Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT01785290 |
Other study ID # |
Delirium_Haldol-prophy |
Secondary ID |
2012-004012-6620 |
Status |
Completed |
Phase |
Phase 4
|
First received |
|
Last updated |
|
Start date |
June 2013 |
Est. completion date |
March 2017 |
Study information
Verified date |
December 2015 |
Source |
Radboud University |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
The aim of this study is to determine the effects of a low dosage of prophylactic haloperidol
in patients with a high risk to develop delirium, defined by an expected ICU length of stay
of >1 day. The investigators hypothesized that haloperidol prophylaxis in patients with a
high risk for delirium reduces 28-day mortality, delirium and delirium related outcome.
Two different dosages of haloperidol are used in this study to compare with placebo. A dosage
of 1mg, or 2mg or placebo three times a day in a double-blinded fashion resulting in a
three-armed multicentre randomized double-blinded placebo-controlled trial. To relate the
potential beneficial effects of haloperidol to the a priori risk to develop delirium, the
PREDELIRIC-model (delirium prediction model for ICU patients) will be used. This will enable
the investigators to determine the preventive efficacy of haloperidol in patient groups based
on their risk to develop delirium.
Description:
In this study high risk patients will be included. Based on historical data the investigators
know that the median predicted delirium risk is 35% in patients with an expected stay on the
ICU of over one day. This is considered a high risk to develop delirium.
To assess patients for delirium using the Confusion Assessment Method (CAM)-ICU is part of
daily clinical practice in all participating centres. In this study, high risk patients will
receive three times a day a study drug of which two groups receive a low dose of haloperidol
(1mg or 2mg) and a third arm will receive placebo.
This drug is worldwide the first choice of drug to treat delirious patients. When delirium is
diagnosed, patients are treated according to delirium protocol, using a higher dosage than in
the prophylactic treatment period as described in the study protocol. It is recognized that
early treatment of delirium has beneficial effects compared with delayed treatment, and there
is also some evidence that delirium prevention in ICU patients has beneficial effects, but
the design of these previous studies was not optimal.
Potential side-effects of haloperidol include, extrapyramidal symptoms, drowsiness,
agitation, and ventricular arrhythmias. The latter are extremely rare (only case-reports are
published) and related to a higher dosage of haloperidol. With the dosage that will be used
in the present study no relevant side-effects are anticipated. Nevertheless, and given the
preventive nature of this study, extra attention is being paid on recognition of possible
side-effects of haloperidol in the protocol. Importantly, in three recent prophylactic
haloperidol studies no relevant side-effects, and in particular no ventricular arrhythmias,
were reported using a similar low dosage of haloperidol as described in the present protocol.
During the study several inter-rater reliability checks (delirium experts versus ICU nurses)
concerning the CAM_ICU assessments will be performed. Also medical and nursing files will be
checked to secure the quality of the delirium diagnose.
The study will be monitored (all sites), randomly included patient data will be checked on
delirium diagnose and endpoints of the study. All data will be collected by Electronic CRF. A
check of completeness on all data is build-in.
All variables are defined using a data dictionary (using the NICE data dictionary)
supplemented with definitions of PREDELIRIC-model predictors, delirium diagnosis (at least
one positive CAM-ICU assessment), and delirium duration.
Sample size calculation is based on the effect on number of days of survival in 28-days
mortality derived from the evaluation study using low dosage of prophylactic haloperidol. If
the true hazard ratio of control patients relative to intervention patients is 0.85, taken
into account an accrual time of 90 days with 28 days of follow-up, the investigators will
need to study 647 patients per intervention group and 647 control patients to be able to
reject the null hypothesis that the experimental and control survival curves are equal with
probability (power) 0.80. The Type I error probability associated with this test of this null
hypothesis is 0.05. Taken into account a drop out of 10% the investigators will include 715
patients per group; in total 2145 patients. The investigators assume that the effect on
number of days of survival in 28-days mortality will be comparable between the two
intervention groups. The Cox-regression analysis group will have three levels (placebo, 1 mg
and 2 mg haloperidol three times daily).
A Data Safety Monitoring Board (DSMB)will monitor the safety of the study including interim
analyses on safety/futility after 175-350 and 500 patients and safety and superiority after
1000 patients. Followed by a final analysis after 2145 patients.
Only for the interim analysis after 500 and 1000 patients adjusting for covariates (age,
gender, delirium prediction score and sepsis) will be performed to determine the effect on
28-day survival
This multicenter study will be performed in:
- Radboud University Nijmegen Medical Centre
- University Medical Centre Utrecht
- Medical Centre Leeuwarden (stopped January 2014)
- Onze Lieve Vrouwen Gasthuis, Amsterdam (stopped March 2015)
- Isala Clinic, Zwolle (stopped June 2014)
- Canisius Wilhelmina Ziekenhuis, Nijmegen
- Medisch Spectrum Twente, Enschede
- Gelre Hospital, Apeldoorn
- Atrium Medical Centre, Heerlen
- Jeroen Bosch Hospital, Den-Bosch
- Atrium Medical Centre, Heerlen
- Medical Centre Haaglanden (Westeinde and Antoniushove), Den-Haag
- Bronovo Hospital, Den-Haag
- St. Jansdal Hospital, Harderwijk
- Maxima Medical Centre, Veldhoven
- University Medical Centre, Groningen
- Amphia Hospital, Breda
- VieCuri Hospital, Venlo
- Scheper Hospital, Emmen (stopped August 2016)
- Diakonessenhuis Hospital, Utrecht
- Haga Hospital, Den-Haag
After the 4th interim analysis the DSMB advised to drop on study arm due to effectivity and
efficiency reasons. Since July 2015 the study has been continued with two study arms and the
included numbers of patients is adjusted to 1800 patients.