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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
May 24, 2010
May 30, 2011
May 16, 2017
July 17, 2017
November 6, 2017
March 2012
December 2015   (Final data collection date for primary outcome measure)
The Length of ICU Stay Defined as the Time Between Randomization and ICU Transfer Orders. [ Time Frame: up to 28 days in hours ]
The time to achieve resolution of AWS/AWD as defined by a score of < 2 on the Minnesota Detoxification Scale (MINDS) [ Time Frame: up to 28 days in hours ]
Complete list of historical versions of study NCT01362205 on ClinicalTrials.gov Archive Site
  • 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 ]
  • The number of delirium-free and ventilator-free days during the first 28 days of hospitalization [ Time Frame: up to 28 days ]
  • The length of ICU and hospital stays [ Time Frame: up to 28 days ]
  • Mini Mental scores on hospital discharge [ Time Frame: up to 28 days ]
  • Psychometric battery: Wechsler Adult Intelligence Test, Revised Wechsler Memory Scale, Revised Verbal Fluency Test, Beck Depression Inventory, Beck Anxiety Inventory, and SF36 instrument for assessment of Quality of Life, at hospital discharge [ Time Frame: Up to 28 days ]
  • Resource utilization costs associated with this hospitalization. [ Time Frame: up to 28 Days ]
  • Blood pressure meeting the definition of an adverse event [ Time Frame: Hours ]
  • Heart rate meeting the definition of an adverse event. [ Time Frame: Hours ]
Not Provided
Not Provided
 
Dexmedetomidine (Precedex®) for Severe Alcohol Withdrawal Syndrome (AWS) and Alcohol Withdrawal Delirium (AWD)
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)

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.

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.

Interventional
Phase 4
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
  • Alcohol Withdrawal Delirium
  • Alcohol Withdrawal Associated Autonomic Hyperactivity
  • Alcohol Withdrawal Hallucinosis
  • Alcohol Withdrawal-Induced Delirium Tremens
  • Drug: Dexmedetomidine
    Other Name: Precedex
  • Drug: Placebos
    Inactive placebo (normal saline)
  • 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.
    Intervention: Drug: Dexmedetomidine
  • Placebo Comparator: Placebo
    Blinded placebo study drug administration in equal volume per hour as active study medication arm.
    Intervention: Drug: Placebos

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
49
September 2016
December 2015   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
18 Years to 89 Years   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01362205
COMIRB 09-0822
Yes
Not Provided
Plan to Share IPD: No
Ivor Douglas, Denver Health and Hospital Authority
Denver Health and Hospital Authority
Not Provided
Principal Investigator: Ivor S Douglas, MD, FRCP Denver Health Medical Center
Denver Health and Hospital Authority
October 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP