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Ketamine vs. Placebo as Adjunctive Therapies for Severe Alcohol Withdrawal

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ClinicalTrials.gov Identifier: NCT02823977
Recruitment Status : Withdrawn (Funding not obtained)
First Posted : July 6, 2016
Last Update Posted : January 19, 2018
Sponsor:
Information provided by (Responsible Party):
University of Colorado, Denver

Tracking Information
First Submitted Date  ICMJE July 1, 2016
First Posted Date  ICMJE July 6, 2016
Last Update Posted Date January 19, 2018
Estimated Study Start Date  ICMJE February 2018
Estimated Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 1, 2016)
  • Cumulative Lorazepam Dose Over the First 12 Hours of Alcohol Withdrawal [ Time Frame: 12 hours ]
    As part of routine care, the bedside nurse will record the administration of all sedative agents. The hourly, daily and cumulative doses of agents will be determined by the sum of as needed doses, scheduled intermittent doses, and hourly infusion rates. All conventional therapies will be guided by the institution-specific, symptom-triggered alcohol withdrawal protocol to maintain CIWA scores ≤ 7. Intravenous lorazepam is the preferred benzodiazepine for management of alcohol withdrawal in the medical ICU. Phenobarbital and propofol are infrequently used and they are not included in the protocol. All benzodiazepine and barbiturate doses, whether oral or intravenous, will be converted to lorazepam equivalents using the following conversion: 1 mg lorazepam = 2 mg midazolam = 7.5 mg clorazepate = 15 mg phenobarbital.
  • Cumulative Lorazepam Dose Over the First 24 Hours of Alcohol Withdrawal [ Time Frame: 24 hours ]
    As part of routine care, the bedside nurse will record the administration of all sedative agents. The hourly, daily and cumulative doses of agents will be determined by the sum of as needed doses, scheduled intermittent doses, and hourly infusion rates. All conventional therapies will be guided by the institution-specific, symptom-triggered alcohol withdrawal protocol to maintain CIWA scores ≤ 7. Intravenous lorazepam is the preferred benzodiazepine for management of alcohol withdrawal in the medical ICU. Phenobarbital and propofol are infrequently used and they are not included in the protocol. All benzodiazepine and barbiturate doses, whether oral or intravenous, will be converted to lorazepam equivalents using the following conversion: 1 mg lorazepam = 2 mg midazolam = 7.5 mg clorazepate = 15 mg phenobarbital.
  • Cumulative Lorazepam Dose Over the 72 Hours of Alcohol Withdrawal [ Time Frame: 72 hours ]
    As part of routine care, the bedside nurse will record the administration of all sedative agents. The hourly, daily and cumulative doses of agents will be determined by the sum of as needed doses, scheduled intermittent doses, and hourly infusion rates. All conventional therapies will be guided by the institution-specific, symptom-triggered alcohol withdrawal protocol to maintain CIWA scores ≤ 7. Intravenous lorazepam is the preferred benzodiazepine for management of alcohol withdrawal in the medical ICU. Phenobarbital and propofol are infrequently used and they are not included in the protocol. All benzodiazepine and barbiturate doses, whether oral or intravenous, will be converted to lorazepam equivalents using the following conversion: 1 mg lorazepam = 2 mg midazolam = 7.5 mg clorazepate = 15 mg phenobarbital.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 1, 2016)
  • Change in 12-Hour Lorazepam Requirement Pre- and Post-Treatment [ Time Frame: 12 hours before treatment, 12 hours after treatment on first day of starting study drug ]
