Delirium Treatment With Transcranial Electrical Stimulation (DELTES)

DELirium Treatment With Transcranial Electrical Stimulation

The goal of this clinical trial is to investigate the effectiveness of standardized and personalized transcranial alternating current stimulation (tACS) in patients with delirium. To investigate this, will perform a double-blind, randomized, sham-controlled, multicenter trial.

To test the safety and feasibility of tACS in delirious patients, the first 30 patients will be randomized to receive either active or sham tACS treatment in a 1:1 ratio through a pilot study. For the main phase of the study, patients will be randomized, resulting in an overall 1:1:1 allocation to standardized tACS, personalized tACS or sham treatment.

Electroencephalogram (EEG) will be measured directly before and directly after the first stimulation session to assess whether tACS can reduce relative delta power. tACS or sham treatment will be given once daily for a maximum of 14 days, or until resolution of delirium or discharge (whichever comes first). During the treatment phase, presence and severity of delirium will be assessed daily. After the treatment phase, an additional EEG will be measured. Cognitive status will be assessed three months after the initial tACS session.

Study Overview

• Status: Recruiting
• Conditions: Delirium
• Intervention / Treatment: Device: transcranial alternating current stimulation (tACS); Device: Sham transcranial alternating current stimulation (tACS)

Detailed Description

Delirium, a prevalent neuropsychiatric syndrome caused by an underlying medical condition, characterized by cognitive deficits such as inattention, extends hospital stay, increases healthcare costs and increases the risk of long-term cognitive decline. Prolonged and severe delirium is associated with worse long-term outcomes. There is currently no treatment that reduces the duration or severity of delirium.

Delirium is consistently characterized by diffuse oscillatory slowing of the EEG, including pronounced loss of alpha activity and increased relative delta power. Additionally, functional connectivity between brain regions is decreased during delirium. In light of this, tACS is a potential treatment option that directly addresses the brain dysfunction observed in delirium. Because tACS has shown the ability to improve multiple domains of cognition, including attention, and modify functional connectivity, we aim to investigate the effectiveness of tACS as treatment for delirium. We will utilize the EEG to measure the effects of tACS, using relative delta power as a primary outcome measure.

Additionally, EEG measurements can capture individual spectral and connectivity changes targeted with tACS, making EEG a promising input for personalized tACS treatment. Neural mass modelling is a way to model the behavior of groups of neurons resulting in oscillatory output similar to EEG. This type of model is able to represent delirium pathology and, when combined with individual EEG input, can be employed to optimize treatment effectiveness, leading to personalized tACS treatment.

The overarching aim of the study is to investigate whether treatment with tACS, either standardized or personalized, induces EEG alterations indicative of reversal of delirium. The primary outcome is relative delta power in the EEG measured after the first tACS session. Secondary outcomes include severity and/or duration of delirium measured with validated delirium assessment instruments.

Patients aged 50 years and older with delirium that persists for at least 2 days, despite adequate treatment of underlying causes will be included in the study (n = 159). Inclusion will take place in the intensive care unit (ICU) and non-ICU wards of the University Medical Centre (UMC) Utrecht, Radboud UMC and HagaZiekenhuis.The proposed tACS protocol is considered safe according to the latest published international safety guidelines. All participants will be screened for their relevant medical history and other tACS safety aspects.

• Study Type: Interventional
• Enrollment (Estimated): 159
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yorben Lodema, MD; Phone Number: 088 7558300; Email: deltes@umcutrecht.nl
• Study Contact Backup: Name: Julia van der A, MSc; Phone Number: 088 756 7523; Email: j.vandera-2@umcutrecht.nl

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Recruiting
      • Radboudumc
      • Contact: Indira Tendolkar, MD, PhD
  • Zuid-Holland
    • Den Haag, Zuid-Holland, Netherlands, 2545 AA
      • Recruiting
      • Hagaziekenhuis
      • Contact: Thomas H Ottens, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age over 50 years.
• Diagnosis of delirium
• Richmond Agitation and Sedation Scale (RASS) score of -2 to +2.
• Delirium duration of at least two days prior to study inclusion, based delirium assessments and/or descriptions in the medical and/or nursing files.
• Known causes underlying delirium are being treated adequately, as assessed by the treating physician.

