HOT or NOT
CLINICAL TRIAL PROTOCOL
The HyperOxia Therapy OR NormOxic Therapy cardiac arrest
study (HOT OR NOT)
A multi-centred phase 2b randomised, parallel groups, single blind, clinical
trial investigating the safety, efficacy and feasibility of a strategy of avoidance
of hyperoxia versus standard care in patients resuscitated from out-of-hospital
VF and VT cardiac arrest
CLINICAL TRIAL PROTOCOL
PROTOCOL NAME: HOT OR NOT
PROTOCOL VERSION: version 2
PROTOCOL DATE: 21/02/12
-
ANZCTRN: TBA
Ethics Approval: MEC 12/01/003
Funding: TBA
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TABLE OF CONTENTS
LIST OF DEFINITIONS AND ABBREVIATIONS ................................................ 4
1. GENERAL INFORMATION ................................................................................. 5
1.1
Title ............................................................................................................................. 5
1.2
Chief investigator ....................................................................................................... 5
1.3
Coordinating and data management centre ............................................................ 5
2. BACKGROUND INFORMATION ...................................................................... 6
2.1 Background.................................................................................................................... 6
2.2 Animal Studies............................................................................................................... 6
2.3 Human Data................................................................................................................... 8
2.4 Rationale for the HOT OR NOT trial ......................................................................... 9
2.5 Trial feasibility .............................................................................................................. 9
3.1 Primary aim ................................................................................................................. 10
3.2 Secondary aims ............................................................................................................ 10
3.3 Tertiary aims ............................................................................................................... 10
5 ASSESSMENT OF EFFICACY ............................................................................ 10
5.1 Specification of the efficacy parameters.................................................................... 10
5.1.1 Primary outcome .................................................................................................................. 10
5.1.2 Secondary outcomes ............................................................................................................ 11
5.1.3 Tertiary outcomes ................................................................................................................ 12
6 SELECTION OF PARTICIPANTS ...................................................................... 12
6.1 Inclusion criteria ......................................................................................................... 12
6.2 Exclusion criteria ........................................................................................................ 12
8 TREATMENT OF PARTICIPANTS ................................................................... 13
8.1 Overview of Study Design .......................................................................................... 13
8.3 Concomitant treatment during trial period .............................................................. 13
8.4 Withdrawal of study treatment.................................................................................. 13
8.4.1 Withdrawal of study treatment criteria................................................................................. 13
8.4.2 Management of patients for whom study treatment has been withdrawn ............................ 14
10 STUDY TERMINATION .................................................................................... 14
11 STUDY PROCEDURES ...................................................................................... 14
11.1 Data collection ........................................................................................................... 14
11.2 Screening Log ............................................................................................................ 14
11.3 Data management of patients for whom study treatment has been withdrawn .. 14
11.4 Method of data collection ......................................................................................... 15
11.5 Case Report Forms ................................................................................................... 15
12 ASSESSMENT OF SAFETY ............................................................................... 15
12.1 Adverse Event and Serious Adverse Event Reporting .......................................... 15
12.1.1 Definitions.......................................................................................................................... 15
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12.2 Study safety reporting............................................................................................... 15
14 STATISTICS ......................................................................................................... 16
14.1 Sample size and justification .................................................................................... 16
14.1.1 Sample size ........................................................................................................................ 16
14.1.2 Justification ........................................................................................................................ 16
14.2 Statistical methods .................................................................................................... 16
14.2.1 Patient Characteristics ........................................................................................................ 17
14.2.2 Efficacy, Safety and Feasibility Analysis .......................................................................... 17
14.2.3 Efficacy, Safety and Feasibility Analysis .......................................................................... 17
14.2.4 Efficacy, Safety and Feasibility Analysis .......................................................................... 17
15 DIRECT ACCESS TO DATA & DOCUMENTS .............................................. 18
16 QUALITY CONTROL AND QUALITY ASSURANCE MONITORING ..... 18
16.1 Responsibilities of the principal investigator at each site ...................................... 18
16.2 Responsibilities of the co-coordinating centre ........................................................ 18
16.3 Source document requirements ............................................................................... 19
16.4 Management of protocol deviations ........................................................................ 19
