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Trial record 6 of 39 for:    FLUMAZENIL

Flumazenil for Hypoactive Delirium Secondary to Benzodiazepine Toxicity (FLYP)

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ClinicalTrials.gov Identifier: NCT02899156
Recruitment Status : Completed
First Posted : September 14, 2016
Last Update Posted : August 9, 2019
Sponsor:
Information provided by (Responsible Party):
University of California, Davis

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 reverses hypoactive delirium associated with BZD toxicity and thereby reduces duration of delirium and ICU LOS.


Condition or disease Intervention/treatment Phase
Delirium Drug: Flumazenil Drug: Placebo 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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 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 Secondary to Benzodiazepine Toxicity in the ICU
Study Start Date : March 2016
Actual Primary Completion Date : April 16, 2019
Actual Study Completion Date : April 16, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Delirium
Drug Information available for: Flumazenil

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
Placebo Comparator: Placebo Infusion
The placebo 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: Placebo
0.9% normal saline




Primary Outcome Measures :
  1. 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.

  2. length of ICU stay defined as the time between randomization and ICU transfer orders [ Time Frame: up to 28 days after randomization ]

Secondary Outcome Measures :
  1. occurrence of agitation while on study infusion [ Time Frame: up to 72 hours after the start of the infusion ]
  2. occurrence of seizure while on study infusion [ Time Frame: up to 72 hours after the start of the infusion ]
  3. occurrence of supra ventricular arrhythmia while on study infusion [ Time Frame: up to 72 hours after the start of the infusion ]
  4. occurrence of agitation requiring use of rescue sedatives while on study infusion [ Time Frame: up to 72 hours after the start of the infusion ]
  5. hospital length of stay [ Time Frame: up to 28 days after randomization ]
  6. average duration of study infusion [ Time Frame: up to 72 hours after the start of the infusion ]
  7. average dose of study infusion [ Time Frame: up to 72 hours after the start of the infusion ]
  8. number of ventilator-free days [ Time Frame: up to 28 days after randomization ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • critically ill adults
  • RASS score of -3 to +1
  • CAM-ICU positive
  • no benzodiazepine therapy within the previous 12 hours

Exclusion Criteria:

  • Contraindications to flumazenil including hypersensitivity and receipt of benzodiazepines for control of potentially life-threatening conditions (eg, 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
  • history of 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 history or available urine drug screening) i.e. tricyclic antidepressants, bupropion
  • children, incarcerated individuals, and pregnant women
  • unable to provide consent and the legally authorized representative is unable to provide consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02899156


Locations
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United States, California
UC Davis Medical Center
Sacramento, California, United States, 95817
Sponsors and Collaborators
University of California, Davis
Investigators
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Principal Investigator: Kendra J Schomer, PharmD University of California, Davis
Principal Investigator: Jeremiah J Duby, PharmD, BCPS University of California, Davis

Publications:

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Responsible Party: University of California, Davis
ClinicalTrials.gov Identifier: NCT02899156     History of Changes
Other Study ID Numbers: 837421
First Posted: September 14, 2016    Key Record Dates
Last Update Posted: August 9, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Additional relevant MeSH terms:
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Flumazenil
Delirium
Confusion
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Neurocognitive Disorders
Mental Disorders
Antidotes
Protective Agents
Physiological Effects of Drugs
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action