A Phase 3, Multicenter, Randomized, Controlled, Open Label, Assessor-Blinded Study to Evaluate the Efficacy and Safety of Inhaled Isoflurane Delivered Via the Sedaconda ACD-S Compared to Intravenous Propofol for Sedation of Mechanically Ventilated Intensive Care Unit Adult Patients (INSPiRE-ICU2)
Phase: PHASE3
Conditions: Sedation
Sponsor: Sedana Medical

 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 3, Multicenter, Randomized, Controlled, Open-Label, 
Assessor-Blinded Study to Evaluate the Efficacy and Safety of 
Inhaled Isoflurane Delivered via the Sedaconda ACD-S Compared 
to Intravenous Propofol for Sedation of Mechanically Ventilated 
Intensive Care Unit Adult Patients (INSPiRE-ICU2) 
Investigational Product: Isoflurane delivered via the Sedaconda ACD-S 
Protocol Number: SED004 
Investigational New Drug Application Number: 
 
 
 
Sponsor: 
Sedana Medical AB 
Vendevägen 89 
SE-182 32, Danderyd 
Sweden 
Telephone: +46(0)8-124 05 200 
 
Original Protocol (Version 1.0): 31 January 2022 
Amendment 1 (Version 2.0): 09 February 2022 
Amendment 2 (Version 3.0): 31 March 2022 
Amendment 3 (Version 4.0): 08 June 2023 
Amendment 4 (Version 5.0): 22 June 2023 
Amendment 5 (Version 6.0): 06 October 2023 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Sedana Medical AB except to the extent that disclosure would be required by law and 
for the purpose of evaluating and/or conducting a clinical study for Sedana Medical AB. You are 
allowed to disclose the contents of this document only to your Institutional Review Board and 
study personnel directly involved with conducting this protocol. Persons to whom the 
information is disclosed must be informed that the information is confidential and proprietary to 
Sedana Medical AB and that it may not be further disclosed to third parties. 

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Sedana Medical AB 
Clinical Study Protocol SED004 (INSPiRE-ICU2) 
Confidential & Proprietary 
Page 3 of 124 
Version 6.0, 06 October 2023 
INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Sedana Medical AB to study personnel under my supervision. I will discuss this material with 
them to ensure they are fully informed about the study product and study procedures. I will let 
them know that this information is confidential and proprietary to Sedana Medical AB and that it 
may not be further disclosed to third parties. I understand that the study may be terminated or 
enrollment suspended at any time by Sedana Medical AB, with or without cause, or by me if it 
becomes necessary to protect the best interests of the study patients. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board Regulations, and International Council for Harmonisation Guidelines 
for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 

Sedana Medical AB 
Clinical Study Protocol SED004 (INSPiRE-ICU2) 
Confidential & Proprietary 
Page 4 of 124 
Version 6.0, 06 October 2023 
SYNOPSIS 
TITLE:  A Phase 3, Multicenter, Randomized, Controlled, Open-Label, Assessor-Blinded Study 
to Evaluate the Efficacy and Safety of Inhaled Isoflurane Delivered via the Sedaconda ACD-S 
Compared to Intravenous Propofol for Sedation of Mechanically Ventilated Intensive Care Unit 
Adult Patients (INSPiRE-ICU2) 
PROTOCOL NUMBER:  SED004 
INVESTIGATIONAL PRODUCT:  Isoflurane delivered via the Sedaconda Anaesthetic 
Conserving Device - S (Sedaconda ACD-S) 
PHASE:  3 
INDICATION:  Sedation of mechanically ventilated patients in the intensive care unit (ICU)  
OBJECTIVES AND ENDPOINTS: 
Objectives 
Endpoints 
Primary 
To compare the percentage of time sedation depth is 
maintained within the target range, in absence of rescue 
sedation, as assessed according to the RASS scale, in 
isoflurane- vs propofol-treated patients 
The percentage of time sedation depth is maintained within 
the prescribed RASS interval through end of study drug 
treatment  
Key secondary 
1. 
To compare the effect of isoflurane vs propofol on use of 
opioids during the study drug treatment period 
Change in mean fentanyl-equivalent opioid dose during the 
study drug treatment period compared to mean opioid dose 
during the 60 minutes prior to randomization  
2. 
To compare the effect of isoflurane vs propofol on the 
wake up time at end of study drug treatment 
Time from stop of study drug treatment to RASS 0, up to 
4 hours 
3. 
To compare the effect of isoflurane vs propofol on 
cognitive recovery after EOT 
Delirium by CAM-ICU-7 assessments 60 minutes 
(10 minutes) after EOT in patients not re-sedated with 
benzodiazepine or propofol infusions 
4. 
To compare the effect of isoflurane vs propofol on 
spontaneous breathing effort during the study drug 
treatment period 
Proportion of ventilator parameter observations with 
spontaneous breathing efforts during the study drug 
treatment period 
Other secondary 
To compare the effect of isoflurane vs propofol on time from 
sedation termination to extubation in patients for whom study 
drug is terminated for extubation 
Time from EOT to extubation if study drug is terminated 
for extubation 
To compare the effect of isoflurane vs propofol on days alive 
and free of mechanical ventilation through Study Day 30 
Days alive and free of mechanical ventilation1 through 
Study Day 30 
To compare the effect of isoflurane vs propofol on days alive 
and free of the ICU 
Days alive and free of the ICU2 through Study Day 30 
To compare the effect of isoflurane vs propofol on delirium 
and coma free days until 7 days after EOT 
Delirium and coma free days from start of study drug until 
7 days after EOT, as assessed with CAM-ICU-7 and RASS 
To compare the effect of isoflurane vs propofol on mortality at 
30 days after randomization 
Mortality rate at 30 days after randomization 
To compare the effect of isoflurane vs propofol on mortality at 
3 months after randomization 
Mortality rate at 3 months after randomization 
 

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Clinical Study Protocol SED004 (INSPiRE-ICU2) 
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Version 6.0, 06 October 2023 
Objectives 
Endpoints 
Other secondary (Continued) 
To compare the effect of isoflurane vs propofol on mortality at 
6 months after randomization 
Mortality rate at 6 months after randomization 
To compare the safety of isoflurane vs propofol 
AEs, clinical laboratory assessments, vital signs, physical 
examination, blood gases, organ function, and ventilator 
parameters 
To assess Sedaconda ACD-S device deficiencies in patients 
receiving isoflurane 
Frequency and type of Sedaconda ACD-S device 
deficiencies in patients receiving isoflurane 
To compare the use of restraints in patients receiving 
isoflurane vs propofol 
Proportion of patients using restraint during the study drug 
treatment period 
Exploratory 
To assess isoflurane dose over time 
 
Isoflurane dose in mL/hour;  
 
Isoflurane dose in mL/hour/L minute ventilation; and 
 
End-tidal isoflurane concentration every 4 hours. 
To compare the effect of isoflurane vs propofol on major ICU 
interventions through Study Day 30 or until ICU discharge, 
whichever comes first 
Need for:  
 
Renal replacement therapy; 
 
ECLS; 
 
Tracheostomy; and 
 
Non-invasive ventilation. 
To compare the effect of isoflurane vs propofol on level of 
care up to 30 days after randomization 
Level of care:  
 
Patient deceased; 
 
Still in ICU; 
 
Intermediary care unit; 
 
General ward; 
 
Another ICU (within or outside the hospital); 
 
Another hospital (unknown ward);  
 
Rehabilitation unit; 
 
Nursing home; 
 
Hospice; and 
 
Home. 
To assess the end-tidal isoflurane concentration and relation to 
RASS scores 
End-tidal isoflurane concentration over time and relation to 
RASS scores 
To compare oxygenation (PaO2/FiO2) over time during the 
study drug treatment period, in patients with ARDS/AHRF, in 
isoflurane vs propofol-treated patients 
Oxygenation (PaO2/FiO2) in patients with ARDS/AHRF 
over time during the study drug treatment period  
To compare memory panorama from time in the ICU in 
isoflurane- vs propofol-treated patients 
Number of factual memories, memories of feelings, or 
delusional memories, as assessed by the ICU Memory Tool, 
collected at 3 months follow-up 
To compare physical outcomes at 3 and 6 months 
post-randomization in isoflurane- vs propofol-treated patients 
Activities of daily living, as assessed by the Katz ADL and 
Pfeffer FAQ, at 3 and 6 months post-randomization 
To compare psychological outcomes at 3 and 6 months 
post-randomization in isoflurane- vs propofol-treated patients 
Depression, anxiety, and post-traumatic stress symptoms, as 
assessed by IES-R and PROMIS Depression and Anxiety 
questionnaires, at 3 and 6 months post-randomization 
To compare cognitive function 3 and 6 months 
post-randomization in isoflurane- vs propofol-treated patients 
Cognitive function, as assessed by TICS, WAIS IV-Digit 
Span, Hayling Sentence Completion Test, Controlled Oral 
Word Association, WMS-IV – Immediate Memory 
(Adult/Older Adult), WMS-IV – Delayed Memory 
(Adult/Older Adult), and PROMIS Cognitive Function 
questionnaire, at 3 and 6 months post-randomization 
To compare quality of life at 3 and 6 months 
post-randomization in isoflurane- vs propofol-treated patients 
Quality of life at 3 and 6 months post-randomization, as 
assessed by WHODAS 2.0 and BPI 
To compare the need for rescue, other sedatives, and 
antipsychotics in isoflurane- vs propofol-treated patients 
Use of rescue sedatives, other sedatives, and antipsychotics 
from randomization to EOT 
To compare the hemodynamic instability in isoflurane- vs 
propofol-treated patients  
Change from Baseline in highest daily vasoactive drug 
requirements during study drug treatment 
 

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Clinical Study Protocol SED004 (INSPiRE-ICU2) 
Confidential & Proprietary 
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Objectives 
Endpoints 
Exploratory (Continued) 
To compare duration of mechanical ventilation in 
isoflurane- vs propofol-treated patients 
Duration of mechanical ventilation 
To compare ICU length of stay in isoflurane- vs 
propofol-treated patients 
ICU length of stay 
To compare minute ventilation in isoflurane- vs 
propofol-treated patients 
Change in minute ventilation every 8 hours during the study 
drug treatment period 
1. 
For Days alive and free of mechanical ventilation, only invasive ventilation will be taken into account. Successful 
ventilator discontinuation is defined as being alive and free of ventilation for 48 hours (inclusive) following 
discontinuation. For example, if a patient was discontinued from mechanical ventilator and ventilation was initiated again 
within the next 48 hours or the patient died within the next 48 hours, then the time (less than 48 hours) that was off 
ventilation did not count as Days alive and free of mechanical ventilation. 
2. 
The Days alive and free of the ICU is defined similarly to the Days alive and free of mechanical ventilation. Successful 
ICU discharge is defined as being alive and out of ICU for 48 hours (inclusive) following discharge.  
AE = adverse event; AHRF = acute hypoxemic respiratory failure; ARDS = acute respiratory distress syndrome; BPI = Brief 
Pain Inventory; CAM-ICU-7 = 7-point scale of the Confusion Assessment Method for the Intensive Care 
Unit; ECLS = extracorporeal life support; EOT = end of treatment; FAQ = functional activities questionnaire; FiO2 = fraction 
of inspired oxygen; ICU = intensive care unit; IES-R = impact of event scale; Katz ADL = Katz Index of Independence in 
Activity of Daily Living; PaO2 = partial pressure of oxygen; PROMIS = Patient-Reported Outcomes Measurement Information 
System; RASS = Richmond Agitation Sedation Scale; Sedaconda ACD-S = Sedaconda Anaesthetic Conserving Device - S; 
SOC = standard of care; TICS = Telephone Interview for Cognitive Status; vs = versus; WAIS = Wechsler adult intelligence 
scale; WHODAS 2.0 = World Health Organization Disability Assessment Schedule 2.0; WMS = Wechsler memory scale. 
 
POPULATION: 
Inclusion Criteria 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Adults 18 years of age; 
2. Patients who are anticipated to require >12 hours of invasive mechanical ventilation and 
continuous sedation in the ICU; and 
3. Receipt of continuous sedation due to clinical need for sedation to Richmond Agitation 
Sedation Scale (RASS) <0. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Need for RASS -5; 
2. Sedation for invasive mechanical ventilation immediately prior to Baseline for >72 hours 
(patients who have been extubated for at least 24 hours and subsequently re-intubated will 
have sedation for invasive mechanical ventilation starting from when they were re-intubated); 
3. Severe neurological condition that causes the patient to lack ability to participate in the study 
(ie, unable to be assessed for RASS and Critical Care Pain Observation Tool), including, but 
not restricted to, patients with acute stroke, severe head trauma, meningitis, suspected of 
having elevated intracranial pressure (ICP), or the need for ICP monitoring; 
4. Ventilator tidal volume <200 or >1000 mL at Baseline; 
5. Need for extracorporeal membrane oxygenation, extracorporeal carbon dioxide removal, high 
frequency oscillation ventilation, or high frequency percussive ventilation at Screening; 
6. Comfort care only (end of life care); 

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Clinical Study Protocol SED004 (INSPiRE-ICU2) 
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7. Contraindication to propofol or isoflurane, including: 
a. Known or suspected personal or family history of malignant hyperthermia (MH) or high 
risk for MH or acute drug-induced muscle injury (eg, muscular dystrophies);  
b. Severe hemodynamic compromise, defined as the need for norepinephrine 
0.3 mcg/kg/min (or equivalent vasopressor dose) to maintain blood pressure within 
acceptable range, assumed to be mean arterial pressure 65 mmHg unless prescribed 
clinically; or 
c. Allergy to isoflurane or propofol, or have propofol infusion syndrome. 
8. History of ventricular tachycardia/Long QT Syndrome; 
9. Requirement of intravenous (IV) benzodiazepine or barbiturate administration for seizures or 
dependencies, including alcohol withdrawal; 
10. Neuromuscular disease that impairs spontaneous ventilation (eg, C5 or higher spinal cord 
injury, amyotrophic lateral sclerosis, etc);  
11. Concurrent enrollment in another study that, in the Investigator’s opinion, would impact the 
patient’s safety or assessments of this study; 
12. Participation in other study involving investigational drug(s) or devices(s) within 30 days prior 
to randomization; 
13. Previous randomization or receipt of treatment in this study or in SED003; 
14. Anticipated requirement of treatment with continuous infusion of a neuromuscular blocking 
agent for >4 hours; 
15. Female patients who are pregnant or breast-feeding; 
16. Imperative need for continuous active humidification through mechanical ventilation circuit; 
17. Attending physician’s refusal to include the patient; or 
18. Inability to obtain informed consent. 
STUDY DESIGN AND DURATION: 
This is a therapeutic confirmatory (Phase 3), multicenter, randomized, controlled, open-label, 
assessor-blinded study. Approximately 235 patients receiving mechanical ventilation and 
requiring continuous sedation at approximately 15 to 20 sites in the United States (US) will be 
randomized in a 1.5:1 ratio to inhaled isoflurane (administered via the Sedaconda ACD-S device) 
or propofol (administered via IV infusion) for sedation, respectively. In addition, approximately 
3 to 5 run-in training patients per site will be enrolled. The treatment duration in this study is 
expected to be at least 12 hours and may last up to 48 (6) hours or to the time for extubation, 
whichever occurs first, with a follow-up period of 6 months. 
Patients eligible for the study will either have planned surgery with anticipated need for sedation 
and mechanical ventilation in the ICU (ie, postoperative patients) for >12 hours or have already 
been admitted to the ICU and anticipate needing sedation and mechanical ventilation for 
>12 hours.  

Sedana Medical AB 
Clinical Study Protocol SED004 (INSPiRE-ICU2) 
Confidential & Proprietary 
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Informed consent must be obtained from the patient or patient’s legally authorized representative 
for all patients.  
The study will comprise the following key study periods: 
 Screening period: Day -30 to randomization; 
o Initial Screening: Day -30 to randomization;  
o Complete Screening: -24 hours to randomization;  
o Randomization; and 
o Baseline: Randomization to initiation of study drug treatment (up to 6 hours). 
 Treatment period: initiation of study drug administration to the end of treatment (EOT) (up to 
48 [6] hours); and 
 Follow-up period: EOT to 6 months (4 weeks) after randomization. 
o Post-treatment monitoring phase: until 24 hours after EOT; 
o 24 hours after EOT until 7 days after EOT: daily follow-up from the time of randomization 
until 7 days after EOT; 
o Follow-up: at Study Day 30 (+5 days) after randomization;  
o 3-month centralized telephone follow-up: 3 months (4 weeks) after randomization; and 
o 6-month centralized telephone follow-up: 6 months (4 weeks) after randomization. 
A schematic of the study flow is shown in Figure S1. 
Figure S1. Study Scheme 
CPOT = Critical Care Pain Observation Tool; D = day(s); EOT = end of treatment; h = hour(s); IV = intravenous; LAR = legally 
authorized representative; M = month; RASS = Richmond Agitation Sedation Scale; Sedaconda ACD-S = Sedaconda Anaesthetic 
Conserving Device - S; SOC = standard of care; W = week(s).  

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Clinical Study Protocol SED004 (INSPiRE-ICU2) 
Confidential & Proprietary 
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For training purposes in the use of Sedaconda ACD-S, approximately 3 to 5 patients at each site 
will be assigned to receive isoflurane via Sedaconda ACD-S in a non-blinded fashion, before any 
patients are randomized.  
An independent Data Safety Monitoring Board (DSMB) will be assembled to safeguard the safety 
of study patients per the DSMB Charter. This DSMB will serve jointly for both this study and the 
SED003 study, a confirmatory study identical to SED004. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Isoflurane for inhalation will be administered via the Sedaconda ACD-S device.  
Propofol will be administered via IV infusion. 
Study drug will be titrated and adjusted by the clinical team throughout the study drug treatment 
period according to the protocol-directed dose titration guide to achieve and maintain the desired 
sedation depth. 
STATISTICAL ANALYSES: 
All efficacy analyses will be performed using both the Intent-to-Treat (ITT) and the modified ITT 
Analysis Sets. Analysis of the ITT Analysis Set will be considered primary. The hypothesis test 
for the primary efficacy endpoint is a non-inferiority test. Hypothesis tests for the other efficacy 
endpoints are superiority tests. 
SAMPLE SIZE: 
A total of 235 randomized patients and approximately 3 to 5 run-in training patients per site will 
be enrolled in the study. 
SITES:  Approximately 15 to 20 sites in the US 
SPONSOR: 
Sedana Medical AB 
Vendevägen 89 
SE-182 32, Danderyd 
Sweden 
Telephone: +46(0)8-124 05 200 

Sedana Medical AB 
Clinical Study Protocol SED004 (INSPiRE-ICU2) 
Confidential & Proprietary 
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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 10 
List of Tables ................................................................................................................................ 16 
List of Figures ............................................................................................................................... 17 
List of Abbreviations and Definition of Terms............................................................................. 18 
1 
Introduction and Background Information ....................................................................... 21 
1.1 
Background ................................................................................................................... 21 
1.2 
Inhaled Isoflurane as an ICU Sedative .......................................................................... 22 
1.3 
The Sedaconda ACD-S ................................................................................................. 22 
1.4 
Sedana Medical Clinical Studies on Isoflurane and Sedaconda ACD .......................... 25 
1.5 
Rationale ........................................................................................................................ 26 
1.5.1  Study Rationale .............................................................................................. 26 
1.5.2  Study Design Rationale .................................................................................. 26 
  RASS target rationale ......................................................................... 26 
  Rationale for 48-hour study drug treatment period ............................. 27 
  Rationale for CAM-ICU-7 assessment 60 minutes post EOT ............ 27 
  Rationale for run-in training patients .................................................. 28 
  Rationale for adaptive expected exposure duration ............................ 28 
1.6 
Risk/Benefit ................................................................................................................... 29 
1.7 
The Coronavirus Disease .............................................................................................. 30 
2 
Study Objectives and Endpoints ....................................................................................... 31 
3 
Study Description.............................................................................................................. 33 
3.1 
Study Indication ............................................................................................................ 33 
3.2 
Summary of Study Design ............................................................................................ 33 
3.3 
Time Portion of Adequate Sedation Depth ................................................................... 35 
3.4 
SOC and ABCDEF Bundle ........................................................................................... 35 
3.5 
Run-In Training Patients ............................................................................................... 35 
3.6 
Randomization and Blinding ......................................................................................... 36 

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3.6.1  Stratified Randomization ................................................................................ 36 
3.6.2  Blinding .......................................................................................................... 36 
3.6.3  Blinded Assessment of RASS and CPOT ...................................................... 36 
3.6.4  Breaking the Blind .......................................................................................... 37 
3.7 
Reduction of SOC Sedatives and Opioids After Randomization .................................. 37 
3.8 
Study Drug Treatment ................................................................................................... 37 
3.9 
End of Treatment ........................................................................................................... 38 
3.10  Extubation ..................................................................................................................... 38 
3.11  Long-Term Outcomes Assessment ............................................................................... 38 
4 
Selection and Withdrawal of Patients ............................................................................... 40 
4.1 
Inclusion Criteria ........................................................................................................... 40 
4.2 
Exclusion Criteria .......................................................................................................... 40 
4.3 
Criteria for Early Study Drug Discontinuation ............................................................. 41 
4.4 
Criteria for Study Withdrawal ....................................................................................... 42 
5 
Study Treatments .............................................................................................................. 43 
5.1 
Drug and Device Supplies ............................................................................................. 43 
5.1.1  Formulation and Packaging ............................................................................ 43 
5.1.2  Storage and Accountability ............................................................................ 43 
5.1.3  Sedaconda ACD-S Supply, Storage, and Accountability ............................... 44 
5.2 
Study Drug Preparation and Dispensing ....................................................................... 44 
5.3 
Study Drug Dosing ........................................................................................................ 44 
5.3.1  Isoflurane Dosing ........................................................................................... 44 
5.3.2  Propofol Dosing ............................................................................................. 45 
5.3.3  Initiation of Study Drug Treatment ................................................................ 45 
5.3.4  Study Drug Treatment Maintenance .............................................................. 46 
5.3.5  Post-Study Drug Treatment ............................................................................ 47 
5.4 
Rescue Medication ........................................................................................................ 47 
5.4.1  Rescue Sedation and Treatment Failure ......................................................... 47 
  Per-protocol rescue sedation ............................................................... 47 
  Treatment failure ................................................................................. 48 
5.5 
Prohibited and Restricted Medications ......................................................................... 48 
5.5.1  Prohibited Medications ................................................................................... 48 

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5.5.2 
Restricted Medications ................................................................................. 49 
  Procedural sedation ............................................................................. 49 
5.5.3 
Restricted Procedures ................................................................................... 50 
5.5.4 
Analgesic Treatment .................................................................................... 50 
6 
Study Procedures .............................................................................................................. 52 
6.1 
Screening Period ......................................................................................................... 52 
6.1.1 
Screening (Day -30 to Randomization) ....................................................... 52 
  Initial Screening (Day -30 to randomization) ..................................... 52 
  Complete Screening (-24 hours to randomization) ............................. 53 
6.1.2 
Randomization ............................................................................................. 53 
6.1.3 
Baseline (Randomization to Initiation of Study Drug Treatment) ............... 54 
6.2 
Treatment Period ......................................................................................................... 54 
6.2.1 
Every 2 (0.5) Hours From Start of Study Drug ......................................... 55 
6.2.2 
Every 4 (0.5) Hours For Isoflurane Patients Only ..................................... 55 
6.2.3 
Every 8 (2) Hours ...................................................................................... 55 
6.2.4 
Daily ............................................................................................................. 55 
6.2.5 
Early Study Drug Discontinuation ............................................................... 56 
6.2.6 
End of Treatment ......................................................................................... 56 
6.3 
Follow-Up Period........................................................................................................ 56 
6.3.1 
Post-Treatment Monitoring .......................................................................... 56 
6.3.2 
Follow-Up Contact ....................................................................................... 57 
  Until Day 7 after EOT (2 days) ........................................................ 57 
  Study Day 30 (+5 days) after randomization ...................................... 57 
  3 months (4 weeks) – telephone call ................................................. 58 
  6 months (4 weeks) – telephone call ................................................. 58 
6.4 
Early Withdrawal From Study .................................................................................... 58 
6.4.1 
Study Withdrawal Prior to EOT................................................................... 58 
6.4.2 
Early Withdrawal After EOT ....................................................................... 58 
7 
Study Assessments ............................................................................................................ 60 
7.1 
Blinded Efficacy Assessments .................................................................................... 60 
7.1.1 
Richmond Agitation Sedation Scale ............................................................ 60 
7.1.2 
Critical Care Pain Observation Tool ............................................................ 61 

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7.1.3  Periods When Blinded RASS and CPOT Assessments Should Not Be 
Performed ....................................................................................................... 61 
7.1.4  Communication of Blinded RASS and CPOT to Bedside Staff .................... 61 
7.1.5  Handling of Interrupted and/or Missing RASS Assessments ........................ 61 
7.1.6  Wake-Up Test ................................................................................................. 62 
7.1.7  CAM-ICU-7 at 60 Minutes After EOT .......................................................... 63 
7.2 
Other Assessments ........................................................................................................ 63 
7.2.1  Prior and Concomitant Medications ............................................................... 63 
7.2.2  Non-Blinded RASS and CPOT ...................................................................... 65 
7.2.3  Non-Blinded CAM-ICU-7 ............................................................................. 65 
7.2.4  Spontaneous Breathing ................................................................................... 65 
7.2.5  Restraints ........................................................................................................ 65 
7.2.6  Organ Failure, SOFA ..................................................................................... 65 
7.2.7  Clinical Laboratory Evaluations ..................................................................... 65 
7.2.8  Physical Examinations ................................................................................... 66 
7.2.9  Pregnancy Test ............................................................................................... 66 
7.2.10  Vital Signs ...................................................................................................... 66 
7.2.11  Ventilator Parameters ..................................................................................... 67 
7.2.12  Blood Gas Analyses ....................................................................................... 68 
7.2.13  Major ICU Interventions ................................................................................ 68 
7.2.14  Level of Care .................................................................................................. 69 
7.2.15  Late Onset Drug-Induced Hepatitis ................................................................ 69 
7.3 
Long-Term Outcomes Assessment ............................................................................... 69 
7.3.1  Cognitive Long-Term Outcomes .................................................................... 69 
7.3.2  Physical Long-Term Outcomes ...................................................................... 70 
7.3.3  Psychological Long-Term Outcomes ............................................................. 71 
7.3.4  Long-Term Quality of Life Outcomes ........................................................... 71 
8 
Safety Assessments ........................................................................................................... 72 
8.1 
AEs ................................................................................................................................ 72 
8.1.1  Adverse (Drug) Reaction ................................................................................ 73 
8.1.2  Unexpected Adverse Drug Reaction .............................................................. 73 
8.1.3  Assessment of AEs by the Investigator .......................................................... 73 
8.1.4  AEs of Special Interest ................................................................................... 75 

