Agents intervening against delirium in the intensive care unit (AID‐ICU) – Protocol for a randomised placebo‐controlled trial of haloperidol in patients with delirium in the ICU

Abstract

Background Delirium among patients in the intensive care unit (ICU) is a common condition associated with increased morbidity and mortality. Haloperidol is the most frequently used pharmacologic intervention, but its use is not supported by firm evidence. Therefore, we are conducting Agents Intervening against Delirium in the Intensive Care Unit (AID‐ICU) trial to assess the benefits and harms of haloperidol for the treatment of ICU‐acquired delirium. Methods AID‐ICU is an investigator‐initiated, pragmatic, international, randomised, blinded, parallel‐group, trial allocating adult ICU patients with manifest delirium 1:1 to haloperidol or placebo. Trial participants will receive intravenous 2.5 mg haloperidol three times daily or matching placebo (isotonic saline 0.9%) if they are delirious. If needed, a maximum of 20 mg/daily haloperidol/placebo is given. An escape protocol, not including haloperidol, is part of the trial protocol. The primary outcome is days alive out of the hospital within 90 days post‐randomisation. Secondary outcomes are number of days without delirium or coma, serious adverse reactions to haloperidol, usage of escape medication, number of days alive without mechanical ventilation; mortality, health‐related quality‐of‐life and cognitive function at 1‐year follow‐up. A sample size of 1000 patients is required to detect a 7‐day improvement or worsening of the mean days alive out of the hospital, type 1 error risk of 5% and power 90%. Perspective The AID‐ICU trial is based on gold standard methodology applied to a large sample of clinically representative patients and will provide pivotal high‐quality data on the benefits and harms of haloperidol for the treatment ICU‐acquired delirium.

The Agents Intervening against Delirium in the Intensive Care Unit Trial (AID‐ICU trial): A detailed statistical analysis plan

“…The AID‐ICU trial will provide high‐quality data on the benefits and harms for the treatment of delirium with haloperidol in adult, delirious patients in the ICU. The strengths and limitations of the trial design and methods have previously been extensively discussed 15 …”

“…It is expected that further 10‐12 sites in Italy, Spain, United Kingdom and the Netherlands will join the trial. The trial background, design and rationale have previously been published 15 …”

“…Previously, we have published the full protocol article on the AID‐ICU trial, 15 but the level of the full detailed statistical analysis plan (SAP) exceeds that of the protocol article. Consequently, and in accordance with the International Conference on Harmonisation (ICH) of Good Clinical Practice (GCP) guideline, we here provide the pre‐specified statistical analysis plan of the AID‐ICU trial, finalized and published before patient enrolment is completed.…”

Mortality and HRQoL in ICU patients with delirium: Protocol for 1‐year follow‐up of AID‐ICU trial

“…Despite limited evidence, treatment of ICU‐acquired delirium with haloperidol is currently the most frequently used pharmacological intervention 13 . The “Agents Intervening against Delirium in the Intensive Care Unit” (AID‐ICU) trial, is a multicentre randomized blinded and placebo‐controlled trial (RCT) that aims to assess benefits and harms of haloperidol for treatment of delirium in adult critically ill patients admitted to the ICU 14 . The trial is ongoing and is expected to complete inclusions in 2021.…”

“…The primary outcome of the AID-ICU trial is days alive out of the hospital within 90 days post-randomization. More details about the AID-ICU trial protocol have beenpublished elsewhere (www.cric.nu/aid-icu-trial -docum ents/) 14,16.…”