17 ETHICAL CONSIDERATIONS ......................................................................... 19
17.1 Ethical Principles ...................................................................................................... 19
17.2 Independent Ethics Committee ................................................................................ 20
17.3 Informed Consent ..................................................................................................... 20
18 DATA HANDLING AND RECORD KEEPING ............................................... 21
19 FINANCING AND INSURANCE ....................................................................... 21
19.1 Funding ...................................................................................................................... 21
19.2 Participating Centres agreement ............................................................................. 21
20 PUBLICATION POLICY .................................................................................... 22
23 REFERENCES ...................................................................................................... 23
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LIST OF DEFINITIONS AND ABBREVIATIONS
ABG
Arterial Blood Gas
AE
Adverse Event
ANZICS-CTG
Australian and New Zealand Intensive Care Society- Clinical
Trials Group
CI
Chief Investigator
CPR
Cardiopulmonary Resuscitation
eCRF
Electronic Case Report Form
FiO2
Inspired Oxygen Concentration
NSE
Neuron specific enolase
NZ
New Zealand
PI
Principal Investigator
ROSC
Return of spontaneous circulation
S-100B
Protein soluble in 100% ammonium sulphate
SAE
Serious adverse event
VF
Ventricular Fibrillation
VT
Ventricular Tachycardia
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1. GENERAL INFORMATION
1.1
Title
The HyperOxia Therapy OR NormOxic Therapy Cardiac Arrest Study (The
HOT OR NOT Cardiac Arrest Study)
1.2 Chief investigator
Name:
Title:
Address:
Contact Number:
Fax number:
Email:
Dr Paul Young
Staff Specialist in Intensive Care,
Wellington Regional Hospital,
Private Bag 7902, Wellington South
(027) 455 2269
(04) 806 0430
paul.young@ccdhb.org.nz
1.3 Coordinating and data management centre
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242
New Zealand
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2. BACKGROUND INFORMATION
2.1 Background
Cardiovascular disease is the leading cause of death in New Zealand (NZ),
accounting for 40% of deaths annually.1 It is responsible for 4200 and 2200
hospitalisations per 100,000 people in Maori and Non-Maori respectively.2 Using
recent Wellington Free Ambulance data,3,4 there are an estimated 1,545 cases of
out-of-hospital cardiac arrest attended by paramedics per year in NZ. The survival of
these patients is poor, with only 36% surviving to hospital admission, and 12%
surviving to discharge from hospital.3 The most common form of out-of-hospital
cardiac arrest is a primary cardiac arrhythmia, either ventricular fibrillation (VF) or
ventricular tachycardia (VT), and in this group the prognosis is relatively better, but
still poor with 21% of patients who suffer a VF or VT arrest surviving to hospital
discharge.3 Although, ischaemic heart disease is the most common cause of such
cardiac arrests, in patients who suffer out-of-hospital cardiac arrest and survive to
reach hospital, much of the morbidity and mortality that occurs is attributable to
neurological injury. When this neurological injury occurs, it is typically devastating
and leads to the patient dying in hospital or being discharged to nursing home care.
Investigating novel management strategies that might improve survival is an
important priority if the considerable public health burden of mortality and significant
morbidity from out-of-hospital cardiac arrest can be reduced in NZ.
2.2 Animal Studies
We have recently completed a systemic review and meta-analysis of animal data
demonstrating that exposure to hyperoxia around the time of cardiac arrest worsens
neurological injury in animal models.5
As summarised in Figure 1, treatment with 100% oxygen results in a significantly
worse neurological deficit scores than oxygen administered at lower concentrations.5
Figure 1: Summary of standardised mean differences in studies comparing
hyperoxic and normoxic regimes in animal cardiac arrest models
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Lipinski15
Brűken11
Zwemer10
Yeh14
Liu8
Balan12
Pooled
-4
Favors normoxia
-3
-2
-0.64 (-1.06 to -0.22)
-1
0
1
2
3
4
Published animal studies generally involve inducing cardiac arrest by electrical 6-12, or
chemical13,14 means; however, the one study15 in our meta-analysis that did not
demonstrate a trend favouring normoxia induced cardiac arrest through asphyxia.
Most animal studies involve the comparison of 100% oxygen during and after
resuscitation (hyperoxia arm) with a regime that involves administration of room air
during cardiopulmonary resuscitation followed by administration of inspired oxygen
between 21 and 30% after return of spontaneous circulation (normoxia group). Such
normoxic regimes are potentially problematic in the setting of human cardiac arrest
given that hypoxia is harmful and some patients do have severe hypoxaemia despite
administration of high concentration of oxygen due to aspiration.
The animal study, which has the most relevance to our proposed study, was
performed in dogs and compared a pulse oximetry-guided strategy (oximetry group)
with administration of 100% oxygen (hyperoxic group).12 This study involved
electrically-induced cardiac arrest followed by 10 minutes without CPR, then 3
minutes of CPR and then, finally, internal defibrillation along with administration of
adrenaline. The hyperoxic group received 100% oxygen during and for 1 hour after
resuscitation after which time arterial blood gas (ABG) guided adjustments were
used to achieve physiological PaO2 levels. In the oximetry group, animals received
100% oxygen during resuscitation. Immediately upon return of spontaneous
circulation (ROSC), oxygen was reduced to 50%. Thereafter, 5% reductions in FiO 2
were performed every 2 minutes until desaturation to less than 96% on pulse
oximeter occurred. Once this occurred, ABG guided adjustments were used to
achieve physiological PaO2 levels. Effectively, this meant an FiO2 of 21% to 30%
was achieved within 12 minutes of ROSC. In this study, histological staining
techniques were used to compare the extent of the neuronal damage in the two
groups and neurological outcomes at 24 hours post ROSC were assessed using a
previously validated neurological deficit score16 comparing 18 parameters in the
following five categories: (i) level of consciousness, (ii) respiration, (iii) cranial nerve
function, (iv) sensory function, (v) behaviour. The possible neurological deficit
scored ranged from 0 (normal) to 100 (brain dead). An oximetry-guided strategy
resulted in better neurological function and reduced hippocampal neuronal injury as
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shown in Figure 2.
