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FLYP: Flumazenil for Hypoactive Delirium Secondary to Benzodiazepine Exposure

Sponsor
University of California, Davis (Other)
Overall Status
Terminated
CT.gov ID
NCT02899156
Collaborator
(none)
22
Enrollment
1
Location
2
Arms
37.5
Duration (Months)
0.6
Patients Per Site Per Month

Study Details

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.

Condition or Disease Intervention/Treatment Phase
Phase 4

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 Design

Study Type:
Interventional
Actual Enrollment :
22 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Effect of Flumazenil on Hypoactive Delirium in the ICU: A Double-Blind, Placebo-Controlled Pilot Study
Study Start Date :
Mar 1, 2016
Actual Primary Completion Date :
Apr 16, 2019
Actual Study Completion Date :
Apr 16, 2019

Arms and Interventions

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.

Drug: Flumazenil
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.

    Drug: Placebo
    0.9% normal saline

    Outcome Measures

    Primary Outcome Measures

    1. Number of Delirium-free Days [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.

    Secondary Outcome Measures

    1. Number of Participants With Delirium Resolution [up to 14 days after randomization]

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

    2. Intensive Care Unit Length of Stay [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

    3. Number of Mechanical Ventilator Free Days [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

    4. Occurrence of Agitation Requiring Use of Rescue Sedatives While on Study Infusion [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

    5. Average Duration of Study Infusion [up to 72 hours after the start of the infusion]

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

    6. Average Maximum Rate of Study Infusion [up to 72 hours after the start of the infusion]

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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 UC Davis Medical Center Sacramento California United States 95817

    Sponsors and Collaborators

    • University of California, Davis

    Investigators

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

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    University of California, Davis
    ClinicalTrials.gov Identifier:
    NCT02899156
    Other Study ID Numbers:
    • 837421
    First Posted:
    Sep 14, 2016
    Last Update Posted:
    Jul 23, 2020
    Last Verified:
    Jul 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by University of California, Davis
    delirium
    flumazenil
    hypoactive delirium
    benzodiazepine
    benzodiazepine antagonist
    critical care
    Additional relevant MeSH terms:
    Delirium
    Hypokinesia
    Flumazenil

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Flumazenil Group Placebo Group
    Arm/Group 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. Flumazenil 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. Placebo: 0.9% normal saline
    Period Title: Overall Study
    STARTED 11 11
    COMPLETED 10 10
    NOT COMPLETED 1 1

    Baseline Characteristics

    Arm/Group Title Flumazenil Infusion Placebo Infusion Total
    Arm/Group 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. Flumazenil 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. Placebo: 0.9% normal saline Total of all reporting groups
    Overall Participants 11 11 22
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    58
    (7)
    59.4
    (7.6)
    58.9
    (7.2)
    Sex: Female, Male (Count of Participants)
    Female
    4
    36.4%
    3
    27.3%
    7
    31.8%
    Male
    7
    63.6%
    8
    72.7%
    15
    68.2%
    Race and Ethnicity Not Collected (Count of Participants)
    Count of Participants [Participants]
    0
    0%
    Region of Enrollment (Count of Participants)
    United States
    11
    100%
    11
    100%
    22
    100%
    Days in Hospital Prior to Enrollment (days) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [days]
    8.5
    (2.8)
    10.6
    (7.5)
    9.5
    (5.8)
    Time Since Last Benzodiazepine (hours) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [hours]
    43
    (23)
    55
    (37.1)
    49
    (31.5)
    Lorazepam Equivalents (milligrams) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [milligrams]
    117
    110.3
    113.6

    Outcome Measures

    1. Primary Outcome
    Title Number of Delirium-free Days
    Description 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.
    Time Frame up to 14 days after randomization

    Outcome Measure Data

    Analysis Population Description
    One patient randomized to the flumazenil and one randomized to the placebo never received the study infusion. The patient in the flumazenil group died from a massive hemorrhage within 1 hour of infusion initiation, and it was deemed nonattributable to study infusion. Twenty patients were included in the final analysis.
    Arm/Group Title Flumazenil Group Placebo Group
    Arm/Group 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. Flumazenil 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. Placebo: 0.9% normal saline
    Measure Participants 10 10
    Median (Inter-Quartile Range) [days]
    12.7
    9.2
    2. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Flumazenil Group Placebo Group
    Arm/Group 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. Flumazenil 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. Placebo: 0.9% normal saline
    Measure Participants 10 10
    Count of Participants [Participants]
    9
    81.8%
    7
    63.6%
    3. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Flumazenil Group Placebo Group
    Arm/Group 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. Flumazenil 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. Placebo: 0.9% normal saline
    Measure Participants 10 10
    Mean (Standard Deviation) [days]
    7.8
    (4.8)
    7
    (6)
    4. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Flumazenil Group Placebo Group
    Arm/Group 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. Flumazenil 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. Placebo: 0.9% normal saline
    Measure Participants 10 10
    Mean (Standard Deviation) [days]
    23.6
    (4.4)
    24.9
    (5)
    5. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Flumazenil Group Placebo Group
    Arm/Group 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. Flumazenil 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. Placebo: 0.9% normal saline
    Measure Participants 10 10
    Count of Participants [Participants]
    0
    0%
    0
    0%
    6. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Flumazenil Group Placebo Group
    Arm/Group 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. Flumazenil 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. Placebo: 0.9% normal saline
    Measure Participants 10 10
    Mean (Standard Deviation) [hours]
    54.8
    (16.8)
    58.2
    (23.5)
    7. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Flumazenil Group Placebo Group
    Arm/Group 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. Flumazenil 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. Placebo: 0.9% normal saline
    Measure Participants 10 10
    Mean (Standard Deviation) [milliliters per hour]
    5
    (2)
    5.2
    (2)

    Adverse Events

    Time Frame 72 hours while on study infusion
    Adverse Event Reporting Description
    Arm/Group Title Flumazenil Group Placebo Group
    Arm/Group 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. Flumazenil 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. Placebo: 0.9% normal saline
    All Cause Mortality
    Flumazenil Group Placebo Group
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/11 (9.1%) 0/11 (0%)
    Serious Adverse Events
    Flumazenil Group Placebo Group
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/11 (0%) 0/11 (0%)
    Other (Not Including Serious) Adverse Events
    Flumazenil Group Placebo Group
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/11 (0%) 0/11 (0%)

    Limitations/Caveats

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

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Kendra Schomer, PharmD
    Organization University of California Davis Medical Center
    Phone 916-734-2243
    Email kjschomer@ucdavis.edu
    Responsible Party:
    University of California, Davis
    ClinicalTrials.gov Identifier:
    NCT02899156
    Other Study ID Numbers:
    • 837421
    First Posted:
    Sep 14, 2016
    Last Update Posted:
    Jul 23, 2020
    Last Verified:
    Jul 1, 2020