2<40%) 
93-85 
<85 
 
5: “Non optimal” or “Optimal” zones according to clinical condition 
 
 
Lung condition 
Non optimal 
Optimal 
Vt (mL/kg IBW) 
Normal lung / ARDS 
Brain injury 
Chronic hypercapnia 
<3 or >12 
<3 or >12 
<3 or >12 
6-10 
6-10 
7-10 
RR (breath/min) 
Normal lung / ARDS 
Brain injury 
Chronic hypercapnia 
<10 or >30 
<10 or >35 
<10 or >35 
12-30 
15-35 
15-35 
Pmax (cmH2O) 
Normal lung / ARDS 
Brain injury 
Chronic hypercapnia 
>30 
>30 
>30 
6-25 
6-25 
6-25 
SpO2 (%) 
Normal lung / ARDS 
 
Brain injury 
Chronic hypercapnia 
<90 
 
<90 
<83 
92-96, or >96 if PEEP<8 cmH2O 
and FIO2<40% 
95-99 
88-94, or >94 if PEEP<8 cmH2O 
and FIO2<40% 
PetCO2 (mmHg) 
Normal lung / ARDS 
Brain injury 
Chronic hypercapnia 
>55 
>26 or >43 
<30 or >65 
25-45 
30-33 
40-50 
 
All studies are monocentric. Subjects recruitment consisted of adult critically ill subjects suffering from respiratory failure requiring invasive 
mechanical ventilation. There are 2 studies on subjects after cardiac surgery in a “fast-track” extubation procedure and 1 study on subjects 
suffering from traumatic brain injury with intracranial pressure monitoring, were the control of PaCO2 is a key aspect of management. In all other 
studies, a mixed population of adult ICU subjects was examined.

 
 
 
 
 
 
 
 
 
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Annex C: INTELLiVENT-ASV Investigational Device Study Training Concept  
Rationale:  
During the study, clinicians at study centers will have to manage subjects included in the INTELLiVENT- ASV 
group. These subjects will be ventilated over several days. The aim of the clinician training prior to the 
initiation of the study is to ensure that users have a full understanding of the INTELLiVENT -ASV mode in 
order to use it safely and efficiently. 
Participants: 
Clinicians interacting with the ventilator in an ICU. Within this document clinician refers to the physician, 
respiratory care practitioner (RCP), and the nurse. All clinicians will be trained at a different level according 
to their involvement in mechanical ventilation. 
Training process: 
The training is divided in basic and advanced modules which consists of e-learning, frontal lectures, 
practical training on a simulator, and bedside training. 
Basic Training:  
The learning objectives are to manage sensors, to understand the ventilation controller, oxygenation 
controller, ASV controller and weaning tool, and to understand the alarms. 
E-learning Module: Participants will be encouraged to use the e-learning modules provided by 
Hamilton Medical: 
- 
ASV module  
- 
Introduction to INTELLiVENT-ASV 
- 
Basic operation of INTELLiVENT-ASV on G5  
Frontal Lectures: A dedicated training session with frontal lectures will be provided covering the 
following topics, if needed: 
- 
ASV and INTELLiVENT-ASV – Basic principles 
- 
Weaning tool 
- 
Sensor management 
- 
Alarm management 
- 
INTELLiVENT-ASV – Monitoring 
Subject Simulator: A practical training using subject simulator will be provided. 
Hamilton Medical developed a physiological model simulating real subject cases / scenarios that interact 
with the ventilator settings. The simulator (VirtuVent) is integrated directly in the Hamilton Medical G5 
and S1 ventilator. 
Participants will work on different scenarios: 

 
 
 
 
 
 
 
 
 
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- 
VirtuVent introduction 
- 
How to set up the ventilator, sensors and initiate INTELLiVENT-ASV 
- 
Monitoring of INTELLiVENT-ASV 
- 
Alarm settings in INTELLiVENT-ASV 
- 
Troubleshooting INTELLiVENT-ASV 
The basic Theoretical and Practical Training program will finish with a test which has to be passed by each 
participant. This will be a web-based test of 20 questions with a pre-defined minimal passing score of 75%. 
Advanced Theoretical and Practical Training:  
The learning objectives are to be able to initiate INTELLiVENT-ASV, adjust the settings, monitor subjects 
and deal with the most frequent clinical situations / subject types.  
E-learning Module: Participants will use the e-learning modules provided by Hamilton Medical: 
- 
ASV module  
- 
Introduction to INTELLiVENT-ASV 
- 
Basic operation of INTELLiVENT-ASV on G5  
Each e-learning module will finish with a test. Each participant will be required to pass this test. 75% 
of good answer will be required to pass the test 
Frontal Lectures: A dedicated training session with frontal lectures will be provided: 
- 
ASV and INTELLiVENT-ASV – Basic principles 
- 
Respiratory mechanics 
- 
ASV controller 
- 
Ventilation controller 
- 
Oxygenation controller 
- 
Quick wean function 
- 
How to use INTELLiVENT-ASV in brain injured subjects, ARDS, and COPD subjects 
- 
Frequently asked questions and troubleshooting 
Subject Simulator: A practical training using subject simulator will be provided. 
Hamilton Medical developed a physiological model simulating real subject cases / scenarios that interact 
with the ventilator settings. The simulator (VirtuVent) is integrated directly in the Hamilton Medical G5 
and S1 ventilator. 
Participants will work on different scenarios: 
- 
VirtuVent introduction 
- 
How to set up the ventilator, sensors and initiate INTELLiVENT-ASV 
- 
Monitoring INTELLiVENT-ASV 
- 
Setting adjustments 
- 
Quick wean setting and monitoring 
 

 
 
 
 
 
 
 
 
 
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- 
Alarm settings and management 
- 
INTELLiVENT-ASV for Normal lung subject / Post cardiac surgery subject, brain injury, ARDS, and 
COPD subjects 
- 
Troubleshooting INTELLiVENT-ASV 
The Advanced Theoretical and Practical Training program will finish with a test which has to be passed by 
each participant. This will be a web-based test of several questions with a pre-defined minimal passing 
score of 75%. 
 
Bedside training (in US this phase of the training will start after obtaining the IDE): As the final 
phase of practical training participants will manage real subjects using INTELLiVENT-ASV in order 
to gain bedside practice under guidance of a trained INTELLiVENT-ASV instructor. Participants 
will have to manage different types of subjects covering: 
- 
Passive subject with normal lung 
- 
Passive subject with brain injury 
- 
Passive subject with ARDS 
- 
COPD subject 
- 
Spontaneously breathing subjects 
- 
Subjects during the weaning phase 
The number of subjects needed to acquire sufficient expertise will depend on the number of ICU beds, 
size of the clinical staff, and on the type of subjects ventilated in the ICU. This number will be adjusted to 
each individual study site and staff.  
At sites who have had previous experience ventilating with INTELLiVENT-ASV, may have the training 
program partially or completely waived. This will be the case especially for sites outside of the US. 
Remark: Subjects ventilated during the practical training phase will be monitored for safety events but 
will not be taken into consideration for the study outcome and statistics. 
 
 

 
 
 
 
 
 
 
 
 
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Annex D: List of Adverse Event  
List if Adverse Event that should be recorded by the investigational sites in the EASiVENT Study.  
Version 1.0 and it subsequent amendment, by reference only.  
 
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