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

A Randomized, Double-Blinded, Placebo-Controlled Study Evaluating Phenobarbital and Ketamine Adjunctive Therapies in the Treatment of Alcohol Withdrawal Syndrome

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.

Study Overview

• Status: Withdrawn
• Conditions: Alcohol Withdrawal Syndrome
• Intervention / Treatment: Drug: Ketamine; Drug: Lorazepam; Drug: Placebo A; Drug: Phenobarbital; Drug: Placebo B

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
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	Drug: Ketamine; Ketamine infusion; Other Names: Ketalar; Drug: Lorazepam; Standard of Care; Other Names: Ativan; Drug: Placebo A; Placebo injection; Other Names: Normal saline
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	Drug: Lorazepam; Standard of Care; Other Names: Ativan; Drug: Phenobarbital; Phenobarbital intravenous injection; Other Names: Solfoton, Luminal; Drug: Placebo B; Placebo infusion; Other Names: Normal saline
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	Drug: Lorazepam; Standard of Care; Other Names: Ativan; Drug: Placebo A; Placebo injection; Other Names: Normal saline; Drug: Placebo B; Placebo infusion; Other Names: Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intensive Care Unit admission rate	Number of admissions to the intensive care unit	Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of withdrawal seizures	Number of patients with documented seizures while treated for alcohol withdrawal syndrome	Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years
Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) scores	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)	Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years
Cumulative dose of medication/s administered	Cumulative dose of Lorazepam, Ketamine, and Phenobarbital	Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years
Incidence of refractory alcohol withdrawal requiring alternative sedation with dexmedetomidine, propofol or midazolam infusions	Number of patients who require Dexmedetomidine, Propofol or Benzodiazepine continuous infusions and average dose while being treated for alcohol withdrawal syndrome	Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years
Rate of mechanical ventilation	Rate of intubation	Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years
Incidence of alcohol withdrawal hallucinations	Number of patients with documented auditory or visual hallucinations	Presentation to Emergency Department through hospital stay, data will be utilized through study completion, anticipated 2 years

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Anticipated): April 12, 2019
• Primary Completion (Actual): April 12, 2019
• Study Completion (Actual): April 12, 2019

Study Registration Dates

• First Submitted: December 22, 2018
• First Submitted That Met QC Criteria: December 27, 2018
• First Posted (Actual): December 28, 2018

Study Record Updates

• Last Update Posted (Actual): September 19, 2019
• Last Update Submitted That Met QC Criteria: September 17, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Ketamine; Lorazepam; Phenobarbital
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Pathologic Processes; Substance-Related Disorders; Disease; Syndrome; Substance Withdrawal Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Antiemetics; Gastrointestinal Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anticonvulsants; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP2B6 Inducers; Ketamine; Lorazepam; Phenobarbital
• Other Study ID Numbers: 18-94

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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