Prehospital Resuscitation Intranasal Cooling Effectiveness Survival Study 2 (PRINCESS2)
Phase: NA
Conditions: Out-Of-Hospital Cardiac Arrest, Hypothermia, Ventricular Fibrillation
Sponsor: Karolinska Institutet

 
 
 
 
 
Study Protocol 
 
Version 1.1 231005 
 
Prehospital Resuscitation Intranasal Cooling 
Effectiveness Survival Study 2  
(PRINCESS2) 
 
NCT06025123 
  
 

Vers.1.1 October 5, 2023 
 
 
 
ii
      
 
 
 
 Prehospital Resuscitation Intranasal Cooling Effectiveness Survival Study 2 
 
Trial registration: NCT06025123 
 
PROTOCOL  
Version.1.1_October 5, 2023 
 
 
PRINCIPAL INVESTIGATOR (PI): 
 
 
 
Per Nordberg, Senior consultant in cardiology and intensive care, Associate Professor 
Department of Thoracic Intensive Care, Karolinska University Hospital 
Center for Resuscitation Science, Karolinska Institute, Stockholm, SWEDEN 
Email: per.nordberg@ki.se, phone: +46 70 280 25 79 
 
 
 
Fabio Taccone, MD. PhD,  Director of the Neuro-ICU, Department of Intensive Care 
Professor of Emergency Medicine, Université Libre de Bruxelles (ULB) 
Laboratoire de Recherche Experimentale, Department of Intensive Care 
Hôpital Erasme, Route de Lennik, 808, 1070 Brussels – BELGIUM 
Email: fabio.taccone@ulb.be 
 

Vers.1.1 October 5, 2023 
 
 
 
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PRINCESS 2 
 
Steering Committee 
Per Nordberg, MD, PhD (PI, Chairman of the committee) 
per.nordberg@ki.se 
 
Fabio Silvio Taccone, MD, PhD (Co PI) 
ftaccone@ulb.ac.be 
 
Hans-Jörg Busch 
hans-joerg.busch@uniklinik-freiburg.de 
 
Michael Holzer  
michael.holzer@meduniwien.ac.at 
 
Graham Nichol 
nichol@uw.edu 
 
Jacob Hollenberg 
Jacob.hollenberg@ki.se 
 
Peter Radsel 
pradsel@gmail.com 
 
Sune Forsberg 
Sune.forsberg@ki.se 
 
Guiseppe Ristagno 
gristag@gmail.com 
 
Esteban Lopez de Sa Areses 
e.lopezdesa@gmail.com 
 
Ervigio Corral Torres 
corralte@madrid.es> 
 
 
Advisory group and support: 
Leif Svensson 
Leif.svensson@ki.se 
 
Fernando Rosell Ortiz 
fernandorosell@gmail.com  
 

Vers.1.1 October 5, 2023 
 
 
 
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Martin Waleij 
martin.waleij@braincool.se 
 
Mohammad Fazel 
mohammad.fazel@braincool.se 
 

Vers.1.1 October 5, 2023 
 
 
 
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Protocol Synopsis PRINCESS II 
 
Purpose: 
To assess the impact on survival with favorable and complete neurologic outcome 
in out-of-hospital cardiac arrest (OHCA) patients of early transnasal evaporative 
cooling initiated at the scene of the arrest. 
Background: 
Despite recent findings the important knowledge gap remains whether very early 
initiation of hypothermia started at the scene of the arrest improve survival with 
good neurologic outcome in patients with initial shockable rhythms.  
Transnasal evaporative cooling is a non-invasive cooling method through which 
rapid cooling is achieved via the trans-nasal delivery of an evaporative coolant 
into the nasopharynx.   
Previous randomized studies (PRINCE and PRINCESS) with a total of 877 
OHCA patients have shown the method safe and feasible for prehospital use 
initiation of intra-arrest cooling and effective to shorten time to target 
temperature. In both individual studies (and pooled data) there was a strong signal 
towards improved neurologic outcome in patients with initial shockable rhythms. 
The study aims to assess outcome when cooling is begun at the scene of the arrest 
by the EMS followed by systemic cooling at the ICU compared to standard ACLS 
and normothermia at the ICU.
Design: 
Investigator initiated, prospective, randomized, controlled study conducted by the 
pre-hospital emergency system with a standardized protocol for post resuscitation 
care and withdrawal of life support for patients admitted at the ICU.  
Study Population: 
OHCA patients (18 to 79 years) with initial shockable rhythms who qualify for 
advanced cardiac life support. 
Intervention: 
Early transnasal evaporative cooling initiated during ACLS at the scene of the 
arrest within 20 minutes from EMS arrival and subsequent hypothermia at 33ºC 
for 24 hours and fever control for 72 hours at the ICU,
Control
Standard ACLS, subsequent fever control (Normothermia) for 72 hours at ICU.
Performance 
Endpoints:  
 
Primary endpoint:  
 
Survival with complete neurologic recovery at 90 days defined 
as modified Rankin scale of 0-1.  
Main secondary endpoint: 
 
Sustained ROSC and admitted alive   
 
Survival at hospital discharge 
 
Modified Rankin scale 0-3 at hospital discharge 
 
Survival at 90 days 
 
Modified Rankin scale 0-3 at 90 days 
Safety Endpoint: 
 Device related adverse event rate within the first 24 hours. 
 Composite serious adverse event rate within the first 7 days. 
 New cardiac arrest prior to hospital admission 

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TABLE OF CONTENTS 
1. 
INTRODUCTION................................................................................................................. 8 
BACKGROUND & STUDY RATIONALE .......................................................................................... 8 
DEVICE DESCRIPTION .................................................................................................................. 9 
NON-CLINICAL STUDIES ............................................................................................................. 13 
CLINICAL STUDIES ..................................................................................................................... 16 
2. 
STUDY OBJECTIVE AND OUTCOMES ....................................................................... 19 
PERFORMANCE ENDPOINTS ........................................................................................................ 19 
SAFETY ENDPOINTS ................................................................................................................... 19 
3. 
INVESTIGATIONAL PLAN ............................................................................................ 20 
STUDY DESIGN .......................................................................................................................... 20 
OVERVIEW ................................................................................................................................. 20 
ETHICAL CONSIDERATIONS ........................................................................................................ 21 
STUDY PROCEDURES .................................................................................................................. 21 
Screening and randomization ................................................................................................ 21 
Resuscitation Attempt ........................................................................................................... 22 
After ROSC - definition and actions ..................................................................................... 22 
At hospital Admission........................................................................................................... 22 
At ICU admission ................................................................................................................. 23 
Post Resuscitation Care protocol .......................................................................................... 23 
Study criteria for a likely poor neurologic outcome ............................................................. 27 
Withdrawal of life supporting therapies (WLST) ................................................................. 27 
Follow-Up and blinding ........................................................................................................ 28 
Concomitant Therapies ......................................................................................................... 29 
Patient Withdrawal................................................................................................................ 29 
4. 
PATIENT POPULATION ................................................................................................. 30 
PATIENT INCLUSION CRITERIA ................................................................................................... 30 
PATIENT EXCLUSION CRITERIA .................................................................................................. 30 
5. 
STUDY MATERIAL & METHODS ................................................................................ 31 
STUDY DEVICE .......................................................................................................................... 31 
STORAGE & LABELING .............................................................................................................. 31 
PREPARATION & APPLICATION .................................................................................................. 31 
PRODUCT ACCOUNTABILITY ...................................................................................................... 31 
6. 
EVALUATION OF SAFETY ............................................................................................ 31 
ADVERSE EVENT DEFINITIONS................................................................................................... 31 
ADVERSE EVENT ASSESSMENTS ................................................................................................ 32 

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ADVERSE EVENTS REPORTING ................................................................................................... 33 
SERIOUS ADVERSE EVENT REPORTING ...................................................................................... 33 
7. 
RISK EVALUATION ......................................................................................................... 34 
POTENTIAL RISKS TO STUDY SUBJECTS ..................................................................................... 34 
METHODS TO MINIMIZE RISKS ................................................................................................... 37 
POTENTIAL BENEFITS OF THE PROCEDURE ................................................................................. 37 
8. 
STATISTICAL CONSIDERATIONS .............................................................................. 37 
POWER CALCULATION ................................................................................................................ 37 
DATA COLLECTION .................................................................................................................... 38 
STATISTICAL ANALYSIS AND SUB-STUDIES ................................................................................ 39 
9. 
STUDY MONITORING .................................................................................................... 40 
10. 
DATA AND QUALITY MANAGEMENT .................................................................... 40 
11. 
ADHERENCE TO PROTOCOL ................................................................................... 41 
12. 
PROTOCOL AMENDMENT......................................................................................... 41 
13. 
INTERIM DATA, PILOT PHASE AND SAFETY MONITORING COMMITTEE41 
14. 
PUBLICATION POLICY ............................................................................................... 42 

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1. 
INTRODUCTION 
Background & Study Rationale  
Severe brain injury is the primary cause of death in resuscitated cardiac arrest patients 
and the evidence-based strategies currently available to improve neurologic outcome are 
limited.1 Therapeutic hypothermia reduces ischemic and reperfusion brain injury in 
experimental models and may have the potential to limit the brain injuries in patients 
resuscitated from a cardiac arrest.2 Animal and recent clinical data suggest a benefit of 
early cooling initiated during CPR (i.e. intra-arrest) compared to cooling started at a later 
stage after return of spontaneous circulation (ROSC) at the intensive care unit (ICU).3,4 5  
 
Pragmatic study designs lead to late or delayed cooling 
Despite these experimental findings of the importance of early cooling, the vast majority 
of all major clinical studies have assessed the effect of ‘delayed’ or ‘late’ therapeutic 
hypothermia, initiated after hospital arrival often 3-4 hours after the arrest with long time 
delay until the target temperature level has been reached.6,7 The reasons for this delayed 
approach is not fully understood, but most likely it is due to pragmatic reasons. IN 
addition, in the clinical practice, more diagnostics and inhospital interventions occur prior 
to admission to the ICU, such as transport to Xray department for CT scan and coronary 
angiography lab as well as transfer between hospital to so called cardiac arrest centers. 
Thus, as there is a very limited number of cooling methods that can be used in the 
settings above and during transport, these measures will further delay or down prioritize 
the initiation of cooling. Applying this delayed cooling strategy could imply that these 
trials may not have adequately addressed the underlying pathophysiology of ischemia and 
reperfusion. Thus, there is an obvious risk that the optimal time window for the greatest 
effectiveness of hypothermia will be missed. 
In the recently published TTM2 trial target, patients were randomized late, up to 3 hours 
after ROSC and cooling was started sometimes after an even longer duration.7 The target 
temperature of 33°C in the intervention/hypothermia arm was achieved as late as after 7-
8 hours after randomization, thus in some cases more than 10 hours after the arrest. 
Furthermore, Cooling in TTM2 was not implemented pre-hospital or even early after 
hospital arrival at the Emergency department. Thus, no trials; TTM2, HACA or Bernard 
trials have really answer the question whether early cooling (define as intra-arrest or very 
early <20 minutes post-ROSC) cooling initiated at the scene of the arrest is beneficial 
 
