Alcohol Withdrawal Syndrome Treated With Adjunctive Phenobarbital or Ketamine (PKAT)

• ClinicalTrials.gov Identifier: NCT03788889
• Recruitment Status: Withdrawn
• First Posted: December 28, 2018
• Last Update Posted: September 19, 2019
• Sponsor: Santa Barbara Cottage Hospital
• Information provided by (Responsible Party): Santa Barbara Cottage Hospital

Tracking Information

• First Submitted Date: December 22, 2018
• First Posted Date: December 28, 2018
• Last Update Posted Date: September 19, 2019
• Estimated Study Start Date: April 12, 2019
• Actual Primary Completion Date: April 12, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 27, 2018)

Intensive Care Unit admission rate [ Time Frame: Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years ]

Number of admissions to the intensive care unit

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 3, 2019)

• Incidence of withdrawal seizures [ Time Frame: Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years ]
  Number of patients with documented seizures while treated for alcohol withdrawal syndrome
• Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) scores [ Time Frame: Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years ]
  CIWA-Ar scores (initial, maximum, discharge); Total score is cumulative of subscale measures: Minimum score is 0 (no evidence of alcohol withdrawal), Maximum score is 67 (severe alcohol withdrawal) Subscale measures: A) Nausea and vomiting (score 0-7); B) Tremor (score 0-7); C) Paroxysmal sweats (score 0-7); D) Anxiety (score 0-7); E) Tactile disturbances (score 0-7); F) Auditory disturbances (score 0-7); G) Visual disturbances (score 0-7); H) Headache, fullness in head (score 0-7); I) Agitation (score 0-7); J) Orientation and clouding of sensorium (score 0-4)
• Cumulative dose of medication/s administered [ Time Frame: Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years ]
  Cumulative dose of Lorazepam, Ketamine, and Phenobarbital
• Incidence of refractory alcohol withdrawal requiring alternative sedation with dexmedetomidine, propofol or midazolam infusions [ Time Frame: Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years ]
  Number of patients who require Dexmedetomidine, Propofol or Benzodiazepine continuous infusions and average dose while being treated for alcohol withdrawal syndrome
• Rate of mechanical ventilation [ Time Frame: Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years ]
  Rate of intubation
• Incidence of alcohol withdrawal hallucinations [ Time Frame: Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years ]
  Number of patients with documented auditory or visual hallucinations

Original Secondary Outcome Measures (submitted: December 27, 2018)

• Incidence of withdrawal seizures [ Time Frame: Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years ]
  Number of patients with documented seizures while treated for alcohol withdrawal syndrome
• Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) scores [ Time Frame: Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years ]
  CIWA-Ar scores (initial, maximum, discharge); Total score is cumulative of subscale measures: Minimum score is 0 (no evidence of alcohol withdrawal), Maximum score is 67 (severe alcohol withdrawal) Subscale measures: A) Nausea and vomiting (score 0-7); B) Tremor (score 0-7); C) Paroxysmal sweats (score 0-7); D) Anxiety (score 0-7); E) Tactile disturbances (score 0-7); F) Auditory disturbances (score 0-7); G) Visual disturbances (score 0-7); H) Headache, fullness in head (score 0-7); I) Agitation (score 0-7); J) Orientation and clouding of sensorium (score 0-4)
• Cumulative dose of medication/s administered [ Time Frame: Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years ]
  Cumulative dose of Lorazepam, Ketamine, and Phenobarbital
• Incidence of refractory alcohol withdrawal requiring alternative sedation with propofol or midazolam infusions [ Time Frame: Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years ]
  Number of patients who require Propofol or Benzodiazepine continuous infusions and average dose while being treated for alcohol withdrawal syndrome
• Rate of mechanical ventilation [ Time Frame: Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years ]
  Rate of intubation
• Incidence of alcohol withdrawal hallucinations [ Time Frame: Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years ]
  Number of patients with documented auditory or visual hallucinations

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Alcohol Withdrawal Syndrome Treated With Adjunctive Phenobarbital or Ketamine
• Official Title: A Randomized, Double-Blinded, Placebo-Controlled Study Evaluating Phenobarbital and Ketamine Adjunctive Therapies in the Treatment of Alcohol Withdrawal Syndrome
• Brief Summary: The goal of this study will aim to determine if adding phenobarbital or ketamine to a symptom-triggered benzodiazepine regimen decreases the rate of intensive care unit admissions during the treatment of alcohol withdrawal syndrome when compared to symptom-triggered benzodiazepine therapy alone.

Detailed Description

The primary objective of this study is to compare phenobarbital and ketamine adjunctive therapies to lorazepam-based therapy in the treatment of acute alcohol withdrawal syndrome.

