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Hope-icu trial


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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.


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: 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.




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 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.

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).



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