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Dexmedetomidine (Precedex®) for Severe Alcohol Withdrawal Syndrome (AWS) and Alcohol Withdrawal Delirium (AWD)

This study has been terminated.
(DSMB recommendation for slow enrollment)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01362205
First Posted: May 30, 2011
Last Update Posted: November 6, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Ivor Douglas, Denver Health and Hospital Authority
  Purpose

This is a prospective, randomized, double-blind, placebo-controlled, parallel-group study of dexmedetomidine versus placebo, with lorazepam rescue, for the management of severe alcohol withdrawal syndrome (AWS) and alcohol withdrawal delirium (AWD) in critically ill adults.

The investigators hypothesize that the integration of dexmedetomidine (Precedex®) with usual therapy for the management of severe alcohol withdrawal syndrome (AWS) and alcohol withdrawal delirium/delirium tremens (AWD) in critically ill adult patients will reduce the time to resolution of AWS/AWD, increase the number of delirium-free and ventilator-free days in the first 28 days of hospitalization, reduce the length of ICU and hospital stays, and improve neurocognitive and quality of life scores on hospital discharge.


Condition Intervention Phase
Alcohol Withdrawal Delirium Alcohol Withdrawal Associated Autonomic Hyperactivity Alcohol Withdrawal Hallucinosis Alcohol Withdrawal-Induced Delirium Tremens Drug: Dexmedetomidine Drug: Placebos Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Placebo-controlled, Parallel-group Study of Dexmedetomidine (Precedex®), With Lorazepam Rescue, for the Management of Severe Alcohol Withdrawal Syndrome (AWS) and Alcohol Withdrawal Delirium (AWD)

Resource links provided by NLM:


Further study details as provided by Ivor Douglas, Denver Health and Hospital Authority:

Primary Outcome Measures:
  • The Length of ICU Stay Defined as the Time Between Randomization and ICU Transfer Orders. [ Time Frame: up to 28 days in hours ]

Secondary Outcome Measures:
  • Average MINDS Score [ Time Frame: up to 28 days ]
    Minnesota Detoxification Scale (MINDS) min score 0, max score 46. The higher the score, the worse the symptoms of AWS/AWD.

  • The Number of CAM-ICU Negative Days After Randomization. [ Time Frame: up to 28 days ]
    The Confusion Assessment Method (CAM)-ICU is a validated instrument used to detect the presence or absence of delirium in the ICU. A delirium free day is counted for any day a patient is negative by the CAM-ICU. The higher the number of CAM-ICU negative days indicates the more days a patient was able to think clearly.

  • Number of Ventilator Free Days After Randomization. [ Time Frame: up to 28 days ]
    A ventilator day is counted for any use of invasive mechanical ventilation during a calendar day

  • The Length in Days of the Hospital Stay [ Time Frame: up to 28 days ]
    A hospital day is counted for any time on a calendar day the patient is admitted to the hospital. Hospital days are inclusive of ICU days.

  • Scores at Hospital Discharge on the Mini Mental Exam. [ Time Frame: up to 28 days ]
    The Mini Mental State Examination or Folstein test is a validated 30-point questionnaire used to measure cognitive impairment (min score 0, max score 30). A score of 24 points (out of a max of 30) indicates normal cognition, less than or equal to 9 points indicates severe impairment, 10-18 indicates moderate impairment and 19-23 mild impairment.

  • Scores at Hospital Discharge on the Beck Depression Inventory. [ Time Frame: Up to 28 days. ]
    The Beck Depression Inventory is a validated questionnaire used to measure severity of depression (min score 0, max score 63). The higher the score the greater the severity of depression. A score of 30-63 indicates severe depression, 19-29 moderate depression, 10-18 mild depression and 0-9 minimal depression.

  • Scores at Hospital Discharge on the Beck Anxiety Inventory [ Time Frame: Up to 28 days. ]
    The Beck Anxiety Inventory is a validated questionnaire used to measure severity of anxiety (min score 0, max score 63). The higher the score the greater the severity of anxiety. A score of 30-63 indicates severe anxiety, 17-29 moderate anxiety, 10-16 mild anxiety and 0-9 minimal anxiety.

