Hope-ICU Trial
(HalOPeridol: Effectiveness trial)
A randomised, double-blind, placebo-controlled trial to compare
the early administration of intravenous haloperidol versus placebo
in the prevention and treatment of delirium in critically ill ventilated
patients
EudraCT Number:
2009-017842-30
REC Number:
10/H0505/65
ISRCTN
83567338
Funding Body:
National Institute for Health Research
Version Number:
8
Version Date
8th April 2012
Stage:
Final
Protocol Substantial Amendments:
Amendment No
1
2
Hope-ICU Version 8: 8th April 2012
Date of Amendment
9th February 2011
21st December 2012
Date of approval
8th April
30th January
Contact Names and Numbers
Role Name, address, telephone
Lead sponsor: West Hertfordshire Hospitals NHS Trust
Vicarage Road
Watford
WD18 0HB
Tel: 01442 213141 Ext: 2473
Email: Fiona.smith@whht.nhs.uk
Chief Investigator: Valerie Page, Consultant Critical Care
Department of Anaesthesia
Watford General Hospital
Vicarage Road
Watford
WD18 0HB
Tel: 01923 217604
Email: Valerie.page@whht.nhs.uk
Trial Co-ordinator: Ms Xiao Bei Zhao
Department of Anaesthesia
Watford General Hospital
Vicarage Road
Watford
WD18 0HB
Tel: 01923 217604
Email: ZhaoBei.Xaio@whht.nhs.uk
Trial Statistician: Dr Simon Gates
Warwick Clinical Trials Unit
University of Warwick
Tel:02476 575850
Email: s.gates@warwick.ac.uk
Health Economist Mr David Meads
University of Leeds
Leeds Institute of Health Sciences
Leeds
Tel: 0113 343 6989
Fax: 0113 246 0899
Email: D.Meads@leeds.ac.uk
Hope-ICU Version 8: 8th April 2012
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Trial Steering Committee
Dr Neil Soni (Chair)
Chelsea and Westminster Hospital
Dr Danny McAuley
Royal Victoria Hospital, Belfast
Dr Valerie Page, Chief Investigator
West Hertfordshire Hospitals NHS Trust
Dr Gavin Perkins
Birmingham Heartlands Hospital
Dr Tom Stambach
West Hertfordshire Hospitals NHS Trust
Ms Fiona Smith
West Hertfordshire Hospitals NHS Trust
Dr Simon Gates
Warwick Clinical Trials Unit
Professor Wes Ely
Vanderbilt Medical Center
Nashville
Dr James Pickett
Research Grants Officer
Alzheimer’s Society
Data Monitoring and Ethics Committee
Dr Martin Kuper (Chair)
Consultant Intensive Care
Whittington Hospital NHS Trust
Dr Mike Grocott
Consultant Intensive Care
Southampton Hospitals NHS Trust
Dr Yogi Amin
Consultant Neuroanaesthetist,
University College Hospital London
Dr David Wellsted
Senior Lecturer
University of Hertfordshire
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Table of Contents
Title Page
Contact Names and Details
Table of Contents
List of abbreviations
1. Lay Summary
2. Background
2.1 Terminology
2.2 Pathophysiology
2.3 Outcomes
2.4 Rationale for using haloperidol
2.4.1 Delirium treatment
2.4.2 Lack of evidence
2.4.3 Potential benefits in ICU patients
2.4.4 Delirium prevention
2.4.5 The intervention is simple and cheap
2.4.6 Acceptable tolerability and side effects
2.4.7 Dosing regimen
2.4.8 Need for a trial
2.5 Rationale for plasma -amyloid levels
2.6 Good Clinical Practice
2.7 CONSORT Guidelines
3. Trial Design
3.1 Trial Summary
3.2 Flow Diagram
3.3 Trial Objectives
3.4 Trial Outcome
3.4.1 Primary Outcome
3.4.2 Secondary Outcomes
3.4.3 Definition primary outcome
3.4.4 Rationale
3.4.5 Definition of delirium and coma
3.4.6 Safety
3.5 Eligibility criteria
3.5.1 Inclusion Criteria
3.5.2 Exclusion Criteria
3.6 Screening of Patients not suitable for Trial
3.7 Consent
3.7.1 Patient Consent
3.7.2 Personal Legal Representative Consent
3.7.3 Professional Legal Representative Consent
3.7.4 Retrospective Patient Information
3.7.5 Withdrawal of Consent
3.8 Randomisation
3.9 Trial Procedures
3.9.1 Test treatment
3.9.2 Control (placebo) Treatment
3.9.3 Treatment Preparation and Supply
3.9.4 Treatment Administration
3.9.5 Treatment Reduction
3.9.6 Treatment termination criteria
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3.9.7 Treatment compliance
3.9.8 Drug Accountability
3.9.10 Blood Sampling Mechanisms
3.10 Clinical Management of Patients in the Trial
3.10.1 Rescue protocol for delirium
3.10.2.Sedation Management
3.10.3 Extrapyramidal Symptoms
3.10.4 Prolonged QTc
3.10.5 Blinding and procedures for unblinding
3.11 Post treatment follow-up
3.12 Pharmacovigilance
3.12.1 Definition of Adverse Events
3.12.2 Assessment of causality
3.12.3 Adverse Event reporting period
3.12.4 Adverse Event reporting requirements
3.12.5 Adverse Event reporting
3.12.6 Serious Adverse Event reporting
3.13 End of Trial
4 Data Management
4.1 Training Issues
4.2 Data Collection and Management
4.3.Follow-up at 6 months
4.4 Data Storage
4.5 Archiving
5. Data Analysis
5.1 Sample Size Calculation
5.2 Statistical Analysis
5.3 Economic Evaluation
6. Trial Organisation
6.1 Sponsor
6.2 Trial Steering Committee (TSC)
6.3 Data Monitoring and Ethics Committee (DMEC)
6.3.1 Safety
6.4 Administration
6.5 Indemnity
6.6 Monitoring and Safety Procedures
6.7 Safety and well being of study subjects
6.8 Safety of Investigators
7. Ethics and Regulatory Approval
8. Protocol Amendments
9. Publication
10. References
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List of Abbreviations
ACh Acetylcholine/Cholinergic
AE Adverse event
APACHE Acute Physiological and Chronic Health Evaluation
CAM-ICU Confusion Assessment Method-ICU
CI Chief Investigator
CLRN Comprehensive Local Research Network
CONSORT Consolidated standards of reporting trials.
CPAP Continuous Positive Airways Pressure
CRF Case Report Form
CTU Clinical Trials Unit
DMEC Data Monitoring and Ethics Committee
DSM-IV Diagnostic and Statistical Manual of Mental Disorders
ECG Electrocardiogram
EQ-5D EuroQol 5 dimension questionnaire
EPS Extrapyramidal Symptoms
HRQoL Health Related Quality of Life
ICNARC Intensive Care National Audit and Research Centre
ICU Intensive Care Unit
IMV Intermittent Mandatory Ventilation
IQCODE Informant Questionnaire on Cognitive Decline in the Elderly
MHRA Medicines and Healthcare products Regulatory Agency
MIND Modifying the Incidence of Delirium Trial
NICE National Institute for Health and Clinical Excellence
NSTS NHS Strategic Tracing Service
PACU Post anaesthetic care unit – the “recovery” area in the operating theatre
PerLR Personal Legal Representative
PIS Patient Information Sheet
ProfLR Professional Legal Representative
QTc Corrected QT time
RASS Richmond Agitation and Sedation Score
R&D Research and Development
SAE Serious adverse event
SOP Standard Operating Procedure
SUSAR Suspected unexpected serious adverse reaction
TICS-M Telephone Interview of Cognitive Status – modified.