Early hypothermia treatment with transnasal evaporative cooling 
To induce early therapeutic hypothermia, especially already during CPR or post-ROSC at 
the scene of the arrest is challenging in real world clinical practice. Therefore, there is a 
need for a portable and bedside cooling device to be able to start cooling at the scene of 
the arrest. 
Transnasal evaporative cooling (RhinoChill) is a cooling method that can be used to 
induce intra-arrest cooling at the scene of the arrest and the method has been tested safe 
and feasible to use prehospital in two randomized trial with a total of 877 out-of-hospital 
cardiac arrest patients (OHCA).8,9  

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The effect of early cooling seems to be most beneficial in shockable rhythm patients 
In the PRINCESS trial, there was a potentially important clinical difference in improved 
neurologic outcome in the subgroup of patients with initial shockable rhythm (i.e. 
ventricular fibrillation or ventricular tachycardia) with an 8.9% absolute difference in 
CPC 1-2 at 90 days (34.8% (48/138) in the intervention group and 25.9% (35/135) in 
controls (difference 8.9%; 95% CI -2.0 to 19.7%; RR 1.28 [0.90–1.72], p= .11) in favor 
of intra-arrest cooling. In patients with shockable rhythms, the differences in complete 
neurologic recovery (CPC 1 at 90 days) were statistically significant (32.6% vs 20%, RR 
12.6 [2.3-22.9].  
In a sub-analysis of the Princess trial in relation to time to initiation of intra-arrest 
cooling, early cooling, started within 20 minutes from the cardiac arrest was associated 
with improved favorable outcome and complete recovery in the subgroup with shockable 
rhythms.5 Furthermore, a recent pooled analysis of the PRINCE and PRINCESS trials 
show a significant difference in neurologic outcome at discharge in the group with initial 
shockable rhythms. In the subgroup with non-shockable rhythms there is no differences 
between groups.10 
 
PRINCESS II 
In the present PRINCESS II trial, therefore only patients with shockable rhythm will be 
included. This subgroup, i.e. initial shockable rhythms, witnessed arrest, limited in age, 
short EMS times, is similar to the patient populations studied in the HACA and Bernard 
studies.6,11 Besides the findings in PRINCE and PRINCESS, the rationale behind this is 
that a first rhythm of ventricular fibrillation or pulseless ventricular tachycardia is a very 
strong factor for cardiac etiologies and therefore improved outcome. This strategy, to 
separate patients with shockable and non-shockable rhythms, is in accordance with the 
clinical management in regards acute myocardial infarction patients with STEMI and 
NSTEMI (intervention strategy vs medical).  
In summary, despite recent findings the important knowledge gap still remains whether 
very, early initiation of hypothermia started at the scene of the arrest improve survival 
with good neurologic outcome in patients with initial shockable rhythms.  
 
Device Description  
The RhinoChill is intended for temperature reduction in patients where clinically 
indicated.  The RhinoChill is contraindicated for patients with known contraindications to 
hypothermia (Raynaud’s disease, Cryoglobulinemia, Sickle Cell disease), have specific 
temperature-sensitive pathologies (e.g., serum cold agglutinins, Buerger’s disease), are 
pregnant, are medically unstable, have bleeding disorders, require oxygen supplied at > 
50% FiO2 to maintain normal saturation (> 98%), intranasal obstruction, or known skull 
base fracture.  
The RhinoChill works by spraying a liquid coolant onto the upper surface of the nasal 
cavity, where it evaporates and absorbs heat from the tissue, thereby cooling the tissue 

Vers.1.1 October 5, 2023 
 
 
 
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and the innate vasculature that supplies blood to the brain (refer to schematic). The 
coolant has a density of 1.68 g/ml and a heat of evaporation of 21cal/g.  Therefore 35 
calories of heat are absorbed for every ml of coolant that evaporates.  Local temperatures 
within the nasal cavity are expected to cool to around 2ｰC.  
The coolant is an inert liquid at one atmosphere of pressure and can carry 20 times more 
oxygen than saline.  It has a surface tension that is lower than water so it will spread 
uniformly and quickly throughout the space in which it is sprayed. Oxygen or air is 
delivered with the liquid coolant to maximize its evaporation.   
Medical grade oxygen or breathing air with a supply pressure of 60 psi and sufficient 
quantity to provide a 40 L/min flow rate over the treatment period is required in order to 
operate the RhinoChill.    
The coolant vapor, along with the gas escapes the nasal cavity through the nostrils or the 
mouth.  In the event that all the coolant is not evaporated, it is possible that it will either 
trickle out of the nostrils or trickle down the pharynx into the mouth or stomach.  
Because the coolant is immiscible in water, it is not absorbed in any significant quantity 
into the body.12,13  The minute quantities that may be absorbed into the blood or inhaled 
into the lungs are expired through the lungs in a relatively short period.  
RhinoChill Schematic 
 
The RhinoChill consists of three components: the tubing set, the control unit, and the 
coolant bottle. The tubing set is a single-use device that delivers the pressurized gas and 
coolant mixture to the patient.  The proximal end attaches to the control unit to which a  
gassource is connected.  Distal to the control unit is the interface for the coolant bottle, 
this consists of a dip tube connected to a bottle interface collar into which is incorporated 
a liquid flow indicator.  Liquid coolant is driven out of the bottle by the pressurized gas, 
through a 0.22 micron filter, and then the gas and coolant are delivered to the nasal 
catheters.  The transnasal catheters are joined together with a hub at the proximal ends; 
the catheters are mated to the gas and liquid delivery lines via an integral manifold.  The 
length of each individual catheter is 10cm, and the outer diameter is 4.0mm.  The 
catheters are designed to be conformable with the anatomy, and have rounded atraumatic 
tips.  The length of the catheter enables deep access into the nasopharynx, and the 
diameter of the catheter is consistent with the size of epistaxis catheters, and enables 
venting through the nostrils.  The catheters have separate gas and liquid capillaries that 
converge at each of 12 spray ports along the dorsal surface of the catheter.  Close contact 
of the liquid PFH with the pressurized gas at each of the spray ports results in efficient 
nebulization of the PFH from each of these ports.  Each catheter also has three pressure 

Vers.1.1 October 5, 2023 
 
 
 
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sensing ports along the ventral surface of the catheter that transmit the local pressure in 
the nasal cavity to the control unit.   

Vers.1.1 October 5, 2023 
 
 
 
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A – Connector 
D – Filter 
G – Catheter Hub 
B – Bottle Interface 
E – Flow Indicator 
H – Nasal Catheters 
 
C – Bottle Cap
F – Delivery Tubing
The control unit is a  component used to both control the flow of the coolant-oxygen 
mixture as well as to act as an over-pressure shut-off valve.  The control unit is composed 
of a oxygen flowmeter that is used to control the flow rate of oxygen as well as electronic 
circuitry to monitor oxygen supply pressure and intranasal pressure in each nostril.  The 
control unit also has a mechanical over-pressure safety valve which is designed to vent 
excess oxygen to prevent a pressure greater than 60 psi  from entering the device.  This 
limiting pressure is set approximately 10% above the 50 psi standard used for medical 
grade oxygen in the hospital setting. The patient pressure safety circuitry switches the 
device to a Stopped/Alarm mode if the pressure in either nasal cavity exceeds 60 cm H20 
.  During the Stopped/Alarm mode, all gas flow is stopped, and all pressure is vented 
from the components downstream of the control unit, including the coolant bottle.  The 
device will remain in the Stopped/Alarm condition until the device is manually reset by 
the operator.   
The control unit circuitry is run by a built in battery that is charged either from a normal 
electrical socket with 230v or a 12v vehicle socket. Fully charged it can run for about 2 
hrs on battery or it can run seamless through connection with socket. 
The control unit has user controls to initiate and stop flow as well as user-feedback 
indicator lights to indicate the operational mode and to alert the user when the circuit 
needs to be reset as well as when the battery power is becoming low and the batteries 
need to be charged. 
The coolant bottle is Polyethylene teraphalate (PET) bottle.  It holds 1 liter of the 
evaporative coolant, perfluorohexane (PFH).  A 1-liter bottle of coolant will last 30 
minutes when the oxygen flow rate is set to 40L/min.   
RhinoChill Tubing Set
A
C
G
E
D
H
B 
F

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The RhinoChill is configured to be used in a stable hospital setting (e.g., hanging from an 
I.V. pole mount) or packaged in a backpack that integrates a 3L (900 liters gas) oxygen or 
air bottle, and weighs approximately 12 kg for use in the ambulance and field setting. 
 
 
 
A Setting control knob  
B Tubing set connection  
C Bottle Holder 
D Bottle Latch 
Indicator lights 
E Battery 
F External power supply 
G Gas cylinder 
H Tubing set connected 
I 
Coolant bottle  
J Flow indicator  
K Nasal catheters 
 
Non-clinical Studies  
Forty-one sheep were studied in the development of the RhinoChill System:  five sheep 
were studied as controls and 36 were studied using a variety of flow conditions and 
relative proportions of PFH to oxygen to effect evaporative cooling within the 
nasopharynx.12  An additional 109 pigs were studied in 9 additional studies of a cardiac 
arrest model in which 68 pigs were cooled with the RhinoChill device and 41 were used 
as controls.  Table 1 summarizes these studies.   
Cardiac arrest studies demonstrated the safety and feasibility of intra-arrest cooling and 
the ability to 1) facilitate resuscitation,14,15 2) increase cardiac recovery time,14 3) increase 
survival,14-16 and 4) increase neurological recovery time.16  In contrast, chilled 
intravenous saline administered intra-arrest had no positive effect on resuscitation.17   
RhinoChill Control Unit 
C 
A 
B
D 
F 
E 
G 
H 
I J K 

 
 
 
 
Table 1.  Animal studies performed with the RhinoChill  
Study Name
Model
Qty
Protocol
Results
Feasibility 
 
Ovine 
20-25kg
 
 
5 
4 
Surface blanket vs. 
Single nozzle jet catheter prototype 
Trans-nasal cooling more effective 
Rectal cooling equivalent in both gr
rate higher with trans-nasal cooling
Flow Optimization  
 
16 
Single nozzle jet catheter prototype – different flow 
Higher O2 and higher PFC flow pro
PFC flow must be matched to O2 fl
High flow rates caused minimal nas
shear damage observed in histomi
Catheter 
Development  
 
14 
Circumferential vs Directed spray catheter designs 
Directed spray design provided con
No bleeding or other adverse effec
PFH Safety  
 