  • Scores at Hospital Discharge on the PTSD Civilian Checklist [ Time Frame: Up to 28 days ]
    PTSD checklist consists of 17 questions graded on a scale of 1 to 5. The PTSD score is comprised from the sum of the scores 17 questions. The PTSD score has possible values from to 17 to 85 with higher values indicating greater symptom severity.

  • Resource Utilization Costs Associated With This Hospitalization Billed by Physicians. [ Time Frame: up to 28 Days ]
  • Resource Utilization Costs Associated With This Hospitalization Billed by Facility. [ Time Frame: Up to 28 days ]

Enrollment: 49
Study Start Date: March 2012
Study Completion Date: September 2016
Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dexmedetomidine
Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician.
Drug: Dexmedetomidine
Other Name: Precedex
Placebo Comparator: Placebo
Blinded placebo study drug administration in equal volume per hour as active study medication arm.
Drug: Placebos
Inactive placebo (normal saline)

Detailed Description:

Severe alcohol withdrawal syndrome (AWS) and alcohol withdrawal delirium (AWD) are frequent principal indication/s for admission to intensive care units. Additionally, unanticipated alcohol withdrawal complicates other critical illnesses and peri-operative states. Alcohol intoxication and withdrawal syndrome are characterized by classic symptoms of adrenergic activation, psychiatric agitation including seizures, as well as metabolic and respiratory dysfunction. The majority of patients with severe AWS are effectively managed with combinations of benzodiazepine (BZD) sedatives (e.g. lorazepam) and butyrophenone antipsychotics (e.g. haloperidol) and require intensive care admission for 2-3 days. However, almost 25% of patients with SAWS have a prolonged critical care course, often complicated by respiratory failure and associated with excessive sedation and risk for complications such as ventilator-associated pneumonia (VAP). AWS is frequently difficult to manage with usual care including benzodiazepines. Additionally, while intermittent bolus dose sedation is recommended for AWS, high dose BZD alone is associated with excessive respiratory suppression and metabolic acidosis. Such therapy increases the likelihood of respiratory failure with its attendant complications of hospital acquired pneumonia and sepsis. Further, patients with underlying chronic liver disease are at greater risk for prolonged sedative effects of BZD and progression of hepatic encephalopathy. The requirement for mechanical ventilation additionally prolongs the course of treatment for AWD because of the need for prolonged sedation. Strategies to control AWS/AWD that control symptoms but avoid adverse effects of excessive respiratory suppression are anticipated to improve the short and medium-term outcomes of AWS.

BZD infusions have also been shown by several investigators to result in excessive and prolonged sedation. However, reasonable alternatives for effective control of psychomotor and adrenergic activation have until recently, been unavailable. The centrally acting alpha-2 receptor agonist, clonidine has been suggested as a useful adjunctive therapy to BZD. However, clonidine is only a mild sedative and can result in significant hemodynamic compromise. By contrast, dexmedetomidine (Precedex), a more potent alpha-2 receptor agonist, is potentially a more effective adjunctive therapy. Precedex is currently marketed in the USA for short-term use as a potent peri-operative sedative and analgesic. This agent has a short circulating half-life and has significantly fewer hemodynamic side effects than clonidine. In addition to its cardiovascular properties, dexmedetomidine possesses anxiolytic, hypnotic/sedative, anesthetic-sparing and analgesic actions and is devoid of significant respiratory depressant effects.

Precedex has been shown to be a safe and effective single agent sedative for critically ill medical and surgical patients in prolonged infusions up to thirty days and is associated with significantly lower incidence of delirium than sedation with the benzodiazepine, midazolam. Preclinical experience and case reports suggest anecdotally Precedex may be of particular benefit in patients with SAWS.