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8.2 
SAEs .............................................................................................................................. 76 
8.3 
SAE Reporting − Procedures for Investigators ............................................................. 76 
8.4 
Pregnancy Reporting ..................................................................................................... 77 
8.5 
Expedited Reporting ...................................................................................................... 77 
8.6 
Special Situation Reporting Requirements Related to Study Drug ............................... 77 
8.7 
Sedaconda ACD-S Deficiencies Reporting ................................................................... 78 
8.7.1  Unresolved Sedaconda ACD-S Device-Related Issues .................................. 78 
8.8 
Data Safety Monitoring Board and Study Stopping Criteria ........................................ 78 
9 
Statistics ............................................................................................................................ 80 
9.1 
Analysis Populations ..................................................................................................... 80 
9.1.1  Intent-to-Treat Analysis Set ........................................................................... 80 
9.1.2  Modified Intent-to-Treat Analysis Set ........................................................... 80 
9.1.3  Per-Protocol Analysis Set ............................................................................... 80 
9.1.4  Safety Analysis Set ......................................................................................... 80 
9.2 
Statistical Methods ........................................................................................................ 80 
9.2.1  Analysis of Efficacy ....................................................................................... 81 
  Primary efficacy analysis .................................................................... 81 
  Secondary efficacy analysis ................................................................ 81 
  Other efficacy analysis ........................................................................ 81 
9.2.2  Analysis of Safety .......................................................................................... 82 
9.2.3  Interim Analysis ............................................................................................. 82 
9.2.4  Sample Size Determination ............................................................................ 82 
10 
Study Management ........................................................................................................... 84 
10.1  Clinical Monitoring ....................................................................................................... 84 
10.2  Audits and Inspections .................................................................................................. 84 
10.3  Training of Study Personnel .......................................................................................... 85 
10.4  Protocol Deviations ....................................................................................................... 85 
10.5  Study Timetable ............................................................................................................ 85 
10.6  Declaration of End of Study .......................................................................................... 85 
10.7  Study Reporting ............................................................................................................. 85 
10.8  Archiving ....................................................................................................................... 85 
10.9  Patient Confidentiality ................................................................................................... 86 

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10.10 Study Agreements ......................................................................................................... 86 
10.11 Publication ..................................................................................................................... 86 
11 
Data Management and Record Keeping ........................................................................... 88 
11.1  Data Management ......................................................................................................... 88 
11.1.1  Data Handling ................................................................................................. 88 
11.1.2  Computer Systems .......................................................................................... 88 
11.1.3  Data Entry ....................................................................................................... 88 
11.1.4  Medical Information Coding .......................................................................... 88 
11.1.5  Data Validation ............................................................................................... 88 
11.2  Source Data ................................................................................................................... 88 
12 
Ethical and Regulatory Requirements .............................................................................. 89 
12.1  Ethical Conduct of the Study ........................................................................................ 89 
12.2  Institutional Review Board ............................................................................................ 89 
12.3  Informed Consent .......................................................................................................... 89 
12.4  Protocol Amendments ................................................................................................... 89 
12.5  Disclosure of Data ......................................................................................................... 90 
12.6  Financial Disclosure ...................................................................................................... 90 
12.7  Insurance and Indemnity ............................................................................................... 90 
13 
References ......................................................................................................................... 91 
Appendix A:  Schedule of Procedures .......................................................................................... 95 
Appendix B:  Clinical Laboratory Analytes ............................................................................... 100 
Appendix C:  The ABCDEF Bundle .......................................................................................... 101 
Appendix D:  Screening for Spontaneous Awakening Trial (SAT) and Spontaneous Breathing 
Test (SBT) ....................................................................................................................... 103 
Appendix E:  Critical Care Pain Observation Tool (CPOT) ....................................................... 106 
Appendix F:  7-Point Scale of the Confusion Assessment Method for the Intensive Care Unit 
(CAM-ICU-7) ................................................................................................................. 112 
Appendix G:  Adverse Event Reporting Guidance ..................................................................... 113 
Appendix H:  Organ Failure, Sequential Failure Assessment (SOFA) ...................................... 119 
Appendix I:  Study Stopping Criteria ......................................................................................... 122 
Appendix J:  Simplified Acute Physiology Score ....................................................................... 123 
Appendix K:  Equivalent Vasopressor Dose .............................................................................. 124 

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LIST OF TABLES 
Table 1. 
Study Objectives and Endpoints ................................................................................. 31 
Table 2. 
Isoflurane/Sedaconda ACD-S Starting Dose and Titration Schedule ......................... 45 
Table 3. 
Propofol IV Infusion Starting Dose and Titration Schedule ....................................... 45 
Table 4. 
AE Causality Assessment Criteria .............................................................................. 74 
Table 5. 
Schedule of Procedures (Screening Period and Treatment Period) ............................ 95 
Table 6. 
Schedule of Procedures (Follow-Up Period and Early Withdrawal) .......................... 97 
Table 7. 
AE Severity Assessment Definitions ........................................................................ 115 
Table 8. 
AE Causality Assessment Criteria ............................................................................ 115 
Table 9. 
List of AESIs............................................................................................................. 116 
Table 10.  Criteria in the Isoflurane Group Triggering an Ad Hoc DSMB Meeting ................. 122 
Table 11.  Vasopressor Conversion Ratios ................................................................................ 124 
 
 

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LIST OF FIGURES 
Figure 1.  Sedaconda ACD Schematic ........................................................................................ 23 
Figure 2.  Study Scheme.............................................................................................................. 34 
Figure 3.  Richmond Agitation Sedation Scale ........................................................................... 60 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
21 CFR 
Title 21 of the Code of Federal Regulations 
ABG 
Arterial blood gas 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
BPI 
Brief Pain Inventory 
CAM-ICU 
Confusion Assessment Method for the Intensive Care Unit 
CAM-ICU-7 
7-point scale of the Confusion Assessment Method for the 
Intensive Care Unit 
CIBS 
Critical Illness, Brain Dysfunction, and Survivorship 
CO2 
Carbon dioxide 
COVID-19 
Coronavirus Disease 2019 
CPAP 
Continuous positive airway pressure 
CPOT 
Critical Care Pain Observation Tool 
CRA 
Clinical Research Associate 
CSR 
Clinical Study Report 
CTIRT 
 Interactive Response Technology 
DILI 
Drug-induced liver injury 
DSMB 
Data Safety Monitoring Board 
ECCO2R 
Extracorporeal carbon dioxide removal 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report form 
EOT 
End of treatment 
EtCO2 
End-tidal carbon dioxide 
FAQ 
Functional activities questionnaire 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice  
HFOV 
High frequency oscillation ventilation 
HFPV 
High frequency percussive ventilation 
HME 
Heat and moisture exchanger 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICP 
Intracranial pressure 

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Abbreviation 
Definition 
ICU 
Intensive care unit 
IES-R 
Impact of event scale 
IQCODE 
Informant Questionnaire on Cognitive Decline in the Elderly 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
Katz ADL 
Katz Index of Independence in Activity of Daily Living 
LAR 
Legally authorized representative 
LTO 
Long-Term Outcomes 
MAC 
Minimal alveolar concentration 
MDR  
Medical Device Regulation 
MH 
Malignant hyperthermia 
mITT 
Modified Intent-to-Treat 
NMBA 
Neuromuscular blocking agent 
P0.1 
Airway occlusion pressure 
PaO2 
Partial pressure of oxygen 
PC 
Pressure assist/control 
pCO2 
Partial pressure of carbon dioxide 
PEEP 
Positive end-expiratory pressure 
PETAL 
Prevention and Early Treatment of Acute Lung Injury 
PP 
Per-Protocol 
PRIS 
Propofol-related infusion syndrome 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PRVC 
Pressure-regulated volume control 
PS 
Pressure support 
PSV 
Pressure support ventilation 
PTSD 
Post-traumatic stress disorder 
RASS 
Richmond Agitation Sedation Scale 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAPS 
Simplified Acute Physiology Score 
SAT 
Spontaneous Awakening Trial 
SBT 
Spontaneous breathing test 
SD 
Standard deviation 
Sedaconda ACD 
Sedaconda Anaesthetic Conserving Device 
Sedaconda ACD-S 
Sedaconda Anaesthetic Conserving Device - S 
SIMV 
Synchronized intermittent mandatory ventilation 
SOC 
Standard of care 
SOFA 
Sequential organ failure assessment 
SpO2 
Peripheral capillary oxygen saturation 

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Abbreviation 
Definition 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TICS 
Telephone Interview for Cognitive Status 
ULN 
Upper limit of normal 
US 
United States 
VC 
Volume control 
WAIS 
Wechsler adult intelligence scale 
WHO 
World Health Organization 
WHODAS 
World Health Organization Disability Assessment Schedule 
WMS 
Wechsler memory scale 
 

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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background 
Invasive mechanical ventilation (later referred to as mechanical ventilation) is life supporting and 
commonly used to support pulmonary gas exchange and/or unload the respiratory muscles in 
critically ill patients.1 Pain, agitation, and delirium are commonly experienced by critically ill 
intensive care unit (ICU) patients.2,3 A significant proportion of intubated, mechanically ventilated 
patients require sedation, in addition to analgesia, to manage these clinical problems for their 
comfort and safety. 
Sedation in mechanically ventilated ICU patients is commonly achieved with the infusion of 
propofol, benzodiazepines, or dexmedetomidine.  
These sedatives used in the ICU are often useful to achieve comfort and safety, but they also have 
significant limitations. Prolonged infusions of benzodiazepines in critically ill patients are 
associated with drug accumulation, prolonged wake-up times, tolerance development, withdrawal 
symptoms, and delirium after discontinuation.3,4,5 Propofol, as an ICU sedative, reduces blood 
pressure and is also associated with hyperlipidemia and the risk of propofol-related infusion 
syndrome (PRIS), a potentially lethal side effect.3 The risk of propofol infusion syndrome is higher 
with high doses and long-term (>48 hours) sedation.6 For this reason, the maximum propofol 
infusion rate in the United States (US) has been limited to 4 mg/kg/hour, which is a dose limit that 
leads to some patients being insufficiently sedated with propofol alone. It is lipophilic and can 
have drug accumulation with longer durations of use leading to delayed arousal.7 
Recent US Society of Critical Care Medicine guidelines2,3 recommend non-benzodiazepine 
sedatives, such as propofol or dexmedetomidine when sedation is required, based on several 
studies demonstrating more favorable short- and long-term outcomes with non-benzodiazepine 
sedatives. The recommendations include cautionary statements regarding potential side effects and 
negative long-term consequences of ICU sedation.3 
Dexmedetomidine as an ICU sedative is useful in certain patients and situations, such as patients 
in distress during noninvasive ventilation8 and patients suffering from agitated delirium at the time 
of extubation.9 Dexmedetomidine appears to be insufficient as a sedative for a proportion of 
mechanically ventilated patients early on during mechanical ventilation, does not induce amnesia 
if deep sedation or neuromuscular blockade is required, and has been associated with a higher 
incidence of bradycardia, hypotension, and asystole than other intravenous (IV) sedatives.3,10 
Thus, there is currently no palatable alternative to propofol for mechanically ventilated patients 
requiring deeper sedation. Safe alternatives to propofol are needed to support patients with 
contraindications to propofol, and to diversify therapeutic options during drug shortages, as has 
occurred several times with propofol over the last decade. Efforts to limit the complications of 
currently available sedatives include strategies such as daily wake-up procedures and light sedation 
strategies, as well as monitoring for PRIS.11,12 
A sedative agent that could achieve the full range of sedation depths and permit rapid wake-up, 
without tolerance development, withdrawal, clinically significant accumulation, or active 
metabolites, suitable for patients with hepatic and renal dysfunction, would be appealing. 
Volatile anesthetics suppress consciousness but leave many autonomic functions intact. In the 
absence of disturbed information processing, the number of adverse experiences in patients during 

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and after treatment should be lower, as indicated in follow-up studies after volatile anesthetic 
sedation in ICU patients.13,14 In studies so far, wake-up after inhaled sedation has been short and 
predictable,15 which implies that extubation can be planned and organized, and the time during 
which the patient needs very close observation between termination of sedative treatment and 
extubation is short. 
1.2 
Inhaled Isoflurane as an ICU Sedative 
Isoflurane has been used for general anesthesia in operating rooms since the early 1980s. Its 
efficacy and safety as a general anesthetic have been evaluated extensively. It is considered one of 
the safest anesthetic drugs and has often been used in clinical practice for patients with marginal 
renal or liver function. Isoflurane is eliminated almost exclusively in unchanged form via 
exhalation after discontinued administration; thus, elimination is independent of renal or liver 
function with only 0.2% of isoflurane being metabolized.16 
Dose recommendations for approved indications of isoflurane with average end-tidal 
concentrations (minimal alveolar concentration [MAC]) required for pain-free general anesthesia 
during surgical stimulation in adults (50 to 70 years of age) are 1.15% and 1.10%, respectively, 
with isoflurane administered in 100% oxygen.16 For sedation, the end-tidal anesthetic gas 
concentration is typically slightly more than one-third of the MAC, ie, slightly above MAC-awake, 
and 0.3% to 0.5% expired volume provides acceptable sedation in adults.15,17,18 
As an alternative to ICU IV sedation, inhaled sedation using isoflurane started during the late 
1980s.19 Isoflurane was used successfully in sedation studies where isoflurane was administered 
via vaporizers using specially adapted high-flow ICU ventilators. While comparisons with 
midazolam and propofol in adults showed acceptable sedation effects and faster emergence, 
without reported tolerance or withdrawal symptoms,15,19 the non-standard delivery of anesthetic 
agent via non-standard adaptations and scavenging issues were stated as major hurdles for more 
widespread use in the ICU environment. Recent technological advances, however, have greatly 
simplified the application of inhalational anesthetics in the ICU. The introduction of a volatile 
anesthetic reflection filter, the Sedaconda Anaesthetic Conserving Device (Sedaconda ACD) in 
2005 enabled the concept of inhalational sedation to be performed in any ICU with standard ICU 
ventilators. 
Isoflurane has been used as an inhaled ICU sedative for over a decade in some clinical centers in 
Europe, and Sedaconda was recently approved for sedation of mechanically ventilated adult 
patients during intensive care in Europe. Inhaled sedation has been one of the suggested options 
for ICU sedation in Germany20 and more recently, it has been included in the Pan-American 
sedation guidelines, as well as suggested as a treatment in acute respiratory distress syndrome 
(ARDS)21 and Coronavirus Disease 2019 (COVID-19).22,23 To date, the growing body of study 
data and clinical experience indicate good sedative properties without significant side 
effects.17,18,24,25 A commonly described feature of inhaled sedation is a short and reliable wake-up, 
regardless of sedation depth.15,17 Other findings in small clinical trials have found a shorter time 
to adequate communication and cooperation and the ability to maintain spontaneous breathing, 
even during deeper levels of sedation.26,18 
1.3 
The Sedaconda ACD-S 
The Sedaconda Anaesthetic Conserving Device - S (Sedaconda ACD-S) is a small, disposable 
volatile anesthetic agent delivery and reflection system, developed for the administration of 

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isoflurane and sevoflurane to mechanically ventilated patients, without the need for an anesthesia 
machine. The Sedaconda ACD is previously known as the AnaConDa. The Sedaconda ACD-L 
(100 mL) and Sedaconda ACD-S (50 mL) are CE-certified, according to European Medical Device 
Regulation 2017/745 (as Risk Classification IIa products according to Annex 9), approved for the 
administration of isoflurane and sevoflurane in mechanically ventilated patients, and have been on 
the market outside the US since 2005 and 2017, respectively. In the planned clinical studies in the 
US, only Sedaconda ACD-S will be used. 
Figure 1. Sedaconda ACD Schematic 
 
 

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Figure 1. Sedaconda ACD Schematic (Continued) 
 
Sedaconda ACD = Sedaconda Anaesthetic Conserving Device; ICU = intensive care unit. 
The Sedaconda ACD-S standard placement is to be integrated into the ventilator circuit in place 
of the commonly used passive heat and moisture exchanger (HME), between the patient’s 
endotracheal tube or tracheostomy and the Y-piece of the ventilator tubing. It contains a miniature 
vaporizer and conserving medium consisting of an interwoven lipophilic active carbon filter that 
also exerts HME properties. The volatile anesthetic is administered continuously via a syringe 
pump into the miniature vaporizer. The evaporator is a porous plastic rod with a large surface area 
that will vaporize isoflurane or sevoflurane with the airflow, due to the volatility of both agents. 
The anesthetic exhaled by the patient enters the reflection medium, is adsorbed to the active carbon 
filter, and is desorbed and returned to the patient in the next breath. Approximately 90% of the 
anesthetic/sedative agent administered will be reflected when the Sedaconda ACD-S is placed at 
the Y-piece of the respiratory circuit. 
The syringe is a standard 50 to 60 mL syringe, coupled with a unique connector system to prevent 
unintentional IV administration of volatile sedatives. Sedation depth can be adjusted by increasing 
or decreasing the syringe pump rate, or by giving a small bolus (0.3 to 0.5 mL) of isoflurane. 
In contrast to an anesthesia machine, there is no need for additional equipment to maintain 
operation of the Sedaconda ACD-S besides the use of a FlurAbsorb filter, the availability of an 
anesthetic gas monitor, and standard ICU equipment. With the gas monitor, the patients end-tidal 
concentration can be measured whenever necessary. There is also no carbon dioxide (CO2) 
absorber to manage, which is a critical element of an anesthesia machine. The Sedaconda ACD-S 
is intended for single use and needs to be replaced every 24 hours or when needed, eg, in patients 
with mobilization of copious airway secretions. 

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When a device such as a Sedaconda ACD-S (which is a modified HME) is placed in the breathing 
circuit it adds volume to the circuit that the patient rebreathes, so-called dead space. The physician 
must, as with the introduction of any HME, determine if the patient’s breathing capacity (tidal 
volume and respiratory status [eg, partial pressure of carbon dioxide (pCO2)/end-tidal carbon 
dioxide (EtCO2) level]) is such that the patient can tolerate the additional dead space.  
The first Sedaconda ACD marketed in Europe had a dead space of 100 mL which occasionally led 
to increases in CO2. The 50 mL Sedaconda ACD-S was developed as a smaller dead space device 
to mitigate the risk of increases in CO2. Preliminary clinical experience and bench testing suggests 
that this device, when attached in the standard mode at the Y-piece of the respiratory circuit, can 
be used in patients with tidal volumes above 200 mL. Due to the 50 mL dead space of the 
Sedaconda ACD-S, clinically significant rebreathing may occur when used in patients with tidal 
volumes below 200 mL, previously demonstrated for the original 100 mL Sedaconda ACD-S.27  
In the current study, only the Sedaconda ACD-S will be used and patients with tidal volumes below 
200 mL will not be included. All sites will receive in-person, discipline-specific device training by 
Sponsor staff (Clinical Education Specialists), who will be available to respond to questions and 
for retraining throughout the study, as needed. The training will include all therapy-related 
standard procedures and troubleshooting and will also cover the pharmacokinetics, 
pharmacodynamics, dosing, and safety of the study drug isoflurane. Access will be given to online 
training materials, such as e-learning and setup videos as well as paper manuals and checklists. 
Local clinical educators will be trained to support staff and respond to basic therapy-related 
questions during patient inclusion. 
1.4 
Sedana Medical Clinical Studies on Isoflurane and Sedaconda ACD 
SED001 was a Phase 3, multicenter, randomized, controlled, open-label study in 301 adults with 
up to 48 (6) hours of treatment of isoflurane administered via Sedaconda ACD and 30 days of 
follow-up. The study was conducted in Germany and Slovenia. The last patient completed the 
study on 11 February 2020.18 
The results from this randomized controlled trial demonstrated that isoflurane delivered via the 
Sedaconda ACD was non-inferior to propofol for sedation (at the prescribed range of Richmond 
Agitation Sedation Scale [RASS] -1 to -4) of invasively ventilated patients with some other merits. 
Opioid doses were lower and spontaneous breathing more common in the isoflurane group 
compared to the propofol group. Its use was associated with short and predictable emergence and 
with an acceptable safety profile, with no new safety signals compared to the anesthesia indication. 
Please refer to the current version of the Investigator’s Brochure for details.  
SED002 is a Phase 3, multicenter, randomized, controlled, open-label study in children between 
3 to 17 years old, with a minimum of 12 hours and up to 48 (6) hours of treatment of isoflurane 
administered via Sedaconda ACD-S compared with IV midazolam, and a follow-up period of 
48 hours after discontinuation of study drug administration and a second longer-term follow-up of 
30 days. SED002 was initiated early 2021 and patient enrollment was completed in January 2023. 
SED004 (this study) and SED003 will be two Phase 3 studies planned to be conducted in the US, 
with a goal to demonstrate non-inferiority of isoflurane administered via Sedaconda ACD-S to the 
current standard of care (SOC), IV propofol infusion, in patients requiring sedation and mechanical 
ventilation in the ICU. In the pre-Investigational New Drug Application feedback from the Food 
and Drug Administration (FDA) 
, the Agency stated that as the proposed use is a 

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new indication for isoflurane, two well-controlled studies are required. The Agency noted that 
SED001 may not satisfy the US regulatory requirements for an adequate and well-controlled study 
due to its open-label design and therefore, two registration studies in the US are proposed. A joint 
Data Safety Monitoring Board (DSMB) will be convened to serve on both clinical studies, and 
data generated from these studies will be subject to study-specific and pooled analyses. 
1.5 
Rationale 
1.5.1 
Study Rationale 
Based on SED001 and previous literature, isoflurane has recently been approved for ICU sedation 
in 17 European countries. The Sedaconda ACD-L/ACD-S is approved in Europe, Australia, 
Canada, Japan, Mexico, South Korea, and other countries for the administration of volatile 
anesthetics for mechanically ventilated patients. Neither the Sedaconda ACD nor isoflurane is 
currently approved for ICU sedation in the US. As part of a New Drug Application seeking 
approval for use, this study will seek to establish the non-inferiority of isoflurane delivered via the 
Sedaconda ACD-S for ICU sedation for a period up to 48 (6) hours compared to IV propofol, a 
SOC sedative.  
1.5.2 
Study Design Rationale 
Due to the medical need for sedation in the study population, a placebo-controlled study is not 
feasible. IV propofol is the most commonly used sedative in mechanically ventilated adult patients 
in the US.10 It is approved and recommended for use in intensive care sedation and therefore is the 
most appropriate active control for this study. A non-inferiority design is chosen based on known 
sedative properties of isoflurane and propofol. 
A randomized, active-controlled, open-label design with a blinded assessment strategy will be used 
in this study. The many differences between the two treatments in route of administration, 
adjustment and pharmacologic effects, as well as blinding challenges for bedside treating staff 
related to the products, make it impractical to conduct a fully double-blind study with acceptable 
quality in the complex setting of the ICU with critically ill patients. An assessor blinding approach 
will be utilized to minimize bias. Treating staff will be unblinded to patient treatment assignments 
but treatment allocation will not be disclosed to potential blinded assessors nor to other members 
of the clinical team not directly involved in the patient’s care. 
The primary objective is to compare the percentage of time sedation depth is maintained within 
the target range, in absence of rescue sedation, as assessed according to the RASS scale, in 
isoflurane- versus propofol-treated patients. The sedation depth will be assessed using the blinded 
RASS assessments every 2 hours throughout the study drug treatment period.  
Clinical staff will be trained by the Investigator in standardized assessment of the RASS and 
Critical Care Pain Observation Tool (CPOT). These individuals will be delegated the task of 
performing the blinded RASS and CPOT assessments during the study drug treatment period for 
each patient per Sections 7.1.1 and 7.1.2. 
 
RASS target rationale 
For mechanically ventilated patients, sedative requirements change over time. In the first days of 
mechanical ventilation, a significant proportion of patients are sedated to moderate or deep levels 
of sedation (RASS -3 or below).10,28 The need for ventilator tolerance and multiple diagnostic and 

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therapeutic procedures may make moderate or sometimes even deep sedation necessary. This is 
especially true for patients with ARDS caused by sepsis (eg, COVID-19, bacterial pneumonia) or 
trauma.25,26 
Similar to several previous sedation studies with RASS range targets,10,29,30 a sedation target 
including 4 steps on the RASS scale is planned to be used, with one step deeper sedation than in 
the PRODEX and MIDEX studies31,32, ie, RASS -1 to -4 compared to RASS 0 to -3.29 The 
inclusion criterion “Receipt of continuous sedation due to clinical need for sedation RASS <0” 
identifies patients in need of continuous sedation and who cannot be managed at RASS 0. 
 
Rationale for 48-hour study drug treatment period 
As discussed with the FDA 
, efficacy and safety data to support the proposed dose 
and duration of isoflurane via the Sedaconda ACD-S should be provided.  
The maximum sedation time planned with the study drug is 48 (6) hours. The sedation period of 
up to 48 hours has been chosen because a large proportion of patients that are anticipated to require 
mechanical ventilation and sedation for more than 12 hours will likely require sedation for an 
additional 24 to 48 hours. Several published, randomized, controlled studies have a median 
sedation time of about 2 days,3,33 and the most common durations of mechanical ventilation in ICU 
patients in the US were 48 to 72 hours.34 The duration of isoflurane sedation described in the 
literature ranges from a few hours35,36 to several weeks.37,38,39 A significant proportion of patients 
can be managed with light sedation after the first days of mechanical ventilation, at which 
timepoint opioid analgesia or other sedatives, promoting greater degree of wakefulness, may be 
preferable.10,18 
The time span for ending study drug treatment permits the treatment to be terminated at an 
appropriate timepoint in relation to other activities, including potential extubation planned in the 
first hours after 48 hours, and also allows a practicable time for the study team to perform end of 
treatment (EOT) assessments. 
Having a fair proportion of patients that are sedated for the full length of the 48-hour study drug 
treatment period is important from a safety evaluation perspective. In parallel, it is important for 
the evaluation of emergence variables that a proportion of patients will be extubated during the 
course of the 48-hour study drug treatment period.  
In SED001, approximately 66% of patients needed more than 24 hours of sedation. In SED004, a 
pre-randomization duration of mechanical ventilation of 0 up to 72 hours is permitted and the 
anticipated need for mechanical ventilation is required to be >12 hours or longer to be eligible. 
These criteria imply that another 24 to 48 (6) hours of study sedation is clinically likely for an 
estimated proportion of approximately 50% of patients. A proportion in this range would give a 
reasonable body of data on both longer durations of isoflurane exposure and wake-up and 
long-term follow-up data from a fair proportion of patients awoken directly from the study drug. 
 
Rationale for CAM-ICU-7 assessment 60 minutes post EOT 
After ending sedation in ICU from different levels of sedation, early restoration of cognitive 
functions is desirable. This makes it safer and easier to prepare for and perform an extubation. The 
patient can cooperate better with the bedside care team in understanding instructions, improve 
secretion clearance, and acceptance of non-invasive ventilation or high flow nasal oxygen. A 

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confused or delirious patient makes liberation from mechanical ventilation complicated and 
potentially unsafe.27 
In study SED001, the majority of patients had reached sufficient RASS levels to permit a 
Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) assessment within 
60 minutes.  
Therefore, 60 minutes after completion of study sedation is considered adequate for cognitive 
follow-up by evaluation of delirium with 7-point scale of the CAM-ICU (CAM-ICU-7). 
 