TSC Trial Steering Committee
VFD Ventilator free days
WHHT West Hertfordshire Hospitals NHS Trust
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1. Lay Summary
Does haloperidol prevent and/or treat delirium in critically ill ventilated patients?
Many circumstances, e.g. severe infection or accident results in a person becoming
critically ill. Patients with critical illness often develop impaired brain function –
“delirium”. This common condition affects up to 2 out of every 3 patients in Intensive
Care Units (ICU), results in a longer ICU and hospital stay and a higher risk of death.
Importantly, even after recovery from the initial illness, patients frequently experience
impaired memory, a lower quality of life, e.g. many are unable to return to work or
even look after themselves, essentially a mild or accelerated “dementia”. There is no
proven effective treatment for delirium. This study will investigate if the drug
haloperidol, commonly used in the management of delirium, is safe and effective.
Our study is a “randomised placebo controlled trial”, widely accepted to be the best
way to find out if a treatment really works or not. There will be 2 groups of 71
patients who will be given either haloperidol or a dummy drug (placebo). The group
that a patient is in will be decided at random, the only difference between the 2
groups will be the treatment. We will count the number of days a patient has
delirium, how fast they recover and how well their brain functions at 6 months using
an approved telephone questionnaire. Haloperidol may reduce the time patients
spend in ICU. Demand for ICU exceeds supply; a treatment that reduced use of ICU
resources would result in increased capacity and improved access to appropriate
facilities for critically ill patients. Furthermore delirium is associated with serious
adverse outcomes; the potential impact of an effective treatment is considerable.
This study is funded by a Research for Patients Benefit grant and run in partnership
with the Alzheimer’s Society.
2. Background
2.1 Terminology
Delirium is a clinical syndrome – an acute confusional state. Hippocrates was
credited with the first description. The Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV) define it as a disturbance of consciousness with inattention,
changes of cognition developing over a short time period caused by direct
physiological consequences of a medical condition.1 Four groups of causes
identified are a general medical condition, substance intoxication, substance
withdrawal or delirium due to multiple aetiologies. There are three subtypes,
hyperactive, hypoactive and mixed. Hypoactive delirium is more common in elderly
patients and associated with worse outcomes than the familiar hyperactive type.2
Hypoactive delirium is categorised by decreased alertness and motor activity, sparse
or slow speech, staring and apathy. Numerous risk factors for patients developing
delirium have been identified in non-ICU populations of which ICU patients have an
average of 11 risk factors.3 Delirium will be overlooked unless a screening tool is
used such as the Confusion Assessment Method – ICU (CAM-ICU).4 In mechanically
ventilated patients, using the CAM-ICU, the incidence is 55 – 69% in the UK. Data
demonstrate an incidence up to 65% in the population to be recruited to this study.5
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2.2 Pathophysiology
The pathophysiology of delirium remains poorly understood. Neurotransmitter
imbalance is the leading hypothesis in delirium – an imbalance in the cholinergic and
dopaminergic neurotransmitter system resulting in a relative cholinergic deficient
state with excess dopamine. Neurotransmitter imbalance can come about from a
number of causes, direct or indirect, which result in oxidative stress. The proposed
mechanisms include cell membrane stability, oxygen supply and utilisation,
imbalance of one, two or many neurotransmitters, false transmitters, stress
hormones, cytokines, inflammation, blood supply, functional connection disruption
and thalamic dysfunction.6,7 Given the nature of delirium it is likely that several
mechanisms contribute to delirium development in patients. Because of its
multifactorial nature it has been thought that delirium from different causes may have
different mechanisms and/or involve different parts of the brain. But it has been
suggested there is always a final common pathway – in other words ultimately
particular neural pathways are always involved resulting in the core symptoms.8 The
neural pathways that may constitute the final common pathway are the prefrontal
cortices, anterior and right thalamus and the right basilar mesial temporoparietal
cortex. Delusions and visual hallucinations in delirium are likely to be related to
dysfunction of frontal and/or temporo-occipital circuits.
Acetylcholine plays an extensive role in attention and consciousness. Extensive
evidence supports the role of a central cholinergic (ACh) deficiency in delirium. 9
The ACh hypothesis cannot be separated from the dopamine excess hypothesis
because they interact so closely with each other in the brain. Dopamine excess itself
has been linked to simultaneous cholinergic deficiency. Dopamine, norepinephrine
and serotonin have roles in arousal and the sleep/wake cycle, mediating responses
to stimuli where the responses are modulated by the cholinergic pathway. There are
several metabolic pathways that lead to significant increases of dopamine under
impaired oxidative conditions. Anatomically the dopaminergic and cholinergic
pathways overlap significantly.
As part of the aging process there is a decrease in the volume of acetylcholine (ACh)
producing cells and a decrease in cerebral oxidative metabolism. Both factors lead
to a normal decline in ACh synthesis, which be the reason increasing age is a risk
factor for developing delirium. These normal processes may then be aggravated by
even mild hypoxia as a result of illness, which also further inhibits ACh synthesis and
release.
2.3 Outcomes
Delirium during hospitalisation is a strong independent marker of high risk of mortality
not just in hospital but for at least 11 months after admission. Among older medical
patients delirium means a doubling of the risk of dying by 12 months.10 The risk is
increased in the first month, and consistently throughout the next 12 months. Each
additional day an ICU patient spends in delirium is associated with a 10% increased
risk of death.11
Delirium is linked to poor cognitive outcomes in a variety of patient populations.
Incident delirium has been shown to accelerate the trajectory of cognitive decline in
hospitalised patients with Alzheimer disease such that over 12 months they will
experience a decline that would otherwise have taken 18 months but for the
delirium.12
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Delirium is associated with worse functional outcomes, it is not necessarily an
accelerated decline but at a lower level than patients who do not become delirious.13
While it can be sustained this is not always the case. How completely a patient
recovers functional status depends on how completely the patient recovers from
delirium, how long the episode lasted and whether it recurs.
Delirium has been shown to be a predictor of patients being discharged to an
institution other than home in several patient groups including critically ill patients.14
Delirium has been shown associated with longer lengths of stay; in some ICU
patients it is the strongest independent determinant of length of hospital stay. 15 In
the original delirium and mortality study by Ely and colleagues this translated to an
additional 10 days in hospital for patients who developed delirium.16 Regarding ICU
stay this is consistently increased in ventilated and non-ventilated patients.
2.4 Rationale for using haloperidol in delirium
2.4.1 Delirium Treatment:
Antipsychotics are the mainstay of drug therapy when treating patients with delirium;
the one most commonly used is haloperidol. The rationale for using these drugs is
that an imbalance of neurotransmitters, a central cholinergic deficiency and a relative
excess of dopamine cause delirium. D2 receptor blockade plus the associated
enhanced acetylcholine release restore the imbalance of neurotransmitters in the
brain. Antipsychotics are used in a range of severe psychiatric disorders including
the short term treatment of acute psychotic, manic and psychotic-depressive
disorders as well as agitated dementia and the long-term treatment of chronic
psychotic disorders including schizophrenia.
Its main action is via dopamine antagonism in the central nervous system. 17 It
exhibits partial selectivity for dopamine 2 receptors particularly in the corpus striatum.
It is this action that is thought to be responsible for its antipsychotic properties. It
also acts on some alpha adrenoreceptors (α-1), opioid, muscarinic cholinergic,
histamine and serotonin receptors. Its actions on 5-HT2 (serotonin) receptors occur
at high doses.