2 
Directed spray catheter, final design 
Dose with 2.5x PFH:O2 x 60min to force uptake 
PFC wash-out from blood at 1 hour
Organ levels after 1-hr wash-out pe
Highest levels in liver (83ｱ57 ng/ml
Cooling Dynamics 
 
Porcine
≈40kg 
 
10 
Compartmental cooling rate as a function of circulatory state: 
3 Spontaneous flow vs. 
3 Untreated VF vs. 
4 VF treated with Mechanical CPR device (LUCAS) 
Brain cooling during spontaneous f
rapid hematagenic cooling followed
Cooling in VF is slower conductive 
over 60 minutes is the same as in s
Cooling during CPR in VF results in
other 2 extremes  
Cardiac Arrest 
Outcome  
(WICCM) 
25     
     
RhinoChill vs. No Cooling vs. Delayed (2H) blanket cooling 
O2 flow = 1L/min/kg 
10 min VF; CPRｱRhinoChill x 5 min; Defibrillation 
RhinoChill cooling x 4H 
Blanket cooling x 8H 
ROSC= 100 vs. 87.5 vs. 87.5% 
24H survival = 100 vs. 25 vs. 75%
Systolic function (EF)  significantly 
cooling and delayed at all time poin
Diastolic function (IVCT) significant
cooling at all time points, and vs bla
Cooling during CPR increased the 
spectra – a prognostic indicator of 
ROSC Rate  
(WICCM) 
16 
RhinoChill vs. No Cooling 
O2 flow = 1L/min/kg 
15min VF; CPRｱRhinoChill x 5 min; Defibrillation 
RhinoChill = 87.5% ROSC vs 
No Cooling = 25% ROSC 
CPP @ 1st shock significantly highe
1st shock success significantly high

 
 
 
 
15 
 
 
Study Name 
Model 
Qty 
Protocol 
Results 
Flow Rate vs ROSC 
Rate  
Porcine
≈40kg 
10 
50%rate (O2 = 0.5L/min/kg) vs. 
25%rate (O2 = 0.25L/min/kg) vs. No Cooling (0 rate) 
15min VF; CPRｱRhinoChill x 5 min; DF 
50% rate = 100% ROSC 
25% rate = 33% ROSC 
0 rate = 33% ROSC 
Duration vs 96H 
Outcome 
10 
Cooling for 1H vs. 4H post ROSC 
10min VF; CPR + RhinoChill x 5 min; DF; survival to 96H 
ROSC & Survival 100%, both groups 
24H neurological tests indicate moderate improvement in pigs 
cooled 4H over those cooled 1H 
96H: all equivalent 
Oxygen vs Air 
6 
O2 vs. Air @ 0.75L/min/kg  
15min VF; CPR+RhinoChill x 5 min; DF
Air: 100% ROSC 
O2: 67% ROSC
PEA (Pulseless 
Electrical Activity) 
16 
RhinoChill vs. No Cooling 
O2 flow = 1L/min/kg 
12min VF; PEA conversion; CPRｱRhinoChill x 5 min; DF 
ROSC = 75 vs 12.5% for RhinoChill vs No Cooling 
CPP significantly higher @ 1st shock for RhinoChill group 
No airway 
2 
15min VF; CPRｱRhinoChill x 5 min; DF 
No airway during VF/resuscitation 
ETT placed immediately post-ROSC 
ROSC successful with un-protected airway 
Post-ROSC PaO2 elevated over baseline values (normally 
decreased)  
CXR post-ROSC showed pulmonary opacification from inhaled PFC 
Appropriate ventilation strategy (PEEP, bpm) enabled lung 
clearance ≤ 60min 
RhinoChill vs cold 
saline 
14 
RhinoChill vs. IV cold saline (30ml/kg over 30 min) 
15min VF; CPR+cooling x 5 min; DF 
Cooling with blankets x 3H @ 1H post ROSC 
 
Pa temperature significantly lower at 1st shock in saline group 
Jv temperature significantly lower at 1st shock in RhinoChill group 
CPP significantly higher at 1st shock in RhinoChill group 
ROSC = 100% RhinoChill vs. 29% cold IV saline 
Mean survival = 27 vs. 67H for saline vs. trans-nasal cooling 
 

 
 
 
16 
 
Clinical Studies 
Cooling after Resuscitation from Cardiac Arrest 
The RhinoChill has been used in the emergency departments or intensive care units in 
84 cardiac arrest patients following ROSC, in a completed feasibility study in 
Europe.18 Cooling was initiated within 35 minutes (median) of patients arriving at the 
hospital, and therapeutic temperature of 34ｰC was reached in 27 minutes and 52 
minutes by the brain (measured at the tympanon) and body, respectively.  Mean 
temperature reduction was 2.4ｰC, 1.6ｰC, and 0.9ｰC for the tympanon, central 
compartment (blood, esophagus), and peripheral compartment (bladder/rectum), 
respectively, within the first 60 minutes of cooling with the RhinoChill.   
There was one device-related serious adverse event.  A patient cooled with the 
RhinoChill device developed discoloration around the nose and upper lip 
approximately 3 hours after RhinoChill use was discontinued.  The patient also 
exhibited skin discoloration of her fingertips and earlobes consistent with a circulatory 
disorder such as Raynaud’s syndrome.  The patient had very high peripheral vascular 
resistance for the six hours prior to study enrollment and throughout therapeutic 
cooling.  The patient died approximately 36 hours after discontinuing RhinoChill use 
due to persistent cardiogenic shock, with no resolution of the skin discoloration.  
Tissue samples were not taken for pathological examination after death, so the 
reversibility of the condition could not be determined. 
 
Cooling during CPR in OHCA (PRINCE and PRINCESS)  
The RhinoChill Device was used in 96 patients randomized to intra-arrest cooling in 
the pre-hospital setting as part of a 200-patient randomized study.8 Cooling was begun 
after the physician team had arrived and had placed an advanced airway, but before 
ROSC.  Thus cooling was not begun until a median of 23 minutes after patient 
collapse.    
There were no significant differences in the proportion of patients achieving return of 
spontaneous circulation (ROSC) (p=0.8). Among patients admitted alive to the 
hospital there was a signal towards increased survival in treated patients (43.8 % vs 
31.0%, p=0.26, Relative Risk (RR) 1.4). In patients admitted alive in whom 
cardiopulmonary resuscitation (CPR) was initiated within 10 minutes (76 % of 
patients) survival to discharge was significantly higher in cooled patients (56.5% vs 
29.4%, p=0.04, RR 1.9). In the subgroup with ventricular fibrillation (VF) as 
presenting rhythm and was admitted alive no significant difference was seen in 
survival rates (62.5% vs 47.6%, p=0.37, RR 1.3).  
More patients were neurologically intact at discharge in the treatment group (34.4% 
vs. 21.4%, p=0.21, RR 1.6) than in controls. Neurologically intact survival to 
discharge was significantly higher in cooled patients in whom CPR was initiated 
within 10 minutes of collapse as compared to no-cool controls (43.5% vs 17.6%, 
p=0.03, RR 2.5). A trend towards good neurologic outcome seen in patients with VF 
as the presenting rhythm (50% vs 28.6%, p=0.11, RR 1.8).  
Neurologically intact survival to discharge was directly related to time to CPR 
initiation. The benefit of intra-arrest cooling on survival, and especially on 
neurologically intact survival, was most marked when CPR was initiated by EMS 
within 10 minutes (refer to Figure).  

 
 
 
17 
 
 
Outcome data on neurologically intact survival (defined as having a cerebral performance category 
(CPC) of 1 or 2) for the two groups in all patients and the subgroups with early CPR and VF.  
 
Nasal whitening occurred in 13 of 93 (14%) patients during nasal cooling and resolved 
spontaneously in all 5 resuscitated patients. There was no relationship between longer 
duration of treatment and nasal discoloration. Nine of the 13 occurred prior to ROSC.  
Epistaxis occurred in 3 (3.2%) treated patients and was serious in one patient with an 
underlying coagulopathy secondary to hepatic failure. This was the only device-
related serious adverse event. Periorbital emphysema occurred 75 minutes into 
treatment in one patient and resolved spontaneously within 24 hours. The total number 
of serious adverse events was 7 in the treatment group, 1 of which was device-related 
(epistaxis) and 14 in the control group (p=0.23). There were no unanticipated adverse 
events in any patient. 
This randomized study demonstrated the safety, feasibility and brain cooling efficacy 
of intra-arrest nasal cooling in the pre-hospital setting. While the study wasn’t 
powered to detect improvement in neurologically intact survival, such an 
improvement was apparent for all patients, irrespective of rhythm, and significant for 
those in whom CPR was initiated within 10 minutes of collapse.  Early nasal cooling 
and early CPR, combined, favorably affected outcome, irrespective of rhythm. In 
practice, these findings argue in favor of trying to initiate both CPR and nasal cooling 
as early as possible during the resuscitation process. 
 
The PRINCESS trial published in JAMA in May, 2019 had very similar study 
criteria.9 The main differences were an upper age limit of <80 years and that the EMS 
response time was to be <15 minutes.  
The safety and feasibility data were similar to the PRINCE study. The time to 
initiation of intra-arrest cooling could be shortened to 19 minutes from the cardiac 
arrest.  

 
 
 
18 
 
The time to target temperature was significantly shortened in the intervention group 
(105 vs 182 minutes, p<0.001).  
The number of patients with CPC 1-2 at 90 days (the primary outcome) was 56 of 337 
(16.6%) in the intervention cooling group vs 45 of 334 (13.5%) in the control group 
(difference, 3.1% [95%CI, −2.3%to 8.5%]; relative risk [RR], 1.23 [95%CI, 0.86-
1.72]; P = .25).  
In the intervention group, 60 of 337 patients (17.8%) were alive at 90 days vs 52 of 
334 (15.6%) in the control group (difference, 2.2% [95%CI, −3.4% to 7.9%]; RR, 1.14 
[95%CI, 0.81-1.57]; P = .44). Minor nosebleed was the most common device-related 
adverse event, reported in 45 of 337 patients (13%) in the intervention group. The 
adverse event rate within 7 days was similar between groups. 
In the subgroup analysis we could see an 8,9% (34.8 vs 25.9, p=0.11) absolute 
difference in favor of the intervention group. In the post hoc analysis in regard to 
complete recovery (CPC 1) at 90 days the difference among patients with initial 
shockable rhythm was 32.6% vs 20%, p=0.02. These differences in neurologic 
outcome among patients with shockable rhythms have been strengthened in a pooled 
analysis of PRINCE and PRINCESS data.10   

 
 
 
19 
 
2. 
STUDY OBJECTIVE AND OUTCOMES  
To study the effect on 90 days survival with complete neurologic outcome (mRs 0-1) 
and good recovery (mRs 0-3) of a strategy with early cooling initiated at the scene of 
the arrest by the EMS within 20 minutes from the EMS arrival followed by systemic 
cooling at the ICU compared to a strategy with standard ACLS followed by 
normothermia applied at the ICU in out of hospital cardiac arrest (OHCA) with initial 
shockable rhythms. In addition to mRs, CPC-scores will be presented to evaluate 
neurologic outcomes. 
Our study hypothesis is that early initiation of transnasal evaporative cooling initiated 
intra-arrest or early post-ROSC in OHCA patients with initial shockable rhythms 
followed by systemic hypothermia to 33C for 24 hours at that target temperature 
level at the ICU increase survival with complete (mRs 0-1) and good neurologic 
outcome (mRs 0-3) at 90 days compared to normothermia at the ICU.   
 