Rationale for run-in training patients 
Unlike in Europe, where the Sedaconda ACD has been marketed for several years, it is a novel 
device in the US and the proficiency in managing the therapy from an efficacy perspective is 
expected to improve through clinical experiences. At each site, approximately 3 to 5 run-in training 
patients will be enrolled. The final number of run-in training patients at each site will be set in 
dialogue between the Sponsor’s clinical educator and the clinical staff. Each ICU will start with 
run-in training patients before any patients are randomized. These training patients will not be 
randomized, and treatment with isoflurane via Sedaconda ACD-S will be open-label in order to 
familiarize the larger clinical staff group who will manage patients in the study. For training 
purposes, patients with expected longer exposure times (ie, 12 to 48 [6] hours) are preferable. 
Inclusion and exclusion criteria will be the same for these patients as for randomized patients. All 
assessments will be the same for the run-in training patients as for the randomized patients, but 
they will be performed in a non-blinded fashion. The efficacy analyses will not include the data 
from these patients but the safety data from these patients will be included in the safety reporting 
from the study. The power calculation of sample size for the primary endpoint will not include 
these run-in training patients. 
 
Rationale for adaptive expected exposure duration 
When enrolling a patient into a clinical trial, predicting with certainty the remaining duration of 
mechanical ventilation and sedation can be difficult and may not reflect the actual later exposure. 
In clinical practice, deterioration with subsequently longer time on mechanical ventilation is more 
common than rapid improvement and shorter time than anticipated. Hence, the anticipated 
minimum duration of mechanical ventilation is set to 12 hours in this clinical trial, despite the need 
for a substantial proportion of patients exposed to longer periods of isoflurane sedation to support 
the intended 48-hour duration of use. 
Data on cognitive recovery and extubation times in patients on study medication when mechanical 
ventilation is stopped are important to address and therefore, it is desirable to balance long-term 
exposures with shorter exposures times, rendering wake-up data.  
Given the above, predicted remaining time on the ventilator for each patient will be collected at 
enrollment. Actual exposure durations and number of patients exposed to the maximum duration 
will be assessed regularly in the study as part of the risked-based monitoring. Based on the 
cumulative exposure times observed as the studies progress, a restriction in enrollment may be 
prospectively imposed to only include patients with anticipated longer (>24 hours) remaining 
duration of mechanical ventilation in recruitment, in order to balance long-term and short-term 
exposures.  

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1.6 
Risk/Benefit 
Patients enrolled in this study will be those who are anticipated to require sedation during 
mechanical ventilation for >12 hours. The study is designed to ensure all patients are provided 
adequate sedation for safety and comfort through administration of study drug and SOC. After 
randomization, patients will be sedated with IV propofol infusion, which is SOC in the vast 
majority of ICUs,10 or the study drug, isoflurane administered via the Sedaconda ACD-S device. 
Isoflurane has been widely used clinically for this indication at the dose proposed.15,20,22,24,40 In 
both treatment groups, patients who are not adequately sedated will receive rescue sedation. 
Patients that experience adverse reactions that require discontinuation of the treatment, or meet 
any other withdrawal criteria as outlined in Section 4.4, will be removed from the study drug with 
sedative choice and sedation management returned to the treating physician for SOC. Unless the 
patient withdraws consent, the patient will continue in the study for assessment and follow-up, per 
the Schedule of Procedures in Appendix A, even if the study drug is discontinued.  
In any ICU study, there is the risk that data collection for the purpose of assessing efficacy and 
safety could interfere with patient safety and comfort. In this study, the risk has been mitigated by 
allowing unblinded treatment of the patient with open-label adjustment of sedation by bedside staff 
caring for the patient, combined with periodic blinded assessment of the primary endpoint by a 
healthcare professional not directly involved in the patient’s ICU care. 
The risks of ICU sedation with IV propofol infusion are well described in the literature3 and 
outlined in the Background (Section 1.1). While no inhaled agent has been approved for ICU 
sedation in the US, there is significant experience with the prolonged use of isoflurane in the 
literature, with no time limit for the duration of anesthesia. The clinical use of isoflurane for 
sedation has expanded vastly since the introduction of the Sedaconda ACD device in Europe and 
other markets where the device is available. No previously unknown side effects have been 
reported, as side effects seen in the ICU are similar to those seen with isoflurane use for general 
anesthesia. This is also the case for SED001, where safety data from 150 patients treated with 
isoflurane via the Sedaconda ACD has been analyzed. Isoflurane sedation using the Sedaconda 
ACD device for up to several days has been described in a number of studies.15,24 
Adverse reactions encountered in the administration of isoflurane are, in general, dose-dependent 
extensions of pharmacophysiologic effects and include respiratory depression, hypotension, and 
arrhythmias. Potential, serious, undesirable effects include malignant hyperthermia (MH), 
anaphylactic reactions, and liver adverse reactions.  
Minimally raised levels of serum inorganic fluoride can occur during and after isoflurane 
anesthesia due to biodegradation of the agent. No cases of isoflurane-related polyuric renal failure 
have been reported after isoflurane sedation with durations beyond that planned in 
SED004.15,24,38,40 It is unlikely that the low levels of serum inorganic fluoride observed (mean 
serum inorganic fluoride level of 25 μmol/L reported in one study41) could cause renal toxicity, as 
these are well below proposed and conservative threshold levels for kidney toxicity (mainly based 
on methoxyflurane-related renal toxic effects). There are no reports of isoflurane sedation-related 
renal dysfunction. 
There are risks with the introduction of a novel device and therapy in critically ill patients. 
Therefore, device- and therapy-specific user-related risks are being mitigated via Human Factors 
engineering, focusing on optimizing design, training, and controls. All participating ICUs will be 
trained and the Sponsor will provide support in this through dedicated clinical educators. The 

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proficiency in providing adequate sedation will also be optimized by the inclusion of 
approximately 3 to 5 run-in training patients per site that will be treated with the support of the 
Sponsor’s clinical educator.  
The Sedaconda ACD-S has a dead space of 50 mL. This dead space is within the range of standard 
HMEs that commonly have a dead space of 29 to 95 mL.42 Training regarding the HME function 
and the dead space of Sedaconda ACD-S will be performed prior to the study. 
As with all standard HMEs, heavy secretions that reach the Sedaconda ACD may increase the 
resistance to flow. Very frequent nebulization may also increase the resistance to flow within the 
Sedaconda ACD. Any of these events would, in turn, lead to increased pressure drop across the 
device, which may affect the ventilation of the patient, either by increased ventilator pressures (if 
a volume-controlled ventilation mode is used) or by reduced tidal volumes (if the patient is on a 
pressure control ventilation mode). Besides standard ventilator alarms indicating such an 
eventuality, the handling of nebulization and secretions is explained in the device instructions for 
use and training. These aspects and other user-related risks have been evaluated in recent Human 
Factors evaluations and are addressed in training, instructions for use, and through controls such 
as ventilator alarms. All study sites will receive specific training in the use of Sedaconda ACD-S 
prior to the study, including the risks of volume or pressure changes due to changes in filter 
resistance. 
1.7 
The Coronavirus Disease 
In March 2020, COVID-19, caused by infection with severe acute respiratory syndrome 
coronavirus 2, was characterized as a pandemic by the World Health Organization (WHO). The 
COVID-19 pandemic has impacted clinical studies worldwide due to quarantines, site closures, 
travel limitations, diversion of resources, and/or general interruptions in study-related procedures.  
Coronavirus vaccinations are underway in the US and other countries. The clinical trial is planned 
to be initiated earliest Quarter 1, 2022. 
This study protocol does not include contingency plans to manage disruptions due to COVID-19 
control measures. Any protocol deviations that result from COVID-19 illness and/or COVID-19 
control measures will be discussed in the Clinical Study Report (CSR). 

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2 
STUDY OBJECTIVES AND ENDPOINTS 
The objectives and endpoints for this study are presented below in Table 1. 
Table 1. 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To compare the percentage of time sedation depth is 
maintained within the target range, in absence of rescue 
sedation, as assessed according to the RASS scale, in 
isoflurane- vs propofol-treated patients 
The percentage of time sedation depth is maintained within 
the prescribed RASS interval through end of study drug 
treatment  
Key secondary 
1. 
To compare the effect of isoflurane vs propofol on use of 
opioids during the study drug treatment period 
Change in mean fentanyl-equivalent opioid dose during the 
study drug treatment period compared to mean opioid dose 
during the 60 minutes prior to randomization  
2. 
To compare the effect of isoflurane vs propofol on the 
wake up time at end of study drug treatment 
Time from stop of study drug treatment to RASS 0, up to 
4 hours 
3. 
To compare the effect of isoflurane vs propofol on 
cognitive recovery after EOT 
Delirium by CAM-ICU-7 assessments 60 minutes 
(10 minutes) after EOT in patients not re-sedated with 
benzodiazepine or propofol infusions 
4. 
To compare the effect of isoflurane vs propofol on 
spontaneous breathing effort during the study drug 
treatment period 
Proportion of ventilator parameter observations with 
spontaneous breathing efforts during the study drug 
treatment period 
Other secondary 
To compare the effect of isoflurane vs propofol on time from 
sedation termination to extubation in patients for whom study 
drug is terminated for extubation 
Time from EOT to extubation if study drug is terminated for 
extubation 
To compare the effect of isoflurane vs propofol on days alive 
and free of mechanical ventilation through Study Day 30 
Days alive and free of mechanical ventilation1 through 
Study Day 30 
To compare the effect of isoflurane vs propofol on days alive 
and free of the ICU 
Days alive and free of the ICU2 through Study Day 30 
To compare the effect of isoflurane vs propofol on delirium 
and coma free days until 7 days after EOT 
Delirium and coma free days from start of study drug until 
7 days after EOT, as assessed with CAM-ICU-7 and RASS 
To compare the effect of isoflurane vs propofol on mortality at 
30 days after randomization 
Mortality rate at 30 days after randomization 
To compare the effect of isoflurane vs propofol on mortality at 
3 months after randomization 
Mortality rate at 3 months after randomization 
To compare the effect of isoflurane vs propofol on mortality at 
6 months after randomization 
Mortality rate at 6 months after randomization 
To compare the safety of isoflurane vs propofol 
AEs, clinical laboratory assessments, vital signs, physical 
examination, blood gases, organ function, and ventilator 
parameters 
To assess Sedaconda ACD-S device deficiencies in patients 
receiving isoflurane 
Frequency and type of Sedaconda ACD-S device 
deficiencies in patients receiving isoflurane 
To compare the use of restraints in patients receiving 
isoflurane vs propofol 
Proportion of patients using restraint during the study drug 
treatment period 
Exploratory 
To assess isoflurane dose over time 
 
Isoflurane dose in mL/hour;  
 
Isoflurane dose in mL/hour/L minute ventilation; and 
 
End-tidal isoflurane concentration every 4 hours. 
To compare the effect of isoflurane vs propofol on major ICU 
interventions through Study Day 30 or until ICU discharge, 
whichever comes first 
Need for:  
 
Renal replacement therapy; 
 
ECLS; 
 
Tracheostomy; and 
 
Non-invasive ventilation. 

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Table 1. 
Study Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
Exploratory (Continued) 
To compare the effect of isoflurane vs propofol on level of 
care up to 30 days after randomization 
Level of care:  
 
Patient deceased; 
 
Still in ICU; 
 
Intermediary care unit; 
 
General ward; 
 
Another ICU (within or outside the hospital); 
 
Another hospital (unknown ward);  
 
Rehabilitation unit; 
 
Nursing home; 
 
Hospice; and 
 
Home. 
To assess the end-tidal isoflurane concentration and relation to 
RASS scores 
End-tidal isoflurane concentration over time and relation to 
RASS scores 
To compare oxygenation (PaO2/FiO2) over time during the 
study drug treatment period, in patients with ARDS/AHRF, in 
isoflurane vs propofol-treated patients 
Oxygenation (PaO2/FiO2) in patients with ARDS/AHRF 
over time during the study drug treatment period  
To compare memory panorama from time in the ICU in 
isoflurane- vs propofol-treated patients 
Number of factual memories, memories of feelings, or 
delusional memories, as assessed by the ICU Memory Tool, 
collected at 3 months follow-up 
To compare physical outcomes at 3 and 6 months 
post-randomization in isoflurane- vs propofol-treated patients 
Activities of daily living, as assessed by the Katz ADL and 
Pfeffer FAQ, at 3 and 6 months post-randomization 
To compare psychological outcomes at 3 and 6 months 
post-randomization in isoflurane- vs propofol-treated patients 
Depression, anxiety, and post-traumatic stress symptoms, as 
assessed by IES-R and PROMIS Depression and Anxiety 
questionnaires, at 3 and 6 months post-randomization 
To compare cognitive function 3 and 6 months 
post-randomization in isoflurane- vs propofol-treated patients 
Cognitive function, as assessed by TICS, WAIS IV-Digit 
Span, Hayling Sentence Completion Test, Controlled Oral 
Word Association, WMS-IV – Immediate Memory 
(Adult/Older Adult), WMS-IV – Delayed Memory 
(Adult/Older Adult), and PROMIS Cognitive Function 
questionnaire, at 3 and 6 months post-randomization 
To compare quality of life at 3 and 6 months 
post-randomization in isoflurane- vs propofol-treated patients 
Quality of life at 3 and 6 months post-randomization, as 
assessed by WHODAS 2.0 and BPI 
To compare the need for rescue, other sedatives, and 
antipsychotics in isoflurane- vs propofol-treated patients 
Use of rescue sedatives, other sedatives, and antipsychotics 
from randomization to EOT 
To compare the hemodynamic instability in isoflurane- vs 
propofol-treated patients  
Change from Baseline in highest daily vasoactive drug 
requirements during study drug treatment 
To compare duration of mechanical ventilation in 
isoflurane- vs propofol-treated patients 
Duration of mechanical ventilation 
To compare ICU length of stay in isoflurane- vs 
propofol-treated patients 
ICU length of stay 
To compare minute ventilation in isoflurane- vs 
propofol-treated patients 
Change in minute ventilation every 8 hours during the study 
drug treatment period  
1. 
For Days alive and free of mechanical ventilation, only invasive ventilation will be taken into account. Successful ventilator 
discontinuation is defined as being alive and free of ventilation for 48 hours (inclusive) following discontinuation. For 
example, if a patient was discontinued from mechanical ventilator and ventilation was initiated again within the next 
48 hours or the patient died within the next 48 hours, then the time (less than 48 hours) that was off ventilation did not 
count as Days alive and free of mechanical ventilation. 
2. 
The Days alive and free of the ICU is defined similarly to the Days alive and free of mechanical ventilation. Successful 
ICU discharge is defined as being alive and out of ICU for 48 hours (inclusive) following discharge.  
AE = adverse event; AHRF = acute hypoxemic respiratory failure; ARDS = acute respiratory distress syndrome; BPI = Brief 
Pain Inventory; CAM-ICU-7 = 7 point scale of the Confusion Assessment Method for the Intensive Care Unit; 
ECLS = extracorporeal life support; EOT = end of treatment; FAQ = functional activities questionnaire; FiO2 = fraction of 
inspired oxygen; ICU = intensive care unit; IES-R = impact of event scale; Katz ADL = Katz Index of Independence in Activity 
of Daily Living; PaO2 = partial pressure of oxygen; PROMIS = Patient Reported Outcomes Measurement Information System; 
RASS = Richmond Agitation Sedation Scale; Sedaconda ACD-S = Sedaconda Anaesthetic Conserving Device - S; 
SOC = standard of care; TICS = Telephone Interview for Cognitive Status; vs = versus; WAIS = Wechsler adult intelligence 
scale; WHODAS 2.0 = World Health Organization Disability Assessment Schedule 2.0; WMS = Wechsler memory scale. 

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3 
STUDY DESCRIPTION 
3.1 
Study Indication 
The indication of this study is for sedation of mechanically ventilated patients in the ICU. 
3.2 
Summary of Study Design 
This is a therapeutic confirmatory (Phase 3), multicenter, randomized, controlled, open-label, 
assessor-blinded study. Approximately 235 patients receiving mechanical ventilation and 
requiring continuous sedation at approximately 15 to 20 sites in the US will be randomized in a 
1.5:1 ratio to inhaled isoflurane (administered via the Sedaconda ACD-S device) or propofol 
(administered via IV infusion) for sedation, respectively. In addition, approximately 3 to 5 run-in 
training patients per site will be enrolled. The treatment duration in this study is expected to be at 
least 12 hours and may last up to 48 (6) hours or to the time for extubation, whichever occurs 
first, with a follow-up period of 6 months. 
Patients eligible for the study will either have planned surgery with anticipated need for sedation 
and mechanical ventilation in the ICU (ie, postoperative patients) for >12 hours or have already 
been admitted to the ICU and anticipate needing sedation and mechanical ventilation for 
>12 hours.  
Informed consent must be obtained from the patient or patient’s legally authorized representative 
(LAR) for all patients according to Section 6.1.  
The study will comprise the following key study periods: 
 Screening period: Day -30 to randomization; 
o Initial Screening: Day -30 to randomization;  
o Complete Screening: -24 hours to randomization;  
o Randomization; and 
o Baseline: Randomization to initiation of study drug treatment (up to 6 hours). 
 Treatment period: initiation of study drug administration to the EOT (up to 48 [] hours); and 
 Follow-up period: EOT to 6 months (4 weeks) after randomization. 
o Post-treatment monitoring phase: until 24 hours after EOT; 
o 24 hours after EOT until 7 days after EOT: daily follow-up from the time of randomization 
until 7 days after EOT; 
o Follow-up: at Study Day 30 (+5 days) after randomization;  
o 3-month centralized telephone follow-up: 3 months (4 weeks) after randomization; and 
o 6-month centralized telephone follow-up: 6 months (4 weeks) after randomization. 
A schematic of the study flow is shown in Figure 2.  

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Figure 2. Study Scheme 
 
CPOT = Critical Care Pain Observation Tool; D = day(s); EOT = end of treatment; h = hour(s); IV = intravenous; LAR = legally 
authorized representative; M = month; RASS = Richmond Agitation Sedation Scale; Sedaconda ACD-S = Sedaconda Anaesthetic 
Conserving Device - S; SOC = standard of care; W = week(s).  
Patients will be screened between Day -30 to randomization to determine study eligibility.  
At randomization, ongoing sedation and opioid infusions will be reduced to half as described in 
Section 3.7. Baseline values will be obtained during the baseline phase (ie, from randomization to 
initiation of study drug administration) as specified in Appendix A and Section 6.1.3.  
Initiating study drug treatment must be performed as close to randomization as possible, and no 
later than 6 hours after randomization. It is recommended to start study drug treatment at the full 
hour to simplify data collection timepoints. The target sedation depth (ie, RASS range of -1 to -4) 
will be valid from randomization.  
Study drug dose titration will be performed by the clinical team to reach the targeted sedation 
depth (ie, RASS range -1 to -4, as set by the clinical team) based on unblinded RASS assessments 
during initial titration and thereafter based on blinded assessments every 2 hours until the patient 
reaches EOT. Sedation will also be adjusted based on non-blinded RASS assessments by bedside 
staff between formal blinded assessments; see Section 7.1.1 for further details.  
Pain level will be assessed using the CPOT, assessed in parallel with the RASS assessment, to 
ensure that pain and sedation are managed properly. 
Study drug treatment will be stopped when the patient is planned to be extubated or reaches the 
maximum treatment duration of 48 () hours, as specified in Section 6.2.5, at which time the 
patient will be transitioned to SOC sedation when clinically indicated.  
Patients will be monitored until 24 hours after EOT, followed-up until Day 7 and at Study 
Day 30 (+5) days, and a consecutive subset of patients still alive will receive a telephone call from 
the Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center in Nashville at 3 months 
(4 weeks) and 6 months (4 weeks), respectively, after randomization to assess long-term 
outcomes (LTO).  

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For training purposes in the use of Sedaconda ACD-S, approximately 3 to 5 patients at each site 
will be assigned to receive isoflurane via Sedaconda ACD-S in a non-blinded fashion according 
to Section 3.5, before any patients are randomized.  
An independent DSMB will be assembled to safeguard the safety of study patients per the DSMB 
Charter. This DSMB will serve jointly for both this study and the SED003 study, a confirmatory 
study identical to SED004, see Section 8.8. 
3.3 
Time Portion of Adequate Sedation Depth 
The primary objective of this study is to compare the percentage of time sedation depth is 
maintained within the target range, in absence of rescue sedation, as assessed according to the 
RASS scale, in isoflurane- versus propofol-treated patients. This parameter will be derived for 
each patient, as follows: 
% 𝑎𝑑𝑒𝑞𝑢𝑎𝑡𝑒 𝑠𝑒𝑑𝑎𝑡𝑖𝑜𝑛ൌ 
𝑠𝑢𝑐𝑐𝑒𝑠𝑠 𝑡𝑖𝑚𝑒
𝑠𝑢𝑐𝑐𝑒𝑠𝑠 𝑡𝑖𝑚𝑒൅𝑓𝑎𝑖𝑙𝑢𝑟𝑒 𝑡𝑖𝑚𝑒 
‘Success time’ is the time during study drug treatment when blinded RASS falls within -1 to -4.  
‘Failure time’ is counted if: 
1. Blinded RASS is outside the target range (ie, less than -4 or greater than -1);  
2. Rescue sedation is needed, ie, RASS target is not achieved, despite use of study drug; or 
3. ‘Treatment failure’, as defined in Section 5.4.1.2. 
If a blinded RASS assessment is not performed per study schedule (missed assessment), the missed 
assessment will not be accounted for in the primary endpoint, but will be counted as failure in a 
sensitivity analysis. 
When SOC procedures imply significant change to sedation level, blinded assessments will not be 
performed. The rules for when not to perform blinded RASS and CPOT assessments due to such 
changes of sedation level are described in Section 7.1.3. Such omitted blinded RASS assessments 
due to SOC procedures in or outside the ICU, as described in Section 7.1.3, are not considered 
protocol deviations and are not counted as failure time. 
3.4 
SOC and ABCDEF Bundle 
ICU care for patients will be managed per SOC during the study using the ABCDEF bundle as a 
guide,43 see Appendix C. 
Regarding screening for unassisted breathing readiness and extubation, additional 
recommendations are provided in Appendix D. The strategy for performing the spontaneous 
breathing test (SBT) readiness screening and subsequent SBT will adhere to current SOC 
(ie, mandated daily screening and, when criteria met, SBT initiation) while allowing for local 
practice variation that reflects usual care. For any sites without an existing clinical SBT protocol, 
recommendations are provided in Appendix D. 
3.5 
Run-In Training Patients 
For training purposes in the use of Sedaconda ACD-S, approximately 3 to 5 run-in training patients 
per site will be assigned to receive isoflurane via Sedaconda ACD-S in an unblinded setting. Each 

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site will start with run-in training patients before any patients are randomized. The number of 
run-in training patients at each site will be set in dialogue between the Sponsor and the local study 
team. The run-in training patients will be assigned a unique identification number but will not be 
randomized. Run-in training patients will perform all assessments according to Appendix A, 
including the long-term follow-up assessments at 3 and 6 months.  
Additional run-in patients will not be allowed at a given site after the first patient is randomized. 
3.6 
Randomization and Blinding 
Patients will be randomized in a 1.5:1 ratio to receive isoflurane (administered via the Sedaconda 
ACD-S device) or propofol (administered via IV infusion), respectively. 
3.6.1 
Stratified Randomization 
Randomization will be stratified by Simplified Acute Physiology Score (SAPS) III (SAPS 0 to 
<40, 40 to <60, and 60) and patient type (medical and surgical [including trauma]) assessed at 
Screening. Surgical patient will be defined as patients who meet either of the following criteria:  
1. Have undergone surgery within the prior 2 weeks and for whom the current respiratory failure 
episode is related to that surgery or surgical disease process, or a complication thereof; or  
2. Patients anticipated to undergo surgery within the next 2 days for a condition that is related to 
etiology of respiratory failure. 
3.6.2 
Blinding 
Bedside treating staff, taking care of the study patient will not be blinded to treatment assignment. 
Besides this group, treatment allocation will not be disclosed unless clinically motivated. The 
blinded RASS and CPOT assessment results will be documented without the blinded assessor and 
the bedside staff discussing study treatment or sedation. After documentation, the scores will be 
communicated to the bedside staff.  
Each patient will have a double drug delivery set-up, 1 for active treatment and 1 nonfunctional 
set-up, to maintain blinding for staff not directly involved in the care of the patient. Measures will 
be taken to visually obscure both drug delivery set-ups.  
The blinded assessors will not have access to the patient during the study drug treatment period 
unless the blinding measures are in place.  
Detailed blinding instructions will be provided, with the option for local optimizations. 
3.6.3 
Blinded Assessment of RASS and CPOT 
Clinical staff will be trained by the Investigator or designee in standardized assessment of the 
RASS and CPOT. 
Blinded assessors will have limited interaction with treating staff and will not participate in 
treatment discussions or decisions. Staff treating the patient should avoid revealing the study 
treatment to other staff members. Unless medically indicated, discussions regarding study patients 
between staff not directly involved in the care of the patient should be avoided until all blinded 

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assessments are completed. These individuals will be delegated the task of performing the blinded 
RASS and CPOT assessments for each patient, with the following guidance: 
 At the time of enrollment, and before each new shift, potential assessors (previously 
experienced or trained in RASS and CPOT) among staff on duty will be notified. At the time 
of blinded assessment, any of these assessors will be asked to perform the blinded assessments; 
 Prior to the blinded assessment, bedside staff will ensure that all devices and equipment are 
covered according to the blinding instruction;  
 Additionally, prior to the blinded assessment, the assessor will confirm the period is eligible 
for assessment, as described in Section 7.1.3. Thereafter, the blinded assessor will have access 
to the patient; 
 At the time of documentation of RASS and CPOT scores, the assessor will certify in writing 
that he/she was not aware of the study drug treatment given;  
 In case the assessor becomes unblinded, a new assessor will be selected among the trained 
clinical staff; and 
 After documenting the RASS and CPOT scores, the results will be relayed to bedside staff for 
consideration of a possible need to titrate sedative and analgesic drugs.  
3.6.4 
Breaking the Blind 
This is an open-label study with blinded assessments. Bedside staff will be unblinded to patient 
treatment assignments. There is no provision for breaking the blind for the blinded assessors. If a 
potential blinded assessor is unintentionally informed of or learns of a patient’s treatment 
assignment, this assessor will not make any further assessments and other assessors, still blinded 
to treatment arm, will conduct the remaining assessments during the study drug treatment period. 
3.7 
Reduction of SOC Sedatives and Opioids After Randomization 
To minimize the effects of different SOC drugs at initiation of study drug treatment, both sedative 
and opioid infusions will be reduced to half, as soon as possible after randomization and prior to 
study drug initiation, unless the patient is agitated or shows signs of ongoing pain (see 
Section 6.1.3). 
If clinically indicated after the dose reductions and prior to the start of study drug treatment, 
titration of SOC sedatives and/or opioid analgesics is permitted. 
3.8 
Study Drug Treatment 
Study treatments will be administered as detailed in Section 5. 
Throughout the study drug treatment period, the study drug dose (isoflurane or propofol) should 
be adjusted to maintain the target RASS range of -1 to -4. Sedation may be paused for clinical 
purposes (eg, decreased sedation for neurological examinations and daily Spontaneous Awakening 
Trials [SATs]). If additional sedation is needed for routine ICU care per SOC (eg, repositioning 
the patient), study drug should primarily be used for this purpose. 