2.4.2 Lack of evidence:
Haloperidol has been used in tens of thousands of patients throughout the world for
years. The evidence regarding the use of haloperidol in delirium is almost entirely
based on case series and case reports. There has been one trial reported in 175
elderly Chinese patients; 29 patients received placebo compared with 72 patients
who received haloperidol 2.5mgs to 10mgs im.18 This demonstrated a significant
reduction in delirium severity. The study is difficult to assess for validity because it is
not reported according to CONSORT guidelines. There have been no placebocontrolled trials in critically ill patients powered for clinical outcomes. Two recent
Cochrane systematic reviews concluded that further trials in the prevention and
treatment of delirium were needed as data on effectiveness of treatment to prevent
and treat delirium were limited.19, 20 Two clinical studies were identified which used
haloperidol to prevent delirium in surgical patients and found haloperidol decreased
the incidence and duration of delirium.21, 22 These studies did not involve critically ill
patients. A retrospective study concluded the use of haloperidol in mechanically
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ventilated patients was associated with lower mortality. 23 These studies support the
concept that haloperidol may improve outcomes in mechanically ventilated patients
at risk of delirium.
Research evaluating the association between the use of typical and atypical
antipsychotics, adverse events and mortality has been published.24, 25 The findings
have been mixed due to differences in data source, methodological approach,
sample size and geographical variation in treatment practices. Although some have
detected a positive association between antipsychotic use and mortality, other
studies report that antipsychotics have no effect – or even a protective effect – on
mortality.26, 27 The difficulty these studies have is controlling for confounding factors,
in particular the patient’s functional status was not taken into account in the large
cohort studies.
2.4.3 Potential benefits in ICU patients:
Haloperidol has sedative sparing effects and so may decrease the amount of
sedative drugs ventilated ICU patients are given, which are thought to be potentially
deliriogenic. Furthermore haloperidol has potentially beneficial immunomodulatory
effects inhibiting the release of proinflammatory cytokines that may reduce multiple
organ dysfunction and improve survival.28 Also as haloperidol improves cognitive
function, it may reduce cognitive impairment and ICU accelerated dementia. 29
Haloperidol is the first-line drug recommended to treat delirium in any guideline
drawn up nationally or internationally. In a UK survey of intensive care consultants,
74% use haloperidol as first-line treatment for hyperactive delirium and of those who
treat hypoactive delirium pharmacologically 80% use haloperidol.30 As more delirium
is recognised in our critically ill patients it is expected that haloperidol will be used in
increasing amounts.31
A randomised placebo-controlled trial pilot study (MIND) demonstrated that
haloperidol was safe as well as confirming the feasibility of a placebo-controlled trial
of haloperidol for the management of delirium in mechanically ventilated patients.32
2.4.4 Rationale for haloperidol to prevent delirium:
If antipsychotics work to help prevent/treat delirium, they could very well increase the
number of patients who emerge from coma into a normal cognitive state rather than
delirium. All mechanically ventilated patients experience coma at least transiently
due to their disease and/or iatrogenically administered medications. Patients who
experience coma and delirium have been shown to have even worse outcomes in
terms of mortality than those who have delirium alone.16 If short term use of these
agents is met with a good safety profile, and the patients who would never have
developed delirium can be exposed to less of the other classes of drugs
(benzodiazepines and narcotics), the investigation may show improved clinical
outcomes both acutely and with respect to long-term cognitive impairment.
2.4.5 The intervention is simple and cheap:
Haloperidol is available in generic form and the intervention is cheap £1.20 per day.
2.4.6 Acceptable tolerability and side effects:
Haloperidol is generally considered to be a safe drug to be used in critically ill
patients. It has limited respiratory depressant and haemodynamic effects, with
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variable but usually mild sedation. A randomised placebo-controlled trial pilot study
(MIND) demonstrated that haloperidol was safe as well as confirming the feasibility of
a placebo-controlled trial of haloperidol for the management of delirium in
mechanically ventilated patients.32
Hypotension – usually mild, can occur with haloperidol, arterial blood pressure
monitoring is routine in ventilated ICU patients. If the blood pressure falls it will be
treated with fluids and/or vasopressors. Other causes for a fall in blood pressure will
be looked for and treated accordingly.
Extrapyramidal side effects (EPS) – parenteral haloperidol causes fewer EPS than
enteral haloperidol. All study patients will be monitored by EPS using a modified
Simpson-Angus scale.33 EPS often is seen as twitching around the mouth and a fine
tremor in the hands and is reversible unless the drug is continued for several weeks.
It is treated by reducing or stopping haloperidol or benztropine if it persists.
Akathisia is a motor restlessness that may be confused with agitation. Akathisia will
be monitored clinically.
QT interval prolongation – torsades de pointes has been reported with the use of
haloperidol. This is a life threatening multiforme ventricular arrhythmia that frequently
degenerates into ventricular fibrillation. All patients who receive haloperidol need an
ECG in order to determine the corrected Q-T time, the QTc, normally 450 msecs or
less. The patient’s QTc interval will be recorded daily on the case report form (CRF).
Torsades de pointes usually develops after large doses of haloperidol; a patient who
already has QTc prolongation is thought to be at higher risk. 34
Neuroleptic malignant syndrome is a rare and serious side effect of haloperidol. This
idiosyncratic drug reaction is characterised by high temperature, muscle rigidity,
metabolic acidosis and autonomic instability. All of these will be monitored in the ICU.
The treatment is ICU support as necessary and it is self-limiting once the drug has
been stopped.
2.4.7 Dosing regimen:
The dosing regimen is based on current clinical practice for managing ICU delirium
amongst UK consultant intensivists as conducted by the Intensive Care Society in
2008. In the pilot feasibility study MIND patients in the haloperidol group received a
median dose of 15.0 mg/day (interquartile range10.8-17.0 mg/day). While the
majority of doses were given enterally, the bioavailability of haloperidol is 60%. This
dosing schedule resulted in plasma haloperidol levels predicted to achieve effective
D2 receptor antagonism for clinical effect. 35
2.4.8 Need for a trial:
Two research groups have demonstrated that duration of ICU delirium is associated
with mortality up to one year after admission even after adjusting for important
potential confounders. Each day of delirium in the ICU increases the hazard of
mortality by 10%. In two studies the presence of delirium and severity, as measured
by number of days of delirium, were independently associated with increased ICU
days and hospital costs. It is not known if decreasing the duration of ICU delirium
improves patient outcomes or decreases length of stay.
Routine screening for delirium in ICU patients is recommended in draft guidelines for
delirium management by the National Institute for Clinical Excellence and from the
Intensive Care Society. It has been demonstrated that the implementation of a
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screening tool for delirium in the ICU increases the number of patients who are given
haloperidol. Local data has shown an increase in the amount of haloperidol used in
Watford critical care unit since the introduction of routine CAM-ICU screening. It is to
be expected that as clinicians recognise delirium in their patients that they will use
more haloperidol. Those clinicians who do not treat delirium pharmacologically, the
main reason is likely to be lack of high quality evidence to support the use of
haloperidol.
2.5 Rationale for plasma -amyloid measurement
Plasma -amyloid measurement has emerged as a promising biomarker to identify
elderly persons at risk of developing dementia.36 Lower -amyloid 42 and 42/40
levels have been associated with increased risk of developing Alzheimer’s Disease.
A recent study suggests that older adults without dementia and with lower -amyloid
42/40 levels have an increased rate of cognitive decline over 9 years compared with
those with higher levels.37 It may be that plasma -amyloid 42/40 levels may be a
predictor of those patients who are most at risk of developing cognitive impairment
following ICU delirium.
2.6 Good Clinical Practice
The trial will be carried out in accordance with the International Conference on
Harmonisation Good Clinical Practice (ICH-GCP) guidelines (www.ich.org), the EU
Clinical Trials Directive and UK legislation.
2.7 CONSORT guidelines
The trial will be reported in accordance with the Consolidated Standards of Reporting
Trials (CONSORT) guidelines (www.consort-statement.org).
