Effects of Dexmedetomidine on Delirium Duration of Non-intubated ICU Patients (4D Trial) (4D)

The primary purpose of the study is to evaluate whether dexmedetomidine is effective in treating agitated delirium of non-intubated ICI patients

Study Overview

• Status: Completed
• Conditions: Delirium; Agitation
• Intervention / Treatment: Drug: Dexmedetomidine; Other: Placebo

Detailed Description

Delirium during intensive care unit (ICU) stay is frequent and associated with significant morbidity, mortality and healthcare related costs. International guidelines suggest its prevention. However, curative treatment remains unclearly established. Despite a non-unequivocal literature, haloperidol is the first line recommended neuroleptic. Dexmedetomidine, an alpha2-adrenergic receptors agonist has shown its efficiency in the treatment of delirium in intubated patients but also in its prevention. Dexmedetomidine represents a widely used alternative to haloperidol. Only few studies have compared the efficacy of dexmedetomidine in non-intubated ICU patients as a first line curative treatment of delirium. Main objective of 4D trial is to demonstrate that dexmedetomidine decreases delirium duration compared to placebo.

The 4D trial is an investigator-initiated, prospective, multicenter, randomized, double-blinded, two-arm trial, randomizing 300 non-intubated ICU patients with diagnosis of agitated delirium to receive dexmedetomidine or placebo as a cure. The primary outcome measure is a composite of duration of agitation or delirium or the use of intubation with deep sedation and mechanical ventilation. Secondary outcomes include mortalities at 7 and 28 days, ICU length of stay and occurrence of adverse effects. The sample size will allow the detection of a 50% decrease of agitation duration (120 minutes), of an absolute reduction of delirium duration (1 day) and of a 50% relative decrease of intubation and mechanical ventilation, with a type 1 error rate of 1.8 % (error risk inflation due to components of composite) and power of 90 %, assuming a 15 % incidence of intubation and mechanical ventilation requirements, an agitation duration of 240 minutes and a delirium duration of 3 days. One hundred and 10 patients by group will be needed. A intermediate analysis is scheduled and requires the inclusion of 150 patients in each group.

The 4D trial may provide important data on the safety of commonly used sedative dexmedetomidine and could have a significant impact on future treatment of non-intubated ICU patients presenting with agitated delirium.

• Study Type: Interventional
• Enrollment (Actual): 168
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Clermont-Ferrand, France, 63003
    • Chu Clermont-Ferrand

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• • Age > 18 years

  • Patient hospitalized in an ICU
  • Presenting a productive delirium according to the following criteria:
  • acute onset (<2h) and fluctuating course during the same day
  • alteration of cognitive functions: disorganization of thought (delirium of persecution, inability to reason logically), abnormal perceptions (hallucinations), memory impairments, temporal disorientation, non- or misrecognitions, difficulties in naming objects or writing)
  • in whom a simple cropping and non-medicated therapeutics are not sufficient to allow symptoms' resolution for few hours
  • CAM-ICU positive AND a RASS > +1
  • Non-intubated or extubated (> 24h)
  • No contraindication of dexmedetomidine or haloperidol uses

Exclusion Criteria:

• • Age <18 years

  • Administration of dexmedetomidine and/or clonidine during the 72 hours before inclusion
  • Contraindication to the use of Dexmedetomidine, clonidine or haloperidol (history of allergy, Parkinson's disease, oro-pharyngeal dysfunction, arterial hypotension or bradycardia, QTc interval prolongation, and hepatic or renal dysfunction), as mentioned in the Summaries of Product Characteristics
  • Neuropsychiatric pathology judged by the investigator as a potential source of bias (in particular: active drug addiction, psychosis...)
  • Parturient or breast-feeding woman
  • Protected major (guardianship)
  • Patient's or relative's refusal to participate

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: dexmedetomidine; Patients in the Dexmedetomidine (interventional) group will be treated with a continuous infusion of dexmedetomidine in case of agitated delirium.	Drug: Dexmedetomidine; The 4D trial is an investigator-initiated, prospective, multicenter, randomized, double-blinded, two-arm trial, randomizing 300 non-intubated ICU patients with diagnosis of agitated delirium to receive dexmedetomidine or placebo as a cure
Placebo Comparator: Normal Saline (NaCl 0.9%); Patients in the Normal Saline (control) group will be treated with a continuous infusion of normal saline in case of agitated delirium.	Other: Placebo; The 4D trial is an investigator-initiated, prospective, multicenter, randomized, double-blinded, two-arm trial, randomizing 300 non-intubated ICU patients with diagnosis of agitated delirium to receive dexmedetomidine or placebo as a cure

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Agitation (in Hours), Defined by a RASS ≥ +1		at day 1
Duration of Delirium (in Days), Defined by a Positive CAM-ICU		Day 30
Requirement of Intubation	requirement of intubation to control delirium with deep sedation and mechanical ventilation	at day 1

Secondary Outcome Measures

Outcome Measure	Time Frame
Length of ICU Stay (in Days)	day 30
Number of Ventilator Free Days	at day 30
Adverse Effects Such as the Occurence of Pneumonia (Following the ATS Definitions) and/or Septicemia	at day 30
Occurrence of Hypotension Requiring Any Vasopressor Administration and / or Tachycardia	at day 30
All-cause Mortality	at day 30
All-cause Mortality	at day 7

Collaborators and Investigators

• Sponsor: University Hospital, Clermont-Ferrand
• Investigators: Principal Investigator: Thomas GODET, University Hospital, Clermont-Ferrand

Publications and helpful links

General Publications

• Louis C, Godet T, Chanques G, Bourguignon N, Morand D, Pereira B, Constantin JM; AZUREA network. Effects of dexmedetomidine on delirium duration of non-intubated ICU patients (4D trial): study protocol for a randomized trial. Trials. 2018 Jun 4;19(1):307. doi: 10.1186/s13063-018-2656-x.
• Godet T, Louis C, Rieu B, De Jong A, Couhault P, Pradel G, Tete H, Bourguignon N, Borao L, Jabaudon M, Futier E, Jaber S, Pereira B, Chanques G, Constantin JM; 4D study group. Dexmedetomidine for treatment of hyperactive delirium in non-intubated ICU patients: the 4D randomized clinical trial. Intensive Care Med. 2025 Dec;51(12):2305-2317. doi: 10.1007/s00134-025-08135-1. Epub 2025 Oct 29.

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2017
• Primary Completion (Actual): May 21, 2021
• Study Completion (Actual): February 23, 2023

Study Registration Dates

• First Submitted: October 9, 2017
• First Submitted That Met QC Criteria: October 17, 2017
• First Posted (Actual): October 23, 2017

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: April 21, 2026
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Sedation; Mechanical Ventilation; Intubation; Agitation; Delirium; Haloperidol; ICU patients; Dexmdetomidine; Productive Delirium; Ventilatory free days
• Additional Relevant MeSH Terms: Aberrant Motor Behavior in Dementia; Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Behavioral Symptoms; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Dyskinesias; Psychomotor Disorders; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Delirium; Psychomotor Agitation; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Imidazoles; Dexmedetomidine
• Other Study ID Numbers: CHU- 356; 2017-000731-14 (Other Identifier: 2017-000731-14)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No