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Procedural sedation for procedures within and outside the ICU is discussed in Section 5.5.2.1. 
Study drug may not be administered outside of the ICU. Re-initiation of study drug, if it is paused 
for procedures, is detailed in Section 5.3.4. 
If adjustments of the study drug are insufficient to reach or maintain the target RASS range, rescue 
sedative agents may be given, as detailed in Section 5.4. 
3.9 
End of Treatment 
EOT is achieved when the patient reaches one of the following scenarios: 
 Study drug administration is stopped for extubation;  
 Reaching 48 (6) hours of study drug treatment; or 
 Any medical condition that indicates to the Investigator that continued treatment is not in the 
best interest of the patient. 
EOT due to transfer from ICU (to other ICU or for procedure outside the ICU with return to the 
ICU >42 hours after initiation of study drug treatment) constitutes a special scenario. In this 
situation, all EOT assessments that are applicable and feasible should be performed prior to 
transfer. 
3.10 
Extubation 
Extubation will be performed per SOC. For any sites without an existing screening for extubation 
readiness protocol, recommendations are provided in Appendix D. 
Patients for whom extubation is attempted but unsuccessful (ie, requiring re-intubation) and any 
EOT assessments have been initiated (wake-up test or CAM-ICU-7 after 60 minutes) will not 
receive further study drug. If sedation is required upon re-intubation, only SOC sedation is 
permitted.  
3.11 
Long-Term Outcomes Assessment 
In drug studies of critically ill patients, outcomes may be assessed at remote timepoints and not 
merely in the ICU. This is because the “success” of interventions is not defined merely by their 
impact in the hospital but also by their persistent effects. The CIBS Center at Vanderbilt University 
Medical Center, LTO Core will conduct the LTO assessments for a consecutive subset of patients 
in this trial.  
Appropriate performance of cognitive assessments, in particular as clinical trial outcomes, requires 
specially trained neuropsychology professionals and standardization of test administration. Results 
from in-person assessment strategies may suffer from bias due to higher loss to follow-up, missing 
and/or partial data (which is not random), and testing in an unfamiliar or uncomfortable 
environment, which will be exacerbated by these assessments being conducted at 30 to 
40 individual sites (ie, de-centralized) by less experienced assessors in the specific test battery. To 
achieve scientific rigor and standardization of assessments and higher rates of complete follow-up, 
validated remote assessments performed by one single centralized team will be utilized for both 
clinical trials. This technique is especially important for multicenter trials where neuropsychology 
resources will vary by center and in-person assessments are often not feasible, practical, or reliable. 
Remote, centralized cognitive assessments have been performed in many landmark trials in 

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critically ill patients, including recent sedation trials and several studies conducted under FDA 
Investigational 
New 
Drug 
applications.10,28,44,45,46 
The 
Vanderbilt 
CIBS 
Center 
(www.icudelirium.org) is an internationally recognized center for its work in acute and long-term 
brain dysfunction from critical illness, including landmark studies on delirium, cognitive 
impairment, and sedation.28,44,47,48,49,50,51 The LTO Core within the CIBS Center, comprised of 
neuropsychology professionals, has been responsible for cognitive assessments performed in CIBS 
Center studies, along with multiple other multicenter trials including several Prevention and Early 
Treatment of Acute Lung Injury (PETAL) network studies in critically ill patients.  
A comprehensive battery slightly less than an hour in duration will be employed, which is 
significantly more sensitive than a brief screening test but less cumbersome than a lengthy 
clinically oriented neuropsychological assessment. This battery combines tests from diverse and 
relevant domains of functioning and balances the need to be sufficiently challenging to patients as 
well as the need to be feasibly administered and well tolerated. Crucially, this battery can be given 
by telephone or videophone, which allows for it to be administered by the CIBS Center’s LTO 
Core to individuals from around the country, regardless of which enrollment sites they are from. 
A description of these Cognitive Assessments, Mental Health, Functioning, and Quality of Life 
Assessments are provided in Section 7.3. 

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4 
SELECTION AND WITHDRAWAL OF PATIENTS  
4.1 
Inclusion Criteria 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Adults 18 years of age; 
2. Patients who are anticipated to require >12 hours of invasive mechanical ventilation and 
continuous sedation in the ICU; and 
3. Receipt of continuous sedation due to clinical need for sedation to RASS <0. 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Need for RASS -5; 
2. Sedation for invasive mechanical ventilation immediately prior to Baseline for >72 hours 
(patients who have been extubated for at least 24 hours and subsequently re-intubated will have 
sedation for invasive mechanical ventilation starting from when they were re-intubated); 
3. Severe neurological condition that causes the patient to lack ability to participate in the study 
(ie, unable to be assessed for RASS and CPOT), including, but not restricted to, patients with 
acute stroke, severe head trauma, meningitis, suspected of having elevated intracranial pressure 
(ICP), or the need for ICP monitoring; 
4. Ventilator tidal volume <200 or >1000 mL at Baseline; 
5. Need for extracorporeal membrane oxygenation (ECMO), extracorporeal CO2 removal 
(ECCO2R), high frequency oscillation ventilation (HFOV), or high frequency percussive 
ventilation (HFPV) at Screening; 
6. Comfort care only (end of life care); 
7. Contraindication to propofol or isoflurane, including: 
a. Known or suspected personal or family history of MH or high risk for MH or acute 
drug-induced muscle injury (eg, muscular dystrophies);  
b. Severe hemodynamic compromise, defined as the need for norepinephrine 
0.3 mcg/kg/min (or equivalent vasopressor dose52 [Appendix K]) to maintain blood 
pressure within acceptable range, assumed to be mean arterial pressure 65 mmHg unless 
prescribed clinically; or 
c. Allergy to isoflurane or propofol, or have propofol infusion syndrome. 
8. History of ventricular tachycardia/Long QT Syndrome; 
9. Requirement of IV benzodiazepine or barbiturate administration for seizures or dependencies, 
including alcohol withdrawal; 
10. Neuromuscular disease that impairs spontaneous ventilation (eg, C5 or higher spinal cord 
injury, amyotrophic lateral sclerosis, etc);  

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11. Concurrent enrollment in another study that, in the Investigator’s opinion, would impact the 
patient’s safety or assessments of this study; 
12. Participation in other study involving investigational drug(s) or devices(s) within 30 days prior 
to randomization; 
13. Previous randomization or receipt of treatment in this study or in SED003; 
14. Anticipated requirement of treatment with continuous infusion of a neuromuscular blocking 
agent (NMBA) for >4 hours; 
15. Female patients who are pregnant or breast-feeding; 
16. Imperative need for continuous active humidification through mechanical ventilation circuit; 
17. Attending physician’s refusal to include the patient; or 
18. Inability to obtain informed consent. 
4.3 
Criteria for Early Study Drug Discontinuation 
A patient should be discontinued from the study drug prior to EOT for any of the following 
reasons:  
 Treatment failure, ie, clinical failure for the patient to be adequately sedated with study drug 
as specified in Section 5.4.1.2; 
 New onset of coma due to structural brain disease such as stroke, intracranial hemorrhage, 
cranial trauma, malignancy, anoxic brain injury, or cerebral edema;  
 Severe or serious adverse events (SAEs): 
o Development of an adverse event of special interest (AESI) that qualifies as a severe 
adverse event (AE) or SAE at least possibly related to study drug, without a clear alternate 
explanation; 
o For any other severe AEs, the decision on whether to continue with study drug will be 
made at the site level by the Investigator and clinical team in accordance with whether 
continuation/reintroduction of study treatment is in the best interest of the patient for the 
first severe AE; or 
o A second severe AE or any SAE without a clear alternate explanation will lead to 
discontinuation of study treatment. 
 Unresolved Sedaconda ACD-S device-related issues; see Section 8.7;  
 Any medical condition that indicates to the Investigator that continued study drug treatment is 
not in the best interest of the patient; 
 Transition to comfort care; 
 Death; 
 Requirement of prohibited concomitant medication; see Section 5.5.1;  

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 Need for ECMO, ECCO2R, HFOV, or HFPV; or 
 Withdrawal of consent to receive study drug. 
See Section 6.2.5 for applicable procedures at the time of study drug discontinuation. 
4.4 
Criteria for Study Withdrawal 
A patient should be withdrawn from the study for any of the following reasons:  
 Any medical condition that indicates to the Investigator that continued participation is not in 
the best interest of the patient; 
 Withdrawal of consent by the patient or LAR or request for discontinuation from the study for 
any reason; 
 Withdrawal of the site by the Sponsor due to Investigator failure to comply with protocol 
requirements or study-related procedures; and 
 Termination of the study by the Sponsor or the regulatory authority. 
See Section 6.4 for related procedures at the time of study withdrawal.  

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5 
STUDY TREATMENTS 
5.1 
Drug and Device Supplies 
5.1.1 
Formulation and Packaging 
Commercially available isoflurane and propofol will be provided by the Sponsor through an 
authorized service provider.  
Isoflurane will be provided in 100 or 250 mL bottles containing 100% v/v of isoflurane for 
inhalation. 
Propofol will be provided as an IV solution for infusion at the dose of 1% w/v (1 g, 10 mg/ml) or 
2% w/v (2 g, 20 mg/mL).  
Study-specific isoflurane and propofol will be labeled in accordance with Good Manufacturing 
Practice and local regulatory guidelines. 
5.1.2 
Storage and Accountability 
All study drugs shall be kept in a secure place with limited access under appropriate storage 
conditions and in accordance with local regulations. See Instructions-For-Use provided for 
additional information on isoflurane storage. 
Isoflurane shall be stored between 20°C to 25°C (68°F to 77°F), with excursions permitted to 15°C 
to 30°C (59°F to 86°F), in order to avoid gas volume expansion upon warming. The bottles should 
be stored in the outer carton to protect from light. Refer to the Pharmacy Manual for detailed 
instructions.  
Propofol shall be stored between 4°C to 25°C (40°F to 77°F). Propofol shall not be frozen. Shake 
well before use. 
Temperature logs shall be kept for the storage room where the study drugs are stored prior to 
dispensing. The minimum and maximum temperature should be noted daily on business days 
(unless automatic temperature readings are available). 
The Investigator is responsible for establishing routines for correct handling of the study drugs at 
the site to ensure the following: 
 Study drugs are correctly received, accounted for, and logged by a designated person; 
 Accurate records are maintained, accounting for the receipt and disposition of the study drugs; 
 Study drugs are handled and stored safely, properly, and in agreement with the given handling 
and storage instructions; 
 Study drugs are prescribed only by the Investigator or designee; 
 Study drugs are only dispensed by designated site staff;  

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 Study drug dispensing is recorded on an appropriate Drug Dispensing Log. At least the 
following information will be documented: patient identification number, the study drug and 
quantity dispensed, date and time of dispensing, and any leftover study drug from the dispensed 
unit returned to storage after patient has completed the study. This record must be kept in 
addition to any study drug administration information recorded in the electronic case report 
form (eCRF) or the patient’s medical chart/source documents; and 
 All unused study drugs and empty containers are stored until they have been checked by the 
Clinical Research Associates (CRAs). 
After verifying drug accountability, all unused study drugs and all empty bottles will be returned 
to the Sponsor or designee for destruction or be destroyed locally upon agreement with, and 
approval from, the Sponsor or designee. 
5.1.3 
Sedaconda ACD-S Supply, Storage, and Accountability  
The Sedaconda ACD-S devices will be manufactured under the responsibility of Sedana Medical 
Limited (Unit 2A, The Village Centre, TwoMileHouse, Naas, Co. Kildare, W91 PWH5, Ireland). 
The Sedaconda ACD-S devices and applicable auxiliaries will be provided and labelled with a 
unique device identifier together with the instructions for use. The Sedaconda ACD-S devices and 
auxiliaries provided for this study will only be used during the study drug treatment period. The 
use of the Sedaconda ACD-S devices will be accounted for during the study using a device 
accountability log. 
In addition to the Sedaconda ACD-S, the study sites will be provided with auxiliary supplies 
required for the use of the Sedaconda ACD-S, such as the unique Sedaconda syringes, gas 
sampling connector, isoflurane filling adapter, FlurAbsorb, and FlurAbsorb accessory kit. 
FlurAbsorb is used for scavenging of waste anesthetic gases from the exhaust port of the ventilator. 
The Sedaconda ACD-S and auxiliaries should be stored at room temperature. 
5.2 
Study Drug Preparation and Dispensing 
Patients will be randomized in a 1.5:1 ratio to receive isoflurane (administered via the Sedaconda 
ACD-S device) or propofol (administered via IV infusion), respectively. The duration of the study 
drug treatment will be up to 48 (6) hours. 
Study drug will be prepared and dispensed by unblinded study site personnel according to the 
research Pharmacy Manual provided in conjunction with this protocol. 
5.3 
Study Drug Dosing 
5.3.1 
Isoflurane Dosing 
The initial dose of isoflurane in this study is 3.0 mL/hour, and dose titration based on frequent 
assessments of the patient’s clinical sedation depth and hemodynamics will occur at dose 
increments or decrements of 0.5 to 1.0 mL/hour. In deeply sedated, hypovolemic or hypotensive 
patients receiving vasopressors, lower doses may be considered. The dose titration is performed 
by the clinical team. During initiation, bolus doses of 0.3 to 0.5 mL can be given, as clinically 
indicated, to obtain rapid deepening of sedation when required to achieve RASS target. Isoflurane 
pump rate should not exceed 15 mL/hour. The dosing schedule is based on clinical experience, 

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dosing from SED001, and pharmacokinetic bench studies on isoflurane dosing for anesthesia.33 
See Table 2 below. 
Table 2. 
Isoflurane/Sedaconda ACD-S Starting Dose and Titration Schedule 
Starting Dose1 
Dose Titration Schedule1 
3.0 mL/hour2 
Stepwise titration2 by 0.5 to 1.0 mL/hour until desired 
clinical effect is achieved. Peak clinical effects are typically 
noticeable within 10 to 15 minutes. 
 
Bolus dose of 0.3 to 0.5 mL 
1. 
Before initiating the starting dose, the Sedaconda ACD-S will be primed with 1.2 mL isoflurane. 
2. 
In deeply sedated, hypovolemic or hypotensive patients receiving vasopressors, lower doses may be considered. 
ACD-S = Sedaconda Anaesthetic Conserving Device – S. 
5.3.2 
Propofol Dosing 
In most patients, the initial infusion should be approximately 10 to 25 μg/kg/minute (0.6 to 
1.5 mg/kg/hour) for at least 5 minutes. Subsequent adjustment may occur in increments or 
decrements of 5 to 10 μg/kg/minute (0.3 to 0.6 mg/kg/h) every 5 to 10 minutes until the target 
sedation depth is achieved. Maintenance doses of 5 to 50 μg/kg/minute (0.3 to 3 mg/kg/hour) or 
higher may be required. Propofol dose should not exceed 66 μg/kg/minute (ie, 4.0 mg/kg/hour) 
according to label instructions.53 
Propofol will be administered via IV infusion. 
The starting dose and titration schedule specified in Table 3 will be followed, unless the patient is 
receiving propofol prior to randomization and is within RASS target range. In such cases, the same 
dose as prior to randomization is recommended as the starting dose. 
Table 3. 
Propofol IV Infusion Starting Dose and Titration Schedule 
Starting Dose 
Dose Titration Schedule 
0.6 to 1.5 mg/kg/hour, or the pre-randomization dose in 
patients already receiving SOC propofol and within the 
targeted RASS range 
Stepwise titration by 0.3 to 0.6 mg/kg/hour every 5 to 
10 minutes 
 
Bolus dose of 0.3 to 0.5 mg/kg 
IV = intravenous; RASS = Richmond Agitation Sedation Scale; SOC = standard of care. 
5.3.3 
Initiation of Study Drug Treatment 
The SOC sedatives and opioid analgesics will be reduced to half as soon as possible after 
randomization and prior to study drug initiation, unless the patient is agitated or shows signs of 
ongoing pain, as described in Section 6.1.3. If clinically indicated after the dose reductions and 
prior to the start of study drug treatment, titration of SOC sedatives and/or opioid analgesics is 
permitted.  
As soon as the study drug treatment has been initiated, the SOC sedative should be stopped 
(ie, slow weaning will not be permitted) to limit the impact of residual SOC sedation.  
Once study drug treatment has been initiated, titration will be based on frequent assessments of 
the patient’s sedation depth, hemodynamics, and end-tidal isoflurane concentration (for isoflurane 
group) by the clinical staff who are unblinded to study drug assignment. The patient’s level of pain 
will also be assessed to inform opioid dose titration.  

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Isoflurane administered via Sedaconda ACD-S  
The Sedaconda ACD-S is set up according to the Instruction-For-Use together with a gas monitor 
and scavenging system and should be used according to the Instruction-For-Use provided. 
The syringe is filled with 50 mL of isoflurane and put into the syringe pump. Isoflurane syringes 
will be prepared according to the instructions for use and local drug guidelines when a patient is 
randomized to isoflurane and delivered to the local drug storage facility at the ICU. Sedation will 
start after priming of the Sedaconda ACD-S agent line with 1.2 mL isoflurane.  
The starting dose and titration schedule are specified in Table 2. 
Propofol IV 
Propofol is set up according to local guidelines. The starting dose and titration schedule are 
provided in Table 3. 
5.3.4 
Study Drug Treatment Maintenance 
Throughout the study drug treatment period, the study drug dose (isoflurane or propofol) should 
be titrated to maintain RASS between -1 to -4. 
If study drug is insufficient to reach or maintain the target RASS range, rescue sedative agents 
should be given in accordance with Section 5.4.  
Sedation may be paused for clinical purposes (eg, decreased sedation for neurological 
examinations, or conduct of a SAT and SBT consistent with best practice in accordance with 
Section 3.4). 
Management of procedural sedation is discussed in Section 5.5.2.1. 
Study drug may not be administered outside of the ICU. In the case of procedures outside the ICU, 
study drug must be stopped (removal of Sedaconda ACD-S, or replacement of propofol dispensed 
as study drug). Study drug should be re-initiated as soon as possible after returning to the ICU, at 
a dose between 50% and 100% of the previously administered dose at the time of treatment 
interruption, and titrated to reach the target RASS range.  
Patients who return to the ICU prior to 42 hours from start of study drug treatment (the earliest 
timepoint for end of study drug treatment) should resume study drug.  
Patients who return to the ICU later than 42 hours from start of study drug treatment, should 
transition to SOC sedation and medical care at the discretion of the treating physician. See 
Section 6.2.6 for related procedures at EOT. 
Isoflurane via the Sedaconda ACD-S  
The syringe pump rate for a given sedation target may need to be adjusted to match the patient’s 
minute ventilation. Significant increases in minute ventilation may require an increase in pump 
rate to maintain the sedation level. Similarly, significant decreases in minute ventilation may 
require a decrease in pump rate to maintain the same sedation depth. 
In absence of other sedatives, but with ongoing IV opioid administration, typical maintenance 
pump rates to achieve RASS -1 to -4 are approximately 0.4 mL/hour isoflurane/L minute 
ventilation, translating to a pump rate of approximately 3 mL/hour for a patient with a minute 
ventilation of 7 L/min. Pump rate should be adjusted to achieve the intended sedation target, 

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considering the patient’s age and medical condition, as well as concomitant centrally acting 
medications. Pump rates of up to 15 mL/hour are allowed. For short procedures or to increase 
sedation quickly, a programmed bolus of 0.3 to 0.5 mL can be given via the pump, see 
Section 5.3.1. 
Long-term end-tidal concentration assessed every 4 hours should not exceed 1%. If end-tidal 
concentration should exceed 1% at 2 consecutive 4-hour end-tidal concentration measurements, 
the isoflurane pump rate should be reduced, and no bolus doses of isoflurane should be used until 
the patient reaches an isoflurane end-tidal concentration below 1%. 
The Sedaconda ACD-S device may be changed as needed or at least after 24 (4) hours of study 
drug administration. The time for the Sedaconda ACD-S device change should be recorded in the 
eCRF. 
When stopping isoflurane administration, the Sedaconda ACD-S must be removed and replaced 
with a standard HME or active humidifier. Removal of the ACD-S is necessary to facilitate rapid 
elimination of isoflurane from the body. 
Propofol 
The propofol and the propofol line or syringe may be changed as needed according to local 
guidelines.  
5.3.5 
Post-Study Drug Treatment 
After EOT or early discontinuation of study drug, study drug should not be resumed or re-initiated, 
and SOC sedatives should be initiated as needed to ensure patients are not restless or agitated for 
any length of time. Patients will transition to medical care per SOC at the discretion of the treating 
physician. The isoflurane, propofol, and Sedaconda ACD-S provided for the study may not be 
used after the completion of the study drug treatment period. 
5.4 
Rescue Medication 
5.4.1 
Rescue Sedation and Treatment Failure 
Whenever possible, the patient’s sedative requirements should be met using only the assigned 
study drug, which may be titrated as necessary in accordance with Section 5.3. If study drug is 
insufficient to reach or maintain the target RASS range or if the patient requires additional sedation 
due to a medical procedure, action may be taken as outlined below. 
 
Per-protocol rescue sedation  
Rescue sedation is defined as sedative agents, other than the study drug, that are allowed in case 
of inadequate sedation, due to reasons such as observed acute agitation or immediate risk of 
extubation that is not controlled by administration of study drug and despite adequate analgesia 
(pain management assessed by CPOT).  

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The use of rescue sedation in this study should be stepwise in the following order: 
First-line rescue: bolus of study sedative drug 
The following rescue medications, with dose ranges, can be given: 
 Bolus doses of the assigned study drug patient is receiving: 
o Propofol 0.3 to 0.5 mg/kg, or isoflurane 0.3 to 0.5 mL; and 
o Maximum 2 bolus doses/hour before use of second-line rescue medication (when used as 
rescue rather than procedural). 
Second-line rescue: rescue sedatives if study sedation is not sufficient 
These medications should not be used routinely. The choice of medications used for second-line 
rescue sedation depends on the clinical scenario and anticipated need for additional sedation.  
The following rescue medications, with dose ranges, can be given: 
 Dexmedetomidine infusion: 0.15 to 0.7 mcg/kg/hour for a maximum of 3 hours accumulated 
per 24 hours; and/or 
 Midazolam bolus: 0.5 to 5 mg per dose, at a maximum of 3 boluses per 24 hours. 
 
Treatment failure 
Treatment failure is defined as when study drug is deemed insufficient to reach or maintain the 
target RASS range for sedation, and the resulting amount of rescue sedation meets either of the 
following criteria: 
 There is a clinical need for infusion of dexmedetomidine for >3 hours per 24 hours; and/or 
 There is a clinical need for >3 midazolam boluses per 24 hours. 
As soon as possible after treatment failure occurs, the patient should discontinue study drug and 
transition to medical care per SOC at the discretion of the treating physician. See Section 6.2.5 for 
related procedures at the time of study drug discontinuation. 
5.5 
Prohibited and Restricted Medications 
5.5.1 
Prohibited Medications 
Medications for purposes of sedation other than the allocated study drug are prohibited throughout 
the study drug treatment period, unless used for procedures outside the ICU. Such prohibited 
medications include the following: 
 Chlorpromazine; 
 Chloral hydrate; 
 Barbiturates; 
 Gamma-hydroxybutyrate;  
 Clonidine;  

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 Ketamine; and 
 Continued treatment with a NMBA for >4 hours during the study drug treatment period. 
If prohibited medications specified above are deemed required for patient safety during the study 
drug treatment period, the patient should discontinue study drug and transition to medical care per 
SOC at the discretion of the treating physician. See Section 6.2.5 for related procedures at the time 
of study drug discontinuation. 
5.5.2 
Restricted Medications 
The following medications are restricted during the study treatment period when in the ICU: 
 Propofol; 
o Non-study drug propofol infusions are not permitted in either of the treatment arms for 
sedation with the exception of procedures inside or outside the ICU, as outlined in 
Section 5.5.2.1. 
 Benzodiazepines (see Section 7.1.6) may only be used as rescue sedatives if study sedation is 
not sufficient; 
 α2-adrenergic agonists (see Section 7.1.6) may only be used as rescue sedatives if study 
sedation is not sufficient and during SATs and the EOT wake-up test (see Section 6); 
 Antipsychotics, eg, haloperidol, quetiapine, olanzapine, or chlorpromazine should not be used 
during study sedation unless the patient has been on these medications before ICU admission, 
except during SATs (see Section 5.5.2.1) and during the EOT wake-up test (see Section 6); 
and 
 NMBAs. 
o Continuous infusions of NMBAs for study drug treatment periods >4 hours are not 
permitted. Shorter infusions of NMBA may be used as indicated for medical procedures as 
described in Section 5.5.2.1. Any infusions of NMBAs 4 hours must be identified and 
recorded by site staff. If a NMBA is given as a bolus, no assessments of RASS, CPOT, or 
spontaneous breathing efforts can be performed until at least 2 hours after the last bolus. If 
a NMBA is given as a continuous infusion (<4 hours), no assessments of RASS, CPOT, or 
spontaneous breathing efforts can be performed until 4 hours after termination of 
continuous infusion. 
 
Procedural sedation 
Sedation for procedures within the ICU 
The infusion rate of study drug may be increased pre-emptively in anticipation of increased 
requirement of sedation due to, or during, a planned minor procedure in the ICU (eg, changing 
dressings, washing or repositioning the patient, bronchoscopy, IV-line placement, radiological 
examination). This is considered a change in sedation level per SOC and should be recorded as 
any other changes in study drug administration.  

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Pre-emptive increase of the study drug and/or additional bolus sedation is permitted during minor 
ICU procedures, as specified below: 
 For procedures not involving the airway; 
o Bolus doses of study drug/temporary increase of study drug dose are allowed. 
 For isoflurane, pump rate may temporarily be increased up to 50% above the sedation 
maintenance pump rate for short periods (eg, up to 30 minutes) during short surgical 
procedures. 
 For airway-related procedures (ie, bronchoscopy and suctioning in the endotracheal tube); and 
o Bolus doses of propofol, 1 to 2 mg/kg, or continuous infusion up to 4 mg/kg/hour 
(66 mcg/kg/min), are allowed in either treatment group; and 
o Additional analgesia is permitted, such as fentanyl and alfentanil. 
Administration of these medications may be repeated, as needed, during the procedure. 
 During daily SATs or during the EOT wake-up test, antipsychotics and/or medications 
(analgesics or α2-adrenergic agonists) intended to reduce autonomic stress are permitted at the 
lowest effective dose and only if the patient does not tolerate the procedure without such drugs. 
α2-adrenergic agonists must not be started earlier than 60 minutes before initiating the SAT or 
EOT wake-up test. If the patient needs re-sedation after a daily SAT, bolus doses of the 
assigned study drug may be given for rapid deepening of sedation.  
Sedation or anesthesia procedures outside the ICU 
In the case of surgical or diagnostic procedure (eg, radiological examination) outside the ICU, 
study drug should be replaced by other medications as indicated regardless of the RASS score, at 
the discretion of the clinical team. The time for leaving and returning to the ICU must be recorded 
in the eCRF.  
Anesthesia and analgesia for these purposes shall be given according to SOC.  
See Section 5.3.4 regarding re-initiation of study drug when the patient returns to the ICU. 
5.5.3 
Restricted Procedures 
Soft physical restraints should be used only after closely weighing the risks and benefits of their 
use in the individual patients. During the study drug treatment period, the use of restraints should 
be assessed and documented in the eCRF. 
5.5.4 
Analgesic Treatment 
Opioids and other analgesic drugs (eg, acetaminophen, ketorolac, ibuprofen) are permitted 
throughout the study to treat pain.54 Study drug and rescue sedation should not be used to treat 
pain; rather, a pain medication should be used. All pain treatment should be used per SOC.  
All study patients should receive adequate analgesia throughout the study at the discretion of the 
Investigator and treating clinical team. Continuous opioid infusions as per SOC are allowed 
throughout the study drug treatment period but should be adjusted as clinically appropriate 
primarily after CPOT assessments.  