3 Trial summary and flow diagram
3.1 A randomised, double-blind, placebo-controlled trial will be performed to compare
the early administration of intravenous haloperidol versus placebo in the prevention
and treatment of delirium in critically ill ventilated patients.
A total of 142 patients will be recruited.
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3.2 Flow diagram
Patients admitted and intubated and ventilated
within 72 hours of admission
Recruited to trial
n = 142
Haloperidol arm
2.5mgs iv 8 hrly until CAM-ICU
negative for 48 hours
n=71
Placebo arm
8 hrly until CAM-ICU
negative for 48 hours
n=71
Loss to follow-up
n=3
Loss to follow-up
n=3
14 day delirium/coma
free days
n=68
14 day delirum/coma
free days
n=68
3.3 Trial Objectives
The primary objective of this trial is to investigate if the early administration of
haloperidol will improve outcomes in critically ill ventilated patients who are at high
risk of developing delirium.
The secondary objective of this trial is to assess the potential of plasma -amyloid
42/40 ratio as a predictor of patients at risk of cognitive impairment following ICU
delirium.
3.4 Trial outcomes
3.4.1 The primary outcome: the number delirium/coma free days.
3.4.2 The secondary outcomes:
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Incidence of delirium
Delirium/coma free days in first 28 days
Number of ventilator free days at 28 days
Length of critical care and hospital stay
Mortality and cause of death at 6 months
Organ failure free days
Cognitive Decline
Health related quality of life.
13
3.4.3 Definition primary outcome
The number of days in the first 14 days following randomisation during which the
patient is alive and free from delirium and coma where days are counted as calendar
days i.e. from 00.00 to 23.59.
3.4.4 Rationale
Delirium/coma free days in order to assess the effect of haloperidol on the duration of
“normal” brain function in critically ill ventilated patients as determined by the
sedation scores and delirium screening. For ICU patients the number of days alive
without delirium or coma is the outcome measure that currently best demonstrates
improvement in the duration of normal cognitive status (devoid of delirium and coma).
Delirium in critically ill patients has been shown to increase length of stay in critical
care and hospital, up to 10 extra days. Delirium free days provide a composite
measure of the benefit of a treatment on delirium and mortality and are a valid and
useful outcome measure used in clinical trials where although mortality is unchanged
a reduction of delirium or ventilation would have a benefit in terms of cost
effectiveness.
Secondary outcomes – Number of ventilator days are often used as an outcome
measure in critical care studies. A statistical evaluation of the use of ventilator-free
days as a trial end point in studies of acute lung injury demonstrated use of
ventilator-free days as a trial end point allows smaller sample sizes if it is assumed
that the treatment being tested simultaneously reduces the duration of ventilation and
improves mortality.38 It is unlikely that a treatment that led to higher mortality could
lead to a statistically significant improvement in ventilator-free days.
Cognitive impairment and health related quality of life (HRQoL) are important and
meaningful to patients and their family. Previous studies have shown an association
between long-term cognitive impairment in survivors. A recent study demonstrated
that episodes of delirium could trigger Alzheimer’s Disease or accelerate the
cognitive decline.12 This translates to a significant reduction in health related quality
of life including symptoms of depression and anxiety. This is also relevant for
primary care and hospital clinicians when considering the resources needed to
implement the NICE guidelines on rehabilitation following critical illness. Cognitive
problems indicate a non-physical morbidity for which a programme of rehabilitation
will be needed for that patient. Cognitive decline will be measured by using a
surrogate assessment of cognitive function - the Informant Questionnaire on
Cognitive Decline in the Elderly (IQCODE) short form13. Where feasible this will be
evaluated at recruitment by a relative or friend who has known the patient for 10
years or more and repeated at 6 months.
Health status of patients at 6 months (from the EQ-5D data) will be converted into
Quality Life Adjusted Life Years (QALYs). These will enable a within trial costeffectiveness analysis, with results presented in terms of cost per quality adjusted life
years. Results will include probabilistic sensitivity analysis as an expression of
uncertainty, as well as appropriate one-way and scenario analysis to assess how
results may be generalised to other settings.
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3.4.5 Definition of delirium and coma
Patients are defined as delirious if they respond to verbal stimulation with eye
opening (RASS scores of –2 to +4) and screen positive for delirium using the
Confusion Assessment Method-ICU. Patients are defined as comatose if they
respond only to physical/painful stimulation with movement but have no eye-opening
(RASS score –3) or if they have no response to verbal or physical stimulation (RASS
score –4 and –5).
Ventilator days
Number of days spent with assisted breathing where unassisted breathing is defined
as:
1. Extubated with face mask, nasal prong oxygen, or room air, OR
2. T-tube breathing, OR
3. Tracheostomy mask breathing, OR
4. CPAP = 5 cm H20 without Pressure Support or IMV assistance.
Cognitive impairment
Cognitive impairment at 6 months will be assessed using the telephone interview of
cognitive status – TICS-M, which is a telephone equivalent of Mini-Mental State
Examination and comparing the result with the IQCODE scored at recruitment (see
3.4.4).
3.4.6 Safety
1) Extrapyramidal side effects.
2) Hypotension
3) Prolongation of QTc interval
4) Other side effects sufficient to stop treatment with trial drug
5) Serious adverse events including torsades de pointes and neuroleptic
malignant syndrome.
6) Suspected unexpected serious adverse events.
3.5 Eligibility Criteria
3.5.1 Inclusion Criteria
Patients who require mechanical ventilation within 72 hours of admission to ICU
regardless of whether they are screened to be positive for ICU delirium.
3.5.2 Exclusion Criteria
Subjects fulfilling any of the criteria below will be excluded from the trial:
1. Allergy to haloperidol
2. Patients with moderate/severe dementia as documented by medical history
3. Chronic antipsychotic use
4. Corrected QTc interval (QTc) > 500 ms
5. History of torsades de pointes
6. History of neuroleptic malignant syndrome
7. Family history of dystonic reactions to drugs
8. Age < 18 years
9. Pregnancy
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10. Parkinson’s Disease
11. Structural brain damage
12. Moribund patients not expected to survive 48 hours
13. Patients predicted to stay less than 48 hours
14. Elective uncomplicated surgery
15. Study patients who are readmitted to ICU.
3.6 Screening of patients not suitable for trial
Limited anonymised routinely collected patient demographics of all patients admitted
to intensive care who require mechanical ventilation within 72 hours of admission but
who do not fulfil the eligibility criteria will be recorded on a Patient Screening Log.
3.7 Consent
The Chief Investigator is responsible for ensuring that informed consent for trial
participation is given by each patient or a legal representative. An appropriately
trained doctor or nurse may take consent. Appropriate signatures and dates must be
obtained on the informed consent documentation prior to collection of trial data and
administration of the trial drug. If no consent is given a patient cannot be randomised
into the trial.
Consent will be sought from the patients themselves if this is possible, but it is
recognised that in the majority of cases patients will be unable to give informed
consent due to delirium itself or alterations in their level of consciousness caused by
illness and therapeutic sedation. In this situation consent will be sought from a
Personal Legal Representative or a Professional Legal Representative.
3.7.1 Patient consent
Whenever possible, informed consent will be obtained from the patient. The patient
will be informed about the trial by the responsible clinician or a member of the
research team and given a copy of the Patient Information Sheet (PIS). Informed
patients will be given an adequate amount of time to consider their decision on trial
entry. If the patient decides to enter the trial they will be asked to sign two copies of
the Patient Consent Form, which will then be countersigned by the responsible
clinician. The patient will retain one copy of the signed consent form. The second
copy will be photocopied and the original placed in the patient’s medical records
while the photocopy will be retained in the Trial Site File.