Performance Endpoints 
 
 
Primary outcome:  
 
 Survival with complete neurologic recovery at 90 days defined as modified 
Rankin scale (mRs) of 0-1.  
 
Main secondary outcomes: 
 Sustained ROSC and admitted alive to hospital   
 Survival at hospital discharge 
 Modified Rankin scale 0-3 at hospital discharge 
 Survival at 90 days 
 Modified Rankin scale 0-3 at 90 days 
 
Tertiary outcomes 
 Distribution of MRs at 90 days 
 Hospital free days alive at 90 days.  
 1-year survival 
 Modified Rankin scale 0-1 at 1 year.  
 Distribution of CPC scores at 90 days 
 Health related outcomes (to be defined) 
 Quality of life EQ5D at 90 days 
 
Safety Endpoints 

 
 
 
20 
 
The main safety endpoints are: 
1. Adverse events, including device related, occurring within 24 hours of enrolment.  
2. The composite serious adverse event (SAE) rate from the time of patient 
randomization through the first seven days of hospitalization (see specified in 
section below).     
3. New cardiac arrest prior to hospital admission 
 
3. 
INVESTIGATIONAL PLAN  
Study Design 
This will be an investigator-initiated, prospective, randomized controlled study 
conducted by the emergency responders in multiple emergency medical systems.  It is 
expected to last approximately 3 years. 
Up to 1022 (including 2,5% lost to follow up) cardiac arrest patients that are eligible 
for cardiac life support procedures will be enrolled in the study if they meet all 
inclusion and exclusion criteria.  This study is powered to detect statistically 
significant improvement in complete neurologic recovery in patients that are cooled 
early during resuscitation compared to normothermia.   
Overview 
Medical personnel (e.g,. nurses or physicians) responding to a cardiac arrest will 
assess each patient for study inclusion.  At the scene of the OHCA, patients with 
initial shockable rhythm will be randomized to receive standard ACLS according to 
ERC guidelines with or without transnasal evaporative cooling.  Thus, also patients 
with initial shockable rhythms that has achieved ROSC will be eligible with a time 
window to inclusion of 20 minutes from EMS arrival at the scene. In general, the 
RhinoChill catheters should be placed and cooling initiated immediately after airway 
management (i.e. laryngeal mask or intubation) for those subjects randomized to early 
cooling. No other experimental procedures or devices will be used during the 
resuscitation attempt or after ROSC is achieved in those subjects that do achieve 
ROSC. Specifically, cooling with chilled saline or cold packs in the field or 
ambulance will not be permitted in subjects randomized to either group.  
Resuscitation attempts should be continued for at least 30 minutes after advanced 
emergency medical personnel arrive on the scene in all patients before deciding that 
further interventions are futile.  Patients that regain consciousness following ROSC 
and prior to hospital transport will be included in the intention to treat analysis, but 
will also be analyzed separately from those that remain comatose. Cooling will be 
halted in the early-cooling group for those that wake up.    
Transnasal cooling will be continued in those subjects randomized to early cooling 
that achieve ROSC and remain comatose.  Bolus doses of sedation and analgesia will 
be administered for their transport to the hospital according to local protocol.  
Transnasal cooling will be continued at the hospital until the subject can be 
successfully transitioned to the standard institutional cooling protocol.  All subjects 
randomized to either group will otherwise be treated according to ERC post-
resuscitation care guidelines.         
Clinical assessments and clinically relevant adverse events will be documented from 
the time the patient is randomized into the study until the first of the following three 

 
 
 
21 
 
events occur: death, hospital discharge, or one week following enrolment.  Subjects 
that survive will undergo a neurological assessment at the time of hospital discharge 
and at 90 days after the cardiac arrest. This assessment will be blinded to the patient 
treatment group.  Acute data concerning the cardiac arrest itself will be gathered 
Utstein Style [21]. It is understood that the time of collapse, and hence the exact 
duration of cardiac arrest is an estimate and cannot be quantified accurately. However, 
a single person will be responsible for collecting an individual patient’s charts and 
personally interviewing the witnesses at each site, therefore imprecision surrounding 
the exact time of recognition of collapse and the accurate time of the emergency 
medical activation will be minimized. In the analysis the time of the emergency call 
from the scene of the arrest to the dispatch centre to start of CPR will be used to get 
more exact event times.   
 
Ethical considerations 
The cooling device (RhinoChill) has received CE marking, however, this study is 
considered to be emergency research, in as much as the eligible patients will be unable 
to provide consent prior to their treatment as they will necessarily be comatose. 
Ethical consideration for treating subjects without their express consent will be in 
accordance with the World Medical Association Helsinki Declaration of 1964, as 
revised at the 59th General Assembly in Seoul in 2008, and the responsible ethic 
committee for clinical research.   
Subjects of this study face a life-threatening condition and treatment by cooling with 
the RhinoChill device prior to ROSC has shown improved rates of complete 
neurologic recovery in a previous study. If cooling is begun at a very early stage (i.e. 
within 20 minutes from the arrest) this seems to be beneficial for neurologic recovery. 
In total, 877 OHCA has been studied in randomized trials with RhinoChill without any 
major safety concerns.  It is therefore expected that the potential benefit of using the 
RhinoChill in this population outweighs the risks.   
The study patients’s next of kin will be informed of the subject’s study participation as 
soon as practical after enrollment.  If the subject regains normal neurological function, 
they too will be informed of their study participation and be asked to provide their 
written consent to use their data and to be included into further follow up.      
 
Study Procedures 
Screening and randomization 
OHCA patients will be screened for study eligibility upon arrival of the first 
EMS team after the first rhythm analysis.  If the patient is found to be eligible 
for the study, the patient will be randomized to receive transnasal evaporative 
cooling started at the scene of the arrest along with standard ACLS or standard 
ACLS alone.   
Trial sites will have access to an internet-based randomization application to 
allow for immediate allocation and to ensure adequate allocation concealment 
and adequate generation of allocation sequence. Each patient will be assigned a 
unique trial and randomization number. Randomization will be performed with 
permuted blocks of concealed size, stratified for trial site. 

 
 
 
22 
 
A screening log will be compiled and include all out-of-hospital cardiac arrest-
patients, whether they are eligible for inclusion, or not. 
 
Resuscitation Attempt 
The resuscitation attempt in both study groups should follow ERC guidelines.  
In the patients randomized to early cooling the RhinoChill catheters should be 
placed and cooling initiated as soon as possible after airway management (i.e. 
laryngeal mask or intubation). To place the nasal catheters and start cooling 
takes approximately 1 minute. Cooling should be performed with the oxygen 
flow set to 40L/min.  
Patients randomized to the control arm will receive ACLS according to the 
ERC guidelines.  
After ROSC - definition and actions 
ROSC will be defined as obtaining an organized rhythm and palpable pulse 
sustained for 20 minutes.  Once an organized rhythm and palpable pulse is 
achieved, subjects will have their temperature taken via the tympanic route 
before transported to the hospital.   
Subjects randomized to early cooling will, only if needed, be given 
intravenously administered bolus doses of sedation for transport to the 
hospital.  Doses of sedation will be dictated by the institutional standard 
cooling protocol.  The oxygen supply in the transport vehicle should be used to 
continue RhinoChill cooling during transport to the hospital.  Normal transport 
procedures will be used for patients randomized to the control arm.   
Subjects in both the early cooling and the control arm will otherwise undergo 
standard post-resuscitation care.  Infusions of chilled saline or cooling with 
cold packs will not be permitted in the pre-hospital setting for either group.   
 
At hospital Admission 
Upon hospital arrival it is very important that the transnasal evaporative 
cooling is continued to be able to reach target temperature as fast as possible 
and avoid rewarming before systemic cooling is initiated at the ICU.  
A systemic temperature probe will be placed (e.g., esophageal or bladder) and 
core temperature will be recorded.  ECG, vital signs, level of consciousness 
and other standard diagnostic measures including serum glucose and arterial 
blood gases will be recorded.  
Clinical decisions regarding diagnostics measures, such as coronary 
angiography or CT scan, prior to ICU admission will be according to local 
protocols.  
If diagnostic measures are performed prior to ICU admission, transnasal 
evaporative cooling should be continued during intra hospital transports and at 
the cathlab, X-ray department etc.  

 
 
 
23 
 
At ICU admission 
At admission to the ICU the start of systemic cooling in the intervention group 
should be prioritized and started as soon as possible. After systemic cooling is 
initiated transnasal cooling could be ended. At admission data in regard to 
Sequential Organ Failure Assessment score will be collected at time of 
admission. Se attachment of SOFA score and ICU CRF for definitions and 
specific variables. The data collected at the ICU will consist of a daily ICU 
CRF for the first 72 hours including SOFA scores, cardiac biomarkers, lactate 
clearance, adverse events, and a summary of ICU measures and findings of 
other diagnostic and therapeutic interventions during the ICU stay.  
Post Resuscitation Care protocol 
All subjects will undergo standard post resuscitation treatment upon hospital 
arrival according to the ERC guidelines 2021. Selected key variables in the 
CRF will be monitored from each site to ensure adherence to guidelines.   
The specific difference between the study groups is that subjects in the 
intervention group will receive: 
(1)   transnasal evaporative cooling initiated at the scene of the arrest and; 
(2) systemic hypothermia treatment at ICU with the core body target 
temperature of 33°C with a duration of that target temperature level for at least 
24 hours. Thereafter, the patients in the intervention group will be rewarmed at 
a rate of 0,25°C/hour until they reach normothermia of 36.5°C.  
Fever, defined core body temperature >37.7°C should be avoided for the first 
72 hours from the cardiac arrest  in both study groups. In first-hand use 
antipyretics according to local treatment guidelines, but use cooling devices if 
needed. 
 
Cooling protocol at ICU for the intervention group 
Treatment with systemic cooling device should be initiated as soon as possible 
after admission to ICU and should not be delayed by other measures.  
After the subject has been prepared with the standard hypothermia device, the 
RhinoChill should be turned off, but the intranasal catheters should be left in 
place while transitioning the subject to the standard hypothermia protocol.  
Intermittent activation of the RhinoChill may be considered if the core 
temperature does not continue to drop via the systemic cooling method.  
Cooling via the RhinoChill system will be halted immediately if any adverse 
event related to the use of the RhinoChill develops.  
Temperature recordings (core and tympanic) should be registered every 20 
minutes until the patient has reached core body temperature of 33C (target).  
In the maintenance phase, the patients should be treated at 33C for at least 24 
hours. During that period, core body temperature should be registered once per 
hour.  
The rewarming rate should be 0,25 per hour until the patient has reached core 
body temperature of 36,5C.   