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The majority of study patients are anticipated to be receiving SOC opioids in parallel with 
sedatives, as opioids are indicated to manage pain, which most mechanically ventilated patients 
experience. As in clinical practice, CPOT scores and other clinical parameters (eg, breathing effort, 
gut mobility) guide dosing. It is recommended to use the lowest possible opioid maintenance dose 
to reach analgesia and comfort goals and minimize opioid side effects. Non-opioid analgesia can 
be considered, when appropriate. 

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6 
STUDY PROCEDURES 
Study procedures will follow the Schedule of Procedures in Appendix A. See Section 7 (Study 
Assessments) and Section 8 (Safety Assessments) for additional information on each assessment. 
6.1 
Screening Period 
6.1.1 
Screening (Day -30 to Randomization) 
The participating patients will be recruited at the study sites. Due to the nature of the study patient 
population, ie, necessitating consent by the study patient or LAR, sedated patients admitted to the 
ICUs will be pre-screened on available clinical data prior to obtaining informed consent. 
Assessments taken in SOC may be used even if they are taken before the informed consent 
procedure. 
The study sites are advised to designate a person responsible for daily pre-screening. Potential 
candidates or their LARs will be contacted and invited to receive written and oral information 
about the study. Thereafter, formal screening will follow. 
Investigators should keep an anonymized record (eg, a patient pre-screening log) of patients who 
entered the pre-study screening and were considered for enrollment, even if they were not 
subsequently enrolled. This information is necessary to verify that the patient population was 
selected without bias (in accordance with International Council for Harmonisation [ICH]-Good 
Clinical Practice [GCP]). The reasons for non-eligibility are to be defined in terms of 1 or more of 
the eligibility criteria. 
A unique patient identification number will be assigned to each patient for whom informed consent 
has been obtained (refer to Section 3.6.1). 
The Screening period may begin up to 30 days prior to initiation of study drug administration to 
allow for postsurgical patients to be assessed preoperatively. Initiation of study drug treatment 
should occur ideally as close to randomization as possible and no later than 6 hours after 
randomization.  
 
Initial Screening (Day -30 to randomization) 
To allow for patient consent, the Initial Screening can be performed up to 30 days prior to 
randomization.  
The following will be performed at the Initial Screening: 
 Informed consent; 
 Inclusion/exclusion criteria; 
 Demographic information; 
 Medical/surgical history; 
 Physical function and outcomes (Katz Index of Independence in Activity of Daily Living [Katz 
ADL] and Pfeffer functional activities questionnaire [FAQ]); and 
o Screening Katz ADL and Pfeffer FAQ data can be collected until 48 hours after initiation 
of study drug treatment as the time period of interest is not synonymous with when data 
needs to be captured. 

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 Cognitive function and outcomes (Informant Questionnaire on Cognitive Decline in the 
Elderly [IQCODE]). 
o Screening IQCODE data can be collected until 48 hours after initiation of study drug 
treatment as the time period of interest is not synonymous with when data needs to be 
captured. 
 
Complete Screening (-24 hours to randomization) 
The Complete Screening shall be performed within 24 hours prior to randomization.  
If the Initial Screening is performed more than 24 hours prior to randomization, the following 
assessments need to be re-assessed: 
 Inclusion/exclusion criteria; and 
 Medical/surgical history. 
For all patients, the Complete Screening will include the following: 
 Prior relevant medications, including the mean opioid dose assessment at 60 minutes prior to 
randomization (see Section 7.2.1); 
 Weight and height; 
 Physical examination; 
 Clinical laboratory assessments; 
o Screening/Baseline clinical laboratory tests, other than those pertaining to trial eligibility, 
may be collected at any time during the Complete Screening or post-randomization period 
prior to initiation of study drug treatment. 
 Pregnancy test (female patients of childbearing potential);  
 Patient characteristics, including SAPS III (see Appendix J); and 
 Anticipated remaining time on the ventilator (at time of randomization). 
6.1.2 
Randomization 
Each eligible patient will be assigned a unique identification number. The Investigator or designee 
must contact the 
 
 Interactive Response Technology (CTIRT) to acquire the 
unique identification number for each patient. Patient numbers will consist of 6 digits. The first 
3 digits will reflect the site number assigned, followed by a 3-digit patient number. The patient 
number will be used to identify the patient throughout the study. 
If a patient is not eligible to receive treatment or if the patient discontinues from the study, the 
unique patient number cannot be reassigned to another patient.  
The run-in training patients will be assigned a unique identification number but will not be 
randomized. 

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Randomization will be stratified by SAPS III (Total score 0 to <40, 40 to <60, and 60) and patient 
type (medical and surgical [including trauma]) assessed at Screening. Surgical patient will be 
defined as patients who meet either of the following criteria:  
1. Have undergone surgery within the prior 2 weeks and for whom the current respiratory failure 
episode is related to that surgery or surgical disease process, or a complication thereof; or  
2. Patients anticipated to undergo surgery within the next 2 days for a condition that is related to 
etiology of respiratory failure. 
Treatment assignments for the individual patients will be determined through a computer 
generated randomization list and accessed using the CTIRT. Instructions for access and use of the 
system are provided in the study manual. 
6.1.3 
Baseline (Randomization to Initiation of Study Drug Treatment)  
As soon as possible after randomization, and no later than 6 hours after randomization, the study 
equipment will be set-up and study drug treatment shall be initiated. 
SOC sedative and opioid infusion doses should be reduced to half as soon as possible after 
randomization and prior to study drug initiation unless the patient is agitated or showing signs of 
ongoing pain. 
As soon as the study drug treatment has been initiated, the SOC sedative should be stopped 
(ie, slow weaning will not be permitted) to limit the impact of residual SOC sedation. Note that 
Baseline procedures should be performed prior to the start of study drug administration. 
The following will be performed: 
 Reduction of SOC sedative and opioid infusion doses to half; 
 Unblinded RASS and CPOT within 30 minutes prior to the initiation of study drug 
administration; 
 Vital signs within 60 minutes prior to the start of study drug administration; 
 Ventilator parameters; 
 Blood gases; 
 Organ function (sequential organ failure assessment [SOFA] on the date of randomization); 
and 
 Concomitant relevant medications (see Section 7.2.1). 
6.2 
Treatment Period 
From start of study drug and throughout the study drug treatment period, the following will be 
performed: 
 Concomitant relevant medications (see Section 7.2.1); 
 Study drug administration; 
 Sedaconda ACD-S device deficiencies; and 
 AEs. 

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Data related to study drug administration, including doses, dose changes, start and stop times, and 
occurrence of any interruptions in study drug administration, will be recorded. The dose of 
isoflurane (mL/hour) and propofol (mg/kg/hour or mcg/kg/min) should be recorded throughout 
study drug treatment and every time study drug dose is adjusted. 
The patient’s sedation level and opioid doses will be assessed frequently by the clinical staff who 
are unblinded to the study drug assignment. Unblinded RASS and CPOT assessments to guide 
titration will, however, not be documented in the study eCRF. 
6.2.1 
Every 2 (0.5) Hours From Start of Study Drug 
From start of study drug and throughout the study drug treatment period, the following will be 
performed every 2 hours: 
 RASS (blinded assessments); and 
 CPOT (blinded assessments). 
6.2.2 
Every 4 (0.5) Hours For Isoflurane Patients Only 
From start of study drug and throughout the study drug treatment period the following will be 
performed every 4 hours: 
 Isoflurane end-tidal concentration measurement. 
6.2.3 
Every 8 (2) Hours 
From start of study drug and throughout the study drug treatment period, the following will be 
performed every 8 hours: 
 Ventilator parameters; 
 Vital signs; and 
 Blood gases (if arterial line is available). 
Note: These assessments will be performed more frequently when clinically indicated (as patients 
will often be observed continuously or more frequently than every 8 hours in clinical practice). 
6.2.4 
Daily 
The following will be performed daily after the initiation of study drug: 
 Non-blinded CAM-ICU-7 (together with non-blinded RASS) according to Section 7.2.3;  
Note: More frequent assessments will be performed when clinically indicated. 
 Clinical laboratory assessments; 
 Organ function (SOFA) (excluding the date of randomization, which is captured in the 
Baseline procedures; see Section 6.1.3); and 
 Restraints assessment. 

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6.2.5 
Early Study Drug Discontinuation 
If study drug is discontinued for any of the reasons listed in Section 4.3, the following assessments 
will be performed at the time of study drug discontinuation: 
 The date, time, and reason(s) for early discontinuation of study drug; 
 Physical examination (unless already performed this calendar date and not required for patients 
transitioned to comfort care);  
 Clinical laboratory assessments (unless already performed this calendar date prior to study 
drug discontinuation. Not required for patients transitioned to comfort care); 
 Organ function (SOFA); and 
 Restraints assessment. 
If patients are discontinued early from study drug, patients will transition to medical care per SOC 
at the discretion of the treating physician. 
Unless the patient or LAR withdraws consent, the patient should continue in the study for safety 
assessments and follow-up even if the study drug is discontinued. All visits and assessments 
required for the rest of the study will be conducted and recorded in the eCRF, if possible. Wake-up 
test and CAM-ICU-7 at EOT per Section 6.2.6 should not be performed. 
6.2.6 
End of Treatment 
The following will be performed at EOT due to end of study treatment or extubation: 
 Wake-up test;  
o Blinded RASS assessments until 4 hours after EOT. 
 Blinded CAM-ICU-7 (not required for patients reaching EOT due to treatment failure, patients 
transitioned to comfort care, or patients continued onto benzodiazepines or propofol sedation 
due to clinical need before 60 minutes after EOT); and 
o Assessment at 60 minutes (10 minutes) after EOT. 
 Physical examination. 
Patients will thereafter transition to medical care per SOC at the discretion of the treating 
physician. 
6.3 
Follow-Up Period 
6.3.1 
Post-Treatment Monitoring 
The following will be performed once until 24 hours after EOT: 
 Physical examination; 
 Vital signs; 
 Clinical laboratory assessments; 

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o To be performed if patient is still in the ICU at 18 hours after EOT. Analyses performed 
with an 18- to 48-hour window after EOT per SOC can be used. 
 Time of extubation; 
o For patients who are extubated on study drug only. 
 Concomitant relevant medications (see Section 7.2.1); and 
 AEs. 
6.3.2 
Follow-Up Contact 
 
Until Day 7 after EOT (2 days) 
The following will be performed from EOT until Day 7 after EOT: 
 Concomitant relevant medications (see Section 7.2.1); and 
 AEs. 
The following will be performed daily until Day 7 after EOT or until discharge, whichever comes 
first: 
 Organ function (SOFA) until ICU discharge; and 
 Delirium and coma assessment with RASS and CAM-ICU-7 until hospital discharge. 
 
Study Day 30 (+5 days) after randomization 
The following will be performed at Study Day 30 or at ICU discharge, whichever comes first: 
 Major ICU interventions (see Section 7.2.13); and 
 Concomitant relevant medications (see Section 7.2.1). 
The following will be performed through telephone call if not possible to retrieve information 
through medical records at Study Day 30 (regardless of ICU discharge status): 
 Level of care (can be collected retrospectively for the whole study period); 
 Duration of mechanical ventilation; 
 Late onset drug-induced liver injury; 
 Mortality; and 
 Follow-up of any unresolved AEs. 
Evidence of late onset hepatitis or drug-induced liver injury (DILI) attributable to study drug 
treatment, as assessed via medical records, laboratory assessments, or diagnosis review should be 
performed at Study Day 30. Any findings should be recorded as AEs. 

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3 months (4 weeks) – telephone call 
The following will be performed through telephone call at 3 months: 
 LTO assessments; and 
o A detailed description of the LTO assessments performed at the 3-month follow-up visit in 
a consecutive subset of patients are described in Section 7.3. 
 Mortality. 
 
6 months (4 weeks) – telephone call 
The following will be performed through telephone call at 6 months in a consecutive subset of 
patients: 
 LTO assessments; and 
o A detailed description of the LTO assessments performed at the 6-month follow-up visit 
are described in Section 7.3.  
 Mortality. 
6.4 
Early Withdrawal From Study 
For patients who are withdrawn from the study prior to completion, all applicable study procedures 
will be performed at an early withdrawal visit. Any assessments done within 2 hours prior to the 
withdrawal can be used as the early withdrawal assessment. 
If a patient withdraws consent, the patient will be encouraged to complete the early withdrawal 
visit, if possible.  
Patients who have discontinued their participation in the study cannot re-enter into the study. 
Withdrawn patients will not be replaced. Patients will transition to medical care per SOC at the 
discretion of the treating physician. 
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s records. 
6.4.1 
Study Withdrawal Prior to EOT 
If patient is withdrawn and study drug is discontinued prior to EOT, see Section 6.2.5 for related 
procedures at the time of study drug discontinuation. 
6.4.2 
Early Withdrawal After EOT 
When study withdrawal occurs after EOT and before the Study Day 30 follow-up, the following 
will be performed, if accepted despite consent withdrawal: 
 The date, time, and reason(s) for study withdrawal;  
 Physical examination (until 24 hours after EOT); 
 Vital signs (until 24 hours after EOT); 
 Level of care (until Study Day 30); 

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 Time of extubation and duration of mechanical ventilation (until Study Day 30);  
 AE collection (until Day 7 after EOT, or unresolved AE until Study Day 30); and 
 LTO assessments at 3 and 6 months. 
o ICU Memory Tool will be assessed at 3 months follow-up only. 

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7 
STUDY ASSESSMENTS 
7.1 
Blinded Efficacy Assessments 
Blinded assessments of RASS, CPOT, and CAM-ICU-7 will be performed, as indicated in 
Appendix A, by designated assessors.  
7.1.1 
Richmond Agitation Sedation Scale 
The RASSa,b shown in Figure 3 will be used to assess agitation and sedation throughout the study. 
Figure 3. Richmond Agitation Sedation Scale 
 
Clarification regarding procedure for RASS Assessment item #3: When no response to verbal stimulation, physically stimulate 
the patient by shaking the shoulder. Rubbing the sternum will NOT be used in the study. 
RASS = Richmond Agitation Sedation Scale. 
In training and written bedside instructions, shaking the patient’s shoulder (not rubbing the 
sternum) will be stated as the method to discriminate between RASS -4 to -5. 
For the primary endpoint, blinded efficacy assessment of RASS will begin 2 hours after initiation 
of study drug administration and every 2 hours thereafter until EOT per Appendix A. In 
accordance with the instructions defined for the instrument, the assessor should observe the patient 
 
Sources: 
a. Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care 
unit patients. Am J Respir Crit Care Med. 2002;166(10):1338-1344. 
b. Ely EW, Truman B, Shintani A, et al. Monitoring sedation status over time in ICU patients: the reliability and validity of the 
Richmond Agitation-Sedation Scale (RASS). JAMA. 2003;289(22):2983-2991. 

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for at least 30 to 60 seconds55 and score the most distressed or painful behavior (ie, the lightest 
RASS) shown during the observation period.  
7.1.2 
Critical Care Pain Observation Tool 
Pain will be assessed using the CPOT every 2 hours until EOT and recorded together with the 
blinded RASS assessment by the blinded assessor. The CPOT is included in Appendix E. 
For the purpose of the study, where the baseline opioid infusion is primarily aimed at alleviating 
pain at rest, the blinded CPOT assessments will be performed when the patient is at rest. Blinded 
CPOT assessments will not be performed during turning or active stimulation, nor to evaluate the 
effect of bolus doses of analgesics. 
7.1.3 
Periods When Blinded RASS and CPOT Assessments Should Not Be Performed 
Blinded RASS and CPOT assessments should not be performed during or shortly after periods of 
intentional deepening of sedation for procedures, nor during SAT. The earliest blinded RASS and 
CPOT assessments allowed after intentional changes in sedation level are as follows:  
 1 hour after intentional deepening of sedation for an in-ICU procedure (eg, following 
bronchoscopy, prone-positioning, or wound dressing); 
 1 hour after resuming study sedation after a procedure outside the ICU (eg, CT scan, 
endoscopy, surgery, etc); 
 1 hour after an SAT; 
 2 hours after a bolus of NMBA; or  
 4 hours after the end of an infusion of NMBA. 
If a clinical event meets more than one scenario with different exclusion periods, then the longer 
time period applies. For example, a patient who undergoes a procedure outside the ICU that 
requires NMBA infusion would have no blinded assessments done for 4 hours after the end of the 
NMBA. 
After the excluded period, blinded assessments should resume per the original schedule (see 
Section 7.1.5). 
7.1.4 
Communication of Blinded RASS and CPOT to Bedside Staff 
The blinded assessor will assess and document the RASS and CPOT scores without any 
interference by the clinical team. After the documentation of RASS and CPOT, the assessor will 
certify in writing that he/she was not aware of the study drug treatment given. Once the blinded 
assessor has left the room, bedside staff should access the documented RASS and CPOT scores 
and adjust the study drug and analgesia, if appropriate.  
The date, time, and result of each blinded RASS and CPOT assessment performed shall be 
recorded in the eCRF. 
7.1.5 
Handling of Interrupted and/or Missing RASS Assessments 
The time frame (every 2 [0.5] hours) for blinded RASS and CPOT gives some flexibility in the 
planning of the blinded assessments in relation to procedures or unexpected events affecting the 

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ability to perform the blinded RASS and CPOT assessments. If it is not possible to perform a 
blinded RASS assessment due to a procedure during the subsequent periods listed in the above 
Section 7.1.3, then that assessment will be skipped and the next assessment (ie, in another 
2 [0.5] hours) will be performed per the original schedule. 
Missed blinded RASS assessments due to procedures per SOC are not considered protocol 
deviations and are not counted as failure time. All missed RASS assessments will be documented, 
with reason for not being done, in the eCRF. 
7.1.6 
Wake-Up Test 
Prior to EOT, a safety screen51 (see Appendix D) will be conducted if RASS <0 to evaluate if it is 
safe to pause or discontinue sedation and allow the patient to wake up. Time to wake-up shall be 
measured for all patients after EOT unless prohibited by patient safety considerations in the 
judgment of the clinical team and Investigator.  
Immediately prior to stopping study drug (within 15 minutes prior to EOT), a blinded RASS 
assessment should be performed and documented. 
Patients whose blinded RASS is 0 or higher will not undergo wake-up testing.  
During the EOT wake-up test, antipsychotics and/or medications (analgesics or α2-adrenergic 
agonists) intended to reduce autonomic stress during wake-up are permitted at the lowest effective 
dose and only if the patient does not tolerate the wake-up test without such drugs. Opioid 
analgesics infusions should be paused, or reduced to a minimum level ensuring comfort 
(CPOT 2). Use of such medications during the wake-up test should be recorded in the eCRF. The 
use of study drug or benzodiazepines is not allowed during the EOT wake-up test.  
The wake-up test starts when study drug is stopped and Sedaconda ACD removed (in isoflurane 
arm). Study drug should not be resumed after this timepoint, and SOC sedatives should instead be 
initiated if needed to ensure patients are not restless or agitated for any length of time. 
Sedation depth will be assessed by a blinded assessor until RASS 0 or lighter is achieved, at a 
minimum frequency of: 
 Every 15 (5) minutes for hour 1; 
 Every 30 (10) minutes for hours 2 to 4; and 
 Earlier, as needed, for safety (eg, patient potential harm to self/others, pulling at devices, etc). 
The blinded assessor may remain at bedside after a prior RASS assessment, if it is deemed likely 
by the blinded assessor that RASS 0 may be achieved within a short time, and if it is agreed with 
bedside staff that the blinding will not be compromised by doing so. 
The wake-up test ends at the first occurrence of the following: 
 RASS 0 or lighter is confirmed by blinded assessment;  
 4 hours after EOT;  
 Time of re-sedation before RASS 0 due to respiratory distress, cardiovascular events, or other 
clinical indication; or 
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 New-onset neurological deficit or detection of intracranial event. 
Note: The diagnosis of neurological deficit or intracranial event should be recorded as an 
adverse event. The time for leaving ICU for diagnostic testing of neurological deficit or 
intracranial event should be recorded as a procedure. 
7.1.7 
CAM-ICU-7 at 60 Minutes After EOT 
Cognitive recovery will be assessed by the 7-point scale of the CAM-ICU-7 at 60 (10) minutes 
after EOT by a blinded assessor, on all patients except those already re-sedated with 
benzodiazepines or SOC propofol. If a planned assessment cannot be performed due to extubation 
procedure, the assessment should be performed as soon as possible after extubation.  
RASS is an integral part of the CAM-ICU-7 assessment and will be assessed first. If RASS is -3, 
CAM-ICU-7 will be performed. If RASS is -4 or -5, CAM-ICU-7 will not be performed.  
The CAM-ICU-7 is provided in Appendix F. 
7.2 
Other Assessments 
In clinical practice, some assessments may be documented frequently. For purposes of data entry, 
it is recommended to utilize the first available data point within the given time frame. However, 
apparently erroneous data should not be used. 
7.2.1 
Prior and Concomitant Medications 
From ICU admission, but not before 24 hours prior to initiation of study drug, until 24 hours after 
EOT all relevant prior and concomitant medications taken by the patient are to be recorded. 
Relevant medications include the following: 
 Opioids and other analgesics; 
 Sedative agents (including prohibited and restricted medications); 
 Antipsychotics/neuroleptics; 
 NMBAs; 
 Vasopressors and inotropes; 
Note: Data on vasopressors and inotropes will be recorded, as highest continuous dose for 
specified medications, per pre-defined time intervals. Bolus doses of vasopressors or inotropes 
will not be accounted for. 
 Any medications used to reverse the effects of the above medications; and 
 Any medications associated with an AE. 
Except for vasopressors and inotropes, data to be recorded are the dose, unit, frequency, route, and 
start and end time. For concomitant sedative and antipsychotics, the indication for administration 
(procedural sedation, rescue sedation, SAT, EOT, other reason) will also be recorded during the 
treatment period only. 

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Specified vasopressors and inotropes (highest continuous dose) include the following: 
 Angiotensin-II (ng/kg/min); 
 Dobutamine (mcg/kg/min); 
 Dopamine (mcg/kg/min); 
 Epinephrine (mcg/kg/min); 
 Norepinephrine (mcg/kg/min); 
 Milrinone (mcg/kg/min);  
 Phenylephrine (mcg/kg/min); and 
 Vasopressin (units/min). 
Pre-defined time intervals for highest continuous dose of vasopressors and inotropes include the 
following: 
 Pre-initiation: during the 24 hours in ICU prior to initiation of study drug (only administration 
in ICU will be considered); 
 Day 1: during the first 24 hours of study drug administration, or until EOT, if EOT occurs 
within the first 24 hours;  
 Day 2 until EOT: during hours 24 to 48 (6 hours) or until EOT, if EOT occurs during 
hours 24 to 48 (6 hours); and 
 From EOT until 24 hours after EOT. 
Receipt (Yes/No) per calendar day of selected medications will be collected in a separate form, 
from 24 hours after EOT until Study Day 30 or ICU discharge, whichever comes first:  
 Opioids and other analgesics; 
 Sedative agents; and 
 Antipsychotics/neuroleptics. 
Medications associated with an AE: 
Any medications associated with an AE should be recorded at the same level of detail as for 
relevant medications before end of the 24 hour post-treatment monitoring period.  
Medications associated with an AE are those that meet either of the following: 
 The medication is at least possibly related to the AE; or 
 The medication is given as treatment for the AE. 
Note that vasopressors and inotropes associated with an AE will be recorded both as highest 
continuous dose and at the more detailed level required for AEs in a standard concomitant 
medication eCRF. 

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7.2.2 
Non-Blinded RASS and CPOT 
Sedation and analgesia will be adjusted based on non-blinded RASS and CPOT by bedside staff 
between formal blinded assessments; however, these non-blinded clinical assessments will not be 
documented in the eCRF. 
7.2.3 
Non-Blinded CAM-ICU-7 
Delirium and coma free days from the start of study drug treatment and up to 7 days after EOT or 
up to hospital discharge, whatever comes first, will be assessed by daily (at a minimum) 
CAM-ICU-7 and RASS as specified in Appendix A. However, more frequent assessments will be 
performed when clinically indicated. RASS will be assessed first. If RASS is -3, CAM-ICU-7 
will be assessed. If RASS is -4 or -5, CAM-ICU-7 will not be assessed.  
If a patient’s RASS is -3 or lighter and negative for delirium per CAM-ICU-7, then the patient will 
be considered delirium and coma free for that assessment timepoint. 
The CAM-ICU-7 is provided in Appendix F. 
7.2.4 
Spontaneous Breathing 
Spontaneous breathing effort is present if any of the following is met: 
 Airway occlusion pressure (P0.1) >0 cmH2O (if available);  
 Pressure support (PS) or other spontaneous ventilator mode is being used; or 
 Observed respiratory rate exceeds set respiratory rate. 
7.2.5 
Restraints 
During the study drug treatment period, the use of restraints should be assessed daily. Soft physical 
restraints should be used only after closely weighing the risks and benefits of their use in the 
individual patients. 
7.2.6 
Organ Failure, SOFA 
Organ failures will be assessed using SOFA.56 The individual scores will be recorded and total 
score for all organs will be calculated; see Appendix H for calculator to be used.  
The function of several organs requires laboratory assessments. The routine laboratory values can 
be used, if available. 
7.2.7 
Clinical Laboratory Evaluations 
Clinical laboratory assessments should be performed at Screening and daily after the start of study 
drug administration. Assessments should also be performed on the calendar day after EOT, if the 
patient is still in the ICU. See Appendix A.  
Local hospital laboratories will be used to assess the safety laboratory parameters (including 
clinical chemistry, lipid profile, hematology, and coagulation). A list of laboratory analyses is 
presented in Appendix B.  
Any significant abnormalities, as assessed by the Investigator, will be followed according to 
clinical practice. Additional tests and other evaluations required to establish the significance or 

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etiology of an abnormal result or to monitor the course of an AE will be obtained when clinically 
indicated. 
7.2.8 
Physical Examinations 
A physical examination will be performed at Screening, at the end of the study drug treatment 
period, and 24 hours after EOT and should be performed, as appropriate, for the patient’s 
condition. 
During the physical examination, the Investigator will also consider results available from 
examinations such as ultrasound, radiology examinations, or laboratory tests and document his/her 
integrated assessment.  
Prespecified examinations will be evaluated as “not clinically significant” or “clinically 
significant” (abnormal). Other examinations and findings can also be recorded. Findings at 
Baseline must be reported in the medical history eCRF and findings at EOT should be reported as 
an AE. 
Pre-specified examinations include the following: 
 Neurologic examination (upper limb motor deficit, lower limb motor deficit, focal deficit); 
 Cardiac examination (heart rate irregular, arrhythmia, cardiac murmur); 
 Pulmonary examination (rhonchi, decreased breath sounds, wheezing, stridor); 
 Abdominal examination (abdominal tenderness, central obesity, scaphoid abdomen, bowel 
sounds decreased, bowel sounds increased); and 
 Extremity examination (peripheral coldness, pulse absent, oedema peripheral). 
7.2.9 
Pregnancy Test 
Female patients of childbearing potential must have a negative (serum or urine) pregnancy test 
prior to randomization. A pregnancy test obtained previously as part of usual care during this 
hospital episode that is documented in the patient’s medical record will suffice. Female patients 
not of childbearing potential are defined as female patients who have been postmenopausal for at 
least 1 year, have been surgically sterilized, or are 60 years of age. If possible, a urine dipstick 
will be used preferentially. If the urine test is positive, a serum chorionic gonadotropin pregnancy 
test must be performed to rule out pregnancy.  
7.2.10 
Vital Signs 
Vital signs are to be collected at Baseline and every 8 (2) hours until 24 hours after EOT. 
However, vital signs will be performed more frequently when clinically indicated. Vital signs will 
include the following: 
 Systolic, diastolic, and mean arterial blood pressure; 
 Heart rate; 
 Peripheral capillary oxygen saturation (SpO2), measured by pulse oximetry; 
o For patients not receiving ventilator treatment (for patients on ventilator support, SpO2 will 
be captured as part of the ventilator parameters). 