Figure 2: Individual variation of neuronal injury in the dorsal CA1 region of the
hippocampus based on cresyl violet-staining and neurological deficit score 24 hours
after return of spontaneous circulation
2.3 Human Data
There is evidence that resuscitation with 100% oxygen has the potential to cause
harm from studies of resuscitation of newborn babies. Until recently, routine clinical
practice was to use 100% oxygen for resuscitation at birth; however, RCTs have
shown that neonatal mortality is reduced by a third with room air compared with
100% oxygen treatment.17 Relevant to our proposal, there is evidence that 40%
oxygen may result in earlier recovery than 100% oxygen in neonatal resuscitation.18
In adult cardiac arrest, existing evidence on oxygen administration is essentially
limited to three large retrospective studies.19-21
The first retrospective study reported that hyperoxia, determined on the first ABG
measurement after ICU admission, was associated with an increased risk of inhospital mortality, compared to patients with either normoxia or hypoxia.19 Unusually,
this study classed all patients with a PaO2/FiO2 ratio of <300 as hypoxic irrespective
of their PaO2. A second retrospective study, based on the same database, but
excluding all patients with a PaO2/FiO2 ratio of <200, found a strong association
between increasing supra-normal levels of PaO2 and mortality.20
In contrast to these studies, data from the Australian and New Zealand Intensive
Care Society Adult Patient Database, which used data from the ‘worst ABG’ in
patients admitted to ICUs in Australia and New Zealand after cardiac arrest, did not
find an association between elevated PaO2 and mortality after adjustment for illness
severity and inspired oxygen concentration.21 However, the Australasian data did
confirm that hypoxia is associated with worse outcome than normoxia and hyperoxia
in patients admitted to ICU following cardiac arrest.
In addition to the large retrospective studies a small pilot randomised controlled trial
has demonstrated that the delivery of lower concentrations than the standard of FiO2
100% by the ambulance is feasible.22 This trial was not powered to determine
whether avoidance of hyperoxia affected outcome.
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The existing literature does not answer the question as to whether avoidance of
hyperoxia might improve neurological outcome after cardiac arrest. Although the
existing retrospective studies were large, all are limited as they used databases that
were not designed to examine the question of whether avoidance of hyperoxia
improves outcome.
Additionally, the two North American studies failed to
appropriately adjust for inspired oxygen concentration or illness severity.
2.4 Rationale for the HOT OR NOT trial
Despite oxygen being a ubiquitous therapy in patients resuscitated from cardiac
arrest, there is very little high quality evidence to guide clinicians and, with the
exception of one small pilot trial,22 no previous prospective study of different oxygen
regimes in patients resuscitated from cardiac arrest has been performed. A
randomised trial of strategy of avoidance of hyperoxia versus standard care in
patients resuscitated from out-of-hospital VF and VT cardiac arrest is being
conducted for several reasons. There is a sound scientific basis for the hypothesis
that avoidance of hyperoxia might reduce neurological injury after resuscitation from
cardiac arrest.
However, existing human data from retrospective trials are
inconclusive and highlight the risks associated with hypoxia. Despite these risks,
high profile retrospective studies19,20 have indicated the possibility that hyperoxia is
harmful and, in the absence of prospective data, may lead to practice change which
potentially exposes patients to the harms of hypoxia.
This aim of this trial is to determine whether avoidance of hyperoxia improves
neurological outcome and reduces levels of NSE (neurone specific enolase), and S100B (protein soluble in 100% ammonium sulphate) compared to standard care.
These validated markers of neuronal injury predict outcome of resuscitation from
cardiac arrest.23-27 Data from this study will determine whether a strategy of
hyperoxia avoidance is feasible and safe. It will also determine how readily patients
can be recruited into the trial and will provide efficacy data in relation to important
clinical end points. Such data are necessary to establish whether a pivotal phase III
trial is needed.
2.5 Trial feasibility
The investigators have an established track record of excellence in the conduct of
both small- and large-scale randomised-controlled trials in intensive care in Australia
and New Zealand. The Saline and Albumin Fluid Evaluation study28 and the
Normoglycaemia in Intensive Care study,29 conducted by the Australian and New
Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG) are regarded as
a benchmark for trials in Critical Care Medicine. Together these trials randomised
13,000 patients. Our team includes established pre-hospital and intensive care
researchers.
Detailed data collected from Wellington Free Ambulance have been used to
determine feasibility.3 The Wellington Free Ambulance services a population of
473,700. Over a two and a half year period between July 2007 and December 2009,
the Wellington free ambulance attended 362 cardiac arrests in which resuscitation
was attempted. Of these, 161 had a presenting rhythm of VF or VT. Of these,
83/161 (48%) survived to hospital. Of those surviving until hospital admission, 9/83
(11%) were admitted directly to a coronary care unit rather than an ICU (and hence
were likely conscious) and 10/83 (12%) died in the emergency department. The
remaining 64 patients would likely fulfil eligibility criteria and survive to reach
assessment of the primary end point at 24 hours post ROSC. Assuming that the
Auckland region (population 1,303,068) had three times as many patients as
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Wellington and the remaining centres (Christchurch, Dunedin and Hawkes Bay) were
able to recruit the same number between them, a total of 320 patients could be
recruited over a two and half year period and expected to survive until 24 hours post
ROSC for assessment of the primary end point.
3 TRIAL AIM & HYPOTHESIS
3.1 Primary aim
The primary aim of this study is to determine whether a strategy that limits exposure
to hyperoxia after out-of-hospital VF/VT cardiac arrest, improves neurological
outcomes and reduces levels of NSE levels measured 24-hour post ROSC.
The study will establish whether a definitive phase III trial is safe, feasible and
justifiable, and will provide essential information on the cost and likely sample size for
such a trial.