3.7.2 Personal Legal Representative Consent
If the patient is unable to give consent, informed consent will be sought from the
patient’s ‘Personal Legal Representative’ (PerLR) who may be a relative, partner or
close friend. The PerLR will be informed about the trial by the responsible clinician or
a member of the research team and provided with a copy of the Covering Statement
for Personal Legal Representative with attached PIS and asked to give an opinion as
to whether the patient would object to taking part in such medical research. If the
PerLR decides that the patient would have no objection to participating in the trial
they will be asked to sign two copies of the PerLR Consent Form which will then be
counter signed by the responsible clinician. The PerLR will retain one copy of the
signed Consent Form. The second copy will be photocopied and the original placed
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in the patients’ medical records whilst the photocopy will be retained in the Trial Site
File.
3.7.3 Professional Legal Representative Consent
If the patient is unable to give informed consent and no PerLR is available, a doctor
who is not connected with the conduct of the trial may act as a Professional Legal
Representative (ProfLR). The doctor will be informed about the trial by the
responsible clinician or a member of the research team and given a copy of the PIS.
If the doctor decides that the patient is suitable for entry into the trial they will be
asked to sign two copies of the Professional Legal Representative Consent Form.
The doctor will retain one copy of the signed Consent Form. The second copy will be
photocopied and the original placed in the patient’s medical records; the photocopy
will be retained in the Trial Site File.
3.7.4 Retrospective Patient Information
Patients for whom consent is given by a PerLR or ProfLR will be informed of their
participation in the trial by the responsible clinician or a member of the research team
once they regain capacity to understand the details of the trial. The responsible
clinician will discuss the study with the patient and the patient will be given a copy of
the PIS to keep. The patient will be asked for consent to participate in the trial and to
sign the Consent to Continue Form.
3.7.5 Withdrawal of Consent
Patients may withdraw or be withdrawn (by PreLR or ProfLR) from the trial at any
time without prejudice. Data recorded up to the point of withdrawal will be included in
the trial analysis. If a patient or PerLR requests termination of infusion of the trial
drug during the treatment period, the study drug will be stopped but the patient will
continue to be followed-up as part of the trial. If a patient or a PerLR withdraws
consent during trial treatment, the trial drug will be stopped but permission will be
sought to access medical records for data related to the trial. If a patient or PerLR
wishes to withdraw from the trial after completion of trial treatment, permission to
access medical records for trial data will be sought.
3.8 Randomisation
Once written informed consent has been obtained for the patient to participate in the
trial the patient will be randomised to treatment with haloperidol or placebo. All
members of the research team will be blinded to whether a patient is allocated to
receive haloperidol or placebo. Patients will be randomised in the operating theatre
post anaesthetic care unit (PACU) – the “recovery area” – a qualified member of the
theatre recovery staff using a secure internet programme. This will be provided by
Sealed Envelope Company -www.sealedenvelope.com. This is a fully audited
internet service, which allows real-time access and unblinding if required. The
randomisation log will be maintained in the PACU where study drugs are kept and
stored in a locked cupboard.
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3.9 Trial procedures
3.9.1 Test treatment
Active ingredient:
Trade name:
Concentration:
Excipient::
Container:
Pharmaceutical form:
Manufacturer:
Haloperidol
Haloperidol
5mgs/ml
Lactic acid, sodium hydroxide and water for injections.
Clear glass ampoules
Sterile injection
Janssen Pharmaceutica
3.9.2 Control (placebo) treatment
Name:
Concentration:
Container:
Pharmaceutical form:
Manufacturer:
Sodium Chloride injection BP 0.9%
9 mg/ml
Clear plastic ampoules
Sterile injection
Braun
3.9.3 Treatment preparation and supply
Study drugs will be prepared in PACU, which is in close proximity, but separate from
the ICU. Once a patient has been enrolled in the trial and allocated a study number
the PACU nurse in charge will be informed. The patient will be then allocated to
receive haloperidol 2.5mgs 8 hourly or placebo 0.5 mls 0.9% saline according to the
randomisation programme. No one on the study team will have access to this
information. The randomisation will be recorded in the study allocation logbook. The
drug will be ordered on the prescription chart as HOPE study drug to be given at
8am, 16.00 and midnight.
Boxes of haloperidol 5mgs/ml and saline 0.9% ampoules will be kept in and identified
as HOPE study drugs in a separate locked drug cupboard on PACU. The ICU
pharmacist will supply and replace these as necessary. The use and replacement of
boxes will be recorded in the study allocation logbook and accountability kept in the
same locked cupboard.
3.9.4 Treatment administration
All the nurses who prepare and administer the study drugs will have been passed as
competent for intravenous drug handling. When the study drug is due the
prescription chart will be brought from ICU to PACU. The ampoule of the study drug
according to randomisation will be then be checked by the 2 nurses or 1 nurse and
an anaesthetist for name of drug and expiry date. The drug will be immediately
drawn up using sterile precautions, labelled with a HOPE study label identifying the
patient by name, date of birth, hospital number and study number. The same nurse
will then immediately bring the capped syringe to the ICU patient. No clinicians
working on the ICU or on the study team will be involved in the preparation of the
blinded syringe. At the bedside the nurse who prepared the drug and ICU nurse
responsible for that patient will then check the patient’s wrist label against the
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prescription chart and the syringe label. Using sterile precautions the nurse who
prepared the drug will then administer the study drug as a slow intravenous injection,
1-2 minutes followed by a saline flush and initial as given on prescription chart. This
will be documented in a separate study drug administration book kept in ICU and the
study drug accountability form stored securely in the PACU where study drugs are
prepared with the randomisation log and study drugs.
This process will be repeated for each individual trial patient.
3.9.5 Treatment reduction
Oversedation
If a patient is oversedated first all sedatives and analgesics should be stopped until
the patient reaches target sedation goal and then restarted at half the rate according
to routine practice. The study drug will be continued.
If patient is still oversedated 24 hours later, then the study drug dose will stopped
until the patient reaches the target sedation score. If the patient still screens positive
for delirium the study drug will be restarted at half the dose – 1.25 mgs haloperidol or
0.25 mls 0.9% saline placebo, same frequency.
If the patient is not on sedatives or analgesics the study drug will be stopped until the
patient reaches target sedation score. If the patient still screens positive for delirium
the study drug will be restarted at half the dose, same frequency.
Dystonia
Dystonia is non-life threatening and a typically transient and dose related
extrapyramidal symptom of antipsychotics. If a patient develops extrapyramidal
symptoms including dystonia and scores less than 3 points on three or more
categories of the modified Simpson-Angus scale the study drug will be halved. If it
persists or the patient requires symptomatic treatment (procyclidine or equivalent) the
study drug will be terminated
Clinician decision
The attending clinician can decide to halve the dose of study drug on safety grounds
e.g. hypotension, akathisia.
3.9.6 Treatment termination criteria
Treatment termination is defined as discontinuing the trial drug without intention to
restart the drug at a later date. Trial drug will be terminated in the following
circumstances:
 Death
 Oversedation despite stopping additional sedative and analgesic drugs and
halving the study drug dose.
 Development of QTc > 500 msecs
 Score of 3 points or more on three or more categories of the modified
Simpson-Angus scale.
 Discharge from the ICU
 Discontinuation of active treatment
 Request to withdraw from PerLR or patient
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

Decision by attending clinician that the drug should be stopped on safety
grounds.
14 days after randomisation
3.9.7 Treatment compliance
Site personnel with relevant training and experience at the hospital will administer the
treatment to patients. Trial drugs given will be recorded in the Case Report Forms to
monitor treatment compliance.
3.9.8 Drug accountability
Preparation of all drug doses will be recorded on the Nursing Staff Drug
Accountability Form and on the patient’s prescription chart.
3.9.10 Blood sampling (mechanisms)
10 mls of blood will be taken for plasma beta amyloid measurement. All study
patients on admission have an arterial line as part of routine ICU monitoring and the
blood sample will be withdrawn from this arterial line.