    As part of routine care, the bedside nurse will record the administration of all sedative agents. The hourly, daily and cumulative doses of agents will be determined by the sum of as needed doses, scheduled intermittent doses, and hourly infusion rates. All conventional therapies will be guided by the institution-specific, symptom-triggered alcohol withdrawal protocol to maintain CIWA scores ≤ 7. Intravenous lorazepam is the preferred benzodiazepine for management of alcohol withdrawal in the medical ICU. Phenobarbital and propofol are infrequently used and they are not included in the protocol. All benzodiazepine and barbiturate doses, whether oral or intravenous, will be converted to lorazepam equivalents using the following conversion: 1 mg lorazepam = 2 mg midazolam = 7.5 mg clorazepate = 15 mg phenobarbital.
  • Change in 24-Hour Lorazepam Requirement Pre- and Post-Treatment [ Time Frame: 24 hours before treatment, 24 hours after treatment on first day of starting study drug ]
    As part of routine care, the bedside nurse will record the administration of all sedative agents. The hourly, daily and cumulative doses of agents will be determined by the sum of as needed doses, scheduled intermittent doses, and hourly infusion rates. All conventional therapies will be guided by the institution-specific, symptom-triggered alcohol withdrawal protocol to maintain CIWA scores ≤ 7. Intravenous lorazepam is the preferred benzodiazepine for management of alcohol withdrawal in the medical ICU. Phenobarbital and propofol are infrequently used and they are not included in the protocol. All benzodiazepine and barbiturate doses, whether oral or intravenous, will be converted to lorazepam equivalents using the following conversion: 1 mg lorazepam = 2 mg midazolam = 7.5 mg clorazepate = 15 mg phenobarbital.
  • The Degree of Alcohol Withdrawal Assessed by Clinical Institute Withdrawal Assessment (CIWA) Scores [ Time Frame: 72 hours ]
    CIWA scores will be assessed hourly by the bedside nurse. The proportion of CIWA scores ≥ 15 (severe withdrawal symptoms), 8 - 14 (moderate withdrawal symptoms), and ≤ 7 (minimal withdrawal symptoms) will be determined.
  • The Occurrence of Adverse Events: hypotension, hypertension, bradycardia, tachycardia [ Time Frame: 72 hours ]
    Blood pressure and heart rate will be assessed hourly by the bedside nurse. Hypotension will be defined as a systolic blood pressure ≤ 90 mmHg or a decrease of systolic blood pressure of 40 mmHg, hypertension will be defined as a systolic blood pressure ≥ 180 mmHg or an increase of systolic blood pressure of 40 mmHg, bradycardia will be defined as a heart rate ≤ 55 beats/minute or a decrease of 20 beats/minutes, and tachycardia will be defined as a heart rate ≥ 120 beats/minute or an increase of 20 beats/minutes. Highest and lowest daily measurements of each will also be collected.
  • Plasma Epinephrine Concentrations Across Groups Over Time [ Time Frame: 96 hours ]
    Plasma epinephrine concentrations will be assessed prior to study drug and at times 24, 48, 72 and 96 hours after initiating study drug
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ketamine vs. Placebo as Adjunctive Therapies for Severe Alcohol Withdrawal
Official Title  ICMJE A Randomized, Double-blind Study of Ketamine / Dexmedetomidine vs. Placebo / Dexmedetomidine as Adjunctive Therapies for Severe Alcohol Withdrawal
Brief Summary This study is designed to evaluate the addition of ketamine to dexmedetomidine as adjunctive therapies of severe alcohol withdrawal in medical ICU patients. Specifically, this study will assess whether the combination of ketamine and dexmedetomidine reduces the doses of conventional agents used for alcohol withdrawal while maintaining patient comfort and safety and will explore if the combination alters the expression of catecholamines in the serum over time.
Detailed Description