3.2 Secondary aims
Secondary aims are to determine whether a strategy that limits exposure to
hyperoxia after out-of-hospital VF/VT cardiac arrest:
1. Reduces S-100B levels measured at hospital admission,12, 24, 48, and 72 hours
post-ROSC
2. Reduces NSE levels measured at hospital admission, 12, 48, and 72 hours postROSC
3. Reduces the duration of ICU and hospital stay
4. Reduces mean PaO2
5. Alters mean PaCO2
6. Alters the number of documented episodes of desaturation
7. Alters the number of documented episodes of hyperoxia
8. Alters the number of episodes of cardiac arrest
9. Reduces high sensitivity troponin levels measured at hospital discharge, 12, 24,
48 and 72 hours post-ROSC
3.3 Tertiary aims
To determine the recruitment rate and incidence of protocol violation with a view to
the feasibility of using this design for a larger phase 3 trial.
4 TRIAL DESIGN
The HOT OR NOT trial is a prospective, phase 2b, multi-centre, single-blinded,
parallel-groups randomised placebo-controlled trial, designed to determine the
safety, efficacy and feasibility of a strategy of avoidance of hyperoxia versus
standard care in patients resuscitated from out-of-hospital VF and VT cardiac arrest.
5 ASSESSMENT OF EFFICACY
5.1 Specification of the efficacy parameters
5.1.1 Main outcomes
Neuron specific enolase
NSE is a glycolytic enzyme that is localised primarily in the neuronal cytoplasm. The
enzyme is released into the cerebrospinal fluid and plasma with neural tissue injury
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and is elevated after a variety of types of neurological injury. In patients who have
suffered out-of-hospital cardiac arrest, numerous studies have demonstrated a
correlation between NSE and poor outcome.23-27 NSE levels are significantly lower in
comatose cardiac arrest survivors who undergo therapeutic hypothermia than those
who do not, indicating that this measurement can potentially guide response to
therapy.26 Therapeutic hypothermia has been conclusively shown to improve
neurological outcome after cardiac arrest.30,31
Assessment of neurological outcome:
The method for assessing neurological outcome will be by assessment of the
proportion of patients who survive to hospital discharge with sufficiently good
neurological function to be discharged home or to a rehabilitation facility. This
method has been used previously in interventional studies of patients post cardiac
arrest.31,33
5.1.2 Secondary outcomes
NSE and S-100B:
In addition to the measurement for primary end point determination at 24 hours, NSE
and S-100B will be measured at hospital admission, 12, 48 and 72 hours post
ROSC. These additional measurements will be used to determine the levels of NSE
and S-100B by ANOVA for repeated measurements. It will also be used to
determine the proportion of patients who have a decrease in NSE and S-100B
between 24 and 48 hours both of which have been shown to predict favourable
neurological outcome.26,32 S-100B is a calcium binding protein located primarily in
astroglial cells. It has been shown to be elevated after a variety of types of
neurological injury including anoxic brain injury following cardiac arrest.26
Duration of ICU and Hospital stay:
These measurements of clinical response to treatment and health service
requirements are important in their own right. In order to deal with the issue of
competing risk of death, we will analyse survivors and non-survivors separately.
Mean PaO2:
Mean PaO2 will be measured 6 hourly in ICU up until extubation or 72 hours
(whichever is first). The purpose of measuring PaO2 is to determine that a strategy
of hyperoxia avoidance in ICU does, in fact, reduce PaO2 levels compared to
standard care.
Mean PaCO2:
Mean PaCO2 will be measured 6 hourly in ICU up until extubation or 72 hours
(whichever is first). PaCO2 has important effects on cerebral blood flow.34 The
purpose of determining PaCO2 is to determine that a strategy of hyperoxia avoidance
in ICU does not have confounding effects on PaCO2.
Episodes of hypoxia
Previous studies have shown that hypoxia is associated with worse outcomes in
patients admitted to ICU after cardiac arrest.19-21 We will record all documented
episodes in which desaturation to below 88% is recorded by pulse oximetry. The
purpose of measuring episodes of desaturation is to determine whether a strategy of
hyperoxia avoidance increases the incidence of desaturation episodes.
Episodes of hyperoxia:
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Previous studies have shown that hypoxia is associated with worse outcomes in
patients admitted to ICU after cardiac arrest. We will record all episodes in which a
PaO2 of > 120mmHg is documented on arterial blood gas. The purpose of
measuring episodes of hyperoxia is to determine whether a strategy of oxygen
titration increases the incidence of hyperoxic episodes.
Episodes of cardiac arrest:
We will record the number of cardiac arrest events after initial ROSC. The purpose
of measuring this is to determine whether a strategy of oxygen titration alters the risk
of further episodes of cardiac arrest.
hsTNT levels:
hsTNT will be measured at hospital admission,12, 24, 48 and 72 hours post ROSC.
These measurements will be used to determine whether the oxygen strategies affect
myocardial injury post resuscitation from cardiac arrest
5.1.3 Tertiary outcomes
Recruitment
To determine the number of patients recruited into the study as a proportion of total
eligible patients.
6 SELECTION OF PARTICIPANTS
Patients who fulfil all of the inclusion criteria and none of the exclusion criteria will be
eligible for enrolment.
6.1 Inclusion criteria
1.
2.
3.
4.