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 Respiratory rate; and 
Note: Respiratory rate will not be recorded as part of vital sign assessments while patient is on 
ventilator support, as it will be captured in the ventilator parameter records as observed 
breathing rate. 
 Body temperature. 
7.2.11 
Ventilator Parameters 
Ventilator parameters will be captured at Baseline and, at a minimum, every 8 hours until EOT. 
Ventilator parameter assessments will be performed more frequently when clinically indicated (as 
patients will often be observed continuously or more frequently than every 8 hours in clinical 
practice).  
The following parameters will be recorded, if available, per ventilator type, mode, and settings: 
 End-tidal concentration of isoflurane for patients randomized to isoflurane (% volume); 
 Ventilator mode, (select one of the below categories): 
o Volume assist/control or volume control (VC); 
o VC with autoflow; 
o Pressure assist/control (PC); 
o Pressure-regulated volume control (PRVC) or volume-targeted pressure control; 
o Pressure support ventilation (PSV);  
o Volume Support; 
o Volume synchronized intermittent mandatory ventilation (SIMV); 
o Pressure SIMV; 
o PRVC SIMV; 
o Airway pressure release ventilation; 
o Bivent or Bilevel; 
o Neurally adjusted ventilatory assist;  
o Adaptive support ventilation;  
o Mandatory minute ventilation; and 
Note: Changes in minute ventilation will be displayed continuously on the ventilator, 
available for bedside staff and for assessment by the clinical team. The documented minute 
ventilation will be based on the actual minute ventilation, including spontaneous breathing 
efforts. 
o Other (includes dual and alternative modes). 
 Set tidal volume (mL) (for volume-targeted modes only); 
 Observed tidal volume (mL); 

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 Set rate (breaths/minute) (for modes with preset rates only); 
 Observed rate (breaths/minute); 
 Observed minute volume (L/minute); 
 Set positive end-expiratory pressure (PEEP) (cmH2O); 
 PS above PEEP (cmH2O) (for PSV mode only); 
 PC above PEEP (cmH2O) (for PC mode only); 
 Peak inspiratory pressure (cmH2O); 
 Plateau pressure, with a 0.5 second end-inspiratory cause (cmH2O) (if available); 
 Mean airway pressure (cmH2O); 
 Fraction of inspired oxygen (%); 
 SpO2 (%); 
 EtCO2; 
 Ventilator trigger (select 1 of the below): 
o Pressure (cmH2O); or 
o Flow (L/minute). 
 P0.1 (if available); 
 Arterial blood gas (ABG) since last evaluation (if available); 
 PCO2 (mmHg); and 
 Partial pressure of oxygen (PaO2) (mmHg). 
7.2.12 
Blood Gas Analyses 
Blood gas analyses will be performed at Baseline and every 8 hours until EOT, if arterial line is 
available. Blood gas analyses will be performed more frequently when clinically indicated. 
If arterial line is available, the following parameters will be obtained from arterial blood samples 
as specified in Appendix A: 
 Arterial pH; 
 Base excess in mmol/L (mEq/L); 
 PCO2 (mmHg); and 
 PaO2 (mmHg). 
7.2.13 
Major ICU Interventions 
Major ICU interventions will be assessed through Study Day 30 or until ICU discharge, whichever 
comes first. New renal replacement therapy or extracorporeal support occurring prior to Study 
Day 7 from the start of study drug should also be reported as AEs. Extubation, tracheostomy, 
non-invasive ventilation, or re-admission to the ICU should, however, not be reported as AEs. 

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The following specific events are major ICU interventions: 
 Renal replacement therapy; 
 Extracorporeal life support; 
 Extubation; 
 Tracheostomy; and 
 Non-invasive ventilation. 
7.2.14 
Level of Care 
The level of care will be assessed as specified in Appendix A and will include the following: 
 Still in ICU; 
 Patients deceased in the ICU; 
 Intermediary care unit; 
 General ward; 
 Another ICU (within or outside the hospital); 
 Another hospital (unknown ward); 
 Rehabilitation unit; 
 Nursing home;  
 Hospice; or 
 Home. 
7.2.15 
Late Onset Drug-Induced Hepatitis 
At Study Day 30, sites should assess for evidence of late onset hepatitis or DILI attributable to 
study drug treatment. This assessment can be done via medical records, laboratory assessments, or 
diagnosis review. Any findings should be recorded as AEs. 
7.3 
Long-Term Outcomes Assessment 
Cognitive, Mental Health, Functioning, and Quality of Life Assessments will be conducted at 
3 and 6 months post-randomization as specified in Section 3.11 and Appendix A. Baseline 
assessments will be conducted by the IQCODE, Katz ADL, and Pfeffer FAQ as specified in 
Appendix A. 
7.3.1 
Cognitive Long-Term Outcomes 
Cognitive LTO will be assessed by: 
 Telephone Interview for Cognitive Status (TICS). 
The TICS is a brief, standardized test developed for use in situations where in-person cognitive 
screening is impractical or inefficient (eg, large-scale population screening, epidemiological 
surveys, with patients who are unable to appear in person for clinical follow-up).  

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 Hayling Sentence Completion Test. 
The Hayling Sentence Completion Test is a measure of executive function consisting of 
two sets of 15 sentences; the examiner reads the questions aloud and patient completes the 
sentences.  
 Wechsler adult intelligence scale (WAIS) IV-Digit Span. 
The WAIS IV-Digit Span involves the recitation of a string of numbers as a measure of 
attention.  
 Controlled Oral Word Association. 
The Controlled Oral Word Association involves generating a list of as many words that start 
with “F,” “A,” and “S” in 60 seconds to measure verbal fluency.  
 Wechsler memory scale (WMS)-IV – Immediate Memory (Adult/Older Adult). 
The WMS-IV – Immediate Memory (Adult/Older Adult) is a test in which a patient 
immediately recalls a short story. The WMS-IV (Adult) is used for adults under the age of 
65 and the WMS-IV (Older Adult) is used for adults 65 and older. The Logical 
Memory I subtest is used to test Immediate Memory on the WMS-IV (both Adult and Older 
Adult).  
 WMS-IV – Delayed Memory (Adult/Older Adult). 
The WMS-IV – Delayed Memory (Adult/Older Adult) is a test in which a patient recalls a 
short story 20 minutes later. The WMS-IV (Adult) is used for adults under the age of 65 and 
the WMS-IV (Older Adult) is used for adults 65 and older. The Logical Memory II subtest is 
used to test Delayed Memory on the WMS-IV (both Adult and Older Adult). 
 Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive Function 
questionnaire. 
The PROMIS Cognitive Function questionnaire is a set of person-centered measures that 
evaluates and monitors physical, mental, and social health. 
 ICU Memory Tool. 
The ICU Memory Tool is a brief tool that evaluates memories during critical illness/intensive 
care. 
7.3.2 
Physical Long-Term Outcomes 
Physical LTO will be assessed by: 
 Katz ADL. 
The Katz ADL is a brief measure of basic activities of daily living. 
 Pfeffer FAQ. 
The Pfeffer FAQ is a brief measure of "higher order" abilities (eg, driving, managing money, 
cooking, understanding the news, etc). 

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7.3.3 
Psychological Long-Term Outcomes 
Psychological LTO will be assessed by: 
 Impact of event scale (IES-R). 
The IES-R is a brief screening tool that measures post-traumatic stress disorder (PTSD) and 
PTSD symptoms. 
 PROMIS Depression and Anxiety Questionnaires. 
The PROMIS Depression and Anxiety questionnaires are a set of person-centered measures 
that evaluates and monitors depression and anxiety. 
7.3.4 
Long-Term Quality of Life Outcomes 
Quality of life will be assessed by:  
 WHO Disability Assessment Schedule 2.0 (WHODAS). 
The WHODAS is a generic assessment instrument for health and disability. 
 Brief Pain Inventory (BPI). 
The BPI is an assessment tool used in pain management. 

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8 
SAFETY ASSESSMENTS 
8.1 
AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and/or unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product. All AEs as described below, including observed or volunteered 
problems, complaints, or symptoms, are to be recorded on the appropriate eCRF.  
In this study of critically ill patients, AEs should be defined in relation to the patient’s condition. 
Fluctuations in clinical state or typical medical occurrences expected in this setting need not be 
recorded as AEs. Some examples of relevant AEs are provided in Appendix G. Note that these are 
examples and not an exhaustive list, so the Investigator should exercise judgment in the collection 
of AEs in the study.  
AEs, which include clinical laboratory test variables, will be monitored and documented from the 
initiation of study drug administration until the 7-day post EOT follow-up. AEs occurring during 
the clinical study will be followed until returned to normal, stabilized, or are no longer clinically 
significant. If remaining clinically significant at the Day 7 follow-up, the patient will be referred 
to an appropriate clinical consultant. Such referrals will be followed-up at Study Day 30 and 
outcomes documented.  
Instructions should be provided to the Investigator and his/her designees to report any AE that 
patients experience, whether or not they think the event is related to study drug. From the start of 
study drug administration, Investigators should continuously monitor for AEs until the end of the 
7-day after EOT follow-up and record the AEs in the eCRF. 
Wherever possible, AEs should be reported as specific diseases or syndromes rather than 
individual associated signs and symptoms. However, if an observed or reported sign or symptom 
is not considered a component of a specific disease or syndrome by the Investigator or designee, 
it should be recorded as a separate AE in the eCRF. Additionally, the condition (eg appendicitis, 
gastrointestinal bleeding, or hemolytic anemia) that led to a medical or surgical procedure (such 
as surgery, endoscopy, or transfusion) should be recorded as an AE, not the procedure itself.  
Any medical condition already present at the start of study drug administration should be recorded 
as medical history and not be reported as an AE unless the medical condition or signs or symptoms 
present at Baseline changes in severity, frequency, or seriousness later during the study. In this 
case, it should be reported as an AE. 
Clinically significant abnormal laboratory or other examination findings that are detected during 
the study or worsen significantly from Baseline during the course of study should be reported as 
AEs, as described below. The Investigator will exercise his or her medical and scientific judgment 
in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. Abnormal test results that are determined to be an error (eg, followed up with a normal 
value shortly after a suspected spurious value) should not be reported as an AE. Laboratory 

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abnormalities or abnormal clinical assessments should be reported as an AE if any of the following 
are applicable: 
 If action taken with the study drug is required as a result of the abnormality;  
 The abnormality deviates from the anticipated critical care course; or 
 Based on the clinical judgment of the Investigator. 
All AEs from patients treated with isoflurane via the Sedaconda ACD-S will be reported together 
with the current isoflurane pump rate, all recorded isoflurane end-tidal concentrations, and total 
exposure time. The use of volatile anesthetics in the 24 hours prior to inclusion is also captured in 
the eCRF.  
AEs and SAEs that result from the Sedaconda ACD-S (defined in Section 8.7) will also be 
considered device deficiencies. Device deficiencies should be reported during the time Sedaconda 
ACD-S is used and recorded on the appropriate eCRF. 
8.1.1 
Adverse (Drug) Reaction 
All harmful and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction (ADR). “Responses” to a medicinal product means that a 
causal relationship between a medicinal product and an AE is at least a reasonable possibility, 
ie, the relationship cannot be ruled out. 
8.1.2 
Unexpected Adverse Drug Reaction 
An unexpected ADR is defined as an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information. 
8.1.3 
Assessment of AEs by the Investigator 
The Investigator will assess the severity (intensity) of each AE as mild, moderate, or severe, and 
will also categorize each AE as to its potential relationship to study drug and device using the 
categories described below. 
Assessment of severity 
Mild – An event that is easily tolerated and generally not expected to interfere with critical care 
course. 
Moderate – An event that is sufficiently discomforting to interfere with critical care course. 
Severe – An event that is incapacitating, leads to major intervention, significantly alters current 
critical care course. 
Causality assessment 
The relationship of an AE to the administration of the study drug and the use of device is to be 
assessed according to the following definitions: 
Not considered causally related – All AEs determined to be not related or unlikely related 
according to Table 4. 
Considered causally related – All AEs determined to be at least possibly related according to 
Table 4. 

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The following factors should be considered when determining the causality of an AE: 
 Underlying, concomitant, intercurrent diseases; 
o The natural history and course of the disease being treated and any other comorbid disease 
the patient may have, as well as prehospital and pre-ICU exposures. 
 Concomitant drug(s) and therapies; 
o The other drug(s) and therapies the patient is receiving should be examined to determine 
whether any of them might be recognized to cause the event in question. 
 The temporal sequence from study drug administration/use of device to the event; 
o The event should occur after the study drug is given/while using the device. The length of 
time from study drug exposure/use of device to event should be evaluated in the clinical 
context of the event. 
 The pharmacology and pharmacokinetics of the study drug; and 
o The known pharmacologic properties (absorption, distribution, metabolism, excretion and 
known ADRs) of the study drug should be considered. 
 Known response pattern for this class of study drug. 
o Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
Table 4. 
AE Causality Assessment Criteria 
Causality Assessment 
Causality Criteria 
Not considered causal 
Not related 
 
The AE follows a temporal sequence different from study drug administration; 
and 
 
The AE is clearly produced by the patient´s clinical condition or by other modes 
of therapy administered to the patient. 
Unlikely to be related 
 
The temporal sequence between the AE and the study drug administration is such 
that the study drug is not likely to be associated with the observed event; and 
 
The AE could easily and more likely have been produced by the patient´s clinical 
condition or by other modes of therapy administered to the patient. 
Considered causal 
Possibly related 
 
The AE follows a reasonable temporal sequence from study drug administration; 
and 
 
The AE could have been, but is equally or less likely produced by the patient´s 
state or by other modes of therapy administered to the patient. 
Probably related 
 
The AE follows a reasonable temporal sequence from study drug administration; 
 
The AE abates upon discontinuation of the study drug (de-challenge); 
 
The AE is likely a reaction to an agent or chemical group, or predicted by known 
pharmacology; and 
 
The AE cannot be reasonably explained by the known characteristics of the 
patient´s clinical state or by other modes of therapy administered to the patient. 
Definitely related 
 
The AE follows a reasonable temporal sequence from study drug administration; 
 
The AE is a known reaction to agent or chemical group, or predicted by known 
pharmacology; 
 
The AE cannot be explained by patient´s clinical state or other factors; 
 
The AE abates upon discontinuation of the study drug (de-challenge); and 
 
The AE is confirmed by reappearance of the reaction on repeat exposure 
(re-challenge). 
AE = adverse event. 

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AEs that are categorized as being at least possibly related to the study treatment will be considered 
to have a reasonable causal relationship to the investigational intervention. 
8.1.4 
AEs of Special Interest 
The Investigator will monitor each patient for clinical and laboratory evidence for pre-defined 
AESIs throughout the patient’s participation in this study. These AESIs are specific AEs, 
potentially associated with the clinical use of one or both study drugs. Most AESIs are however 
not per se causally related with the study drugs and causality assessment must be done for AESIs 
as with all AEs. 
The Investigator will assess and record any additional information on the AESI in detail on an AE 
form, which must be submitted within 24 hours of awareness of the event. 
The definitions for each AESI grade are described in Appendix G. 
For this study, AESIs include the following:  
 MHc suspected by the Investigator in a patient recently exposed to volatile anesthetic or 
succinylcholine. No consensus diagnostic criteria exist for MH, but manifestations may include 
muscle rigidity; unexplained hypercapnia resistant to increasing minute ventilation; elevated 
creatine kinase or urine myoglobin suggesting rhabdomyolysis; acute hyperkalemia 
>6 mmol/L potentially resulting in electrocardiogram changes of peaked T-waves, increased 
ventricular ectopy, ventricular tachycardia, or ventricular fibrillation; and hyperthermia; 
 PRIS suspected by the Investigator in a patient recently exposed to propofol. PRIS is defined 
as the development of metabolic acidosis and cardiac dysfunction along with at least one of 
rhabdomyolysis, hypertriglyceridemia, or renal failure after the initiation of propofol therapy;57 
 Hypoxemia; 
 Hypercapnia; 
 Hypotension; 
 Liver injury, defined as: 
o Alanine aminotransferase (ALT) 3  upper limit of normal (ULN); 
o Aspartate aminotransferase (AST) 3  ULN; 
o Total bilirubin >2  ULN; 
o Alkaline phosphatase >2  ULN; 
o Hy’s Law criteria (ALT or AST 3  ULN and total bilirubin >2  ULN); 
 Accidental self-extubation during active study drug administration; 
 Hyperkalemia; and 
 Rhabdomyolysis independent of MH. 
During the course of the study, additional AESIs may be identified by the Sponsor. 
 
c. 
Will be collected for 24 hours post EOT. 

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A severe AESI or SAE deemed as possibly, probably, or definitively related to the study drug 
should lead to discontinuation of study drug. 
8.2 
SAEs 
An AE or adverse reaction is considered serious if, in the view of either the Investigator or Sponsor, 
it results in any of the following outcomes: 
 Death; 
 A life-threatening AE; 
Note: An AE or adverse reaction is considered “life-threatening” if, in view of either the 
Investigator or Sponsor, its occurrence places the patient at immediate risk of death. It does 
not include an event that, had it occurred in a more severe form, might have caused death. 
 Requires hospitalization or prolongation of existing hospitalizations; 
For the purpose of this study, all patients are hospitalized at the start of the study and 
hospitalization is in itself does therefore not define an SAE. However, if prolongation of 
hospitalization is necessary, the reason for this prolongation may contribute to the 
categorization of an SAE. 
 A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions; 
 A congenital anomaly/birth defect; 
 Requires medical or surgical intervention to preclude permanent impairment or prevent 
permanent damage to a body structure; and  
 An important medical event. Important medical events that do not meet any of the above 
criteria may be considered an SAE when, based upon appropriate medical judgment, they may 
jeopardize the patient’s health and may require medical or surgical intervention to prevent one 
of the outcomes listed above.  
8.3 
SAE Reporting − Procedures for Investigators 
Initial Reports 
All SAEs occurring from initiation of study drug administration until 7 days after the completion 
of study drug administration must be reported to 
 Clinical Safety within 24 hours of the 
knowledge of the occurrence. After the 7-day post EOT reporting window, any SAE that the 
Investigator considers related to study drug must be reported to the 
 Clinical Safety or the 
Sponsor/designee. 
To report the SAE, the Investigator or designee will complete the SAE form electronically in the 
study eCRF. When the form is completed, 
 Safety personnel will be notified electronically 
by the electronic data capture system and will retrieve the form. If the event meets serious criteria 
and it is not possible to access the eCRF, send an email to 
 Safety at 
or call the 
 SAE reporting line (telephone 
number listed below), and fax/email the completed paper SAE form to 
 (contact 
information listed in Section 8.6) within 24 hours of awareness. When the eCRF becomes 
available, the SAE information must be entered within 24 hours of the system becoming available. 

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Follow-Up Reports 
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the eCRF for the study and submit any supporting documentation (eg, patient 
discharge summary or autopsy reports) to 
 Clinical Safety via fax or email. If it is not 
possible to access the eCRF, refer to the procedures outlined above for initial reporting of SAEs.  
8.4 
Pregnancy Reporting 
Due to the nature of the patient population and testing prior to enrollment, it is not anticipated that 
pregnancy will be detected during the 48-hour study drug treatment period in the ICU and at the 
7-day follow-up after EOT. However, if pregnancy is detected during this period, applicable 
procedures will be followed to report the outcome of the pregnancy. 
8.5 
Expedited Reporting 
The Sponsor/designee will report all relevant information about Suspected Unexpected Serious 
Adverse Reactions (SUSARs) that are fatal or life-threatening as soon as possible to the FDA, and 
in any case no later than 7 calendar days after knowledge by the Sponsor/designee of such a case. 
Relevant follow-up information will subsequently be communicated within an additional 
8 calendar days.  
All other SUSARs will be reported to the FDA as soon as possible but within a maximum of 
15 calendar days of first knowledge by the Sponsor/designee.  
The Sponsor/designee will also report any additional expedited safety reports required in 
accordance with the timelines outlined in US legislation.  
The Sponsor/designee will also inform all Investigators as required per local regulation. 
The Sponsor/designee will also inform all reviewing Institutional Review Boards (IRBs) and 
participating Investigators per local regulations. 
8.6 
Special Situation Reporting Requirements Related to Study Drug 
Occurrences of events of overdose and medication error must be reported to the Sponsor or 
designee. Any AEs/SAEs associated with either an overdose or medication error should be 
reported, as appropriate. 
 Overdose: Refers to the administration of a quantity of a medicinal product given per 
administration or cumulatively (accidentally or intentionally), which is above the maximum 
recommended dose according to the protocol. Clinical judgment should always be applied.  
 Medication error: A medication error is defined as an error made in prescribing, dispensing, 
administration, and/or use of study drug. The administration and/or use of expired study drug 
should be considered as a reportable medication error.  
All special situation events as described above must be reported on the Special Situations Report 
form and faxed/emailed to 
 Clinical Safety (contact information listed below) within 
24 hours of knowledge of the event. All AEs associated with these Special Situation Reports 

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have completed the 30-day follow-up period. The run-in patients will also be included in the 
analyses. Subsequent planned meetings will occur at an appropriate time after 50% and 75% of 
patients in the 2 trials combined have completed the 30-day follow-up.  
Accrued and cumulative moderate AEs, severe AEs, and SAEs will be monitored throughout the 
conduct of the study. The causality and expectedness of SAEs, as evaluated by the Sponsor based 
on aggregate data, will also be reviewed. 
If stopping criteria described are met (Appendix I), recruitment into both studies will be paused, 
and an ad hoc DSMB meeting will be held within 10 working days for the DSMB to cumulatively 
review AEs in both studies. The DSMB will provide recommendations to the Sponsor concerning 
any actions that may be necessary in the light of their assessment (eg, the studies may be continued 
without amendment, paused and recruitment temporarily suspended, amended, or stopped 
completely). Given the similar exposures to the study drug in the studies SED003 and SED004, 
the DSMB recommendations will apply to both studies. The Sponsor will notify the FDA of any 
DSMB recommendations related to the safety of the study drug, leading to any changes in the 
conduct of the study. 
The DSMB will receive all SUSARs and SAEs with the outcome of “death” with determined 
causality related to study drug for ad hoc review. 
A DSMB charter will be established to outline the DSMB’s responsibilities and procedures. 

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9 
STATISTICS 
9.1 
Analysis Populations 
Detailed statistical analyses will be provided in the Statistical Analysis Plan (SAP). 
9.1.1 
Intent-to-Treat Analysis Set 
The Intent-to-Treat (ITT) Analysis Set will include all randomized patients who receive any 
amount of study drug. The ITT Analysis Set will follow the intention-to-treat principle, ie, patients 
will be analyzed according to the treatment group assigned at randomization. The primary efficacy 
analysis will be performed using the ITT Analysis Set. 
9.1.2 
Modified Intent-to-Treat Analysis Set 
The modified Intent-to-Treat (mITT) Analysis Set will include all patients in the ITT Analysis Set 
who have at least a 6-hour sedation period and at least 3 blinded RASS assessments. All efficacy 
analyses will be performed on the mITT Analysis Set in addition to the ITT Analysis Set. 
9.1.3 
Per-Protocol Analysis Set 
The Per-Protocol (PP) Analysis Set will include all patients in the ITT Analysis Set without any 
major protocol deviation affecting the primary efficacy analysis.  
In order to be included in the PP Analysis Set, patients need to have been sedated for at least 
8 hours, with at least 50% of the planned RASS assessments performed. Additional criteria for 
inclusion in the PP Analysis Set will be specified in the SAP. The main statistical analysis for 
primary efficacy endpoint will be repeated on the PP Analysis Set. 
9.1.4 
Safety Analysis Set 
The Safety Analysis Set will include all patients who receive any amount of study drug including 
the run-in training patients and will be analyzed in accordance with the actual treatment received. 
9.2 
Statistical Methods 
Categorical data will generally be summarized with counts and percentages of patients. The 
denominator used for the percentage calculation will be clearly defined. Continuous data will 
generally be summarized with descriptive statistics including n (number of non-missing values), 
mean, median, standard deviation (SD), minimum, and maximum.  
A fixed sequential testing procedure will be implemented. In a hierarchical step-down manner, the 
primary efficacy endpoint will be tested at the 1-sided 0.025 level first (non-inferiority test), 
followed by testing the key secondary efficacy endpoints at the 2-sided 0.05 level (superiority test) 
in the following hierarchical manner:  
1. Change in mean fentanyl-equivalent opioid dose during the study drug treatment period 
compared to mean opioid dose during the 60 minutes prior to randomization;  
2. Time from stop of study drug treatment to RASS 0, up to 4 hours;  

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3. Delirium by CAM-ICU-7 assessments 60 (10) minutes after EOT in patients not re-sedated 
with benzodiazepine or propofol infusions; and 
4. Proportion of ventilator parameter observations with spontaneous breathing efforts during the 
study drug treatment period. 
Inferential conclusions about these efficacy endpoints will require statistical significance of the 
previous endpoints (in favor of the isoflurane-treated patients) and the primary efficacy endpoint. 
Only the primary efficacy endpoint analysis will use non-inferiority test; the other efficacy 
endpoints analyses will all use superiority test. 
9.2.1 
Analysis of Efficacy 
All efficacy analyses will be performed using both the ITT and the mITT Analysis Sets. Analysis 
of the ITT Analysis Set will be considered primary. 
 