Plasma from each sample will be stored at –20oC at the local site until analysis.
Blood will be stored beyond study completion for additional biomarker studies
pending additional ethical approval.
3.10 Clinical management of Patients in the Trial
Patients involved in the HOPE trial will be managed according to best practice
established on the ICU. Particular care regarding ECG monitoring and extrapyramidal symptoms is required.
3.10.1 Rescue protocol for delirium
If patients who develop acute agitation while on the study drug the following steps will
be taken until the patient’s agitation has settled:
1. Manage reversible cause such as pain or a blocked urinary catheter.
2. If they are on an opioid infusion give a bolus dose of 1-2 mls and increase the
infusion.
3. If the patient is on a sedative infusion of propofol, give a bolus dose of 20
mgs, repeat as necessary and increase the infusion until the patient’s
agitation settles.
4. If the patient’s agitation does not settle with these measures give the patient
up to 10mgs of haloperidol in divided doses intravenously and document in
CRF.
After the study period the attending clinician will decide how to treat a patient’s
delirium. The number and dose of any antipsychotics given to any study patient
following the end of the study period and before discharge will be recorded in the
CRF.
3.10.2 Sedation management
The daily sedation goal for all patients will be RASS –1 unless a patient’s clinical
condition requires a deeper level of sedation e.g. patient with severe ARDS or the
patient is weaning from ventilation.
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The drugs used before patients are consented for the study will be the decision of the
responsible intensivist. Once consented for the study patients will be maintained
using fentanyl and propofol infusions while requiring ventilation. The infusion rate will
be titrated according to RASS assessment and the nurse’s assessment of when a
patient is experiencing pain. Daily sedation breaks will be done in all patients
according to normal practice. Daily spontaneous breathing trials will be done at the
discretion of the consultant Intensivist responsible for clinical management according
to routine unit practice.
3.10.3 Extrapyramidal symptoms
Patients will be monitored for extrapyramidal symptoms using a modified SimpsonAngus scale. If a patient develops extrapyramidal symptoms the study drug dose will
be halved. If the symptoms continue despite dose reduction the study drug will be
stopped.
If the intensivist responsible for the clinical supervision of the patient considers the
EPS requires symptomatic treatment with intravenous procyclidine the study drug will
be stopped.
3.10.4 Prolonged QTc
Study patients will have an ECG recorded before commencing the study and then
every 24 hours while on the study drug. If the QTc is longer than 500 msecs any
study drug administration will be stopped until any hypokalaemia or
hypomagnesemia is corrected. Once the QTc is less than 500 msecs the study drug
will then be restarted at half the dose. If the patient was already on half the dose –
1.25 mgs haloperidol or 0.25 mls 0.9% saline – due to other reasons (oversedation or
EPS) the study drug will be stopped.
If the potassium and magnesium is normal and the QTc is over 500 msecs the study
drug will be stopped.
All the study patients will have routine continuous ECG monitoring display. This will
started before the first dose of study drug is administered and continued
uninterrupted throughout the study period. The screen is on clear display at the
patient’s bedside and viewed from the nurses station on a central screen. All ICU
ventilated patients have a dedicated ICU nurse.
3.10.5 Blinding and procedures for unblinding trial patients
As a placebo controlled double blind trial, patients, clinicians caring for the patient
and investigators will be blinded to the patient’s allocation. A qualified nurse will
bring the trial drug to the patient’s bedside already prepared in a syringe and labelled
only with patient name and number.
Emergency unblinding may be requested on the grounds of safety by any Intensive
care consultant. Emergency unblinding will be performed by telephone contact with
the recovery area. This option may be used ONLY if the patient’s future treatment
requires knowledge of the treatment assignment. If the responsible Intensive care
consultant decides that there is justification to unblind a patient, they should make
every effort to contact the Chief Investigator (Dr Valerie Page) or a site coinvestigator to discuss the necessity of unblinding.
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3.11 Post treatment follow-up
Any patient who remains in the Critical Care unit for more than 14 days following
randomisation (end of study period for primary outcome) will continue to be
monitored on a daily basis until discharged to a ward. The date and place of
discharge will be obtained from the hospital records.
All patients discharged from the hospital will be followed-up six months after
randomisation by phone using a telephone cognitive examination, the modified
telephone interview of cognitive status (TICS-M), and EQ-5D questionnaire40. The
telephone EQ-5D questionnaire will collect data on disability and health-related
quality of life. If the patient cannot be contacted on the phone numbers collected at
the time of hospital admission one set of questionnaires with accompanying letter will
be sent out to the patients last known address.
Where feasible there will be a surrogate assessment of any perceived cognitive
decline by a carer or relative using a telephone version of the Informant
Questionnaire on Cognitive Decline in the Elderly.
3.12 Pharmacovigilance
There will be timely, accurate and complete recording and analysis of safety
information required for protection of patients and mandated by regulatory agencies.
3.12.1 Definition of adverse events: The EU Clinical Trials Directive 2001/20
provides the definitions in Table 1:
Table 1
Term
Definition
Adverse Event (AE)
Any untoward medical occurrence in a patient or clinical trial
subject to whom a medicinal product has been administered
including occurrences which are not necessarily caused by or
related to that product.
Adverse Reaction (AR)
Any untoward and unintended response to an investigational
medicinal product related to any dose administered.
Unexpected Adverse
Reaction (UAR)
An adverse reaction, the nature or severity of which is not
consistent with the information about the medicinal product in
question set out in the summary of product characteristics (or
Investigator brochure) for that product.
Serious Adverse Event
(SAE) or Serious
Adverse Reaction
(SAR) or Suspected
Unexpected Serious
Adverse Reaction
(SUSAR)
Respectively any adverse event, adverse reaction or
unexpected adverse reaction that:

results in death

is life-threatening

requires hospitalisation or prolongation of existing
hospitalisation

results in persistent or significant disability or incapacity

consists of a congenital anomaly or birth defect*

is any other important medical event(s) that carries a real,
not hypothetical, risk of one of the outcomes above
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*In the case of Hope-ICU it is anticipated that all women of child bearing age
admitted will have a pregnancy test. If, however, a subsequent pregnancy is
discovered the pregnancy will be followed in order to assess the outcome regarding
any adverse event.
3.12.2 Assessment of causality
Each AE should be clinically assessed for causality based on the information
available, i.e. the relationship of the AE to the study drug. For the purposes of this
trial the causality will be assessed by the Chief Investigator then the DMEC.
For AEs not judged to be serious the causality will be assessed as present if the
Chief Investigator judges it as probable or definite according to the following
definitions:
Probable – clinical event with a reasonable time relationship to the study drug
administration, and is unlikely to be attributed to concurrent disease or other drugs or
chemicals.
Definite – clinical event with plausible time relationship to study drug administration,
and that cannot be explained by concurrent disease or other drugs or chemicals.
For all SAEs the causality will be evaluated for causality using the following guide:
Unrelated – clinical event with an incompatible time relationship to study drug
administration, and that could be explained by underlying disease, or other drugs or
chemicals
Unlikely – clinical event whose time relationship to study drug administration makes a
causal connection improbable, but that could plausibly be explained by underlying
disease or other drugs or chemicals
Possible – clinical event with reasonable time relationship to study drug
administration, but that could also be explained by concurrent disease or other drugs
or chemicals
Probable – clinical event with a reasonable time relationship to study drug
administration, and is unlikely to be attributed to concurrent disease or other drugs or
chemicals
Definite – clinical event with plausible time relationship to study drug administration,
and that cannot be explained by concurrent disease or other drugs or chemicals
3.12.3 Adverse Event reporting period
The AE reporting period for this trial begins on enrolment into the trial and ends 30
days following the administration of the study drug. All AEs assessed as possibly
related to the study drug and all SAEs that occur during this time will be followed until
they are resolved or are clearly determined to be due to a patient’s stable or chronic
condition or intercurrent illness(es).