Cardiac arrest due to a primary cardiac cause with an initial rhythm of VF or VT
Aged 16-90 years
Ventilated via endotracheal tube or laryngeal mask airway
Working pulse oximetry obtained within 15 minutes of ROSC
6.2 Exclusion criteria
1. obvious pregnancy
2. dependant on others for activities of daily living (i.e. in supported care or nursing
home residents),
3. terminal disease
7 RANDOMISATION AND ALLOCATION OF
TREATMENT
Randomisation will be achieved by sequential numbered sealed envelopes, which
will be prepared by a third party, who will receive a randomisation schedule
generated by a statistician. There will be block randomisation with a block size of 6,
stratified by study centre. Patients will be randomly assigned to either the ‘avoidance
of hyperoxia’ or ‘standard care’ in a 1:1 ratio by the paramedics when they fulfil
eligibility criteria.
Note: where the ‘first responder’ to the cardiac arrest is the Fire Service,3 paramedics
may still randomise patients provided that randomisation can be achieved within 15
minutes of return of spontaneous circulation
Patients will be blinded as to the treatment allocation; however, due to the nature of
the intervention, blinding of investigators will not be possible.
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8 TREATMENT OF PARTICIPANTS
8.1 Overview of Study Design
This study is a multicentre, randomised, single-blind, parallel, phase 2b study
investigating the safety, efficacy and feasibility of a strategy of avoidance of
hyperoxia versus standard care in patients resuscitated from out-of-hospital VF and
VT cardiac arrest.
8.2 Study treatment and dosage regimen
Patients assigned to the ‘standard care’ arm will receive usual care. This will involve
administration of 100% oxygen by the ambulance officers and in the initial period in
the emergency department. Subsequently, the oxygen target will be determined by
the treating clinician in accordance with usual clinical practice. Data from our
multicentre retrospective cohort study indicate that this standard care arm will lead to
significant exposure to hyperoxia during ICU phase of management.35 It is
anticipated that usual care will involve targeting oxygen saturation of >95% on a
pulse oximeter. The use of such a ‘standard care’ arm is important because it will
increase the generalisability of results and help to lay the ground work for a large
pragmatic phase III trial (if our results indicate that such a trial is justified)
Patients assigned to the ‘avoidance of hyperoxia’ arm will receive titrated oxygen
from the time of ROSC aiming to achieve oxygen saturation of 90-94% via pulse
oximeter. After randomisation patients in the ‘avoidance of hyperoxia’ arm will
continue to receive titrated oxygen in the ambulance with delivery adjusted by
adjustment of the oxygen flow meter. Titrated oxygen therapy will be maintained
throughout the period of treatment in the emergency department and ICU up until
extubation or 72 hours post ROSC (whichever is sooner).
8.3 Concomitant treatment during trial period
Apart from the randomised oxygen interventions, patients will receive standard care
(including therapeutic hypothermia if clinically appropriate). If a patient has further
cardiac arrest after their initial return of spontaneous circulation, oxygen may be
increased irrespective of which group the patient is assigned to at the discretion of
the treating paramedic or doctor. If the patient is successfully resuscitated, oxygen
should again be titrated according to the treatment to which the patient has been
assigned.
8.4 Withdrawal of study treatment
The patient (or the person responsible for the patient) may withdraw from study
treatment at any time, irrespective of the reason. The treating clinician may also
withdraw the patient from study treatment if it is felt that withdrawal from study
treatment is in the patient’s best interests. The reason for withdrawal of treatment
will be recorded in the electronic case report form (eCRF). All treatment
discontinuation should also be recorded by the investigator in the source notes.
8.4.1 Withdrawal of study treatment criteria
There are no pre-specified criteria for mandatory treatment withdrawal
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8.4.2 Management of patients for whom study treatment has been
withdrawn
Patients withdrawn from the randomised treatment for any reason will be followed up
according to the study follow up schedule and analysed according to the intention-totreat-principle unless the patient or their legal surrogate has specifically withdrawn
consent to follow up data being used. A withdrawal form will be completed if a
patient or their legal surrogate withdraws consent for data collection. Where a
patient or their legal surrogate withdraws consent, the patient will be considered as
lost to follow-up.
9 DURATION OF PARTICIPATION
All patients will be followed until the earliest of any of the following:
 Discharge from acute hospital
 Withdrawal of consent, by subject or legal surrogate
 Patient death
10 STUDY TERMINATION
The study may be terminated at any time at the request of the study management
committee, the Investigator, or a regulatory authority, with proper and timely
notification of all parties concerned. The Ethics Committee will be informed promptly
and the co-ordinating centre or the investigator will supply reason(s) for the
termination or suspension, as specified by the applicable regulatory requirements.
Otherwise, the study is considered terminated upon completion of all patient
treatments and evaluations.
11 STUDY PROCEDURES
11.1 Data collection
Data collection will be collected by ICU research co-ordinators at each participating
hospital and entered electronically via a secure web-based data entry system. The
coordinating centre will take responsibility for the data management of the study.
This includes programming and data management support of the database during
the study.
11.2 Screening Log
The screening log is designed to monitor patient recruitment and will allow the
construction of a CONSORT diagram.36 A screening log of cardiac arrest patients
will be maintained by ambulance services in respective regions with data entry into
an online screening log performed by ambulance service representatives.
