A Phase 4 interventional study of Dexmedetomidine and Placebos in Alcohol Withdrawal Delirium, Alcohol Withdrawal Associated Autonomic Hyperactivity and Alcohol Withdrawal Hallucinosis, sponsored by Denver Health and Hospital Authority. Terminated at 7 sites in United States. Open to participants aged 18 Years to 89 Years. Per ClinicalTrials.gov, last updated 2017-11-06.
Sponsored by Denver Health and Hospital Authority · Phase 4, Interventional, and Treatment
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.
1,057 studies on the registry are indexed under Delirium; 238 are open to participants now.
This study's enrollment of 49 is below the median of 120 across 599 interventional studies indexed under Delirium.
Browse Delirium studies →Denver Health and Hospital Authority is the lead sponsor of 84 studies on the registry; 4 are open to participants now.
Of its 9 completed or terminated interventional studies of FDA-regulated products, 8 (89%) have results posted.
Counted across the registry records on this site, refreshed daily.
Meets DSM-IV diagnostic criteria for 291.8 Alcohol Withdrawal Syndrome:
Two (or more) of the following, developing within several hours to a few days after Criterion A:
AND Meets DSM-IV diagnostic criteria for 291.0 Alcohol Intoxication or Withdrawal Delirium
Exclusion Criteria:
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
Blinded placebo study drug administration in equal volume per hour as active study medication arm.
Drug: Placebos
Also known as: Precedex
Inactive placebo (normal saline)
The Length of ICU Stay Defined as the Time Between Randomization and ICU Transfer Orders.
Time frame: up to 28 days in hours
Average MINDS Score
Minnesota Detoxification Scale (MINDS) min score 0, max score 46. The higher the score, the worse the symptoms of AWS/AWD.
Time frame: up to 28 days
The Number of CAM-ICU Negative Days After Randomization.
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.
Time frame: up to 28 days
Number of Ventilator Free Days After Randomization.
A ventilator day is counted for any use of invasive mechanical ventilation during a calendar day
Time frame: up to 28 days
The Length in Days of the Hospital Stay
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.
Time frame: up to 28 days
Scores at Hospital Discharge on the Mini Mental Exam.
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.
Time frame: up to 28 days
Scores at Hospital Discharge on the Beck Depression Inventory.
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.
Time frame: Up to 28 days.
Scores at Hospital Discharge on the Beck Anxiety Inventory
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.
Time frame: Up to 28 days.
Scores at Hospital Discharge on the PTSD Civilian Checklist
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.
Time frame: Up to 28 days
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
| Milestone | Dexmedetomidine | Placebo |
|---|---|---|
| Started | 22 | 27 |
| Completed | 22 | 27 |
| Not completed | 0 | 0 |
| hours | Dexmedetomidine | Placebo |
|---|---|---|
| The Length of ICU Stay Defined as the Time Between Randomization and ICU Transfer Orders. | 79.2 (43.9 to 134.6) | 104.9 (63.7 to 183.1) |
Minnesota Detoxification Scale (MINDS) min score 0, max score 46. The higher the score, the worse the symptoms of AWS/AWD.
| units on a scale | Dexmedetomidine | Placebo |
|---|---|---|
| Average MINDS Score | 8.2 (4.6 to 11.0) | 9.4 (7.8 to 11.6) |
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.
| days | Dexmedetomidine | Placebo |
|---|---|---|
| The Number of CAM-ICU Negative Days After Randomization. | 0.3 (0.0 to 0.5) | 0.3 (0.1 to 0.7) |
A ventilator day is counted for any use of invasive mechanical ventilation during a calendar day
| days | Dexmedetomidine | Placebo |
|---|---|---|
| Number of Ventilator Free Days After Randomization. | 27.5 (25.0 to 28.0) | 28.0 (26.0 to 28.0) |
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.
| days | Dexmedetomidine | Placebo |
|---|---|---|
| The Length in Days of the Hospital Stay | 8.0 (5.0 to 13.0) | 12.0 (6.0 to 16.0) |
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.
| units on a scale | Dexmedetomidine | Placebo |
|---|---|---|
| Scores at Hospital Discharge on the Mini Mental Exam. | 25.8 ± 2.53 | 23.1 ± 6.09 |
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.