Primary efficacy analysis 
The primary efficacy analysis will be performed on the ITT Analysis Set. The primary analysis on 
the primary efficacy endpoint will be performed based on an analysis of variance (ANOVA) 
model, including treatment group and stratification factor (SAPS III [0 to <40, >40 to <60, and 
60] and patient type [medical and surgical (including trauma)]) as fixed effects. Surgical patient 
will be defined as patients who meet either of the following criteria:  
 Have undergone surgery within the prior 2 weeks and for whom the current respiratory failure 
episode is related to that surgery or surgical disease process, or a complication thereof; or  
 Patients anticipated to undergo surgery within the next 2 days for a condition that is related to 
etiology of respiratory failure. 
The treatment comparisons will be estimated together with a one-sided 97.5% confidence interval 
and p-value for the hypothesis testing. Least squares mean for each treatment group will also be 
provided. The hypothesis test for primary efficacy endpoint analysis is based on a 1-sided 
significance level of 0.025. The primary efficacy endpoint will be summarized by stratification 
factor. ANOVA model will be used to analyze the primary efficacy endpoint for each subgroup, 
which will include randomized treatment group as a fixed effect. Sensitivity analyses will be 
performed if more than 20% (inclusive) of the total number of patients are included at one study 
site. 
The detail of the analysis and the description of the estimand and missing data handling will be 
provided in the SAP. 
 
Secondary efficacy analysis 
The analyses of the key secondary efficacy endpoints will be performed on both the ITT and mITT 
Analysis Sets (superiority analysis), unless otherwise specified. The hypothesis test for the key 
secondary endpoint analyses is based on a 2-sided significance level of 0.05.  
 
Other efficacy analysis 
The detail of the analyses for the exploratory efficacy endpoints will be described in detail in the 
final SAP.  

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9.2.2 
Analysis of Safety 
All safety analyses will be performed on the Safety Analysis Set. Patients will be analyzed by the 
treatment received. 
Safety measures will be summarized descriptively. Qualitative variables will be summarized using 
counts and percentages by treatment group at each study visit.  
Laboratory and vital sign parameters will be presented using descriptive statistics for observed 
values at each visit and changes from Baseline, as appropriate. Abnormal physical examination 
findings will be presented in a by-patient data listing. Details of any abnormalities will be included 
in patient listings. 
9.2.3 
Interim Analysis 
No interim analysis of outcome data is planned for this study; however, a primary analysis will be 
performed to evaluate the primary and key secondary efficacy endpoints as well as safety data and 
all outcomes related to the first 30 days when all patients complete the Study Day 30 visit, or 
would have completed the Study Day 30 visit, in the case of patients who discontinue the study 
early. The study (blinded RASS assessment results) will be unblinded at that time.  
A separate analysis and study report will be performed for the LTO (3 and 6 months), once all 
patients have performed the 6-month follow-up. 
9.2.4 
Sample Size Determination 
The study will be powered for a non-inferiority test of isoflurane via Sedaconda ACD-S compared 
to propofol via IV infusion in maintaining a target depth of sedation. 
The proposed non-inferiority margin in the planned clinical trials is 15%. In clinical sedation trials 
such as the PRODEX, MIDEX, and SED001 studies, as well as in the proposed US clinical trials, 
sedation level is commonly assessed at approximately 2-hour intervals. A 15% absolute difference 
is equal to a difference of 3.6 hours in a 24-hour period. This is roughly the time span of 2 routine 
assessments of sedation and is therefore likely to be detectable and is clinically relevant. In the 
planned clinical trials, a 15% non-inferiority margin would imply that failing to reach the RASS 
target at 2 or more occasions in the isoflurane arm compared to the propofol arm in a 24 hour 
period would signify inferiority.  
Previous studies assessing sedation success in mechanically ventilated patients with propofol have 
shown varying proportions of time within target sedation level. Targets have been defined as a 
4-step range on the RASS score between 0 to -3 (PRODEX, MIDEX) or -1 to -4 (SED001). 
Proportions of time within target range during propofol sedation in these studies were between 
64.7% (PRODEX) and 92% (SED001).  
In SED001, the proportion of time within target RASS range for isoflurane was approximately 
91%, with a SD of 12.4%. In SED001, staff in all participating European ICUs were familiar with 
both sedation methods since Sedaconda ACD had been available in Europe for many years and 
only sites with prior experience administering sedation with Sedaconda ACD participated in the 
study.  
In the planned US clinical trials, patients are anticipated to be in the target RASS range on average 
75% of the time when receiving standard sedative treatment, and on average 70% with isoflurane 

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via the Sedaconda ACD-S with an SD of approximately 20%. A total of 235 randomized patients 
will provide 95% power for the non-inferiority test with 1-sided α 0.025 assuming attrition rate 
of 5%. 
Generally, the estimated proportions and higher variance compared to what was found in SED001 
are due to assessor blinding. Further, in SED004, the experience with the Sedaconda ACD-S will 
be very limited prior to and during the trial, as the Sedaconda ACD-S is not approved for use in 
the US, and we anticipate a recruitment rate of approximately 2 to 3 patients/month at each study 
site. Hence, a slightly lower success rate for the isoflurane/Sedaconda ACD-S group and a larger 
variance in both groups is anticipated compared to the European SED001 trial. 

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10 
STUDY MANAGEMENT 
10.1 
Clinical Monitoring 
Before the initiation of the study at the study site, the study monitor will: 
 Determine the adequacy of the facilities; and 
 Discuss with the Investigator (and study personnel if applicable) their responsibilities with 
regards to GCP, protocol adherence, and local regulations. 
At an initiation meeting, the study monitor will review the study procedures with the Investigator 
(and the study personnel, as applicable) and document this in compliance with the ICH-GCP 
guidelines. 
During the study, the monitor will pay visits to the study site in order to complete the following: 
 Provide information and support to the Investigator; 
 Confirm that facilities remain acceptable; 
 Confirm that the study team is adhering to the protocol; 
 Confirm that data are being accurately recorded in the eCRF; 
 Ensure that accountability checks for the study drug and device are being performed; and 
 Conduct source data verification, which will require direct access to all original records for 
each patient (eg, medical records). Definition of key variables to be source data verified will 
be described in the Monitoring Plan.  
The frequency of the monitoring visits per site will be determined through a risk-based approach 
depending on recruitment rate, observed data quality, and overall site performance. The monitor 
will be available (by telephone and email) between visits if the Investigator or other study 
personnel at the study site needs information, advice or help. 
10.2 
Audits and Inspections 
The purpose of an audit or inspection is to systematically and independently examine all 
study-related activities to document that they were conducted, recorded, analyzed, and accurately 
reported according to the study protocol, ICH-GCP including the Declaration of Helsinki, and all 
other relevant regulations. 
Audits or inspections may therefore be performed by authorized representatives of the Sponsor, 
the CRO, or a competent authority at the study site during or after the study. These visits may 
include source data verification, and confidentiality documents are therefore created. This implies 
that auditors/inspectors will have the right to inspect the study sites at any time during and/or after 
completion of the study and will have direct access to source documents, including patients’ 
medical records. By participating in this study, the Investigator agrees to this requirement. 
The Investigator should contact the monitor and/or Sponsor immediately if they are contacted by 
a competent authority about an inspection at their study site. 

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10.3 
Training of Study Personnel 
The Investigator will maintain records of all individuals involved in the study (medical, nursing, 
and other personnel). The Investigator will ensure that appropriate training relevant to the study is 
given to the personnel involved in the study, and that any new information of relevance to the 
conduct of the study is forwarded to the persons involved. 
10.4 
Protocol Deviations 
Deviations from the protocol should not occur. If a deviation occurs, the Investigator (or designee) 
will inform the monitor about the deviation, and the implications of the deviation must be reviewed 
and discussed. The deviation will be logged by the monitor, including documentation of the reason 
and date for the deviation.  
10.5 
Study Timetable 
The recruitment period is planned to proceed until approximately 3 to 5 run-in training patients 
per site and 235 randomized patients have been enrolled, where the intended first patient’s first 
visit is in Q1 2022 and the intended last patient’s last visit in Q4 2023.  
10.6 
Declaration of End of Study 
The end of the study is defined as the last patient’s last visit. 
The competent authority and the IRB will be informed that the clinical study has ended within 
90 days of the end of the clinical study. If the study has to be terminated early, this period will be 
reduced to 15 days and the reasons will be clearly explained. 
10.7 
Study Reporting 
The data and information collected during this study will be reported in a CSR prepared by the 
Sponsor. The final study summary results shall be submitted to the regulatory authority as well as 
to the IRB as required by local legislations, within 12 months after completion of the study. The 
trial and a summary of the trial results will be made publicly available at clinicaltrials.gov. Trial 
registration may occur in other registries in accordance with local regulatory requirements.  
Any confidential information relating to the study drug or the study, including any data and results 
from the study, will be the exclusive property of the Sponsor. The Investigators and any other 
persons involved in the study will protect the confidentiality of this proprietary information 
belonging to the Sponsor. 
10.8 
Archiving 
After the end of the study, the Investigator shall keep records of the study for the period mandated 
by local requirements or as specified in the clinical trial agreement. This includes any original 
source documents related to the study, including the Patient Identification List, which provides the 
link between the named patient source records and pseudonymous eCRF data; the original signed 
informed consent forms (ICFs); and detailed records of administration of study drug. The Sponsor 
should be contacted before any study related documentation is planned for destruction. 

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10.9 
Patient Confidentiality 
The Investigator will ensure that the confidentiality of the patients’ data is preserved; any 
documents identifying the patient, such as the signed ICF, will be maintained by the Investigator 
in strict confidence. Patients will be assigned a unique identifier. Any records or datasets that are 
transferred to the Sponsor will contain the identifier only; patient names or any information which 
would make the patient identifiable will not be transferred. 
The patient will be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to the 
patient who will be required to give consent for their data to be used as described in the informed 
consent. The patient must be informed that his/her medical records may be examined by auditors 
or other authorized personnel appointed by the Sponsor and by inspectors from regulatory 
authorities.  
10.10 
Study Agreements 
The Investigator at the study site must comply with all the terms, conditions, and obligations of 
the clinical study agreement for this study. In the event of any inconsistency between this protocol 
and the clinical study agreement, the protocol shall prevail. 
Agreements between the Sponsor and the Investigator must be in place before any study-related 
procedures can take place.  
10.11 
Publication 
The Sponsor is the sole owner of the results from the study. No data can be shared or published 
before written approval has been received from the Sponsor.  
By signing the protocol, the Investigator agrees that the results of the study may be used for the 
purposes of national and international registration, publication, and information for medical and 
pharmaceutical professionals by the Sponsor.  
The information obtained during the conduct of this study is considered confidential and will be 
used by the Sponsor for registration purposes and for the general development of the study drug. 
Data will not be made available to any third party other than the authorized representatives of 
relevant authorities. Study progress and results of the project will be summarized in a CSR as 
described in Section 10.7. The report will also form the basis for scientific publications at the 
appropriate time. 
All information supplied by the Sponsor in connection with this study shall remain the sole 
property of the Sponsor and is to be considered confidential information. No confidential 
information shall be disclosed to others without prior written consent from the Sponsor and shall 
not be used except in the performance of this study. The information obtained during this study 
may be made available to other physicians who are conducting other clinical studies with the study 
drug, if deemed necessary by the Sponsor.  
Results from the study may be published, and then authorship of a manuscript for publication in a 
peer-reviewed journal will be offered in compliance with the Vancouver guidelines.  

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The Sponsor determines when to publish. No other publications or presentations resulting from 
the study may be made until the study is completed and the primary study results have been 
published. 

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11 
DATA MANAGEMENT AND RECORD KEEPING 
11.1 
Data Management 
11.1.1 
Data Handling 
Data will be recorded at the site in eCRFs and reviewed by the CRAs during monitoring visits. 
The CRAs will verify data recorded in the eCRF with source documents. All corrections or changes 
made to any study data must be appropriately tracked in an audit trail in the eCRF.  
11.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
11.1.3 
Data Entry 
Data must be recorded using the eCRF as the study is in progress. All site personnel must log into 
the system using their secure username and password in order to enter, review, or correct study 
data. These procedures must comply with Title 21 of the Code of Federal Regulations (21 CFR) 
Part 11 and other appropriate international regulations. All passwords will be strictly confidential. 
11.1.4 
Medical Information Coding 
For medical information, the latest version of the following thesauri will be used: 
 Medical Dictionary for Regulatory Activities for medical history and AEs; and 
 WHO Drug Dictionary for prior and concomitant medications and coding of procedures. 
11.1.5 
Data Validation 
Validation checks programmed within the eCRF, as well as supplemental validation performed via 
review of the downloaded data, will be applied to the data in order to ensure accurate, consistent, 
and reliable data. Data identified as erroneous, or data that are missing, will be referred to the 
investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
11.2 
Source Data 
Records of patients, source documents, delegation logs, training logs, monitoring visit logs, 
eCRFs, inventory of study product, regulatory documents, and other Sponsor correspondence 
pertaining to the study must be kept in the appropriate study files at the site. Source data are defined 
as all information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the evaluation and reconstruction 
of the clinical study. Source data are contained in source documents (original records or certified 
copies). These records will be retained in a secure file for the period as set forth in the Clinical 
Study Agreement. Prior to transfer or destruction of these records, the Sponsor must be notified in 
writing and be given the opportunity to further store such records.  

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12 
ETHICAL AND REGULATORY REQUIREMENTS 
12.1 
Ethical Conduct of the Study 
GCP is an international ethical and scientific quality standard for designing, conducting, recording, 
and reporting studies that involve human patients. Compliance with this standard provides public 
assurance that the rights, safety, and well-being of study patients are protected, consistent with the 
principles that have their origin in the Declaration of Helsinki, and that the clinical study data are 
credible. 
12.2 
Institutional Review Board 
The IRB will review all appropriate study documentation in order to safeguard the rights, safety, 
and well-being of patients. The study will only be conducted at sites where IRB approval has been 
obtained. The protocol, Investigator’s Brochure, ICF, written information given to the patients, 
safety updates, annual progress reports, and any revisions to these documents will be provided to 
the IRB by the Investigator. 
Federal regulations and ICH Guidelines require that approval be obtained from an IRB prior to 
participation of patients in research studies. Prior to study onset, the protocol, any protocol 
amendments, ICFs, and any other written information regarding this study to be provided to a 
patient or patient’s LAR must be approved by the IRB. 
No study drug will be released to the site for dosing until written IRB authorization has been 
received by the Sponsor. 
12.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements. 
The Investigator must ensure that each study patient or LAR is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator will obtain written informed 
consent from each patient or LAR before any study-specific activity is performed and should 
document in the source documentation that consent was obtained prior to enrollment in the study. 
The original signed copy of the ICF must be maintained by the Investigator and is subject to 
inspection by a representative of the Sponsor, their representatives, auditors, the IRB, and/or 
regulatory agencies. A copy of the signed ICF will be given to the patient and LAR. If the initial 
informed consent is given by the LAR, then the information about the study will be given to, and 
consent obtained from, the patient as soon as the patient’s condition allows.  
12.4 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by 
 or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been submitted to FDA 
for review and approved by the IRB, unless immediate implementation of the change is necessary 
for patient safety. In this case, the situation must be documented and reported to FDA and the IRB 
within 5 working days. 

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12.5 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB, as appropriate. Patients or their LAR 
may request their medical information be given to their personal physician or other appropriate 
medical personnel responsible for their welfare. 
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
12.6 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, Investigators should commit 
to promptly updating this information if any relevant changes occur during the study and for a 
period of 1 year after the completion of the study. 
12.7 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out patient liability 
insurance for all patients who have given their consent to the clinical study. This cover is designed 
for the event that a fatality, physical injury, or damage to health occurs during the clinical study’s 
execution. 

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13 
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Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure 
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Roberts RJ, Barletta JF, Fong JJ, et al. Incidence of propofol-related infusion syndrome in 
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APPENDIX A:  SCHEDULE OF PROCEDURES 
Table 5. 
Schedule of Procedures (Screening Period and Treatment Period) 
 
Screening Period 
Treatment Period 
 
Screening/Randomization 
Baseline 
Hour, Day, or Month 
( Window) 
Initial Screening 
D -30 to 
Randomization 
Complete 
Screening 
-24h to 
Randomization Randomization 
Randomization 
to Initiation of 
Study Drug 
(up to 6 hours) 
Q2h 
(0.5h) 
Q4hnn 
(0.5h) 
Q8h 
(2h) 
Daily 
EOT/ 
Up to 
48h 
(6h) 
Informed consentd 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xe 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
Xe 
 
 
 
 
 
 
 
Prior/concomitant relevant 
medicationsf 
 
X 
 
X 
X 
Weight and heightg 
 
X 
 
 
 
 
 
 
 
Physical examinationh 
 
X 
 
 
 
 
 
 
X 
Clinical laboratory 
assessmentsi 
 
X 
 
 
 
 
 
X 
 
Pregnancy testl 
 
X 
 
 
 
 
 
 
 
Physical function and 
outcomesm 
Xkk 
 
 
 
 
 
 
 
 
Cognitive function and 
outcomesn 
Xkk 
 
 
 
 
 
 
 
 
Reduction of SOC sedation 
and opioids to half 
 
 
 
Xo 
 
 
 
 
 
Discontinuation of SOC 
sedatives and opioids 
 
 
 
Xll 
 
 
 
 
 
Patient characteristicsp 
 
X 
 
 
 
 
 
 
 
Predicted time remaining on 
ventilatorq 
 
X 
 
 
 
 
 
 
 
Ventilator parametersr 
 
 
 
X 
 
 
Xs 
 
 
Blood gasest 
 
 
 
X 
 
 
Xs 
 
 
Organ function (SOFA)u 
 
 
 
X 
 
 
 
X 
 
Randomizationv 
 
 
X 
 
 
 
 
 
 
Vital signsw 
 
 
 
Xx 
 
 
Xs 
 
 
RASS 
 
 
 
Xx 
Xy 
 
 
Xz 
Xy 
CPOT 
 
 
 
Xx 
Xy 
 
 
 
 
Study drug administrationv 
 
 
 
X 
X 

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Screening Period 
Treatment Period 
 
Screening/Randomization 
Baseline 
Hour, Day, or Month 
( Window) 
Initial Screening 
D -30 to 
Randomization 
Complete 
Screening 
-24h to 
Randomization Randomization 
Randomization 
to Initiation of 
Study Drug 
(up to 6 hours) 
Q2h 
(0.5h) 
Q4hnn 
(0.5h) 
Q8h 
(2h) 
Daily 
EOT/ 
Up to 
48h 
(6h) 
Isoflurane end-tidal 
concentration measurementaa 
 
 
 
 
 
X 
 
 
 
Sedaconda ACD-S device 
deficiencies 
 
 
 
 
X 
Adverse eventscc 
 
 
 
 
X 
Restraints 
 
 
 
 
 
 
 
X 
 
CAM-ICU-7ee 
 
 
 
 
 
 
 
Xz 
Xee 
Wake-up testff 
 
 
 
 
 
 
 
 
X 
Footnotes appear at the end of Table 6. 
 
 

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Table 6. 
Schedule of Procedures (Follow-Up Period and Early Withdrawal) 
 
Follow-Up Period 
EWc 
 
Post-Treatment 
Monitoring 
Follow-Up Contact 
3-Month Phone Call 
6-Month Phone 
Call 
Hour, Day, or Month ( Window) 
Until 24h after EOT 
Until D7 
after EOT 
(2D) 
D30 (+5D)a 
3M (4W)b 
6M (4W)b 
UNS 
Prior/concomitant relevant medicationsf 
X 
Xf 
Xf 
 
 
 
Physical examinationh 
X 
 
 
 
 
X 
Clinical laboratory assessmentsi 
Xj 
 
 
 
 
Xk 
Physical function and outcomesm 
 
 
 
X 
X 
Xoo 
Cognitive function and outcomesn 
 
 
 
X 
X 
Xoo 
Organ function (SOFA)u 
 
X 
 
 
 
 
Vital signsw 
X 
 
 
 
 
X 
RASS 
 
Xz 
 
 
 
 
Major ICU interventionsbb 
 
 
X 
 
 
 
Adverse eventscc 
X 
X 
Xdd 
 
 
X 
CAM-ICU-7ee 
 
Xz 
 
 
 
 
Time of extubationgg 
X 
 
 
 
 
 
Duration of mechanical ventilation 
 
 
X 
 
 
Xhh 
Level of care 
 
 
X 
 
 
X 
Mortality 
 
 
X 
X 
X 
 
ICU Memory Tool 
 
 
 
Xii 
 
Xoo 
Psychological outcomesjj 
 
 
 
X 
X 
 
Late onset of drug-induced liver injury 
 
 
X 
 
 
 
Quality of lifekk 
 
 
 
X 
X 
 
a. 
Major ICU interventions, information on ICU care, and relevant concomitant medications are to be collected at Study Day 30 or at ICU discharge, whichever comes first. Level 
of care (can be collected retrospectively for the whole study period), duration of mechanical ventilation, late onset drug-induced liver injury, mortality, and follow-up of any 
unresolved AEs are to be performed through telephone call if not possible to retrieve information through medical records at Study Day 30 (regardless of ICU discharge status). 
b. 
Patients will be followed-up via telephone call at 3 and 6 months (4 weeks). 
c. 
Unless consent is withdrawn, the patient should continue in the study for assessment and follow-up even if study drug is discontinued. If consent is withdrawn, patients will be 
encouraged to complete the EW visit, if possible. 
d. 
Informed consent must be obtained from patient or patient’s LAR before any study-related procedures are performed. If the patient is unable to consent at the time of Screening, 
informed consent may be obtained from the patient’s LAR; however, information about the study will be given to, and consent obtained from, the patient as soon as the patient’s 
condition allows. 
e. 
To be assessed only if Initial Screening is performed more than 24 hours prior to the Complete Screening. 
f. 
All relevant prior and concomitant medications (see Section 7.2.1) are recorded from ICU admission or 24 hours prior to initiation of study drug treatment, whichever is shortest, 
until the end of the 24-hour post-treatment monitoring period. After this, only receipt of specific sedative, antipsychotic, and analgesic medications and relevant concomitant 
medications associated with ongoing AEs will be collected from 24 hours after EOT until Study Day 30 or ICU discharge, whichever comes first. All administered opioids, 
including the mean opioid dose assessment at 60 minutes prior to randomization, are to be collected also during Screening (Section 3.7). 
g. 
Body weight (lb) and height (inch) should be measured when possible or be estimated. Weight and height available in patient’s records can be used if measured within the last 
7 days. 

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h. 
Physical examinations should be performed appropriately, per the patient’s condition. Any findings should be recorded on the physical examination eCRF. 
i. 
Includes clinical chemistry, lipid profile, hematology, and coagulation. See Appendix B for a list of clinical laboratory analytes. Screening/Baseline clinical laboratory tests, 
other than those pertaining to trial eligibility, may be collected at any time during the Complete Screening (-24 hours to 0 hour) or post-randomization period (0 hour to +6 hours) 
prior to initiation of study drug treatment. 
j. 
Assessment should be performed once during post-treatment monitoring period, if the patient is still in the ICU. Analyses performed per SOC with an 18-to-48-hour window 
after EOT can be used.  
k. 
Only applicable if EW is during study drug treatment period.  
l. 
Female patients of childbearing potential must have a negative (serum or urine) pregnancy test prior to randomization. A pregnancy test obtained previously as part of usual 
care during this hospital episode that is documented in the patient’s medical record will suffice. Female patients not of childbearing potential are defined as female patients who 
have been postmenopausal for at least 1 year, have been surgically sterilized, or are 60 years of age. 
m. Physical outcomes assess activities of daily living by the Katz ADL and Pfeffer FAQ. 
n. 
Cognitive baseline will be assessed by the IQCODE. LTO will be assessed by TICS, WAIS IV-Digit Span, Hayling Sentence Completion Test, Controlled Oral Word 
Association, WMS-IV – Immediate Memory (Adult/Older Adult), WMS-IV – Delayed Memory (Adult/Older Adult), and PROMIS Cognitive Function questionnaire. 
o. 
To be performed within 30 minutes from randomization; see Section 3.7.  
p. 
SAPS III, reasons for ICU admission, ICU diagnosis criteria, hospital and ICU admission, time for intubation, and exposure of volatile anesthetics in the past 24 hours (and if 
yes, what drug [sevoflurane/isoflurane/desflurane]) to be assessed at Complete Screening. 
q. 
Predicted remaining time on the ventilator for each patient to be collected just shortly before randomization in order to monitor the proportion of patients with longer (>24 hours) 
versus shorter (12 to 24 hours) exposure times. 
r. 
Ventilator parameters include ventilator mode, set tidal volume, observed tidal volume, set rate, observed rate, observed minute volume, set PEEP, PS above PEEP, PC above 
PEEP, PIP, plateau pressure (once daily only), mean airway pressure, FiO2, SpO2, EtCO2, ventilator trigger, P0.1, and ABG. 
s. 
These assessments will be performed more frequently when clinically indicated (as patients will often be observed continuously or more frequently than every 8 hours in clinical 
practice). 
t. 
Only applicable when arterial line is available. 
u. 
Organ function will be assessed by SOFA once daily at Baseline, during the study drug treatment period, the 24-hour post-treatment period, and until 7 days after EOT. 
v. 
After randomization, the study equipment will be set-up and study drug treatment shall be initiated as close to randomization as possible and no later than 6 hours after 
randomization. 
w. Vital signs include systolic, diastolic, and mean arterial blood pressure, heart rate, SpO2, (measured by pulse oximetry; will not be assessed while patients are on ventilator 
support, as it will be captured as a ventilator parameter), respiratory rate (will not be recorded as part of vital sign assessments while patient is on ventilator support, as it will 
be captured in the ventilator parameter records as observed breathing rate), and body temperature. 
x. 
Unblinded baseline assessment for RASS and CPOT should be performed within 30 minutes prior to initiation of study drug administration. Vital signs should be performed 
within 60 minutes prior to initiation of study drug administration.  
y. 
Assessment will be performed in a blinded manner by a blinded assessor. 
z. 
CAM-ICU-7 and RASS will be performed daily (at a minimum) during the study drug treatment period and until 7 days after EOT or until hospital discharge, whichever comes 
first. However, more frequent assessments will be performed when clinically indicated. RASS will be assessed first. If RASS is -3, CAM-ICU-7 will be assessed. If RASS is 
-4 or -5, CAM-ICU-7 will not be assessed. 
aa. A separate gas monitor will be readily available during the study drug treatment period for measurement of end-tidal isoflurane concentrations. Only applicable for 
isoflurane-treated patients. 
bb. Major ICU interventions through Study Day 30 or until ICU discharge, whichever comes first, include the following: renal replacement therapy, ECLS, tracheostomy, 
non-invasive ventilation, and re-admission to the ICU. 
cc. Recording of AEs will start at the initiation of study drug administration and continue until Day 7 post EOT.  
dd. Only AEs unresolved at D7 to be followed-up. 
ee. CAM-ICU-7 will be assessed 60 (10) minutes after EOT in all patients by a blinded assessor. CAM-ICU-7 will not be required for patients reaching EOT due to treatment 
failure, patients transitioned to comfort care, or patients continued onto benzodiazepines or propofol sedation due to clinical need before 60 minutes after EOT. 
ff. 
Wake-up test will be assessed through blinded RASS assessments.  
gg. To be collected for patients who are extubated on study drug only. 