3.12.4 Adverse Event reporting requirements
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AEs will be reported and documented on the relevant pages of the CRF, in
accordance with the procedures outlined below.
3.12.5 Adverse Event reporting
Because Hope-ICU is recruiting a population that is already in a life-threatening
population, it is expected that many of the participants will experience AEs. Events
that are expected in this population (i.e. events that are in keeping with the patient’s
underlying medical condition) will not be reported as AEs. An adverse reaction (AR)
is an AE which is related to the administration of the study drug. If any AEs are
related to the study drug (i.e. are ARs) they will be reported on the AE form within the
CRF.
The following are expected ARs and will be recorded on the CRF:
 Oversedation.
 QTc > 500 msecs
 Extrapyramidal symptoms that persist despite halving the drug.
An unexpected adverse reaction (UAR) is an AE which is related to administration of
the study drug and that is unexpected, in that it has not been previously reported in
the current Summary of Product Characteristics (SPC). All UARs will be reported on
the AE form within the CRF.
These events will be included as part of the safety analysis for the trial and do not
need to be reported separately.
3.12.6 Serious Adverse Event Reporting
A SAE is defined as an AE that fulfils one or more of the criteria for severity as
defined in Table 1.
Because Hope-ICU is recruiting a population that is already in a life-threatening
situation, it is expected that many of the participants will experience SAEs. Events
that are expected in this population (i.e. events that are in keeping with the patient’s
underlying medical condition) and are collected as outcomes of the trial, including
death and organ failure will not be reported as SAEs. Other SAEs will be reported.
A serious adverse reaction (SAR) is an SAE which is related to the administration of
the study drug. If any of the above are related to the study drug (i.e. they are SARs)
they will be reported to the sponsor, DMEC and MHRA according to research
governance requirements.
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are
considered to be caused by the study drug and are unexpected i.e. their nature or
severity is not consistent with the SPC.
If an SAE occurs, reporting will follow the regulatory requirements as appropriate and
all SUSARs will be the subject of expedited reporting. SAEs will be evaluated for
causality (relationship to the study drug) and expectedness. SAEs will be reported
using the SAE form in the CRF and will be reported to the sponsor within 24 hours of
becoming aware of the event. Information not available at the time of the initial report
will be documented on a follow-up SAE form.
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The Chief Investigator or her site co-investigator Dr Stambach is responsible for
reporting SAEs to the Sponsor, ethics committee, MHRA and IMB within the required
time lines as per the regulatory requirements. The Chief Investigator or Dr Stambach
will ensure that all relevant information about a SUSAR that is fatal or life-threatening
is reported to the relevant competent authorities and ethics within 7 days after
knowledge of such an event and that all relevant information is communicated within
an additional 8 days. All other SUSARs will be reported to the relevant competent
authorities and research ethics committees within 15 days after knowledge of such
an event.
.
3.13 End of trial
The DMEC will look at the data after 9 months to determine whether there is any
reason why recruitment should not continue. The trial will be stopped prematurely if:
 Mandated by the Ethics Committee
 Mandated by the Medicines and Healthcare products Regulatory Agency
(MHRA)
 Decided by the Trial Steering Committee after consideration of
recommendations from the Data Monitoring and Ethics Committee (DMEC)
 Funding for the trial ceases
4 Data management
4.1 Training issues
To ensure accurate, complete and reliable data before recruitment starts the
Principal Investigator and research nurse will:
 Provide instructional material to all staff
 Provide an initiation training session to instruct Consultant Intensive Care
colleagues and trial nurses. This session will give instructions on the
protocol, the completion of the Case Report Forms and trial procedures.
 Be available for consultation by e mail and/or telephone
 Review and evaluate the Case Report Form (CRF) data, detect errors in data
collection and request data collection.
4.2 Data collection and management
The Chief Investigator or a delegated nominee will collect all study data for an
individual patient and record it in the CRF. The CRFs will be anonymised. Patient
identification in the CRF will be through their unique Patient Trial Number allocated at
the time of randomisation and initials. Data will be collected from the time the patient
is considered for entry into the trial through to their discharge from hospital.
APACHE II scores will be used as part of the description of the trial population. The
APACHE II score will be obtained from the Intensive Care National Audit and
Research Centre (ICNARC) Case Mix Programme. All completed CRFs will be
forwarded to the database office at Warwick CTU after being checked. Submitted
data will be reviewed for completeness and entered onto a secure, backed-up
custom database. Due care will be taken to ensure data safety and integrity, and
compliance with the Data Protection Act 1998.
The trial number, name, address and other contact details of all patients who survive
will be kept separately to allow the patients to be contacted at 6 months for the
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telephone cognitive status evaluation and the follow-up questionnaires to be posted
to them. These details will be kept in a locked filing cabinet in a secure office in the
anaesthetic department, Watford General Hospital.
4.3 Follow-up at six months
All survivors will be contacted at six months by phone by an investigator for an
assessment of cognitive function using the modified Telephone Interview of Cognitive
Status – TICS-M. Any deaths after discharge from hospital will be identified using
the NWW Connecting for Health ERS, death status notification reports, to avoid
ringing the homes of patients who have died. Trial patients will be asked to let the
Chief Investigator know if they move house at any time after hospital discharge;
Connecting for Health NWW will enable us to locate any who move without informing
the Chief Investigator.
Additionally all survivors will be followed up at six months after randomisation by
telephone. The follow-up questionnaire will collect data on disability and health
related quality of life, using the telephone version of the EQ-5D questionnaire.
Where feasible a surrogate assessment of cognitive function will be obtained using a
telephone version of the IQCODE.
4.4 Data storage
All essential documentation and trial records will be stored in conformance with the
applicable regulatory requirements and access to stored information will be restricted
to authorised personnel.
4.5 Archiving
Trial documentation and data will be archived for at least five years after completion
of the trial.
5 Data analysis
5.1 Sample size calculation
The sample size calculation for this study has been based on data from the ABC trial
conducted by our US collaborator Professor Ely. In this trial the median number of
coma-delirium free days in the control group was 10. Because the primary outcome
is expected to be bimodal (many participants will have zero or close to the maximum
number) and hence cannot be transformed to a normal distribution, it is proposed to
analyse the data using non-parametric statistics. This will require a higher sample
size than a t-test to achieve the same power. The power-efficiency of the Wilcoxon
rank sum test is expected to be about 95% compared to a t-test (Segal & Castellan
1988), and would be at worst 86.4% (Randles & Wolfe 1979) suggesting that the
necessary sample size would be between 1.053 and 1.157 times that needed for a ttest.
To detect a true difference of 0.5 standard deviations using a t-test requires 64
participants per group (128 in total). Allowing for 1.053 times as many recruits
because of the use of a Wilcoxon rank sum test (the best case scenario), and 5%
loss to follow-up, the sample size required is 142. In the worst case scenario, this
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sample size would have equal power to a t-test using a sample size of 121, which
would have 77.5% power to detect a detect a difference of 0.5 standard deviations.
5.2 Statistical analysis
Data analysis:
Data analysis will be undertaken by the trial statistician. Analyses of effectiveness
end-points will be on an intention-to-treat basis. The primary outcome (deliriumcoma free days) is a heavily skewed distribution and (bimodal with peaks at 0 and 28
days) which cannot be reliably transformed to a normal distribution. The primary
outcome will therefore be measured using the Wilcoxon Rank sum test. For
dichotomous outcomes, risk ratios and 95% confidence intervals will be calculated.
Continuous variables over time will be analysed by generalised linear modelling.