The combination of ketamine and dexmedetomidine for alcohol withdrawal is pharmacologically rationale and may provide additive benzodiazepine-sparing effects. All subjects will receive benzodiazepine therapy as standard of care.

The objectives of this randomized, double-blind pilot study of 20 subjects with severe alcohol withdrawal are to a) determine if adding ketamine 0.5 mg/kg per hour to dexmedetomidine 0.6 µg/kg per hour (both agents administered for up to 72 hours) as adjunctive therapies to a symptom-triggered benzodiazepine protocol reduces the dose requirements of conventional sedatives while maintaining patient comfort and safety; and to b) explore whether epinephrine, a marker of autonomic activity, is expressed differently when ketamine is added to dexmedetomidine as adjunctive therapies.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Alcohol Withdrawal
Intervention  ICMJE
  • Drug: Ketamine
    Blinded study drug administered to experimental arm
    Other Name: Ketalar
  • Drug: Dexmedetomidine
    Open-label study drug administered to both arms
    Other Name: Precedex
  • Drug: Normal saline
    Blinded comparator administered to control arm
    Other Name: 0.9% NaCl in water
Study Arms  ICMJE
  • Experimental: Ketamine / Dexmedetomidine
    Ketamine 0.25 mg/kg bolus followed by 0.5 mg/kg per hour AND Dexmedetomidine by continuous infusion at a fixed rate of 0.6 µg/kg per hour, both administered for up to 72 hours
    Interventions:
    • Drug: Ketamine
    • Drug: Dexmedetomidine
  • Placebo Comparator: Placebo / Dexmedetomidine
    Normal saline, as a 500 mL infusion bag, to represent placebo AND Dexmedetomidine by continuous infusion at a fixed rate of 0.6 µg/kg per hour, both administered for up to 72 hours
    Interventions:
    • Drug: Dexmedetomidine
    • Drug: Normal saline
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Withdrawn
Actual Enrollment  ICMJE
 (submitted: January 17, 2018)
0
Original Estimated Enrollment  ICMJE
 (submitted: July 1, 2016)
20
Estimated Study Completion Date  ICMJE December 2018
Estimated Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Severe alcohol withdrawal defined by a CIWA score ≥ 15 and the need for at least 16 mg of lorazepam equivalents over a four-hour period. All benzodiazepine and barbiturate doses, whether oral or intravenous, will contribute to the cumulative amount using the following conversion: 1 mg lorazepam = 2 mg midazolam = 7.5 mg clorazepate = 15 mg phenobarbital.
  2. Patients receiving standard therapy for severe alcohol withdrawal according to the UCH-specific, symptom-triggered alcohol withdrawal protocol in the ICU (or admission to the ICU is anticipated). Lorazepam is the preferred benzodiazepine agent for patients requiring ICU admission due to alcohol withdrawal.
  3. Informed consent within 36 hours of qualifying for the study.

Exclusion Criteria:

  1. Patients < 18 years of age or > 85 years of age.
  2. Patients receiving benzodiazepine therapy for purposes other than alcohol withdrawal (e.g. sedation, seizure control other than alcohol withdrawal).
  3. Patients with alcohol withdrawal not requiring ICU admission.
  4. Patients receiving epidural administration of medication(s).
  5. Comatose patients by metabolic or neurologic affectation.
  6. Patients with active myocardial ischemia or second- or third-degree heart block.
  7. Patients with Child-Pugh score of C.
  8. Moribund state with planned withdrawal of life support.
  9. Patient pending transfer to another facility.
  10. Patients with known or suspected severe adverse reactions to dexmedetomidine (or clonidine) or ketamine.
  11. Pregnant females or females suspected of being pregnant.
  12. Prisoners or active parolees.
  13. Previous study participation.
  14. Patients already receiving ketamine for alcohol withdrawal. Patients receiving dexmedetomidine will be excluded if the infusion exceeds 1 µg/kg per hour for more than two hours or any rate for a cumulative duration of 12 hours.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02823977
Other Study ID Numbers  ICMJE 16-1303
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Aggregate data will be presented and published in a peer reviewed journal. Individual data will not be shared.
Responsible Party University of Colorado, Denver
Study Sponsor  ICMJE University of Colorado, Denver
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Robert MacLaren, PharmD, MPH University of Colorado, Denver
PRS Account University of Colorado, Denver
Verification Date January 2018

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