Flumazenil for Hypoactive Delirium Secondary to Benzodiazepine Exposure (FLYP)

July 8, 2020 updated by: University of California, Davis

Effect of Flumazenil on Hypoactive Delirium in the ICU: A Double-Blind, Placebo-Controlled Pilot Study

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Benzodiazepines are commonly used for discomfort, anxiety, agitation, and alcohol withdrawal syndrome (AWS) in the ICU. End organ dysfunction and extended exposure can increase the risk of complications associated with BZDs, which include increased ICU LOS, time on mechanical ventilation, and mortality.

Flumazenil as a 1, 4-imidazobenzodiazepine is a competitive antagonist for the benzodiazepine binding site with weak intrinsic or partial agonistic activity on the GABA receptor. Multiple studies have confirmed the safety and effectiveness of flumazenil for the reversal of sedation. Pilot studies have demonstrated safe reversal of over-sedation and statistically significant improvements in patient cooperation and time to extubation. The current standard for suspected BZD-associated hypoactive delirium is cessation of benzodiazepine administration and supportive care.

The role of continuous infusion flumazenil for rapid and sustained reversal of hypoactive delirium in the ICU has not been evaluated prospectively and therefore remains poorly defined.

Study Type

Interventional

Enrollment (Actual)

22

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • California
      • Sacramento, California, United States, 95817
        • UC Davis Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

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

Exclusion Criteria:

  1. contraindications to flumazenil including hypersensitivity
  2. receipt of benzodiazepines for control of potentially life-threatening conditions (e.g., control of intracranial pressure or status epilepticus)
  3. active seizure disorder or on current anti-convulsant therapy for history of seizure disorder. Seizures secondary to alcohol withdrawal will NOT be excluded.
  4. history of traumatic brain injury complicated by seizures
  5. acute episode (within prior 30 days) of severe traumatic brain injury
  6. history of structural lesion (e.g. subarachnoid hemorrhage, cerebrovascular accident, intra-parenchymal hemorrhage) complicated by seizures
  7. acute episode (within prior 14 days) of structural lesion (e.g. subarachnoid hemorrhage, cerebrovascular accident, intra-parenchymal hemorrhage)
  8. brain tumor complicated by seizure
  9. history of anoxic brain injury
  10. third-degree burn with total body surface area (TBSA) burn greater than 20%
  11. chronic benzodiazepine (clonazepam:lorazepam:diazepam approximately 4:8:40 mg per day) for 7 consecutive days with no taper
  12. chronic delirium that is attributable to other causes
  13. anticipated to transfer to lower level of care within 24 hours
  14. admitted for polysubstance overdose as determined by initial drug toxicity screening
  15. 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)
  16. children, incarcerated individuals, and pregnant women
  17. unable to provide consent and the legally authorized representative is unable to provide consent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Flumazenil Infusion
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.
Other Names:
  • Romazicon
Placebo Comparator: Placebo Infusion
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.
0.9% normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Delirium-free Days
Time Frame: up to 14 days after randomization
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Delirium Resolution
Time Frame: up to 14 days after randomization
defined by the proportion of patients who were delirium free at 14 days after randomization
up to 14 days after randomization
Intensive Care Unit Length of Stay
Time Frame: duration of admission to the intensive care unit
length of time that the patient was admitted to an intensive care unit service during the hospital stay
duration of admission to the intensive care unit
Number of Mechanical Ventilator Free Days
Time Frame: up to 28 days after randomization
number of days within the first 28 days after enrollment that the patient was free from needing mechanical ventilation
up to 28 days after randomization
Occurrence of Agitation Requiring Use of Rescue Sedatives While on Study Infusion
Time Frame: up to 72 hours after the start of the infusion
number of times that a RASS score of + 2 to +4 occurred that did not resolve with decreasing study infusion
up to 72 hours after the start of the infusion
Average Duration of Study Infusion
Time Frame: up to 72 hours after the start of the infusion
average duration of time patient was randomized to each infusion up to 72 hours
up to 72 hours after the start of the infusion
Average Maximum Rate of Study Infusion
Time Frame: up to 72 hours after the start of the infusion
average maximum rate (ml/hr) during the 72 hours after study infusion
up to 72 hours after the start of the infusion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Kendra J Schomer, PharmD, University of California, Davis
  • Principal Investigator: Jeremiah J Duby, PharmD, BCPS, University of California, Davis

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2016

Primary Completion (Actual)

April 16, 2019

Study Completion (Actual)

April 16, 2019

Study Registration Dates

First Submitted

July 27, 2016

First Submitted That Met QC Criteria

September 8, 2016

First Posted (Estimate)

September 14, 2016

Study Record Updates

Last Update Posted (Actual)

July 23, 2020

Last Update Submitted That Met QC Criteria

July 8, 2020

Last Verified

July 1, 2020

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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