Exclusion Criteria:

• Inability to conduct delirium assessment (e.g. coma, deaf, blind) or inability to speak Dutch or English.
• A moribund state.
• Alcohol/substance abuse withdrawal or stroke as precipitating factor for delirium.
• Diagnosis of dementia, based on medical record review and/or a score of ≥4.5 on the short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)

• One or more contra-indications for tACS:

  1. History of serious head trauma or brain surgery;
  2. Large or ferromagnetic metal parts in the head (except for a dental wire);
  3. Implanted cardiac pacemaker or neurostimulator;
  4. Skin diseases or inflammations;
  5. Epilepsy.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standardized treatment arm; Standardized tACS will be applied with 2.0 mA (peak-to-peak) intensity for 30 minutes, with a 10 Hz frequency. Two 5x5 cm saline-soaked electrodes located at the frontal and occipito-parietal part of the scalp will be utilized (corresponding to 10-20 EEG electrode locations POz-Oz and AFz), including in the stimulation field the DLPFC, precuneus and posterior cingulate cortex. At the beginning of stimulation, the intensity will ramp up for 30 seconds to 2.0 mA peak-to-peak, while at the end of stimulation, the intensity will ramp down for 30 seconds.	Device: transcranial alternating current stimulation (tACS); tACS is a non-invasive brain stimulation technique which involves the application of a low intensity electric current between two or more surface electrodes. tACS uses stimulation with a current alternating at a specific frequency that can entrain endogenous neuronal oscillations by inducing neural synchronization. The administration of tACS is proposed to phase-lock large populations of neurons in the superficial layers of the cerebral cortex causing neural synchronization in the corresponding frequency, thereby altering connectivity. tACS will be delivered via a transcranial electrical stimulation (tES) device (Nurostym tES, Brainbox Ltd, United Kingdom). This device has been CE-marked for use as a medical device for the treatment of mental and neurological disorders.
Experimental: Personalized treatment arm; Personalized tACS will be applied with 2.0 mA (peak-to-peak) intensity for 30 minutes with a 30 second ramp up and ramp down. Treatment will be personalized based on a delirium neural mass model. After fitting the model to the individual EEG, a virtual tACS trial allows for optimization of treatment parameters for each individual patient. Treatment optimization will take place through changing stimulation location and/or frequency. After determining the optimal individual treatment strategy, settings of the personalized stimulation will remain constant during the treatment phase.	Device: transcranial alternating current stimulation (tACS); tACS is a non-invasive brain stimulation technique which involves the application of a low intensity electric current between two or more surface electrodes. tACS uses stimulation with a current alternating at a specific frequency that can entrain endogenous neuronal oscillations by inducing neural synchronization. The administration of tACS is proposed to phase-lock large populations of neurons in the superficial layers of the cerebral cortex causing neural synchronization in the corresponding frequency, thereby altering connectivity. tACS will be delivered via a transcranial electrical stimulation (tES) device (Nurostym tES, Brainbox Ltd, United Kingdom). This device has been CE-marked for use as a medical device for the treatment of mental and neurological disorders.
Sham Comparator: Sham treatment arm; At the beginning and end of this 30-minute protocol, the tACS device will ramp up to 2.0 mA peak-to-peak intensity for 30 seconds, stimulate for 60 seconds and ramp down for 30 seconds, which mimics the sensation of actual tACS stimulation and improves blinding.	Device: Sham transcranial alternating current stimulation (tACS); Sham-tACS is a form of non-effective stimulation which can mimic the subjective sensation of active tACS treatment. During sham-tACS, the device will ramp up to 2.0 mA peak-to-peak intensity for 30 seconds, stimulate for 60 seconds and ramp down for 30 seconds, which mimics the sensation of actual tACS stimulation and improves blinding.The sham-tACS will be delivered via a transcranial electrical stimulation (tES) device (Nurostym tES, Brainbox Ltd, United Kingdom). This device has been CE-marked for use as a medical device for the treatment of mental and neurological disorders.