Rivastigmine for the Treatment of Hypoactive Anticholinergic Delirium and CNS Depression Associated Mainly With Clozapine Poisoning.

NCT07545382 | Completed Phase 4

• 1 other identifier: 0202283
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

This study aims to evaluate the clinical efficacy of rivastigmine in reversing the full spectrum of toxic anticholinergic delirium, with a specific focus on hypoactive delirium and CNS depression. These presentations were predominantly associated with clozapine toxicity, accounting for 90% of the study population. Additionally, the research investigates the safety and efficacy of rivastigmine in reversing CNS depression caused by Tricyclic Antidepressants (TCAs), challenging traditional concerns regarding the use of cholinesterase inhibitors in such cases. The study was conducted on 100 patients at the Poison Control Center of Alexandria University Main Hospital. The primary objective is to assess the effectiveness of rivastigmine in restoring consciousness and improving cognitive function in patients presenting with delirium and depressed mental status.

Conditions

Anticholinergic Delirium; Clozapine Poisoning; Antipsychotic Toxicity; CNS Depression; Hypoactive Delirium; Tricyclic Antidepressant Poisoning; Procyclidine Induced Delirium

Keywords

Rivastigmine; Clozapine; Quetiapine; Carbamazepine; Procyclidine; Cyproheptadine; Acetylcholinesterase Inhibitors; CNS depression; Hypoactive dilirium; Anticholinergic delirium

Outcome Measures

Primary Outcomes (2)

• Change in Glasgow Coma Scale (GCS) Score.

  The Glasgow Coma Scale (GCS) is a clinical scale used to assess a patient's level of consciousness. The total score was recorded for all participants at baseline and subsequent intervals to evaluate the clinical response to rivastigmine. The GCS score ranges from a minimum of 3 to a maximum of 15, where higher scores indicate a better neurological outcome (improved consciousness). For the oral/NGT group, assessments were performed 2 hours after the initial dose and after each supplemental dose. For the transdermal group, monitoring included a 6 to 8-hour window and at 12 hours. Clinical resolution is defined as reaching a GCS score of 15 and a RASS score of 0.

  Baseline (0 hour), 2 hours post-administration (all patients), 6-8 hours, and 12 hours (transdermal group). For patients receiving additional oral/NGT doses, assessments were repeated 2 hours after each supplemental dose up to 6 hours after resolution.

• Change in Richmond Agitation-Sedation Scale (RASS) Score

  The Richmond Agitation-Sedation Scale (RASS) is used to evaluate the clinical response to rivastigmine. The RASS is a 10-point scale ranging from a minimum value of -5 (denoting unarousable/deep sedation) to a maximum value of +4 (denoting combative/extreme agitation). A score of 0 represents an alert and calm state, which indicates the best clinical outcome for this study. Scores were recorded for all participants at baseline and 2 hours to evaluate the initial response. For the oral/NGT group, additional assessments were performed 2 hours after each supplemental dose. For the transdermal group, monitoring focused on the 6 to 8-hour window and at 12 hours. Clinical resolution is defined as reaching a RASS score of 0 and a GCS score of 15.

  Baseline, 2h (all), 6-8h & 12h (patch group), and up to 6h post-resolution (both groups)

Secondary Outcomes (4)

• Post-Resolution Clinical Stability and Safety Profile.

  From initial administration up to 6 hours post-resolution of delirium.

• Median Time to Clinical Resolution.

  From the time of initial administration until the achievement of clinical resolution.

• Resolution of Peripheral Antimuscarinic Features.

  From initial administration up to the point of CNS manifestation resolution (variable, typically within 2-12 hours).

• The requirement for Additional Interventions

  From Initiation of Rivastigmine Treatment Until 6 Hours After Recovery of Consciousness

Study Arms (1)

Rivastigmine Treatment Group

EXPERIMENTAL

A total of 100 patients presenting with toxic anticholinergic delirium (including both hyperactive and hypoactive variants) were enrolled. Each participant received rivastigmine according to the established clinical titration protocol.

Drug: Rivastigmine

Interventions

Rivastigmine DRUG

Initial Dose: A starting dose of 6 mg is administered either orally or via a Nasogastric Tube (NGT) for patients with impaired swallowing or depressed consciousness. Titration: Additional 6 mg doses are repeated every 2 hours based on clinical need until the resolution of delirium. Alternative Route: Transdermal patches (9.5 mg/24h) are applied in cases where enteral administration is not feasible or based on clinical judgment. Maintenance: Dosing or continuous patch application is maintained until full clinical resolution of toxic anticholinergic symptoms is achieved.

Rivastigmine Treatment Group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients aged 18 years and older. Exposure: Confirmed or strongly suspected acute exposure to anticholinergic agents (e.g., clozapine, tricyclic antidepressants).
• Clinical Presentation: Presence of toxic anticholinergic delirium (hyperactive/agitated, hypoactive, or CNS depression/coma).

You may not qualify if:

• Non-Toxic Delirium: Delirium of multifactorial origin or other medical causes (e.g., sepsis, hepatic encephalopathy, alcohol withdrawal, or metabolic disturbances).
• Cardiac Contraindications: Baseline bradycardia, Atrioventricular (AV) block, or significant QTc prolongation.
• Severe Organ Impairment: Known severe renal or hepatic impairment. Neurological Conditions: History of pre-existing seizure disorders or epilepsy. Respiratory Conditions: Severe asthma or Chronic Obstructive Pulmonary Disease (COPD) due to the risk of bronchoconstriction.
• Obstructions: Mechanical bowel obstruction or urinary tract obstruction. Hypersensitivity: Known history of hypersensitivity to rivastigmine or other carbamates.
• Pregnancy/Lactation: Pregnant or lactating women.

Sponsors & Collaborators

• Alexandria University: lead

Study Sites (1)

Poison Control Center (PCC), Alexandria University Main Hospital

Alexandria, 21131, Egypt

Location

MeSH Terms

Interventions

Rivastigmine

Intervention Hierarchy (Ancestors)

Phenylcarbamates; Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals

Study Officials

• Naima A Sherif, Professor of Forensic Medicine

  University of Alexandria

  STUDY CHAIR

• Ragaa T Darwish, Professor of Forensic Medicine

  University of Alexandria

  STUDY CHAIR

• Sahar Y Issa, Assoc Prof Forensic Med

  University of Alexandria

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Masking Details: This is an open-label study in which all participants received the active intervention. Blinding was not feasible due to the clinical status of the participants, who presented with significantly impaired consciousness or toxic delirium (including CNS depression and coma). This clinical state rendered the participants unaware of the intervention at the time of administration. Furthermore, the emergency nature of the toxicological intervention and the need for rapid clinical assessment made masking impractical.
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant lecturer of forensic medicine and clinical toxicology

Model Details: This is a single-arm, open-label prospective study involving 100 patients who met the inclusion criteria for toxic anticholinergic delirium. All enrolled participants received the intervention (rivastigmine) following a standardized titration protocol. The study uniquely focuses on the reversal of CNS depression and hypoactive delirium, in addition to agitated states. Clinical response and level of arousal were quantitatively monitored using the Glasgow Coma Scale (GCS) to assess the depth of consciousness and the Richmond Agitation-Sedation Scale (RASS) to evaluate the degrees of sedation and agitation, ensuring a comprehensive assessment of the drug's efficacy across the full spectrum of delirium.

Study Record Dates

• First Submitted: April 15, 2026
• First Posted: April 22, 2026
• Study Start: December 8, 2025
• Primary Completion: April 15, 2026
• Study Completion: April 15, 2026
• Last Updated: April 22, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

EG (1)