11.3 Data management of patients for whom study treatment
has been withdrawn
In patients in whom allocated study treatment is been discontinued for any reason,
the follow-up schedule must continue unchanged for all randomised participants
unless the patient or their representative has specifically withdrawn consent to follow
up.
Efforts will be made to follow all study participants, irrespective of their adherence to
the randomised therapy. All losses to follow-up with reason will be reported to the
coordinating centre and reviewed by the Study Management Committee.
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Patients withdrawn from randomised study treatment will be categorised as lost to
follow-up and, where possible, will be included in the final analysis on an intention to
treat basis.
11.4 Method of data collection
Data collected while the patient is in the ICU will be from the ambulance record and
the patient medical record and will be performed by trained ICU research coordinator.
11.5 Case Report Forms
The electronic case report form (eCRF) will be developed by the management
committee. Research co-coordinators will enter all required data described in the
protocol onto eCRF.
Information recorded in the CRF should accurately reflect the subject’s
medical/hospital notes. Information must be completed in the eCRF as soon as it is
available for recording. The intent of this process is to improve the quality of the
clinical study by providing prompt feedback to the investigators on the progress of
the data submitted and to enhance the ability to collect early safety information in a
more timely fashion.
12 ASSESSMENT OF SAFETY
12.1 Adverse Event and Serious Adverse Event Reporting
12.1.1 Definitions
12.1.1.1 Adverse events (AEs)
AEs are defined as any untoward medical occurrence in a patient administered an
investigational intervention and which does not necessarily have to have a causal
relationship with that intervention.
12.1.1.2 Serious adverse events (SAEs)
SAEs are defined as any untoward medical occurrence that meets one of more of the
following criteria:
 Results in death
 Is life threatening
 Requires inpatient hospitalisation or prolongation of existing
hospitalisation
 Results in persistent or significant disability or incapacity
 Is a congenital anomaly or birth defect
 Is an important medical event, other than listed above, that the clinician
believes may jeopardise the patient or require intervention to prevent
one of the above outcomes
12.2 Study safety reporting
It is recognised that the patient population post cardiac arrest will experience a
number of aberrations in laboratory values, signs and symptoms due to the severity
of the underlying disease and the impact of standard therapies. In this study, only
those AEs and SAEs which are thought to have a causal relationship with study
treatment should be reported.
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All SAEs should be reported by telephone to the coordinating centre within 24 hours
of the awareness of the event. All non-serious AEs, that are not already captured on
the eCRF should be reported to the coordinating centre within 48 hours of the
awareness of the event.
The co-ordinating centre staff will be responsible for following-up adverse events to
ensure all details are available. The co-ordinating centre is also responsible for
alerting other participating centres of the report of an AE and reporting AEs to the
Multi-region Ethics Committee for New Zealand.
13 DATA MONITORING COMMITTEE
A Data Monitoring Committee (DMC), independent from the investigators, will
perform an ongoing review of predefined safety parameters and overall study
conduct. The DMC will be comprised of experts in clinical trials and methodology.
The DMC’s primary function is to ensure the safety and welfare of the patients. The
DMC will review data on patient characteristics, specified outcomes and reportable
adverse events at predetermined intervals during the study or as deemed
appropriate by the DMC.
Independent monitoring of data collected at participating centres in this study will be
undertaken by the Medical Research Institute of New Zealand.
14 STATISTICS
14.1 Sample size and justification
14.1.1 Sample size
The planned sample size is 150 patients.
14.1.2 Justification
We have chosen a sample size of 150 participants with ROSC in each group to
account for both the NSE measure and the categorical clinical outcome variable. If
64 participants in each group survive to reach assessment of NSE this sample size
will provide 80% power with a type I error rate of 5%, to detect a decrease in NSE
levels at 24 hours after ROSC from a mean (standard deviation) 13.0 +/- 7.3 µg/L
based on reference22 9.35 +/- 7.3 µg/L. This difference represents 0.5 of a standard
deviation and is less than the 0.6 standard deviation difference in neurological deficit
score observed in our meta-analysis of animal models of cardiac arrest and oxygen
use5. For the categorical outcome variable, survival to hospital discharge with a
sufficiently good neurological outcome to be discharged home or to a rehabilitation
facility, we plan to detect an increase in the proportion of patients with a good
outcome from 49% based on reference31 to 71%, again with 80% power and an
alpha of 0.05. This sample size provides greater power than the New England
Journal of Medicine paper which used this outcome variable and studied a total of 77
subjects demonstrating that therapeutic hypothermia following cardiac arrest
increases the number of patients with good neurological outcome31.
14.2 Statistical methods
A detailed statistical analysis plan will be developed before completion of recruitment
and published in a public domain before commencement of analysis.
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14.2.1 Patient Characteristics
The distribution of participant characteristics will be explored. These variables will be:
 age
 sex
 ethnicity
 whether the cardiac arrest was witnessed
 whether bystander CPR was performed
 time from pick up of ambulance call until first ambulance arrival
 time from first ambulance arrival until ROSC
 time from pick up of call until ROSC
 time from pick up of call until defibrillation
 number of defibrillations
 number of doses of adrenaline prior to ROSC
 systolic blood pressure immediately post ROSC
 heart rate immediately post ROSC
 oxygen saturation post ROSC
 end tidal CO2 post ROSC
14.2.2 Efficacy, Safety and Feasibility Analysis
The main analysis of NSE at 24 hours after ROSC, will be a t-test as long as
statistical assumptions are met. If normality assumptions are not met then we plan to
try first a simple data transformation, such as a logarithm transformation, and if this
fails to proceed to a Mann-Whitney rank based test. The proportion of patients
achieving a good neurological outcome in each group will be compared using
Fisher’s Exact test. Because this study has feasibility and planning aims secondary
analyses of the main outcome variables will be multivariate regressions to determine
if there are important co-variates that contribute to the outcomes. These might form
the basis of stratified randomisation in a larger study. These will be explored using
simple plots, tables, and univariate linear regressions, followed by model building to
find a single or small set of models that provide a good fit to the data. We plan to use
best sub-sets analysis although this model building will necessarily be iterative.