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative delta power	Calculated by dividing the absolute power in the delta frequency range by the total power, assessed using 64-channel resting-state EEG directly before and after tACS.	1 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of delirium	Delirium duration is evaluated by counting the number of days delirium is observed during the treatment period. We utilize the Intensive Care Delirium Screening Checklist (ICDSC), comprising 8 items, with a score of 4 or higher indicating the presence of delirium. Additionally, the Richmond Agitation-Sedation Scale (RASS), a 10-point scale ranging from +4 to -5, is used to assess the level of sedation (-5 indicating total sedation, +4 indicating combative behavior). A RASS score of -4 or lower, followed by an ICDSC score of 4 or higher, is also considered a delirium day.	Two weeks
Severity of delirium	The cumulative score on the Intensive Care Delirium Screening Checklist (ICDSC), which includes 8 items and has a score range of 0-8, is documented for each day where delirium is observed during the hospital admission. In instances where the ICDSC score is unavailable, it will be approximated using information retrieved from the electronic patient record and standard delirium assessment tools routinely conducted.	Two weeks
Length of hospital stay	The total number of days admitted to hospital	3 months
Cognitive status three months post delirium	Score on the Telephone Interview for Cognitive Status Modified (TICS-M). The TICS-M is a brief, 13-item test of cognitive functioning with scores ranging from 0 to 50, with higher scores indicating better cognitive performance.	3 months
Subjective sensations during treatment	Score on three-point Likert-type scale to assess sensations experienced during transcranial alternating current stimulation (tACS). The scale ranged from 0, indicating 'no sensation,' to 1, indicating 'slight sensation,' and 2, indicating 'intense sensation.' These sensations included itch, pain, burning sensation, heat, iron taste, headache, neck pain, phosphenes, dizziness, and nausea.	Two weeks
Average peak frequency	Average peak frequency values will be calculated by averaging, over epochs, the peak frequency, assessed using 64-channel resting-state EEG before and after tACS and during the follow-up measurement.	Two weeks
Phase Lag Index	Phase lag index captures phase synchronization between different EEG channels, assessed using 64-channel resting-state EEG before and after tACS and during the follow-up measurement.	Two weeks
Corrected Amplitude Envelope Correlation (AECc)	AECc captures amplitude synchronization between different EEG channels, assessed using 64-channel resting-state EEG before and after tACS and during the follow-up measurement.	Two weeks
Relative power	Relative power will be calculated by dividing the absolute power of the frequency band by the total absolute power in the EEG, assessed using 64-channel resting-state EEG before and after tACS and during the follow-up measurement.	Two weeks

Collaborators and Investigators

• Sponsor: A.J.C. Slooter
• Collaborators: Radboud University Medical Center; HagaZiekenhuis
• Investigators: Principal Investigator: Arjen JC Slooter, MD, PhD, UMC Utrecht

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2024
• Primary Completion (Estimated): January 31, 2027
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: February 19, 2024
• First Submitted That Met QC Criteria: February 28, 2024
• First Posted (Actual): February 29, 2024

Study Record Updates

• Last Update Posted (Actual): July 26, 2024
• Last Update Submitted That Met QC Criteria: July 24, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: transcranial alternating current stimulation; electroencephalography
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium
• Other Study ID Numbers: DELTES

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Patients can specify whether they agree to share their data with other research institutes. Depending on consent of participants, we might be able to share IPD after publication of results.
• IPD Sharing Time Frame: After first published results, no end date
• IPD Sharing Access Criteria: After approval of the consortium members

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No