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hh. Only applicable if EW is after EOT. 
ii. 
Memory panorama from time in the ICU will be assessed by the ICU Memory Tool at the 3-month follow-up visit only. 
jj. 
Psychological outcomes will be assessed by the PROMIS Depression and Anxiety questionnaires and IES-R. 
kk. Quality of life will be assessed by the WHODAS 2.0 and BPI questionnaires. 
ll. 
Baseline data can be collected until 48 hours after initiation of study drug treatment as the time period of interest is not synonymous with when data needs to be captured. 
mm. As soon as the study drug treatment has been initiated, the SOC sedative should be stopped (ie, slow weaning will not be permitted) to limit the impact of residual SOC sedation. 
nn. For isoflurane-treated patients only. 
oo. LTO assessments will be completed at 3 and 6 months. ICU Memory Tool will be assessed at 3 months follow-up only. 
ABG = arterial blood gas; AE = adverse event; BPI = Brief Pain Inventory; CAM-ICU-7 = 7-point scale of the Confusion Assessment Method for the Intensive Care Unit; 
CPOT = Critical Care Pain Observation Tool; D = day; ECLS = extracorporeal life support; eCRF = electronic case report form; EOT = end of treatment; EtCO2 = end-tidal carbon 
dioxide; EW = early withdrawal; FAQ = functional activities questionnaire; FiO2 = fraction of inspired oxygen; h = hour; ICU = intensive care unit; IES-R = impact of event scale; 
IQCODE = Informant Questionnaire on Cognitive Decline in the Elderly; Katz ADL = Katz Index of Independence in Activity of Daily Living; LAR = legally authorized 
representative; LTO = Long-Term Outcomes; M = month; P0.1 = airway occlusion pressure; PC = pressure assist/control; PEEP = positive end-expiratory pressure; PIP = peak 
inspiratory pressure; PROMIS = Patient-Reported Outcomes Measurement Information System; PS = pressure support; Q = every; RASS = Richmond Agitation Sedation Scale; 
SAPS = Simplified Acute Physiology Score; Sedaconda ACD-S = Sedaconda Anaesthetic Conserving Device - S; SOC = standard of care; SOFA = sequential organ failure 
assessment; SpO2 = peripheral capillary oxygen saturation; TICS = Telephone Interview for Cognitive Status; UNS = unscheduled; W = week(s); WAIS = Wechsler adult 
intelligence scale; WHODAS 2.0 = World Health Organization Disability Assessment Schedule 2.0; WMS = Wechsler memory scale. 

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APPENDIX B:  CLINICAL LABORATORY ANALYTES 
Clinical Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine kinase 
Creatinine 
Estimated glomerular filtration rate 
(calculated) 
Glucose 
Inorganic phosphorus 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Uric acid 
 
 
Coagulation 
International normalized ratio (INR) 
Partial thromboplastin time (PTT) 
Prothrombin time (PT) 
 
 
Lipid Profile 
High-density lipoprotein-cholesterol 
Low-density lipoprotein-cholesterol 
Total cholesterol 
Triglycerides 
 
Hematology 
Hematocrit 
Hemoglobin 
Platelets 
White blood cell count and differential [1] 
1. 
Manual microscopic review is performed only if white blood cell count and/or differential values are out of reference 
range. 
 
Other Tests 
Blood gas analysis [1] 
Serum and urine pregnancy test [2] 
1. 
If arterial line is available. 
2. 
Female patients of childbearing potential must have a negative serum or urine pregnancy test prior to randomization. 

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APPENDIX C:  THE ABCDEF BUNDLE 
The care for patients in the intensive care unit (ICU) will be managed per standard of care during 
the study using the ABCDEF bundle as a guide.1 Study personnel will be encouraged to emphasize 
and follow the ABCDEF bundle. 
The ABCDEF bundle includes the following components:  
a. ABCDEF (assess and monitor pain). Monitor and manage pain level in all patients daily with 
the validated pain scales (ie, Critical Care Pain Observation Tool), in accordance with practice 
guidelines and local ICU policies; 
b. ABCDEF (both awakening and breathing trials). This component includes standardized 
Spontaneous Awakening Trials (SATs) (ie, daily interruption of sedation) paired with 
spontaneous breathing tests, both administered only when specific safety criteria are met. 
Sedation held for the SAT will be restarted, if needed, at the lowest possible rate that is needed 
to achieve the target Richmond Agitation Sedation Scale score. All study centers will use 
validated sedation scales to facilitate goal-directed sedation, a practice that will continue 
throughout the study. Ventilator management will be standardized according to each 
institution’s approved protocols; 
c. ABCDEF (choice of analgesia and sedation). To improve patient outcomes, choice of sedatives 
and analgesic medications, as well as careful consideration regarding medication doses, 
titration, and discontinuation, should be continually assessed. Decreased exposure to sedatives, 
particularly benzodiazepines, to achieve target sedation scores should be recommended. 
Sedation should be continually monitored and documented; 
d. ABCDEF (delirium monitoring and management). The delirium component will include 
nonpharmacologic strategies, given that the majority of delirium in the ICU is the hypoactive 
subtype. The protocol includes nonpharmacologic strategies that have been shown to reduce 
delirium in non-ICU settings. Study personnel will encourage members of the ICU team to 
perform the following tasks:  
 Reorient and cognitively stimulate patients by conveying the day, date, place, and reason 
for hospitalization; updating whiteboards with caregiver names; requesting placement of a 
clock and calendar in the room; and discussing current events; 
 Determine the need for hearing aids and/or eyeglasses from the surrogate and request that 
the surrogate provide these to the patient when appropriate; and 
 Maintain sleep preservation using techniques including noise reduction strategies 
(eg, minimize noise outside the room and offer white noise or earplugs), normalizing 
day-night variation in illumination, minimizing interruptions during normal sleeping hours 
via a “time out” strategy, maintaining ventilator synchrony, and promoting comfort and 
relaxation (eg, back care, massage, oral care, washing face/hands, and daytime bath). 
 
1. 
Marra A, Ely EW, Pandharipande PP, et al. The ABCDEF bundle in critical care. Crit Care Clin. 2017;33(2):225-243. 

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e. ABCDEF (early mobility and exercise). The exercise component of the ABCDEF bundle will 
include strategies to promote mobility and exercise in the earliest phases of critical illness. 
Early physical/occupational therapy have been shown to significantly reduced delirium 
duration for mechanically ventilated ICU patients. Study personnel will encourage members 
of the ICU team to evaluate each patient’s readiness for mobility and exercise and coordinate 
the following activities: removal of restraints, active range of motion, sitting on the side of the 
bed, sitting in a chair, standing in place, and ambulation; and 
f. ABCDEF (family engagement). Family members and surrogate decision makers should be 
encouraged to become active partners in multi-professional decision-making and treatment 
planning. Active family involvement has been shown to increase both provider and family 
satisfaction within the ICU without interfering with patient care or provider education. 
 

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APPENDIX D:  SCREENING FOR SPONTANEOUS AWAKENING TRIAL 
(SAT) AND SPONTANEOUS BREATHING TEST (SBT) 
Eligibility: Patients are candidates if they are on mechanical ventilation. 
Step 1: Spontaneous Awakening Test (SAT) Safety Screen- pass/fail 
If the patient has any of the following criteria, he/she fails the safety screen and should not have 
an SAT at that time. 
The SAT safety screen criteria include the following: 
 Active seizures- the patient is currently receiving medications for active seizures; 
 Alcohol withdrawal- the patient is currently receiving medications for alcohol withdrawal; 
 Agitation- the patient is currently or has recently (in the last 2 hours) receiving medications for 
agitation (Richmond Agitation Sedation Scale [RASS] 2); 
 Paralytics- the patient is currently on a paralytic infusion; 
 Myocardial ischemia- the patient has documentation of myocardial ischemia in the last 
24 hours; 
 High ICP- there is evidence of elevated ICP (ICP >20); and 
 Patient off the unit- effort should be made to attempt the safety screen when the patient returns 
to unit. 
If the patient fails the SAT safety screen 
If the patient does not pass the safety screen, it is not considered safe to turn off the sedatives. No 
further action is needed. Bedside staff should try the safety screen again in 24 hours; bedside staff 
can reassess safety criteria before 24 hours if the patient’s condition has changed and bedside staff 
or the clinical team think the patient would pass the safety screen. 
If the patient passes the SAT safety screen 
Perform SAT (Step 2). 
Step 2: Perform the SAT 
The SAT is defined as the discontinuation of all sedatives being given for sedation; administration 
of medications being used for the purpose of analgesia should continue. 
If the patient fails the SAT 
Bedside staff should restart at the lowest possible infusion rate that is needed to achieve target 
RASS. Typically start at ½ of the most recent dose and titrate, as needed.  
The SAT failure criteria include the following: 
 Sustained anxiety or agitation; 
 Respiratory rate >35 breaths/minute for 5 minutes; 
 Peripheral capillary oxygen saturation (SpO2) <88% for 5 minutes; 

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 Respiratory distress; and 
 Acute cardiac dysrhythmia. 
If the patient passes the SAT 
If the patient exhibits either of the pass criteria below and no failure criteria, he/she is advanced to 
Step 3 (SBT Safety Screen). 
The SAT pass criteria include the following: 
 The patient opens their eyes to voice (RASS -3) and is tolerating sedative cessation for any 
amount of time; or 
 The patient is comatose and tolerating sedative cessation for >4 hours. 
Step 3: Spontaneous Breathing Trial (SBT) Safety Screen- pass/fail 
If the patient has any of the following criteria, he/she fails the safety screen and should not have 
an SBT at that time. 
The SBT safety screen criteria include the following: 
 Agitation- the patient is currently agitated (RASS +2); 
 Oxygen saturation <88%; 
 Fraction of inspired oxygen (FiO2) >50%; 
 Positive end-expiratory pressure (PEEP) >7.5 cmH2O; 
 Myocardial ischemia- the patient has documentation of myocardial ischemia in the last 
24 hours; 
 Vasopressor use- the patient has documented significant use of vasopressors, including the 
following: 
o Dopamine or dobutamine infusion >5 mcg/kg/minute;  
o Norepinephrine or epinephrine infusion >2 mcg/minute; or 
o Vasopressin or milrinone at any dose. 
 Patient off the unit- effort should be made to attempt the safety screen when the patient returns 
to unit. 
If the patient fails the SBT safety screen 
Bedside staff should try the safety screen again in 24 hours; bedside staff can reassess safety 
criteria before 24 hours if the patient remains off sedatives, his/her condition has changed, and 
bedside staff or the clinical team think the patient would pass the safety screen. 

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If the patient passes the SBT safety screen 
Perform SBT (Step 4). 
Step 4: Perform the SBT 
The SBT is defined as discontinuation of active ventilator support so that the patient is allowed to 
breathe through a T-tube circuit or the ventilator circuit with continuous positive airway pressure 
(CPAP)/PEEP 7.5 cmH2O and pressure support of 7 cmH2O. 
If the patient fails the SBT 
Bedside staff should return the ventilatory support to the previous settings. 
The SBT failure criteria include the following: 
 Sustained respiratory rate >35/minute; 
 Sustained respiratory rate <8/minute; 
 Sustained SpO2 <88%; 
 Respiratory distress; 
 Mental status change; or 
 Acute cardiac arrhythmia. 
If the patient passes the SBT 
Passing the SBT is defined as the patient exhibiting no failure criteria for 2 hours. At this end of 
the 2 hours, the clinical team should consider extubation. 
 
 

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APPENDIX E:  CRITICAL CARE PAIN OBSERVATION TOOL (CPOT) 
 

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APPENDIX F:  7-POINT SCALE OF THE CONFUSION ASSESSMENT 
METHOD FOR THE INTENSIVE CARE UNIT (CAM-ICU-7) 
 

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APPENDIX G:  ADVERSE EVENT REPORTING GUIDANCE 
Most intensive care unit (ICU) patients have ongoing and fluctuating variations in their vital 
parameters and laboratory values. A typical ICU patient will experience multiple such variations 
on a daily basis, of which many are minor and routinely managed. 
In parallel there is a need to establish the safety profile of the sedative drugs in the clinical trial, 
using adverse event (AE) reporting. 
AE reporting should be based on events and results from assessments that indicate new-onset 
pathology and that require more than minor routine adjustments of slight physiologic deviations.  
The list below is not to be seen as a complete list of reportable AEs but may aid in exemplifying 
some of the AEs that should be recorded. Similar events not listed here should also be recorded. 
Neurological 
 New-onset ischemic or hemorrhagic stroke; 
 New-onset neurological deficits; or 
 Seizures. 
Cardiovascular  
 New-onset arrhythmia (atrial fibrillation, supraventricular or ventricular tachycardia, 
bradycardia, or other) leading to intervention (eg, cardioversion, defibrillation, pacemaker, or 
drug treatment); 
 New-onset electrocardiogram abnormalities requiring specific monitoring, treatment or 
follow-up; 
 Myocardial ischemia, clinical angina pectoris, or myocardial infarction; 
 New-onset regional or global myocardial dysfunction, visualized by echocardiogram; 
 Circulatory shock, regardless of relation/causality to study drug; or 
 Pericardial effusion. 
Respiratory  
 Hypoxia; 
 New-onset increase of oxygen requirements of more than 20%; 
 Self-extubation; 
 Respiratory acidosis; 
 Pneumothorax; or 
 Aspiration. 

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Gastrointestinal  
 Gastrointestinal bleeding; 
 Gastric or duodenal ulcer; 
 Ileus; or 
 Worsening of liver function tests requiring intensified/follow-up monitoring or consultation. 
Renal  
 Polyuric renal failure; or 
 New-onset anuria or oliguria. 
Hematology 
 Anemia not explained by recent trauma or surgery; 
 New-onset thrombocytopenia; or 
 New-onset thrombocytosis. 
Infection 
 New-onset verified infection (eg, urinary tract infection, pneumonia, sepsis, or other) requiring 
treatment. 
 
THIS IS NOT TO BE VIEWED AS A CHECKLIST, MERELY A GUIDANCE ON 
SOME POTENTIAL AEs, AIMED TO GUIDE AE REPORTING. 
 
Other AEs not listed here but that are similar in type, severity, or out of the normal fluctuations of 
physiological variability seen in an ICU patient should be reported. 
If in doubt, the Investigator should report. 
 
 

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Table 7. 
AE Severity Assessment Definitions 
Assessed from the 
initiation of study 
drug administration 
and until 7 days post 
EOT 
Mild AE 
Moderate AE 
Severe AE 
Serious AE 
Definitions 
An event that is 
easily tolerated 
and generally 
not expected to 
interfere with 
critical care 
course. 
An event that is 
sufficiently 
discomforting to 
interfere with critical 
care course. 
An event that is 
incapacitating, leads to 
major intervention, 
significantly alters 
current critical care 
course. 
Death; prolonged 
hospitalization; persistent or 
significant 
disability/incapacity or 
substantial disruption of the 
ability to conduct normal life 
functions; congenital 
anomaly/birth defect; 
requires medical or surgical 
intervention to preclude 
permanent impairment or 
prevent permanent damage 
to a body structure; medical 
event eg, convulsions, 
asthma requiring acute 
treatment to prevent an 
outcome above. 
AE = adverse event; EOT = end of treatment. 
 
Table 8. 
AE Causality Assessment Criteria 
Causality Assessment 
Causality Criteria 
Not considered causal 
 
Not related 
 
The AE follows a temporal sequence different from study drug administration; 
and 
 
The AE is clearly produced by the patient´s clinical condition or by other modes 
of therapy administered to the patient. 
Unlikely to be related 
 
The temporal sequence between the AE and the study drug administration is such 
that the study drug is not likely to be associated with the observed event; and 
 
The AE could easily and more likely have been produced by the patient´s clinical 
condition or by other modes of therapy administered to the patient. 
Considered causal 
 
Possibly related 
 
The AE follows a reasonable temporal sequence from study drug administration; 
and 
 
The AE could have been, but is equally or less likely produced by the patient´s 
state or by other modes of therapy administered to the patient. 
Probably related 
 
The AE follows a reasonable temporal sequence from study drug administration; 
 
The AE abates upon discontinuation of the study drug (de-challenge); 
 
The AE is likely a reaction to an agent or chemical group, or predicted by known 
pharmacology; and 
 
The AE cannot be reasonably explained by the known characteristics of the 
patient´s clinical state or by other modes of therapy administered to the patient. 
Definitely related 
 
The AE follows a reasonable temporal sequence from study drug administration; 
 
The AE is a known reaction to agent or chemical group, or predicted by known 
pharmacology; 
 
The AE cannot be explained by patient´s clinical state or other factors; 
 
The AE abates upon discontinuation of the study drug (de-challenge); and 
 
The AE is confirmed by reappearance of the reaction on repeat exposure 
(re-challenge). 
AE = adverse event. 
 
 

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Table 9. 
List of AESIs 
List of AESIs 
Mild 
Moderate 
Severe 
SAE 
Hypoxemia 
Oxygen desaturation 
event that requires an 
increase in FiO2 of 
>10% or any increase 
in PEEP for 
>60 minutes to 
maintain SpO2 of at 
least 88%, despite 
ventilator 
optimization. 
Oxygen desaturation 
event that requires an 
increase in FiO2 >20% 
or increase in PEEP of 
>5 cmH2O for 
>60 minutes to 
maintain SpO2 of at 
least 88%, despite 
ventilator 
optimization. 
Refractory 
hypoxemia, defined as 
SpO2 <88% lasting for 
30 minutes or longer, 
despite ventilator 
optimization. 
Need for respiratory 
rescue therapy, 
defined as ECMO, 
ECCO2R, inhaled 
nitric oxide, or inhaled 
epoprostenol initiated 
for life threatening 
refractory hypoxemia, 
or other 
life-threatening 
manifestations of 
hypoxemia. 
Hypercapnia 
PCO2 10 to 15 mmHg 
above baseline on 
2 consecutive blood 
gases at least 
60 minutes apart, 
despite ventilator 
optimization. 
pCO2 16 to 20 mmHg 
above baseline on 
2 consecutive blood 
gases at least 
60 minutes apart, 
despite ventilator 
optimization. 
pCO2 >20 mmHg 
above baseline on 
2 consecutive blood 
gases at least 
60 minutes apart, 
despite ventilator 
optimization. 
ECMO support or 
life-threatening 
manifestations of 
respiratory acidosis. 
MH 
 
 
 
Any episode of MH, 
which may be 
characterized by 
muscle rigidity; 
unexplained 
hypercapnia resistant 
to increasing minute 
ventilation; elevated 
CK or urine 
myoglobin suggesting 
rhabdomyolysis; acute 
hyperkalemia 
>6 mmol/L potentially 
resulting in ECG 
changes of peaked 
T-waves, increased 
ventricular 
tachycardia, or 
ventricular fibrillation 
and hyperthermia in a 
patient exposed to 
volatile anesthetic or 
succinylcholine. 
 
 

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Table 9. 
List of AESIs (Continued) 
List of AESIs 
Mild 
Moderate 
Severe 
SAE 
PRIS suspected 
by the 
Investigator in a 
patient recently 
exposed to 
propofol 
 
 
 
Any episode of PRIS, 
characterized by the 
development of 
otherwise unexplained 
metabolic acidosis and 
cardiac dysfunction 
with at least 1 of 
rhabdomyolysis, 
hypertriglyceridemia, or 
renal failure after 
initiation of propofol. 
Accidental 
self-extubation 
Accidental 
self-extubation will be 
recorded as an AESI, 
but grading is 
unnecessary, per FDA 
guidance  
 
 
 
Hypotension 
New episode of SBP 
<90* mmHg or MAP 
<65* mmHg lasting at 
>60 minutes OR fluid 
bolus 1000 mL over 
<60 minutes OR new 
low dose vasopressor 
<0.05 mcg/kg/min 
norepinephrine 
equivalent >60 minutes 
OR increase of existing 
vasopressor by 0.05 to 
0.1 mcg/kg/min 
norepinephrine 
equivalent over from 
baseline and increase 
lasting >60 minutes. 
New low dose 
vasopressor 0.05 to 
<0.2 mcg/kg/min 
norepinephrine 
equivalent OR increase 
over <60 minutes of 
vasopressor(s) by 0.1 to 
<0.2 mcg/kg/min 
norepinephrine 
equivalent and lasting 
>60 minutes, to 
maintain SBP 
90* mmHg or MAP 
65* mmHg. 
New vasopressor 
0.2 mcg/kg/min 
norepinephrine 
equivalent or increase 
over <60 minutes of 
vasopressor(s) by 
0.2 mcg/kg/min 
norepinephrine 
equivalent and lasting 
>60 minutes, to 
maintain SBP 
90* mmHg or MAP 
65* mmHg. 
Immediate 
life-threatening 
hypotension, requiring 
intervention eg, CPR, 
mechanical circulatory 
support. 
Liver injury 
1) ALT 3  ULN; or 
2) AST 3  ULN; or 
3) Total bilirubin 
>2  ULN; or 
4) Alkaline phosphatase 
>2  ULN. 
Hy’s Law criteria (ALT 
or AST 3  ULN and 
total bilirubin 
>2  ULN). 
Mild encephalopathy 
and Hy’s Law criteria 
(ALT or AST 3  ULN 
and total bilirubin 
>2  ULN). 
Life-threatening 
consequences; moderate 
to severe 
encephalopathy; coma 
and Hy’s Law criteria 
(ALT or AST 
>3  ULN and total 
bilirubin >2  ULN). 
Hyperkalemia 
>5.5 mEq/L 
(>5.5 mmol/L) in a 
non-hemolyzed sample 
and in absence of 
respiratory acidosis. 
>6.0 to 6.5 mEq/L 
(6.0 to 6.5 mmol/L) in a 
non-hemolyzed sample 
for which a medication 
or dialysis to lower 
potassium was 
prescribed. 
>6.5 to 7.0 mEq/L 
(6.5 to 7.0 mmol/L) in 
a non- hemolyzed 
sample for which a 
medication or dialysis 
to lower potassium was 
prescribed. 
>7.0 mEq/L 
(>7.0 mmol/L) in a 
non-hemolyzed sample 
for which a medication 
or dialysis to lower 
potassium was 
prescribed, or 
life-threatening 
arrhythmia due to 
hyperkalemia. 
 

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Table 9. 
List of AESIs (Continued) 
List of AESIs 
Mild 
Moderate 
Severe 
SAE 
Rhabdomyolysis 
independent of 
MH 
CK 10,000 to 
20,000 U/L  
CK >20.000 U/L with 
moderate renal failure 
graded as AKIN1 
Stage 3. 
CK >20.000 U/L 
requiring dialysis. 
Life-threatening 
consequences of 
rhabdomyolysis. 
* Unless a different clinical target is selected by the clinical team prior to randomization.  
AESI = adverse event of special interest; AKIN = Acute Kidney Injury Network; ALT = alanine aminotransferase; 
AST = aspartate aminotransferase; CK = creatine kinase; CPR = cardiopulmonary resuscitation; ECCO2R = extracorporeal 
carbon dioxide removal; ECG = electrocardiogram; ECMO = extracorporeal membrane oxygenation; FDA = Food and Drug 
Administration; FiO2 = fraction of inspired oxygen; MAP = mean arterial pressure; MH = malignant hyperthermia; 
pCO2 = partial pressure of carbon dioxide; PEEP = positive end-expiratory pressure; PRIS = propofol-related infusion 
syndrome; SAE = serious adverse event; SBP = systolic blood pressure; SpO2 = peripheral capillary oxygen saturation; 
ULN = upper limit of normal. 
 
 
1. 
Lopes JA, Jorge S. The RIFLE and AKIN classifications for acute kidney injury: a critical and comprehensive review. 
Clin Kidney J. 2013;6(1):8-14. 

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APPENDIX H:  ORGAN FAILURE, SEQUENTIAL FAILURE 
ASSESSMENT (SOFA) 
 

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APPENDIX I:  STUDY STOPPING CRITERIA 
Table 10. Criteria in the Isoflurane Group Triggering an Ad Hoc DSMB Meeting 
Occurrence of moderate or severe AEs related to 
isoflurane or the device (no plausible alternative 
explanation; assessed as being possibly, probably, or 
definitely related to the study drug by Investigator or 
Sponsor) 
Events observed in the isoflurane group 
SAE – death 
>1 patient 
SAE (events listed in the reference safety information)* 
5 patients 
 
 
SUSAR (events not listed in the reference safety information)* 
3 patients 
 
 
Malignant hyperthermia 
>2 patients 
 
 
Hypoxemia – moderate 
>10 patients 
Hypoxemia – severe 
>5 patients 
 
 
Hypercapnia – moderate 
>10 patients 
Hypercapnia – severe 
>5 patients 
Accidental self-extubation 
10 patients 
 
 
Hypotension – moderate 
>10 patients 
Hypotension – severe 
>5 patients 
 
 
Drug-induced liver injury – moderate and severe 
2 patients  
 
 
Hyperkalemia – moderate 
>10 patients 
Hyperkalemia – severe 
>5 patients 
 
 
Rhabdomyolysis independent of malignant hyperthermia – moderate 
5 patients 
Rhabdomyolysis independent of malignant hyperthermia – severe 
2 patients 
*The reference safety information is defined in the IB (Section 7.7, Reference Safety Information). 
AE = adverse event; DSMB = Data Safety Monitoring Board; IB = Investigator’s Brochure; SAE = serious adverse event; 
SUSAR = suspected unexpected serious adverse reaction. 
No action will be taken on a study level for any of the expected adverse drug reactions (ADRs) 
labelled in the propofol United States product info. The action taken at a patient level for these 
ADRs is at the discretion of the Investigator. 
If >5 reports of Suspected Unexpected Serious Adverse Reactions (SUSARs) concerning the same 
type of medical event (ie, unlabeled events with a suspected relationship to treatment), there will 
be an ad hoc Data Safety Monitoring Board meeting.  
Definitions and grading of each AE of special interest is described in Appendix G.  
 
 

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APPENDIX K:  EQUIVALENT VASOPRESSOR DOSE 
The vasopressor equivalent dose will be calculated using the conversion factors presented in 
Table 11. 
Table 11. Vasopressor Conversion Ratios 
Vasopressor 
Range of Ratiosa 
Suggested Ratioa 
Equivalent Dose 
Norepinephrine 
1 
1 
0.1 mcg/kg/min 
Epinephrine 
0.7-1.4 
1 
0.1 mcg/kg/min 
Dopamine 
75.2-144.4 
100 
10 mcg/kg/min 
Metaraminol 
8.3 
8 
0.8 mcg/kg/min 
Phenylephrine 
1.1-16.3 
10 
1 mcg/kg/min 
Vasopressin 
0.3-0.4 
0.4 
0.04 units/min 
Angiotensin II 
0.07-0.13 
0.1 
0.01 mcg/kg/min 
Formula: norepinephrine equivalents = norepinephrine + epinephrine + phenylephrine/10 + dopamine/100 + metaraminol/8 + 
vasopressin  2.5 + angiotensin II  10. 
a. 
Reported in reference to 1 unit of norepinephrine. For calculations, all doses are in mcg/kg/min with the exception of 
vasopressin in units/min. Angiotensin II is usually dose in ng/kg/min and must be converted to mcg/kg/min for calculations. 
Source: Goradia S, Sardaneh AA, Narayan SW, et al. Vasopressor dose equivalence: A scoping review and suggested formula. 
J Crit Care. 2021;61:233-240.