 
 
 
24 
 
Fever control (avoid and treat core body temperatures >37,7 with antipyretics 
or cooling device) should be done for 72 hours.  
Shivering should be assessed using the The Bedside Shivering Assessment 
Scale (BSAS) and treated with buspirone, magnesium, clonidine, meperidine 
or increased sedation or, if needed, neuromuscular blocking agents.  
 
Specific mandatory measures in the study protocol of post resuscitation 
management for both study groups 
 
Sedation  
Sedation will be mandatory for 40 hours after randomization in both study 
groups. Sedation strategies will follow international guidelines with short 
acting drugs and opiods. Avoid using a neuromuscular blocking drug routinely 
in patients undergoing TTM, but it may be used in case of severe shivering. 
The drugs used will be recorded for each patient and we will perform stratified 
analyses according to different sedation strategies (e.g. propofol vs no 
propofol).   
The sedative should be titrated to achieve deep sedation, a Richmond 
Agitation-Sedation Scale (RASS) of minus 4 should be targeted (No response 
to voice, but any movement to physical stimulation).  
This approach with a minimal time for sedation is to facilitate a true 
comparison of two study groups.  
 
Haemodynamic and respiration 
Regarding coronary reperfusion, emergent cardiac catheterisation laboratory 
evaluation (and immediate PCI if required) should be performed in adult 
patients with ST-elevation on the ECG. In patients without ST-elevation on the 
ECG, emergent cardiac catheterization laboratory evaluation may be 
considered if there is an estimated high probability of acute coronary 
occlusion. 
In study sites with the capacity, cardiac function will be followed. If feasible, 
echocardiographic examinations should be performed and recorded at 24 hours 
and after 72 hours to measure left ventricular ejection fraction (LVEF). 
Biomarkers such as Troponin and NTproBNP will also be registered at specific 
time points (se section on data collection).  
 
Targets for circulation and respiration follow the ERC guidelines. Please see 
summary from Figure below (adapted from guidelines document).  

 
 
 
25 
 
 
 
Control of seizures 
Electroencephalography (EEG) is recommended to be used to diagnose 
electrographic seizures in patients with clinical convulsions and to monitor 
treatment effects. To treat seizures after cardiac arrest, we suggest 
levetiracetam or sodium valproate as first-line antiepileptic drugs according to 
local treatment guidelines in addition to sedative drugs. 
 
Prognostication and withdrawal of care 
Prognostication will be performed on all participants still in the ICU after 72 
hours after randomization. The prognostication will be based on the ERC and 
European Society for Intensive Care Medicine recommendations. The 
prognostication may be delayed due to practical reasons (such as weekend or 
national holiday). The physician performing the prognostication will be a 
neurologist, intensivist or other specialist experienced and will be blinded for 
group allocation, but not for relevant clinical data. Prognostication and the 
potential decision to withdraw active intensive care are closely related but will 
be considered separate entities. 
The result of the prognostication will be categorised as “YES” or “NO”, based 
on the answer to the question “Does this patient fulfil the criteria for a likely 
poor neurological outcome?”. This assessment will be recorded in the case 
report form and will be communicated to the treating clinician. 

 
 
 
26 
 
Any decision to withdraw active life support will be made by the treating 
physicians, together with the patient’s relatives or legal surrogates, as required 
by local legislation. The blinded external physician will not make any 
recommendation on WLST. Prognostication may need to be delayed to ensure 
that any lingering effects of sedative agents will not affect the assessment. 
Prognostication at 72 hours will be based on two mandatory (clinical 
examination and EEG), and four optional (NSE, Brain CT, Brain MRI, SSEP) 
modalities: 
 
Clinical examination including assessment of brainstem reflexes and response 
to pain and other stimuli will be performed.  
Absent or extensor motor response to pain at 72h or later in a patient who is 
considered unaffected by sedative agents, is a prerequisite to consider the 
neurologic prognosis poor.  
The bilateral absence of pupillary and corneal reflexes at 72h after CA or later, 
is a finding indicative of a poor prognosis. 
The clinical examination by the ICU-staff should also include an assessment of 
status myoclonus (continuous and generalised myoclonus persisting for at least 
30 min). A prospectively documented early status myoclonus (within 48 hours) 
is indicative of a poor prognosis. 
 
An EEG performed between 36h and 72h after randomization will be 
performed on all participants who survive, and remain unconscious to this 
point, in line with standard clinical practice. If it is not possible to perform an 
EEG study in the specified time frame due to practical reasons (such as 
weekend or national holiday), the EEG should be performed as soon as 
possible after 72h. An EEG with a highly malignant pattern, and without 
reactivity to sound and pain is indicative of a poor prognosis. 
If a brain-CT shows signs of global ischaemic injury, such as: generalised 
oedema with reduced grey/white matter differentiation and sulcal effacement, 
this is indicative of a poor prognosis. A CT should be considered in patients 
who remain unconscious to exclude other pathologies such as intracranial 
haemmorrhage or infarction.  
A brain MRI at 3-5 days may be incorporated into prognostication if it has 
been performed. Signs of global, diffuse, or bilateral multifocal ischaemic 
lesions is indicative of a poor prognosis. 
High levels of Neuron-specific enolase (NSE) are indicative of a poor 
prognosis. If serial samples are available, and these are consistently higher 
than locally established levels associated with a poor outcome, this may be 
seen as indicative of a poor outcome. 
Absent SSEP N20-responses bilaterally may be seen as indicative of a poor 
prognosis, if SSEP is performed more than 48h after randomisation. 
 

 
 
 
27 
 
In the cases where ICU care is withdrawn due to poor prognosis, the reasons 
(prognostic measures besides clinical examination) for this should be clearly 
stated in the Case Report Form (CRF) (e.g. MRI, neuro markers, EEG, SSEP).  
 
Study criteria for a likely poor neurologic outcome  
 
The following criteria, evaluated at the earliest at 72 hours after randomisation 
or later, need to be fulfilled to establish a likely poor neurological outcome. 
 
• Unconscious patient with absent or extensor motor response to pain (no 
confounders e.g. sedation) 
 
AND at least two of the following: 
 
• Bilaterally absent pupillary and corneal reflexes 
• Bilaterally absent SSEP N20-responses 
• Diffuse anoxic brain injury on CT or MRI 
• Documented status myoclonus within 48h of randomisation 
• High levels of serum NSE (>60ug/L at 48 h and/or 72 h) 
• An EEG with a highly malignant pattern and without any observed reactivity 
to sound or pain. Patterns that are considered highly malignant are:  
1. Suppressed background (amplitude <10mV, 100% of the recording) 
without discharges. 
2. Suppressed background with superimposed continuous periodic 
discharges. 
3. Burst-suppression (periods of suppression with amplitude <10mV 
constituting 50% of the recording) without discharges. 
4. Burst-suppression with superimposed discharges. 
 
 
 
Withdrawal of life supporting therapies (WLST) 
 
All participants in the trial will be actively treated until at least 72 hours after 
randomization. There will be two exemptions from this rule. 
• Participants in whom further treatment is considered unethical due to 
irreversible organ failure, a documented medical comorbidity, or other reasons. 
The reason for WLST must be documented comprehensively in the CRF. 

 
 
 
28 
 
• Participants in whom brain death is established, however this will be defined 
as death and not WLST 
 
The assumption of a poor neurological prognosis alone by one treating 
physician will not be considered sufficient to employ withdrawal of active 
intensive care prior to 72 hours after randomisation. After prognostication has 
been performed, WLST due to a presumed poor prognosis will be allowed if 
trial criteria for a likely poor neurological outcome are fulfilled and all effects 
of sedation on consciousness are ruled out. Participants who have an unclear 
prognosis at 72h after randomisation should be reexamined daily and WLST 
may be considered if neurological function does not improve and, metabolic 
and pharmacological reasons for prolonged coma are ruled out. If a decision of 
WLST is made, the time point and the main reasons for withdrawing life-
supporting therapies will be recorded. However, supporting therapy may also 
be continued regardless of the neurological assessment of prognosis, at the 
discretion of the treating physician. 
 
Follow-Up and blinding 
 
Neither EMS or hospital personnel will be blinded to treatment, since the control 
patients are easily distinguishable from patients undergoing device placement 
and nasal cooling and subsequently systemic cooling at the ICU.  However, 
study personnel making the final neurological assessment of the patient prior to 
discharge and at the earliest 90 days (as close as possible to 90 days but not 
before 90 days) follow up will be blinded as to the patient’s group assignment. 
In addition assessment at 72 hours in regard to fulfilling criteria for withdrawal 
of care will be performed by a blinded assessor.  
Overall survival will be reported at 30 days, 90 days and after 1 year. mRS will 
be assessed at hospital discharge and at 90 days and after 1 year. Long trem 
outcomes (1-year survival and mRS at 1 year) will be presented in a separate 
analysis. 
The formal follow-up with blinded outcome assessor will take place at 90 days 
after cardiac arrest. Participants will be assessed according to the mRS-scale. 
This can be done via a structural telephone interview or at a clinic visit, if 
possible together with a relative or close friend. At these calls/visits the specially 
trained, blinded assessors will perform structured interviews and administer tests 
according to the secondary and exploratory outcomes. The assessment will focus 
on cognitive function, quality-of-life, return to work, participation in society. 
The outcome-assessor may be an occupational therapist, physician, research 
nurse, psychologist or similar. Outcome-assessors will be provided with a 
written trial manual with detailed guidelines for performing the questionnaires 
and assessments. 
If needed, training sessions will be provided by the trial coordinating team.  
 