For the secondary outcome variables which can be treated as continuous a similar
analysis strategy will be used. For categorical outcome variables logistic regression
will be used after simple tabulations and measures of association with a similar
model building strategy.
Some variables are measured repeatedly and for these variables plots supplemented
by linear mixed models will be used to determine if there is a different pattern of
change with time by randomised group.
14.2.3 Subgroup Analysis
There are no pre-specified subgroup analyses
14.2.4 Data Monitoring Committee
The Data Monitoring Committee will perform one interim analyses when 50% of
participants have had assessment of the primary end point. For the main outcome
variable and analysis a P-value of 0.047 will be used. For the planned interim
analysis after half the data collection, a P-value of 0.00305 will be used with a group
sequential alpha spending function calculated by the method of O’Brien and Fleming
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using two sided symmetric bounds.37 This will preserve an overall P-value for the
study of 0.05.
Additional reviews of the data may be performed at the discretion of the Data
Monitoring Committee and will require recalculation of the interim P-values.
The Data Monitoring Committee will also review summaries of all SAEs that occur
during the study.
15 DIRECT ACCESS TO DATA & DOCUMENTS
The study may be audited by government regulatory authorities, representatives of
the management committee, or, the Medical Research Institute of New Zealand.
Therefore access to medical records, other source documents such as ICU charts
and other study related files must be made available at all study sites for monitoring
and audit purposes during the course of the study and after its completion.
Participants will not be identified by name, and confidentiality of information in
medical records will be preserved. The confidentiality of the participant will be
maintained unless disclosure is required by regulations.
16 QUALITY CONTROL AND QUALITY ASSURANCE
MONITORING
16.1 Responsibilities of the principal investigator at each site
The principal investigator (PI) is required to ensure compliance with all procedures
required by the clinical trial protocol and with all study procedures provided by the cocoordinating centre.
The PI agrees to provide reliable data and all information requested by the clinical
trial protocol in an accurate and legible manner according to the instructions
provided. The investigator agrees to allow representatives of the co-coordinating
centre to have direct access to source documents.
16.2 Responsibilities of the co-coordinating centre
The co-coordinating centre is responsible for taking all reasonable steps to ensure
the proper conduct of the clinical trial protocol.
Prior to initiation of the study at each participating site, the co-ordinating centre will
be responsible for providing adequate training to the PI and study personnel. The
training will cover all aspects of the study protocol and procedures and will include
practical training in completing the eCRF and the study materials. All study materials
will be provided at or before the training sessions.
During the trial, the sites will be contacted, through monitoring visits, letters or
telephone calls, by the study monitor to review study progress, investigator and
patient compliance with study protocol requirements and any emergent problems.
The main duty of the study monitor is to help the investigator and the coordinating
centre maintain a high level of ethical, scientific, technical and regulatory quality in all
aspects of the trial.
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Site monitoring visits will be performed periodically and in accordance with the
Monitoring Plan. The investigator and study personnel will assist the study monitor by
providing all appropriate documentation, and being available to discuss the study.
These monitoring visits will include but not be limited to review of the following
aspects:








Adherence to the protocol including consistency with inclusion and exclusion
criteria;
The completeness and accuracy of the eCRFs and source documentation,
patient informed consent;
Patient recruitment and follow-up;
AE and SAE documentation and reporting;
Study treatment allocation;
Patient compliance with the study treatment regimen;
Study treatment accountability;
Compliance with regulations.
At completion of the trial, a final monitoring and close out visit will be conducted by
the study monitor in accordance with the Monitoring Plan. Secure facilities for the
storage of study data for 15 years will also be re-checked at this visit.
16.3 Source document requirements
The monitoring team will check the eCRF entries against the source documents.
The purpose of source documents is to document the existence of the participant
and substantiate the integrity of the study data collected. Source documents include
the original documents related to the trial, to medical treatment, and to the history of
the subject. Adequate and accurate source documents allow the investigator and the
site monitor to verify the reliability and authenticity of data recorded on the eCRFs
and ultimately to validate that the clinical study was carried out in accordance with
the protocol.
16.4 Management of protocol deviations
A protocol deviation is an unanticipated or unintentional departure from the expected
conduct of an approved study that is not consistent with the current research protocol
or consent document. A protocol deviation may be an omission, addition or change in
any procedure described in the protocol.
The investigator should not implement any deviation from or changes of the protocol
without agreement by the study management committee and documented approval
from the Independent Ethics Committee of the amendment, except where necessary
to eliminate an immediate hazard(s) to trial participants. In the event of an
emergency intended to eliminate an apparent immediate hazard to participants the
Investigator may implement any medical procedure deemed appropriate.