Time to event outcomes such as duration of hospital stay will be analysed by survival
methods and reported as hazard ratios and 95% CI’s. Primary analyses will be based
on patients with outcome data (i.e. available case analysis) but we will carry out
sensitivity analyses using methods such as multiple imputations to assess the impact
of missing data due to withdrawal of consent or loss to follow-up. The randomisation
process will ensure balance in baseline variables but in the unlikely event of a
chance imbalance, we will conduct a secondary analysis by constructing a multiple
logistic regression model to adjust for these differences. A detailed analysis plan will
be developed during the trial and submitted to the DMEC for approval prior to
commencement of analysis.
Plasma -amyloid 42/40 levels are being collected as part of an exploratory analysis
and as such no formal power calculation is required, it is estimated that 60 samples
would be adequate.
5.3 Economic evaluation
A within trial cost-effectiveness analysis, with results presented in terms of cost per
quality adjusted life years. Results will include probabilistic sensitivity analysis as an
expression of uncertainty, as well as appropriate one-way and scenario analysis to
assess how results may be generalised to other settings. The primary analysis will
take the perspective of the service provider including the costs of health and social
care. Data will be collected over the course of the intervention at appropriate time
points and at appropriate follow-up points. Resource use data associated with each
group will be collected during the intervention to contribute to a health economics
analysis of costs related to the intervention and the study. Unit costs for health and
social services resources will be obtained from national sources such as the PSSRU,
the BNF and NHS reference cost database along with other appropriate resources as
required.
The analysis will use quality adjusted life years (QALYs) as the outcome measure.
The estimation of QALYs requires the production of utility weights for each health
state observed in the trial population. We will use the EQ-5D (Euroqol) for this
purpose. The evaluation will also inform us about the responsiveness of the EQ-5D in
this population. The EQ-5D is a simple instrument to complete and will be collected
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at the same time and using the same methods as the other outcome data, including
at baseline and at follow-up. This will limit the need to interpolate quality of life
between observation points and the associated inaccuracy in the estimation of the
health related quality of life differences between the control and intervention group.
6 Trial Organisation
6.1 Sponsor
The West Hertfordshire Hospitals NHS Trust will act as sponsor for this trial.
6.2 Trial steering committee (TSC)
The trial will be guided by a group of respected and experienced critical care
personnel and trialist as well as a lay representative from the Alzheimer’s Society.
Meetings will be held at regular intervals determined by need but not less than twice
a year. Routine business is conducted by e mail, post or teleconferencing.
The Steering committee, in the development of this protocol and throughout the trial
will take responsibility for:
 Major decisions such as a need to change the protocol for any reason
 Montoring and supervising the progress of the trial
 Reviewing relevant information from other sources
 Considering recommendations from the DMEC
 Informing and advising on all aspects of the trial
6.3 Data Monitoring and Ethics Committee (DMEC)
A DMEC will be appointed independent of the study team comprising of two clinicians
with experience in undertaking clinical trials/caring for critically ill patients. The study
statistician will provide a report on safety data.
The DMEC will reach agreement as to their conduct and remit in the setting of this
trial. They will discuss trial progress as and when required but at least every 9
months. An interim analysis of efficacy is not planned although this can be requested
by the DMEC as required.
6.3.1 Safety:
The DMEC will function primarily as a check for safety reviewing adverse events.
They will specifically review the incidence and severity of side effects, SAEs and
SUSARs and produce a safety report following each meeting. Early termination of
the study in response to safety issues will be addressed via the DMEC. They will
report any issues pertaining to safety to the Chief Investigator. It will be the
responsibility of the Chief Investigator to inform the sponsor who will take appropriate
action to halt the trial if concerns exist about participant safety.
6.4 Administration
Chief Investigator (CI) will assume overall responsibility for ensuring the trial is run in
accordance with Good Clinical Practice and to the highest ethical and scientific
standards. She will have regular meetings with the Trust Research and
Development (R&D) department.
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West Hertfordshire hospitals NHS Trust R&D department, represented by Fiona
Smith (manager) will be responsible for overseeing the financial management of the
trial and as Sponsors for ensuring that statutory regulations and reporting
requirements are fulfilled.
The senior research nurse will be based at Watford General Hospital and supervised
on a day to day basis by the CI. The trial will be conducted according to Standard
Operating Procedures agreed in advance. The senior nurse will be the main contact
between the trial office, CLRN network and the Alzheimer Society representatives.
The CI and the nurse will also support the intensive care clinicians in facilitating
recruitment and data collection. During the working week there are 2 consultants
working in critical care, one is responsible for the ICU patients, the second for
patients outside the ICU and as a supporting consultant. For this study a second
consultant or the on call consultant will be responsible for recruitment on a daily
basis.
Patient confidentiality will be maintained at every stage and we comply with the Data
Protection Act.
6.5 Indemnity
NHS indemnity covers NHS staff and those conducting the trial.
6.6 Monitoring and Safety Procedures
The West Hertfordshire Hospitals NHS Trust indemnifies the study. In the case of
negligent harm the Trust will accept full financial responsibility. NHS bodies carry this
risk themselves or spread it through the Clinical Negligence Scheme for Trusts,
which provides unlimited cover for this risk. NHS indemnity covers NHS staff, medical
academic staff with honorary contracts, and those conducting the trial.
6.7 Safety and well being of study subjects
Subject safety and well-being are protected by implementation of the sponsoring
organisation’s standard operating procedures (SOPs) as set out in the Research
Governance Framework and The Medicines for Human Use (Clinical Trials)
Regulations 2004.
Systems are in place to ensure that all investigators are able to demonstrate that
they are qualified by education, training or experience to fulfil their roles, and that
systems and procedures are in place which can assure the quality of every aspect of
the trial. If new safety information becomes available, then study subjects will be
informed of this and asked if they wish to continue in the study. If a subject wishes to
continue in the trial they will be formally asked to read a revised approved subject
information sheet and sign a new consent form.
Early termination of trial in response to safety issues will be addressed via the Data
Monitoring and Ethics Committee (DMEC) as discussed below in 9.3.1.
Day to day management will be undertaken via a trials management group
composed of the chief investigator and supporting staff. They will meet on a monthly
basis.
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6.8 Safety of investigators
West Hertfordshire Hospitals NHS Trust has Health and Safety Policies applicable to
all employees. All personnel should also ensure they adhere to any other Health and
Safety regulations relating to their area of work. The Chief Investigator will ensure
that all personnel have been trained appropriately to undertake their
specific tasks.
As the study fits closely to standard practice, there are few risks identified which are
hazardous to the investigators. The study team will complete Good Clinical Practice
(GCP) and consent training prior to start up.
7. Ethics and regulatory approval.
The study will be conducted in accordance with the ethical principles that have their
origin in the Declaration of Helsinki. The study will be submitted for Research Ethics
Committee and MHRA approval.
Following detailed discussion of the study, written, informed consent will be obtained
from each subject. In line with The Medicines for Human Use (Clinical Trials)
Regulations 2004 and to comply with the Research Governance Framework,
consenting processes are standardised, and are reinforced via training prior to study
start-up.
Clinical Trial Authorisation will be sought from the MHRA and the trial will be
registered with the International Standard Randomised Controlled Trial Number
register.
8. Protocol Amendments
Any amendments to the final protocol will be clearly documented and forwarded to
the Research Ethics Committee for approval prior to implementation.
9. Publication
The results of the trial will be reported first to trial collaborators. The trial office team
will draft the main report. The final version will be agreed by the
Steering Committee then submitted for publication, on behalf of the collaboration.
At the end of the trial, all subjects will be written to thanking for their participation in
the study and provided with a short summary of the trial findings. Further details
about the trial results may be obtained by visiting the trial website or requesting a
copy of the final report.
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