Modified Rankin Score

 
 
 
29 
 
0
No symptoms at all
1 
No significant disability despite symptoms; able to carry out 
all usual duties and activities
2 
Slight disability: unable to carry out all previous activities, 
but able to look after own affairs without assistance
3 
Moderate disability: requiring some help, but able to walk 
without assistance
4 
Moderately severe disability: unable to walk without 
assistance and unable to attend to own bodily needs without 
assistance
5 
Severe disability; bedridden, incontinent and requiring 
constant nursing care and attention
6
Dead
 
Concomitant Therapies 
Concomitant interventions (e.g., PCI, aortic balloon pump, bypass surgery, 
ECMO, ICD placement) will be recorded.    
Medications and/or treatments that are considered to be experimental in nature 
and are intended to improve outcomes after cardiac arrest are prohibited from 
use. 
Patient Withdrawal 
Subjects will be enrolled in the study by rescue personnel if they meet all of 
the study’s inclusion criteria, but none of the exclusion criteria.  Subjects will 
necessarily be comatose and unable to provide consent prior to their being 
enrolled in the study.  The subject’s closest relative or legal representative will 
be informed of the study as soon as it is practical to do so.  Subjects that 
recover will be informed of their study participation and be asked to provide 
their written consent for the use of their study data and further follow up.   
The Principal Investigator, Steering Committee and the individual site 
investigators and site Ethic Committees (ECs) also have the right to 
discontinue a patient or terminate the trial for the following reasons: 
 A Site Investigator may withdraw a subject from the study for safety 
reasons (i.e. a device-related serious adverse event).  In these cases, data 
surrounding the event leading to subject withdrawal will be retained for 
safety analyses.   
 The EC at any participating site may decide to withdraw the site from the 
study for safety reasons. 
 The EC at the principal investigator site and Principal Investigator may 
terminate the study for safety reasons. 
 A decision on the part of the Principal Investigator to suspend or 
discontinue testing, evaluation, or development of the product for any 
reason. 

 
 
 
30 
 
 The Principal Investigator may decide to close a study site when one of the 
following occurs:  
 The Site Investigator at an individual site fails to enrol patients into the 
study at an acceptable rate. 
 A Site Investigator at an individual site fails to comply with pertinent 
regulations of appropriate regulatory authorities. 
 A Site Investigator fails to adhere sufficiently to protocol requirements 
 A Site Investigator knowingly submits false information from the 
research facility to the Principal Investigator, Steering Committee or 
appropriate regulatory authority. 
If the study is terminated early, all specified follow-up data on subjects 
enrolled prior to termination will be collected and reported.   
 
4. 
PATIENT POPULATION 
Subjects with OHCA with initial shockable rhythms will be recruited by EMS personnel at the 
scene of the cardiac arrest. Thus, patients will be eligible for enrolment as soon as the first 
rhythm has been assessed.  
Patient Inclusion Criteria  
Adult patients (age 18 years) are eligible if they meet all of the following criteria:     
1. Adult out-of-hospital cardiac arrest patients with initial shockable rhythm (i.e. 
ventricular fibrillation or pulseless ventricular tachycardia or ‘shock advised’ by 
an automated external defibrillator) 
2. Unconsciousness defined as Glasgow Coma Scale  8 
3. Inclusion within 20 minutes from EMS arrival 
 
Patient Exclusion Criteria 
Patients are not eligible if they meet one or more of the following criteria: 
1. Age 80 years  
2. Obvious non-cardiac causes to cardiac arrest (trauma, head trauma, severe 
bleeding, drug overdose, cerebrovascular accident, drowning, smoke inhalation, 
electrocution, hanging, choking due to foreign body airway obstruction, burns or 
exsanguination).  
3. Obvious already hypothermic (e.g. found in the snow) 
4. Obvious barrier to placing intra nasal catheters (e.g., intranasal obstruction) 
5. Have a known Do Not Attempt to Resuscitate (DNAR) order or other limitations 
in care. 
6. Have a known terminal disease 
7. Known or clinically apparent pregnancy 
 
If a patient is unaccompanied or accompanied by a person or persons unfamiliar with 
their history, determination of these exclusion criteria will be left to the best 

 
 
 
31 
 
estimation of the emergency personnel.  At no time should an attempt to determine 
these criteria be allowed to delay the administration of life-saving treatment. 
 
5. 
STUDY MATERIAL & METHODS 
Study Device 
The investigational sites will use the RhinoChill control units and tubing sets and 
bottles of liquid coolant at the standard cooling rate of 40l per minute of oxygen/air 
flow.  It is expected that at least one tubing set and 1bottles of coolant will be needed 
for each subject enrolled in the early cooling arm.  Patients that are resuscitated after 
RhinoChill cooling is initiated will likely require 1-2 additional bottles of coolant 
before in-hospital systemic cooling can be initiated. Participating institutions have 
been provided RhinoChill units to use to continue cooling patients randomized to early 
cooling until systemic cooling can be initiated in the hospital.  No specific surgical 
skills are necessary to use the device, but basic knowledge of cardiac life support, 
therapeutic hypothermia and the associated effects are required.    
Participating sites are required to supply the pressurized gas source (oxygen or 
breathing air) that will be used in the field, ambulance, and hospital settings.    
Storage & Labeling  
Components are designed to withstand standard transportation, storage and operating 
temperatures for both ambulance and hospital use.  Product provided for the study will 
carry the CE Mark.       
Preparation & Application 
The RhinoChill system will be packaged in a portable pack.  A medical grade supply 
of oxygen will be integrated into the pack by site personnel prior to placing it on the 
emergency response vehicle.  A brief functionality test of the tubing set and control 
unit pressure relief valve should be performed prior to placing the nasal catheters in 
the subject.   
The individual nasal catheters will be advanced through each nostril so that the distal 
end is well within the nasal cavity.  Care should be taken not to force the individual 
catheters into the nostrils, but to advance them gently.  Once the catheters are placed, 
cooling will be initiated by turning on the RhinoChill gas supply and adjusting it to 
40L/min.  The nostrils are to be kept unobstructed to allow venting of the PFH vapor. 
 
Product Accountability 
Product is CE-marked and labeled by lot and serial number where appropriate.   
 
6. 
EVALUATION OF SAFETY 
Adverse Event Definitions 
An Adverse Event (AE) is any untoward medical occurrence in a subject.  
A Serious Adverse Event (SAE) is any adverse event that: 
a) leads to death  

 
 
 
32 
 
b) leads to a serious deterioration in the health of the patient that: 
1. results in a life-threatening illness or injury 
2. results in a permanent impairment of a body structure or a body function 
3. requires in-patient hospitalization or prolongation of existing hospitalization 
4. results in medical or surgical intervention to prevent permanent impairment to 
a body structure or a body function 
 
Adverse Device Effects and Serious Adverse Device Effects are those AEs and SAEs 
that occur as an untoward or unintended response to a medical device.  These events 
include those which result from insufficiencies or inadequacies in the Instructions for 
Use or deployment of the device as well as user error. 
An Unanticipated Adverse Device Effect (UADE) is defined as any serious adverse 
effect on health or safety or any life-threatening problem or death caused by – or 
associated with – the device, if that effect, problem or death was not previously 
identified in nature, severity, or degree of incidence in the investigational plan 
(including documents such as the protocol, Investigator’s Brochure, informed consent 
form or other study-related documents), or any other unanticipated serious problem 
associated with the device that relates to the rights, safety or welfare of subjects.  
A Technical Device Failure is defined as a failure of the device to perform its intended 
function when used in accordance with the Instructions for Use.  Technical device 
failures will be recorded and evaluated for possible untoward effects on the subject.  If 
a device failure results in an adverse experience in the subject, this adverse experience 
should be considered an adverse device effect and recorded on the Adverse Event 
pages of the CRF. Device failures that do not result in a clinically significant adverse 
effect on the patient will be noted on the CRF pages regarding device performance but 
will not be considered an adverse device effect.     
Adverse Event Assessments 
The relation of the event to the investigational device will be categorized by the 
Investigator as follows: 
Not related – AE is due to the underlying disease state or concomitant 
medication or therapy, and was not caused by the investigational device. 
Probably not related– AE had minimal or no temporal relationship to the use of 
the investigational device and/or a more likely alternative etiology exists. 
Probably related – AE had a strong temporal relationship to the use of the 
investigational device and an alternative etiology is less likely compared to the 
potential relationship to the investigational device. 
Definitely related – AE had a strong temporal relationship to the use of the 
investigational device and another etiology is highly unlikely. 
For the purposes of reporting, an event will be considered associated with the use of 
the device if it is believed to be due either directly to the mechanical aspects of the 
device itself (e.g., nosebleed) or the ensuing device-related cooling.  
Events believed to be due to study procedures other than the device/cooling (such as 
events believed to be side effects of the standard hypothermia maintenance) will be 
recorded but will not be categorized as device-related. 

 
 
 
33 
 
Subjects enrolled in the study will have a high morbidity and mortality rate associated 
with their cardiac arrest and the ensuing global ischemia.  Therefore, careful attention 
shall be made to assessing the causality of any serious adverse events. 
Adverse Events Reporting 
All clinically significant AEs or those that appear to be related to the use of the 
RhinoChill (e.g., whitening of the nose) as well as those that could potentially harm 
the patient (e.g. barotrauma) will be recorded on in a special section of the CRF from 
ROSC through the first 24 hours from inclusion.  Abnormal laboratory values are 
expected in these patients, and these are not to be recorded as AEs.  The date of 
occurrence, severity, duration, management, technical issues and relationship to 
cooling with the RhinoChill Device will be recorded. 
Serious Adverse Event Reporting 
All SAEs listed below are considered as common complications after cardiac arrest 
and do not need to be reported other than in the CRFs.  These complications that occur 
within seven days after enrolment will be presented to the DSMB at the time of the 
interim analysis and presented in the main publication.  
 
SAEs in both groups (thus not specifically device related) that should be reported in 
the CRF:   
 New cardiac arrest after enrollment.  
 Arrhythmias resulting hemodynamic compromise  
 Bradycardia necessitating pacing 
 Cerebrovascular lesion during ICU stay (bleeding or infarction)  
 Sepsis and septic shock, according to the 3rd international consensus 
definitions for sepsis and septic shock 
 Moderate or severe bleeding, according to the GUSTO criteria 
 
Unexpected SAE that needs to be reported to the principal investigator: 
Unanticipated Adverse Device Effect (UADE) and other unexpected SAE should be 
followed until resolution; this includes those patients that were terminated early or 
withdrawn.  These must be reported to the study sponsor at The Karolinska Institutet 
(see contact information with email and phone to the principal investigator and study 
coordinator on the first page of the protocol) and at the same time to the company 
BrainCool AB as soon as possible, preferably within 24 hours of their occurrence as 
well as following their resolution. SAE:s such as those listed below will be reported in 
a separate electronic CRF in the database. When inserting data regarding adverse 
events in the database, the PI will automatically receive an email with information of 
the adverse event.  
 
 Device related skin complications (blistering or skin necrosis) 
 Device related bleeding requiring transfusion 
 Barotrauma such as pneumocephalus 

 
 
 
34 
 
 Other, unexpected serious adverse events 
 
The Principal Investigator, Per Nordberg and senior adviser professor Leif Svensson  
at the Department of Clinical Science and education, Karolinska Institutet, will review 
all SAE reports as soon as possible with regard to their causal relationship to use of 
the cooling method.   
Reporting to the regulatory authorities will be performed per European vigilance 
requirements and other local requirements. This is a responsibility of the PI.  
 