Deviations from the protocol must be documented and promptly reported to the study
management committee. The report should summarise the event and action taken.
17 ETHICAL CONSIDERATIONS
17.1 Ethical Principles
This trial will be conducted in accordance with the principles laid down by Health
Research Council of New Zealand and other Local Ethics Committees.
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17.2 Independent Ethics Committee
The CI is responsible for submitting this protocol to the Independent Ethics
Committee. An application for Ethics Approval will be lodged with the Multi-region
Ethics Committee of the Health Research Council of New Zealand.
The content and format of the patient and next-of-kin information statements and
consent forms will be approved by the Ethics Committee(s) and produced in line with
their own guidelines and requirements.
During the trial, any amendment or modification to the study protocol will be notified
to the Ethics Committee by the CI and approved by the Ethics Committee before
implementation, unless the change is necessary to eliminate an immediate hazard to
the patients, in which case the Ethics Committee should be informed as soon as
possible.
The CI will be responsible for informing the Ethics Committee of any event likely to
affect the safety of patients or the continued conduct of the clinical trial, in particular
any change in safety.
The CI will produce progress reports, adverse event reports, and any other
documentation required by the Multi-region Ethics Committee in accordance with
their guidelines.
The CI will keep an up to date record of all correspondence with the Ethics
Committee.
A clean copy of the consent forms and information statements that are to be used at
each hospital, together with a copy of all signed consent forms and any other
consent related correspondence must also be kept in a separate file for this study, in
case of any future requirement for audit purposes.
17.3 Informed Consent
The Health Research Council Statement on Research Involving Unconscious
Participants acknowledges that research involving patients who are heavily
dependent on medical care, such as the patients in this study, is necessary to assess
and improve the efficacy and safety of interventions used in their treatment.
Obtaining written and informed consent from patients who are highly dependent on
medical care, such as patients in ICU is difficult because Intensive Care patients are
often unconscious, sedated, intubated and too ill to understand information relating to
clinical trial participation. It is anticipated that all patients in this trial will be critically
unwell and unable to give consent at the time that they are enrolled into the trial.
Patients who are eligible for this trial will be in an emergency situation where
decisions about their treatment will have to be made too quickly to consult with
families and/or legal representatives. As a consequence, we plan that the
paramedics will randomise patients into the clinical trial with a plan to obtain ‘delayed
consent’.
Patients, their families and/or legal representatives will be provided with pertinent
information when, and if, it becomes possible and appropriate to do so after the
patient arrives in hospital. Irrespective of the consent of surrogates, the patients
themselves will be given the opportunity to provide informed consent as soon as it is
possible for them to do so.
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18 DATA HANDLING AND RECORD KEEPING
Folders will be provided for the research co-ordinator to file any paper documents
used for any form of data collection for each patient and to store the signed and
dated consent forms. A comprehensive guide to the data collection with definitions
and rationale will be provided together with a paper version of the data collection
forms. Paper documents will be stored in secure locked cabinets with access limited
to authorized persons. All of the documents will be available in PDF format for
printing. The aim is to assist the research co-ordinator to ensure high-quality data
collection and data entry.
Data management will be provided by the co-ordinating centre. The principle means
of data collection and data processing will be via online data entry performed by
research co-ordinators at each site. All forms will be signed and dated by the
authorised study staff and all changes made following data submission will be
recorded.
When archiving or processing data pertaining to the investigator and/or to the
patients, the co-ordinating centre shall take all appropriate measures to safeguard
and prevent access to this data by any unauthorized third party.
The PI must maintain confidential all study documentation, and take measures to
prevent accidental or premature destruction of these documents. It is recommended
that the Investigator retain the study documents at least fifteen years after the
completion or discontinuation of the study. The PI must notify the Study Management
Committee prior to destroying any study essential documents following the study
completion or discontinuation. If the PI's personal situation is such that archiving can
no longer be ensured by him/her, the PI shall inform the Study Management
Committee and the relevant records shall be transferred to a mutually agreed upon
designee.
If any PI retires, relocates, or otherwise withdraws from conducting the study, the
responsibility for maintaining records may be transferred to the another designated
PI at the study centre. All associated documentation must also be updated.
19 FINANCING AND INSURANCE
19.1 Funding
Funding is being sought from the Health Research Council of New Zealand.
19.2 Participating Centres agreement
Participating centre agreements will be signed between the participating sites and
the Medical Research Institute of New Zealand and cover:
 Trial work and duration
 Obligations of the CI
 Confidentiality
 Intellectual property
 Indemnity
The Co-ordinating Centre will complete Form A ‘Declaration of Eligibility of a Clinical
Trial for Consideration of Coverage under Accident Compensation Legislation’ and
anticipate that participants in the clinical trial will be insured under accident
compensation legislation for injury caused as a result of their participation in the
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research. Indemnity for clinical trial staff will be provided by individual participating
hospitals.
20 PUBLICATION POLICY
The study will be conducted in the name of the HOT OR NOT investigators. The
central project coordination and data management will be by the CI at the Medical
Research Institute of New Zealand.
The principal publication from the study will be in the name of the HOT OR NOT
Investigators with full credit assigned to all collaborating investigators, research
coordinators and institutions. Where an individuals’ name is required for publication
it will be that of the writing committee, with the chair of the writing committee listed
first and subsequent authors listed alphabetically.
21 PROJECT TIMELINE
To be confirmed.
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