It is hypothesized that the use of an alternative agent, either phenobarbital or ketamine, when used as an adjunct to symptom-triggered lorazepam therapy will significantly reduce the rate of intensive care unit admissions and thereby reduce the total cost associated with hospital admission for treatment of alcohol withdrawal syndrome.

Enrolled patients will be admitted to Santa Barbara Cottage Hospital where they will be monitored with continuous pulse oximetry and cardiac telemetry. They will remain hospitalized while undergoing study-guided therapy in addition to supportive care for acute alcohol withdrawal syndrome. Patients will undergo standard of care therapy with lorazepam symptom-triggered therapy regardless of study participation.

• Study Type: Interventional
• Study Phase: Phase 4

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

prospective, randomized control trial

Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:

Each participant will be randomized according to a web-based randomization program employed by a research pharmacist once the Emergency Department provider deems the patient appropriate for inpatient treatment of alcohol withdrawal syndrome.

Each medication will be packaged by Santa Barbara Cottage Hospital pharmacy. In order to blind both the clinicians and the participants, the pharmacy will provide medication bags that are identical. Therefore, Emergency Department nursing staff and physicians will be unaware of which study drug is being provided to the patient. Normal saline will be used as a placebo to mimic study drugs (phenobarbital and ketamine). Pharmacy will remain unblinded and maintain records of which treatment assignment is prepared for each patient.

Treatment will be provided for the duration of the patient's hospitalization; therefore, treatment compliance will be documented in the electronic health record using the medication bag identifier.

Primary Purpose: Treatment

• Condition: Alcohol Withdrawal Syndrome

Intervention

• Drug: Ketamine
  Ketamine infusion
  Other Name: Ketalar
• Drug: Phenobarbital
  Phenobarbital intravenous injection
  Other Name: Solfoton, Luminal
• Drug: Lorazepam
  Standard of Care
  Other Name: Ativan
• Drug: Placebo A
  Placebo injection
  Other Name: Normal saline
• Drug: Placebo B
  Placebo infusion
  Other Name: Normal saline

Study Arms

• Active Comparator: Lorazepam + Ketamine + Placebo A

  Ketamine - infusion (0.15 - 0.4 mg/kg/hr) and placebo injections titrated by increases of 0.075 mg/kg/hr every 30 minutes for Clinical Institute Withdrawal Assessment for Alcohol (revised version) (CIWA-Ar) greater than or equal to 10 in addition to lorazepam symptom-triggered therapy

  Ketamine dosing will be based on ideal body weight

  Ketamine infusion will be discontinued once CIWA-Ar less than 10 for 4 hours

  Interventions:

  • Drug: Ketamine
  • Drug: Lorazepam
  • Drug: Placebo A
• Active Comparator: Lorazepam + Phenobarbital + Placebo B

  Phenobarbital - IV push (260 mg loading followed by 130 mg q1 hour) with placebo infusion until CIWA-Ar less than 10 with a maximum daily dose of 10mg/kg in addition to lorazepam symptom-triggered dosing for recurrent symptoms (Gold 2007)

  Maximum daily dose will be used in order to prevent over sedation as well as provide adequate storage in pharmacy monitored refrigerators for study drugs

  Interventions:

  • Drug: Phenobarbital
  • Drug: Lorazepam
  • Drug: Placebo B
• Placebo Comparator: Lorazepam + Placebo A + Placebo B
  Lorazepam will be administered every 30 minutes as indicated based on CIWA-Ar protocol for Cottage Health in addition to placebo injections and placebo infusion
  Interventions:

  • Drug: Lorazepam
  • Drug: Placebo A
  • Drug: Placebo B

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Withdrawn
• Actual Enrollment (submitted: September 17, 2019): 0
• Original Estimated Enrollment (submitted: December 27, 2018): 222
• Actual Study Completion Date: April 12, 2019
• Actual Primary Completion Date: April 12, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Primary admitting diagnosis of acute alcohol withdrawal syndrome based on International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10), code F10.3, F10.4.

Exclusion Criteria:

• Significant comorbid medical illness requiring Intensive Care Unit admission;
• Pregnancy;
• Inability to obtain intravenous access;
• Child Pugh Class C; and
• Allergy to study medications (phenobarbital, ketamine, lorazepam).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT03788889
• Other Study ID Numbers: 18-94
• 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
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Santa Barbara Cottage Hospital
• Study Sponsor: Santa Barbara Cottage Hospital
• Collaborators: Not Provided

Investigators

• Principal Investigator: Noah Stites-Hallet, MD; Santa Barbara Cottage Hospital

• PRS Account: Santa Barbara Cottage Hospital
• Verification Date: September 2019