7. 
RISK EVALUATION  
Potential Risks to Study Subjects  
For purposes of this study, adverse events that may be anticipated and are associated 
with the use of the device include those associated with the RhinoChill Device or from 
the device-induced mild hypothermia.  
Device Use 
Potential risks associated with the use of the RhinoChill Device include those 
associated with the mechanical aspects of an intranasal catheter as well as 
those associated with the delivery of the PFH-oxygen mixture.   
The following events are those most likely, non-serious events to occur with 
the use of the RhinoChill Device:  
Peri-nasal tissue discoloration due to local evaporation of the coolant on the 
external facial structures that is expected to resolve after normal circulation is 
restored. This occurred in about 7 % of the patients in the PRINCESS trial.  
Mucosal irritation/dryness caused by high oxygen flows during cooling that 
would resolve with over the counter medications or on its own. Has not been 
reported in surviving patients from the PRINCE and PRINCESS trials.   
Epistaxis, minor: bleeding arising from the nasal cavity or paranasal sinuses 
that would resolve on its own or would be easily controlled with cauterization 
or simple nasal packing.  This occurred in about 13% of the patients in the 
PRINCESS trial.  
Para-sinus emphysema: gas entrapment in the sinus region that will resolve 
on its own; associated with chronic sinusitis. Has been reported in 2 patients.  
The following events are those least likely, non-serious events to occur with 
the use of the RhinoChill Device:  
Gastrointestinal discomfort caused by accidental ingestion of PFH that 
would resolve without intervention; Has not been reported in surviving 
patients from the PRINCE and PRINCESS trials.  
Frostbite/necrosis to the nasal tissues caused by excessive local cooling that 
might require intervention; Has not been reported in surviving patients from 
the PRINCE and PRINCESS trials.  
Diminished sense of smell caused by PFH evaporation in the nasal cavity. 

 
 
 
35 
 
The following serious events are anticipated to very rarely occur with the use 
of the RhinoChill Device: Has not been reported in surviving patients from the 
PRINCE and PRINCESS trials 
Hypoxia: depletion of oxygen supply due to saturation with PFH requiring 
prolonged mechanical ventilation with 100% oxygen; Has not been observed 
in the ICU data.  
Epistaxis, major: bleeding arising from the nasal cavity or paranasal sinuses 
that would be characterized by brisk bleeding with no accessible source.  A 
major nosebleed of this type would require posterior nasal packing or balloon 
packs, or even an arteriogram with embolization of the internal maxillary 
artery.  A transfusion would be required in those cases in which 
hemoglobin/hematocrit falls significantly due to the bleed. Major nosebleed 
was reported in 4 patients in the PRINCESS Trial where cooling had to be 
interrupted. 
Infection: presenting as a wound infection in the nasal cavity, or alternately as 
bacteremia with sepsis, that requires medical or surgical intervention, such as 
antibiotic therapy and prolonged hospitalization; Has not been reported in 
surviving patients from the PRINCESS trial 
Barotrauma: Trauma caused by rapid or extreme changes in gas pressure, 
especially affecting enclosed cavities within the body such as the nasal cavity 
and lungs.  This could cause tearing of mucosal tissue in the nasal cavity and 
possibly the displacement of the nasal septum that would require endoscopic 
evaluation and surgical repair.  Lung barotrauma could cause tearing of lung 
tissue and rupture of alveoli/small bronchi or entry of gas into the blood 
vessels that would require surgical intervention and prolonged hospital stay; 
One case of pneumocephalus was reported in the PRINCESS trial, which 
resolved without intervention and the patient survived with good neurologic 
function. 
Air embolus: air circulating in the blood that results in clinical sequelae that 
are life threatening and may be amenable to surgical intervention; Has not been 
reported in patients from the PRINCE and PRINCESS trials 
Pulmonary aspiration: soiling of the respiratory tract by foreign, non-gaseous 
substances (e.g., PFH or food particles) that could result in aspiration 
pneumonitis or aspiration pneumonia where the former represents 
inflammation of the lung tissue without infection, whereas the latter also has 
superimposed infection.  Systemic medication with prolonged hospital stay 
would be required in the event of either developing; Has not been reported in 
patients from the PRINCE and PRINCESS trials 
Burns: due to oxygen-enhanced fire/explosion that could be life threatening, 
requiring prolonged hospital stay and potential surgical intervention; Has not 
been reported.  
Intracranial pressure increases due to uncontrolled re-warming of the brain 
during the transition to systemic cooling after it has been cooled with the 
RhinoChill Device.  Uncontrolled re-warming of the brain from a cooled state 
can lead to severe levels of intracranial pressure that could herniate the 
brainstem and lead to death. Has not been reported in patients from the 
PRINCE and PRINCESS trials 

 
 
 
36 
 
Mild Hypothermia 
Hypothermia results in various physiological effects on the body which are 
generally managed with medical care.  These effects include the following: 
 The oxyhemoglobin-dissociation curve shifts to the left. 
 Metabolic acidosis results from lactate generation from shivering and 
decreased tissue perfusion; this is exacerbated by hypothermia-induced 
impairment of hepatic metabolism and impaired acid excretion. 
 Hematocrit increases 2% per 1C decline in temperature, resulting in 
increased blood viscosity. 
 Hypokalemia may occur due to inhibition of the sodium-potassium ATP 
pump. 
 Hyperglycemia may occur due to decreased insulin release and increased 
peripheral insulin resistance. 
 Coagulopathies may arise due to hypothermia induced impairment of the 
enzymatic reactions of the coagulation cascade (despite normal clotting 
factor levels). 
 Platelet activity is impaired because platelet production of thromboxane 
B2 is temperature-dependent; in addition, bone marrow production can be 
suppressed and hepatosplenic platelet sequestration can be increased; 
 Direct impairment of immune function (especially via oxidative killing by 
neutrophils) can increase susceptibility to infection. 
The magnitude and clinical significance of the effects of hypothermia are 
generally dependent upon the degree and duration of systemic hypothermia.  
The depth and duration of hypothermia used in this study is mild hypothermia 
(33ｰC).  The use of a mild level of hypothermia will therefore minimize the 
risk of hypothermia-associated effects.  
Anticipated events associated with mild hypothermia include the following: 
 CNS:  linear depression of cerebral metabolism; amnesia; apathy; 
dysarthria; impaired judgment; maladaptive behavior; 
 Cardiovascular: tachycardia, then progressive bradycardia; cardiac-cycle 
prolongation; vasoconstriction; increase in cardiac output and blood 
pressure;  
 Respiratory: tachypnea, then progressive decrease in respiratory minute 
volume; declining oxygen consumption; bronchorrhea; bronchospasm; 
 Renal, Endocrine, Metabolic: hyperglycemia, hypokalemia, lactic 
acidosis; cold diuresis; increase in catecholamine, adrenal steroids, 
triiodothyronine, thyroxine; increase in metabolism with shivering; 
 Neuromuscular: increased pre-shivering muscle tone, then fatiguing; 
shivering induced thermogenesis; ataxia; 
 Infectious: pneumonia, sepsis; 
 Coagulopathy: hemorrhagic conversion of an ischemic infarct. 

 
 
 
37 
 
Methods to Minimize Risks 
 
The target patient population is comatose and will die with no intervention.  Even with 
advanced cardiac life support interventions, mortality is high following cardiac arrest. 
All serious adverse events related to the use of the RhinoChill have been analyzed 
with respect to their likelihood and severity, and have been minimized through both 
the design and manufacture of the device and the design of the study.       
Potential Benefits of the Procedure 
The brain protective effect of hypothermia is most likely depending on the timing and 
effect of the cooling initiation. The RhinoChill has been demonstrated as feasible and 
effective to shorten time to target temperature in OHCA patients in two randomized 
trials including a total of 877 patients. Outcome data form these trials suggest a benefit 
in survival with good and complete neurologic outcome in patients with initial 
shockable rhythms.  In secondary analysis, a time to initiation of cooling within 20 
minutes from the cardiac arrest was beneficial. 
  
8. 
STATISTICAL CONSIDERATIONS   
 
 
Power calculation 
This study is powered to detect clinically significant changes in survival with complete 
neurologic recovery (mRS 0-1) at 90 days after cardiac arrest.  
 
Sample size calculation was based on the preceding clinical trials (i.e. PRINCESS and 
other recent trials in OHCA such as TTM2. In PRINCESS, the survival rate with CPC 
1-2 at 90 days in VF-patients was 34.8% vs 25.9% and in CPC 1 at 90 days 32.6% vs 
20%.  
 
Among patients with VF that was admitted alive, the survival with CPC 1-2 at 90 days 
was 57.8% vs 44.9% and in CPC 1 at 90 days 54.2% vs 33.6%.  
 
Assuming a neurological intact (mRS 0-1) survival rate among admitted patients of 
45% in the control group and 54% (Cohen’s h = 0.18) in the intervention group we 
estimated that 483 patients would be needed in each group (966) to detect a 
statistically significant difference using a one-sided alpha of 0.025 and a beta of 0.2 
(80% power). To adjust for 1 interim analysis (Haybittle-Peto) after 40% inclusion 
(approximately 400 patients), with 1 test of efficacy and 1 test of futility the sample 
size is inflated to 996 patients. 
  
If the z-value is over 3.0 in the interim analysis the trial can be stopped for efficacy. 
Similarly, if the z-value is below 0, the trial can be adviced by the DSMB to be 
stopped for futility. The decision to stop the trial for efficacy or futility is taken by the 
Steering committe.  
  
Assuming a lost to follow-up on neurological intact survival of 2.5% the sample size 
will be 1022 patients. 
  

 
 
 
38 
 
  
R script for power calculation: 
  
Library(rpact) 
princess2samplesize <-  getDesignGroupSequential(typeOfDesign = "HP", 
                                    kMax = 2, 
                                    alpha = 0.025, 
                                    sided = 1, 
                                    beta=0.2, 
                                    futilityBounds = c(0), 
                                    informationRates = c(0.40, 1)) 
  
summary(getSampleSizeRates(princess2samplesize, pi1 = 0.54, pi2 = 0.45)) 
 
Data Collection  
Data collection will be reported in the different stages of the study;  
Prehospital; 
Emergency department; 
ICU;  
Discharge; 
Follow up at 30 + 90 days + 1 year.  
Data will include ROSC rate, resuscitation parameters, early cardiac performance, and 
outcome measures (total survival and neurological intact survival at 90 days).  These 
parameters will be compared between those patients that receive nasal cooling during 
ACLS and those that do not. For details see study CRFs for each of these phases.  
1. Resuscitation parameters will be calculated for all randomized patients.  
2. Early post-resuscitation cardiac performance parameters, such as ECG, cardiac 
biomarkers, arterial blood gas and neurologic assessment, along with core and 
tympanic temperatures will be calculated for those patients that survive to hospital 
admission.  
3. At ICU a short daily CRF will be used for the first three days to collect data on 
organ dysfunction (SOFA score and biomarkers) and cooling intervals. Thereafter a 
summary of ICU measures (diagnostics, treatments etc) will be collected at discharge 
from the ICU.  
4 .Main outcome parameters will be: 
 
Primary outcome:  
 
 Survival with complete neurologic recovery at 90 days defined as modified 
Rankin scale (mRs) of 0-1.  
 
