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Flumazenil for Hypoactive Delirium Secondary to Benzodiazepine Exposure (FLYP)

Primary Purpose

Hypoactive Delirium

Status

Terminated

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Flumazenil

Placebo

About this trial

This is an interventional treatment trial for Hypoactive Delirium focused on measuring delirium, flumazenil, hypoactive delirium, benzodiazepine, benzodiazepine antagonist, critical care

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:

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)
children, incarcerated individuals, and pregnant women
unable to provide consent and the legally authorized representative is unable to provide consent

Sites / Locations

UC Davis Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Flumazenil Infusion

Placebo Infusion

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Number of Participants With Delirium Resolution

defined by the proportion of patients who were delirium free at 14 days after randomization

Intensive Care Unit Length of Stay

length of time that the patient was admitted to an intensive care unit service during the hospital stay

Number of Mechanical Ventilator Free Days

number of days within the first 28 days after enrollment that the patient was free from needing mechanical ventilation

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

number of times that a RASS score of + 2 to +4 occurred that did not resolve with decreasing study infusion

Average Duration of Study Infusion

average duration of time patient was randomized to each infusion up to 72 hours

Average Maximum Rate of Study Infusion

average maximum rate (ml/hr) during the 72 hours after study infusion

Full Information

NCT ID

NCT02899156

First Posted

July 27, 2016

Last Updated

July 8, 2020

Sponsor

University of California, Davis

1. Study Identification

Unique Protocol Identification Number

NCT02899156

Brief Title

Flumazenil for Hypoactive Delirium Secondary to Benzodiazepine Exposure

Acronym

FLYP

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2020

Overall Recruitment Status

Terminated

Why Stopped

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

Study Start Date

March 2016 (undefined)

Primary Completion Date

April 16, 2019 (Actual)

Study Completion Date

April 16, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of California, Davis

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypoactive Delirium

Keywords

delirium, flumazenil, hypoactive delirium, benzodiazepine, benzodiazepine antagonist, critical care

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

22 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Flumazenil Infusion

Arm Type

Active Comparator

Arm Description

Arm Title

Placebo Infusion

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Flumazenil

Other Intervention Name(s)

Romazicon

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

0.9% normal saline

Primary Outcome Measure Information:

Title

Number of Delirium-free Days

Description

Time Frame

up to 14 days after randomization

Secondary Outcome Measure Information:

Title

Number of Participants With Delirium Resolution

Description

defined by the proportion of patients who were delirium free at 14 days after randomization

Time Frame

up to 14 days after randomization

Title

Intensive Care Unit Length of Stay

Description

length of time that the patient was admitted to an intensive care unit service during the hospital stay

Time Frame

duration of admission to the intensive care unit

Title

Number of Mechanical Ventilator Free Days

Description

number of days within the first 28 days after enrollment that the patient was free from needing mechanical ventilation

Time Frame

up to 28 days after randomization

Title

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

Description

number of times that a RASS score of + 2 to +4 occurred that did not resolve with decreasing study infusion

Time Frame

up to 72 hours after the start of the infusion

Title

Average Duration of Study Infusion

Description

average duration of time patient was randomized to each infusion up to 72 hours

Time Frame

up to 72 hours after the start of the infusion

Title

Average Maximum Rate of Study Infusion

Description

average maximum rate (ml/hr) during the 72 hours after study infusion

Time Frame

up to 72 hours after the start of the infusion

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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: 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) children, incarcerated individuals, and pregnant women unable to provide consent and the legally authorized representative is unable to provide consent

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kendra J Schomer, PharmD

Organizational Affiliation

University of California, Davis

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Jeremiah J Duby, PharmD, BCPS

Organizational Affiliation

University of California, Davis

Official's Role

Principal Investigator

Facility Information:

Facility Name

UC Davis Medical Center

City

Sacramento

State/Province

California

ZIP/Postal Code

95817

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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Flumazenil for Hypoactive Delirium Secondary to Benzodiazepine Exposure

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