| units on a scale | Dexmedetomidine | Placebo |
|---|---|---|
| Scores at Hospital Discharge on the Beck Depression Inventory. | 26.5 ± 9.14 | 21.4 ± 10.95 |
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.
| units on a scale | Dexmedetomidine | Placebo |
|---|---|---|
| Scores at Hospital Discharge on the Beck Anxiety Inventory | 30.3 ± 10.83 | 21.6 ± 11.55 |
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.
| units on a scale | Dexmedetomidine | Placebo |
|---|---|---|
| Scores at Hospital Discharge on the PTSD Civilian Checklist | 45.5 (39.0 to 59.5) | 32.5 (27.5 to 37.0) |
| Dollar (United States) | Dexmedetomidine | Placebo |
|---|---|---|
| Resource Utilization Costs Associated With This Hospitalization Billed by Physicians. | 3482 (2068 to 9326) | 4461 (2926 to 8001) |
| USD | Dexmedetomidine | Placebo |
|---|---|---|
| Resource Utilization Costs Associated With This Hospitalization Billed by Facility. | 81234 (51437 to 137272) | 91651 (67341 to 132458) |
Collected over The first 28 days of hospitalization after randomization.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Dexmedetomidine | 0/21 (0%) | 5/21 (23.8%) | 12/21 (57.1%) |
| Placebo | 0/27 (0%) | 3/27 (11.1%) | 17/27 (63%) |
| Event | Dexmedetomidine | Placebo |
|---|---|---|
| Respiratory failureRespiratory, thoracic and mediastinal disorders | 2/21 | 1/27 |
| Atrial fibrillationCardiac disorders | 1/21 | 0/27 |
| Cardiac arrestCardiac disorders | 1/21 | 0/27 |
| Hepatitis alcoholicHepatobiliary disorders | 1/21 | 0/27 |
| Enterococcal infectionInfections and infestations | 1/21 | 0/27 |
| Septic shockInfections and infestations | 1/21 | 1/27 |
| Haemorrhage intracranialNervous system disorders | 1/21 | 0/27 |
| Osmotic demyelination syndromeNervous system disorders | 1/21 | 0/27 |
| Acute kidney injuryRenal and urinary disorders | 1/21 | 0/27 |
| BacteraemiaInfections and infestations | 0/21 | 1/27 |
| Event | Dexmedetomidine | Placebo |
|---|---|---|
| HypokalaemiaMetabolism and nutrition disorders | 10/21 | 16/27 |
| HypertensionVascular disorders | 5/21 | 13/27 |
| Oedema peripheralGeneral disorders | 6/21 | 11/27 |
| HypotensionVascular disorders | 6/21 | 4/27 |
| PyrexiaGeneral disorders | 4/21 | 3/27 |
| HypophosphataemiaMetabolism and nutrition disorders | 3/21 | 5/27 |
| ThrombocytosisBlood and lymphatic system disorders | 1/21 | 4/27 |
| DiarrhoeaGastrointestinal disorders | 3/21 | 4/27 |
| HypernatraemiaMetabolism and nutrition disorders | 1/21 | 4/27 |
| HypoalbuminaemiaMetabolism and nutrition disorders | 1/21 | 4/27 |
| Age, Continuous(years) | Dexmedetomidine | Placebo | Total |
|---|---|---|---|
| Mean | 46.5 ± 11.54 | 48.2 ± 11.82 | 47.4 ± 11.61 |
| Sex: Female, Male(Participants) | Dexmedetomidine | Placebo | Total |
|---|---|---|---|
| Female | 6 | 3 | 9 |
| Male | 16 | 24 | 40 |
| Ethnicity (NIH/OMB)(Participants) | Dexmedetomidine | Placebo | Total |
|---|---|---|---|
| Hispanic or Latino | 2 | 8 | 10 |
| Not Hispanic or Latino | 20 | 19 | 39 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Dexmedetomidine | Placebo | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 1 | 1 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 3 | 2 | 5 |
| White | 19 | 24 | 43 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | Dexmedetomidine | Placebo | Total |
|---|---|---|---|
| United States | 22 | 27 | 49 |
Plan to share: No
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Denver Health and Hospital Authority