Rivastigmine to Prevent Recurrence of Antimuscarinic Delirium (RIVA-AP)

Rivastigmine to Prevent Recurrence of Antimuscarinic Delirium After Initial Control With Physostigmine (RIVA-AP): a Randomized, Placebo-controlled Trial

Antimuscarinic delirium (AMD) is a common and dangerous toxicology condition caused by poisoning by medications and other chemicals that block muscarinic receptors. Physostigmine is effective in reversing AMD but has a short duration of action, and patient commonly experience recurrence of AMD after initial control with physostigmine.

Recent case reports and small observational studies suggest that rivastigmine, which has a longer duration of action than physostigmine, might be useful in the treatment of AMD. In order to investigate the effectiveness of rivastigmine in preventing recurrence of AMD after initial control with physostigmine, the investigators propose a randomized, placebo-controlled clinical trial of rivastigmine for AMD. The investigators hypothesize that patients treated with rivastigmine after initial control of AMD with physostigmine will experience less recurrence of antimuscarinic delirium than those treated with placebo.

Study Overview

• Status: Recruiting
• Conditions: Anticholinergic Toxicity
• Intervention / Treatment: Drug: Rivastigmine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 42
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Kevin Baumgartner, MD; Phone Number: 3142731109; Email: baumgartner.k@wustl.edu

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Contact: Kevin Baumgartner; Phone Number: 3142731109; Email: baumgartner.k@wustl.edu

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 10 years of age or older
• Diagnosis of antimuscarinic delirium by history and physical examination, in the opinion of the treating attending toxicologist.
• Treatment with physostigmine according to the local standard of care is planned or has been administered by the treating attending toxicologist and is acceptable to the patient's primary attending physician and surrogate decision maker.
• Antimuscarinic delirium is reasonably controlled after initial physostigmine treatment, as determined by treating toxicologist on bedside physical examination. (Patients may begin the screening and enrollment process prior to physostigmine administration, but will not undergo final initiation of study treatment until after response to physostigmine has been confirmed).

Exclusion Criteria:

• Age less than 10 years at time of enrollment
• Surrogate decision maker not available to provide informed consent for enrollment.
• Patient is pregnant or a ward of the state.
• Inability to safely tolerate oral medication, in the judgement of the treating attending physician.

• Evidence of significant risk for serious cardiac or neurologic sequelae of antimuscarinic poisoning:

  a. Any known or suspected seizure activity prior to enrollment b. QRS duration >100 milliseconds on EKG at enrollment c. Any ventricular dysrhythmia prior to enrollment d. Respiratory failure of any etiology requiring endotracheal intubation e. Any hypotension at enrollment: i. Adults: systolic blood pressure (SBP) <90 mmHg ii. Children ≥10: systolic blood pressure (SBP) <90 mmHg, as per Pediatric Advanced Life Support (PALS) age-based cutoff for children 10 years of age or older3 f. Any administration of sodium bicarbonate, hypertonic saline, vasopressors, inotropes, antiarrhythmic agents, or intravenous lipid emulsion prior to enrollment.

  g. Unacceptable risk of serious medical sequelae of antimuscarinic poisoning in the judgment of the treating attending toxicologist.

• Evidence of significant risk of adverse effect of AChE-I:

  a.Bradycardia or risk of AChE-I induced bradycardia at enrollment: i. Adults: heart rate (HR) <80 beats per minute ii. Children: heart rate below the median heart rate for age as proposed by Fleming et al.33:

  1. Ages 10-12: HR <84 beats per minute 2. Ages 12-15: HR <78 beats per minute 3. Ages 15-18: HR <73 beats per minute b. Known or suspected seizure disorder. c. History of asthma or COPD or wheezing during index presentation d. Known or suspected physical obstruction of intestinal or urogenital tract i. Ileus and/or urinary retention due to antimuscarinic poisoning do not exclude patients from enrollment.

  e. Known or suspected peptic ulcer disease.

• Any known allergy or intolerance to rivastigmine or other AChEI.
• Failure to achieve reasonable initial control of antimuscarinic delirium after physostigmine administration, as assessed by treating toxicologist on bedside physical examination.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rivastigmine; Patients in the rivastigmine arm will receive rivastigmine 3mg by mouth once, followed by rivastigmine 1.5mg by mouth every 1 hour as needed for ongoing delirium or agitation (at the discretion of the treating physician), for up to three doses.	Drug: Rivastigmine; Rivastigmine 3mg by mouth once, followed by rivastigmine 1.5mg by mouth every 1 hour as needed for ongoing delirium or agitation (at the discretion of the treating physician), for a maximum of three doses
Placebo Comparator: Placebo; Patients in the placebo arm will receive oral placebo by mouth once, followed by oral placebo every 1 hour as needed for ongoing delirium or agitation (at the discretion of the treating physician), for up to three doses.	Drug: Placebo; Matching oral placebo by mouth once, followed by placebo by mouth every 1 hour as needed for ongoing delirium or agitation (at the discretion of the treating physician), for a maximum of three doses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of AMD recurrence	Incidence of AMD recurrence, as defined by the development of agitation (Richmond Agitation-Sedation Scale of +1 or higher) and delirium (Confusion Assessment Method for the ICU positive) after initial control of AMD with physostigmine.	Typically 8-36 hours after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of agitation and delirium	Total duration of time during which patient is experiencing agitation and delirium (defined and assessed as above)	Typically 8-36 hours after randomization
Total amount of sedatives administered	Total amount of sedatives (antipsychotics, benzodiazepines, dexmedetomidine, propofol, fentanyl, ketamine) administered during the study period.	Typically 8-36 hours after randomization
Use of sedative infusions	Any use of continuous sedative infusion (dexmedetomidine, benzodiazepine, propofol, fentanyl) during the study period.	Typically 8-36 hours after randomization
Use of physical restraints	Any use of physical restraints during the study period	Typically 8-36 hours after randomization
Disposition	Disposition to ICU, stepdown/intermediate care unit, or floor level of care	Typically 8-36 hours after randomization
Time to medical clearance	Time from presentation to medical clearance by the toxicology consult service	Typically 8-36 hours after randomization
Oversedation	Incidence of oversedation, defined as RASS lower than -2	Typically 8-36 hours after randomization
Intubation	Incidence of intubation and mechanical ventilation during the study period	Typically 8-36 hours after randomization
Seizure	Incidence of epileptic seizure during the study period	Typically 8-36 hours after randomization
Gastrointestinal upset	Incidence of clinically significant gastrointestinal upset during the study period	Typically 8-36 hours after randomization
Bradycardia	Incidence of any bradycardia (as defined using age-based heart rate cutoffs) during the study period	Typically 8-36 hours after randomization

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: American Academy of Clinical Toxicology
• Investigators: Principal Investigator: Kevin Baumgartner, MD, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2024
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): November 1, 2026

Study Registration Dates

• First Submitted: April 30, 2024
• First Submitted That Met QC Criteria: April 30, 2024
• First Posted (Actual): May 6, 2024

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 17, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Pathologic Processes; Disease Attributes; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Recurrence; Organic Chemicals; Acids, Acyclic; Carboxylic Acids; Carbamates; Phenylcarbamates; Rivastigmine
• Other Study ID Numbers: 202403052

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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