Measures of sedation and delirium will be assessed with the Minnesota Detoxification Scale (MINDS) derived for use in critically ill adults from the validated Clinical Institute Withdrawal Assessment (CIWA-r) scale.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 89 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female patients, 18 years or older, with severe AWS or AWD per DSM-IV definitions (below) requiring admission to the ICU for medical management
  • Ability to provide informed consent (via a proxy decision maker or patient).
  • Within 96 hours of ICU admission.
  • Meets DSM-IV diagnostic criteria for 291.8 Alcohol Withdrawal Syndrome:

    • Cessation of (or reduction in) alcohol use that has been heavy and prolonged.
    • Two (or more) of the following, developing within several hours to a few days after Criterion A:

      1. autonomic hyperactivity (e.g., sweating or pulse rate greater than 100)
      2. increased hand tremor
      3. insomnia
      4. nausea or vomiting
      5. transient visual, tactile, or auditory hallucinations or illusions
      6. psychomotor agitation
      7. anxiety
      8. grand mal seizures
  • The symptoms are not due to a general medical condition and are not better accounted for by another mental disorder.

AND Meets DSM-IV diagnostic criteria for 291.0 Alcohol Intoxication or Withdrawal Delirium

  • Disturbance of consciousness
  • A change in cognition
  • The disturbance develops over a short time and can fluctuate
  • Onset is temporal associated with Alcohol Withdrawal Syndrome

Exclusion Criteria:

  • Age < 18 years
  • Physician anticipates ICU transfer orders in less than 12 hours from time of consent.
  • Recent traumatic brain injury
  • Active status epilepticus
  • Pregnancy or lactation
  • Known allergy or adverse response to any of the study medications
  • Requiring glucocorticoid therapy for treatment of acute hepatitis or Stage III (advanced) decompensated liver failure and encephalopathy
  • Trauma or burns as admitting diagnoses
  • Neuromuscular blockade other than for intubation
  • Epidural or spinal analgesia
  • General anesthesia 24 hours prior to, or planned after, the start of study drug infusion
  • Serious central nervous system pathology (acute stroke, uncontrolled seizures, severe dementia),
  • Unstable angina or acute myocardial infarction
  • Left ventricular ejection fraction less than 30%
  • Heart rate less than 50/min
  • Second- or third degree heart block
  • Systolic blood pressure less than 90 mm Hg despite continuous infusions of 2 vasopressors before the start of study drug infusion.
  • Previous randomization into this study.
  Contacts and Locations
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): NCT01362205


Locations
United States, Colorado
Memorial Hospital Central
Colorado Springs, Colorado, United States, 80909
Memorial Hospital North
Colorado Springs, Colorado, United States, 80920
Denver Health Medical Center, Medical ICU
Denver, Colorado, United States, 80204
Porter Adventist Hospital
Denver, Colorado, United States, 80210
St. Anthony Hospital
Lakewood, Colorado, United States, 80228
United States, Louisiana
Louisiana State University
New Orleans, Louisiana, United States, 70112
United States, Texas
Ben Taub Hospital
Houston, Texas, United States, 77030
Sponsors and Collaborators
Denver Health and Hospital Authority
Investigators
Principal Investigator: Ivor S Douglas, MD, FRCP Denver Health Medical Center
  More Information

Publications:
Responsible Party: Ivor Douglas, Professor of Medicine, Denver Health and Hospital Authority
ClinicalTrials.gov Identifier: NCT01362205     History of Changes
Other Study ID Numbers: COMIRB 09-0822
First Submitted: May 24, 2010
First Posted: May 30, 2011
Results First Submitted: May 16, 2017
Results First Posted: July 17, 2017
Last Update Posted: November 6, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Ivor Douglas, Denver Health and Hospital Authority:
Severe Alcohol Withdrawal Delirium Tremens

Additional relevant MeSH terms:
Delirium
Substance Withdrawal Syndrome
Alcohol Withdrawal Delirium
Confusion
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Neurocognitive Disorders
Mental Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Alcohol-Induced Disorders, Nervous System
Neurotoxicity Syndromes
Poisoning
Alcohol-Induced Disorders
Alcohol-Related Disorders
Ethanol
Dexmedetomidine
Lorazepam
Anti-Infective Agents, Local
Anti-Infective Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Hypnotics and Sedatives
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Adrenergic alpha-2 Receptor Agonists