Flumazenil for Hypoactive Delirium Secondary to Benzodiazepine Exposure

NCT02899156 | Terminated Phase 4 Results DMC

• 1 other identifier: 837421
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

Delirium within the intensive care unit (ICU) is associated with poor outcomes such as increased mortality, ICU and hospital length of stay (LOS), and time on mechanical ventilation. Benzodiazepine (BZD) exposure is an independent risk factor for development of delirium. Reversal of hypoactive delirium represents a potential opportunity for reducing duration of delirium and subsequent complications. This is a single-center randomized, double-blind, placebo-controlled study of critically ill adult patients with benzodiazepine-associated hypoactive delirium. The hypothesis is that flumazenil continuous infusion may reverse hypoactive delirium associated with BZD exposure and thereby reduce duration of delirium and ICU LOS.

Conditions

Hypoactive Delirium

Keywords

delirium; flumazenil; hypoactive delirium; benzodiazepine; benzodiazepine antagonist; critical care

Outcome Measures

Primary Outcomes (1)

• Number of Delirium-free Days

  Defined by the number of days in the 14-day period after randomization that the patient was alive and not delirious (i.e. CAM-ICU negative). Zero delirium-free days will be observed for patients that die within the 14-day period.

  up to 14 days after randomization

Secondary Outcomes (6)

• Number of Participants With Delirium Resolution

  up to 14 days after randomization

• Intensive Care Unit Length of Stay

  duration of admission to the intensive care unit

• Number of Mechanical Ventilator Free Days

  up to 28 days after randomization

• Occurrence of Agitation Requiring Use of Rescue Sedatives While on Study Infusion

  up to 72 hours after the start of the infusion

• Average Duration of Study Infusion

  up to 72 hours after the start of the infusion

Study Arms (2)

Flumazenil Infusion

ACTIVE COMPARATOR

The flumazenil continuous infusion is started at an initial dose of 0.1 mg/hr., and can be titrated up to a maximum of 0.3 mg/hr. Dose titrations may occur every 60 minutes to maintain RASS scores of 0 to +1. The maximum rate is 0.3 mg/hr.

Drug: Flumazenil

Placebo Infusion

PLACEBO COMPARATOR

The placebo continuous infusion is started at an initial dose of 0.1 mg/hr (2 ml/hr)., and can be titrated up to a maximum of 0.3 mg/hr. Dose titrations may occur every 60 minutes to maintain RASS scores of 0 to +1. The maximum rate is 0.3 mg/hr.

Drug: Placebo

Interventions

Flumazenil DRUG

Also known as: Romazicon

Flumazenil Infusion

Placebo DRUG

0.9% normal saline

Placebo Infusion

Eligibility Criteria

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

You may qualify if:

• critically ill adults
• RASS score of -3 to 0 after receiving benzodiazepine therapy
• CAM-ICU positive
• no benzodiazepine therapy within the previous 12 hours

You may not qualify if:

• contraindications to flumazenil including hypersensitivity
• receipt of benzodiazepines for control of potentially life-threatening conditions (e.g., control of intracranial pressure or status epilepticus)
• active seizure disorder or on current anti-convulsant therapy for history of seizure disorder. Seizures secondary to alcohol withdrawal will NOT be excluded.
• history of traumatic brain injury complicated by seizures
• acute episode (within prior 30 days) of severe traumatic brain injury
• history of structural lesion (e.g. subarachnoid hemorrhage, cerebrovascular accident, intra-parenchymal hemorrhage) complicated by seizures
• acute episode (within prior 14 days) of structural lesion (e.g. subarachnoid hemorrhage, cerebrovascular accident, intra-parenchymal hemorrhage)
• brain tumor complicated by seizure
• history of anoxic brain injury
• third-degree burn with total body surface area (TBSA) burn greater than 20%
• chronic benzodiazepine (clonazepam:lorazepam:diazepam approximately 4:8:40 mg per day) for 7 consecutive days with no taper
• chronic delirium that is attributable to other causes
• anticipated to transfer to lower level of care within 24 hours
• admitted for polysubstance overdose as determined by initial drug toxicity screening
• recent exposure (prior 7 days) to pro-convulsant medications (identified via medication list, medication reconciliation performed by PI/pharmacy medication reconciliation team, or urine drug screening)

Sponsors & Collaborators

• University of California, Davis: lead

Study Sites (1)

UC Davis Medical Center

Sacramento, California, 95817, United States

Location

Related Publications (31)

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MeSH Terms

Conditions

Delirium

Interventions

Flumazenil

Condition Hierarchy (Ancestors)

Confusion; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Benzodiazepinones; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

A planned interim analysis led to the trial being stopped early based on the observed size effect and power analysis.

Results Point of Contact

• Title: Kendra Schomer, PharmD
• Organization: University of California Davis Medical Center

kjschomer@ucdavis.edu

916-734-2243

Study Officials

• Kendra J Schomer, PharmD

  University of California, Davis

  PRINCIPAL INVESTIGATOR

• Jeremiah J Duby, PharmD, BCPS

  University of California, Davis

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 27, 2016
• First Posted: September 14, 2016
• Study Start: March 1, 2016
• Primary Completion: April 16, 2019
• Study Completion: April 16, 2019
• Last Updated: July 23, 2020
• Results First Posted: July 23, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)