Main secondary outcomes: 
 Sustained ROSC and admitted alive   

 
 
 
39 
 
 Survival at hospital discharge 
 Modified Rankin scale 0-3 at hospital discharge 
 Survival at 90 days 
 Modified Rankin scale 0-3 at 90 days 
 
Tertiary outcomes 
 1-year survival 
 Modified Rankin scale 0-1 at 1 year.  
 Distribution of CPC scores at 90 days 
 Health related outcomes (to be defined) 
 Quality of life EQ5D at 90 days  
 Distribution of MRs at 90 days 
 Hospital free days alive at 90 days.  
 
 
 
Statistical Analysis and sub-studies 
A separate statistical analysis plan is attached to this protocol. In summary, descriptive 
statistics will be calculated for all performance, safety, demographic, and baseline 
variables.  Means, standard deviations, and ranges will be used to describe continuous 
measurements.  Counts and percentages will be used to describe categorical 
parameters.  Differences between variables associated at different time points will be 
evaluated using an appropriate comparative statistic.  Data from the two treatment 
groups will be analyzed for treatment effect.  A 2-sided p-value less than 0.05 will be 
considered to be statistically significant. 
Outcome analyses will be performed as Intention to treat, se separate statistical 
analysis plan. Secondary analyses will be performed according to ‘Modified Intention 
to treat’ where post randomization data on the patients appear, such as existing DNAR 
or severe comorbidities that upon admission to hospital will lead to restrictions in care 
and interruption of the study intervention, ‘Per protocol’ and ‘As treated’ for all 
randomized patients.  No imputed values will be used for patients for whom data is not 
available. 
Stratified analyses will be performed for patients where cooling is started intra-arrest 
versus post-ROSC; if cooling was started within 20 minutes from the cardiac arrest vs 
after 20 minutes; men vs women; above median age vs  median age; patients 
receiving ECPR vs not receiving ECPR; STEMI vs non-STEMI.  
Several predefined substudies will be performed with additional data compared to the 
core CRF. One such substudy is ECPR-patients where a separate power analysis will 
be performed. Protocol synopsis for substudies will be added as an appendix to the 
protocol.  

 
 
 
40 
 
9. 
STUDY MONITORING  
 
The trial will be monitored by national monitoring offices coordinated by the study sponsor, 
Karolinska Institute, Stockholm, Sweden, Forum South. The frequency of on-site monitoring 
will depend on compliance with the protocol, number of enrolled participants and data 
handling. At a minimum, there will be a pre-trial meeting, mandatory monitoring after the 
trial and once during the trial period. Source data verification will be performed according to 
a monitoring plan of patient consent and key study variables which will be available only to 
the trial monitors before the start of the trial. 
All trial sites will be provided with sufficient information to participate in the trial. This 
document, CRFs, instructions for registration, checklists for inclusion/exclusion and 
randomization, and a protocol for medical treatment will be distributed to all sites. The site 
investigator will be responsible for that all relevant data are entered into the electronic CRFs. 
The CRFs will be constructed in order to assure data quality with predefined values and 
ranges on all data entries.  
10. 
DATA AND QUALITY MANAGEMENT  
A digital Case Report Forms (CRFs) will be used a login will provided to each site for each 
subject enrolled in the study.  Required data concerning patient treatment and test results will 
be recorded on the CRFs at the time of the procedure or as soon as possible thereafter.  
Information recorded in the CRFs will be corroborated by data in the subject’s medical 
records.Data on safety will be provided to the Steering Committee with regular time intervals. 
The Steering Committee will review study integrity, safety and risk/benefit issues at periodic 
intervals throughout the study.  The frequency of these reviews will be dependent upon the 
rate of patient enrolment and relevant safety issues.  Independent analyses of serious adverse 
events will be performed and adjudicated if the frequency or nature of serious adverse events 
warrants it.  
Individual Site Investigators shall maintain all study-related correspondence, CRFs, device 
disposition records, and information on Ethics Committee approvals for a minimum of ten 
years.  Individual Site Investigators shall maintain all patient records, plus the investigator’s 
copy of the CRFs, device disposition records, and signed informed consent forms for a 
minimum of ten years.   
 
We strongly recommend using an internal study group to ensure high quality data collection.  
Previous studies have successfully used an interdisciplinary internal study group that periodically 
reviews data masked to treatment outcome to improve study performance. They assess whether 
prespecified targets for performance are met for measures such as enrollment and eligibility rates, 
provider adherence rate, retention rate, currentness of data capture as well as key elements of 
concurrent care. They make recommendations about steps to be implemented to improve these rates. 
The group may have semi-independent membership that includes individuals who do not have 
leadership responsibility for the trial (e.g. site EMS provider, site study coordinator). Its main findings 
will be summarized in the report to an independent data safety monitoring board (DSMB) and the 
study EC. Both committees will assess the appropriateness of trial continuation in an EMS agency if 
there are serious uncorrected deficiencies in trial conduct. 
 

 
 
 
41 
 
11. 
ADHERENCE TO PROTOCOL 
 
A deviation from the protocol will be allowed without a protocol amendment if generally 
accepted standards of clinical research and medical practice relating to the safety of research 
subjects require such deviation from the protocol.  In those cases in which the deviation was 
made emergently to protect the life or physical well-being of a subject.  The Karolinska 
Institutet will be notified within 48 hours of any deviations required due to device-related 
adverse events.  Deviations that represent major, serious, or significant departures from the 
investigational plan shall be recorded on the CRF along with an explanation for the deviation.  
The site investigator will analyze and assess the significance of deviations as they occur, and 
the Steering Committee will assess site-specific devations.  Significant Deviations will be 
reported to the EC as required. 
12. 
PROTOCOL AMENDMENT  
Changes to the protocol that may be made during the clinical study will be made by the 
Principal Investigator and the Steering committee.  An amendment will be effective when: a) 
signed by the Principal Investigator, b) the individual site investigators, and c) the amendment 
has been approved by the EC, if required by the Institution’s policies.   
 
13. 
INTERIM DATA, PILOT PHASE AND SAFETY MONITORING 
COMMITTEE 
 
 
The PRINCESS2 trial design is similar to the prior PRINCESS study in many ways. 
There are however some important differences. The PRINCESS2 trial is the first study 
on prehospital transnasal cooling that will include only patients with initial shockable 
rhythm. It is also the first study on prehospital transnasal cooling that will include 
patients treated with ECPR, and feasibility aspects in this patient group have not been 
investigated. There is also a more comprehensive protocol for post resuscitation care, a 
new eCRF and new recruiting centers. Moreover, in the PRINCESS2 trial inclusion 
can be made both intra-arrest and early post-ROSC (with a maximum of 20 minutes 
from EMS arrival), while patients were included only intra-arrest in the PRINCESS 
study. This might possibly affect the balance between patients included intra-arrest vs 
post ROSC at different sites. These new aspects of the PRINCESS2 study design are 
the reason we will perform and publish this pilot study during the first phase of the 
main trial. Thus, the pilot phase will be analyzed after the first 100 patients to ensure 
the adherence protocol and assess the balance between the different patient categories 
as listed above. No primary or secondary endpoints will be presented in this pilot 
phase study.  
 
An interim analysis for safety and futility will be performed by an external Data and 
Safety Monitoring Committee (DSMC) after the first 400 patients have provided 
endpoint data. Conditional power for meeting the primary endpoint will if needed, be 
computed at that time, and if the interim results do not correspond to the primary 
endpoint, termination of the study for futility will be considered. Early stopping for 
efficacy reasons will only be considered if major outcome differences are seen 
between the groups according to the Haybittle rule with a p-value ≤0,001.  The DSMC 
will be able to request additional data if they find it necessary.  If the z-value is over 
3.0 in the interim analysis the trial can be stopped for efficacy. Similarly, if the z-value 

 
 
 
42 
 
is below 0, the trial can be adviced by the DSMC to be stopped for futility. The 
decision to stop the trial for efficacy or futility is taken by the Steering committee.  
 
 
14. 
PUBLICATION POLICY 
 
At the conclusion of the study, a multi-center abstract reporting the primary results will be 
prepared and presented at key Cardiology/Resuscitation/Intensive care Symposia. A multi-
center publication will also be prepared by the Steering committee for publication in a 
reputable scientific journal.  The steering committee, via the principal investigators Per 
Nordberg and Fabio Taccone, will finally decide the list of authors and how these will be 
ordered in the final publication. The author list will include the steering group members, 
national investigators and additional names. Centres recruiting >30 participants will be 
entitled to one name, >60 two names, >100 three names, >150 four names, >220 five names 
in the author list (additional names). After the author list there will be added: "and the 
PRINCESS II trial group" and a reference to an appendix with all sites, site investigators and 
number of participants enrolled.  
 
Publication of the principal results from any single center experience within the study is not 
allowed until both the preparation and publication of the multi-center results.  Thus, no 
publication or presentation of the data or results of the study may be presented until The 
Principal Investigator determines that the database for the study is clean and locked and that 
the primary and secondary endpoint analyses are consistent with the protocol. 
 

 
 
 
43 
 
APPENDIX 1: STUDY FLOW DIAGRAM 
 

 
 
 
44 
 
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Froehler MT, Geocadin RG. Hypothermia for neuroprotection after cardiac arrest: 
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Abella BS, Zhao D, Alvarado J, Hamann K, Vanden Hoek TL, Becker LB. Intra-arrest 
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Dankiewicz J, Cronberg T, Lilja G, et al. Hypothermia versus Normothermia after 
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Castren M, Nordberg P, Svensson L, et al. Intra-arrest transnasal evaporative cooling: 
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Nordberg P, Taccone FS, Truhlar A, et al. Effect of Trans-Nasal Evaporative Intra-
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Taccone FS, Hollenberg J, Forsberg S, et al. Effect of intra-arrest trans-nasal 
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Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-
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12. 
Wolfson MR, Malone DJ, Wu J, et al. Intranasal perfluorochemical spray for 
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Dodd DE, Brashear WT, Vinegar A. Metabolism and pharmacokinetics of selected 
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Tsai MS, Barbut D, Tang W, et al. Rapid head cooling initiated coincident with 
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Wang H, Barbut D, Tsai MS, Sun S, Weil MH, Tang W. Intra-arrest selective brain 
cooling improves success of resuscitation in a porcine model of prolonged cardiac arrest. 
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Guan J, Barbut D, Wang H, et al. A comparison between head cooling begun during 
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cardiac arrest. Critical care medicine 2008;36:S428-33. 

 
 
 
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17. 
Yu T, Barbut D, Ristagno G, et al. Survival and neurological outcomes after 
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Busch HJ, Eichwede F, Fodisch M, et al. Safety and feasibility of nasopharyngeal 
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