Phenobarbital for Severe Acute Alcohol Withdrawal Syndrome

NCT03586089 | Terminated DMC

• 1 other identifier: 18-285
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

Severe acute alcohol withdrawal syndrome is a potentially life-threatening condition characterized by agitation, confusion, abnormal heart rhythms and seizures. Typically, clinicians treat the symptoms of alcohol withdrawal with a class of medications known as benzodiazepines (e.g., Valium). These medications have a short duration of activity and require repeated administration, often every hour or less, to reduce the symptoms of alcohol withdrawal. Many patients suffer complications related to inadequate treatment of alcohol withdrawal (e.g., abnormal heart rhythms, aspiration, seizures) resulting in admission to an intensive care unit and prolonged hospital stay, all of which increase healthcare costs. Although alcohol withdrawal is common, especially among disadvantaged (e.g., homeless) patients, limited funding is available to advance the care of patients suffering from alcohol withdrawal. A safe and effective treatment for severe alcohol withdrawal would benefit patients and our healthcare system. Phenobarbital is an inexpensive, commonly available medication that is typically used to treat seizures. A key advantage of phenobarbital is that its calming effect lasts for a long period of time and it can be given as a 'one-time-dose' intravenously, so that it both prevents and treats withdrawal symptoms and reduces the need for repeated benzodiazepines. Through better symptom control, phenobarbital is expected to reduce the costs and complications of alcohol withdrawal. At present, physicians rarely use phenobarbital for this purpose, and additional research is needed for this medication to become part of routine care in clinical practice. The PHENOMANAL pilot trial will assess safety and whether clinicians can administer a single dose of phenobarbital intravenously, in addition to benzodiazepines, compared to benzodiazepines alone for treating patients with severe alcohol withdrawal. This information will inform the design of a larger clinical trial. For patients, the PHENOMANAL trial has the potential to revolutionize how patients suffering from severe alcohol withdrawal are treated. For society and the healthcare system, phenobarbital is expected to reduce the complications and costs associated with severe alcohol withdrawal.

Conditions

Alcohol Withdrawal Delirium; Alcohol Withdrawal; Alcohol Withdrawal Seizures

Keywords

Phenobarbital; Alcohol; Withdrawal

Outcome Measures

Primary Outcomes (1)

• Safety: adverse event rate

  The rates of severe adverse events, including aspiration events and endotracheal intubation, will be compared between treatment and placebo groups.

  18 months

Secondary Outcomes (1)

• Protocol feasibility: recruitment rate

  18 months

Other Outcomes (1)

• Protocol adherence: crossover rate

  18 months

Study Arms (2)

Phenobarbital

EXPERIMENTAL

Patients will receive a single dose of phenobarbital (7.5 mg/kg of ideal body weight, IV) in addition to usual therapy.

Drug: Phenobarbital Sodium

Placebo

PLACEBO COMPARATOR

Patients will receive an inactive placebo (IV).

Drug: Inactive placebo

Interventions

Phenobarbital Sodium DRUG

Single IV dose of phenobarbital (7.5 mg per kg of body weight prepared in 250 ml D5W)

Also known as: Symptom-triggered benzodiazepines (e.g., Valium)

Phenobarbital

Inactive placebo DRUG

Single dose of inactive placebo prepared in 250 ml D5W).

Also known as: Symptom triggered benzodiazepines (e.g., Valium)

Placebo

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Alcohol withdrawal syndrome (regardless of admitting diagnosis).
• Severe symptoms, as defined by a 'Clinical Institute for Withdrawal Assessment Adult revised' (CIWA-Ar) score of 16 or more, or delirium severe enough to prohibit assessment with the CIWA-Ar, or observed withdrawal seizures, in each case despite treatment with at least 60 mg of diazepam (or an equivalent dose of another benzodiazepine) in the previous 16 hours, regardless of route of administration..
• Early alcohol withdrawal, broadly defined as the first 16 hours after the diagnosis of acute alcohol withdrawal has been made. The time of diagnosis will be taken to be the time of prescription of symptom-triggered benzodiazepine therapy ("CIWA protocol"), or the time of consultation to ICU/Emergency Department, Internal Medicine, or the Addictions Service (Psychiatry) for the management of alcohol withdrawal.
• Anticipated need for hospitalization (i.e. admission to ICU, medical step-up unit, or wards).

You may not qualify if:

• an alternate etiology for delirium thought to be more likely than alcohol withdrawal;
• age \<16 years;
• pregnancy (positive assay for ßhCG). A urine assay or blood test will be performed for all women \< 55 yrs;
• current breastfeeding;
• severe acute hepatitis (AST or ALT \>500); liver failure (INR \>2 not otherwise explained);
• a presenting complaint of neurotrauma, brain mass, or intra-cranial bleed; abnormal cell count or gram stain on lumbar puncture (if performed);
• strong clinical suspicion of recent co-ingestion of depressant drugs (e.g. opioids, toxic alcohols, gamma-hydroxy-butyrate);
• hemodynamic instability (systolic blood pressure \[SBP\] \< 90 mmHg);
• history of barbiturate allergy;
• history of porphyria;
• history of myasthenia gravis;
• inability to obtain IV access;
• anticipated transfer to another centre;
• stated intent to leave against medical advice;
• active outpatient prescription for anti-retroviral therapy for HIV

Sponsors & Collaborators

• Unity Health Toronto: lead

Study Sites (1)

St. Michael's Hospital

Toronto, Ontario, M5B 1W8, Canada

Location

Related Publications (1)

• Filewod N, Hwang S, Turner CJ, Rizvi L, Gray S, Klaiman M, Buell D, Ailon J, Caudarella A, Ginocchio GF, Santos M, Sandhu G, Dewhurst N, Sequeira K, Burns KEA. Phenobarbital for the management of severe acute alcohol withdrawal (the PHENOMANAL trial): a pilot randomized controlled trial. Pilot Feasibility Stud. 2022 Jan 22;8(1):14. doi: 10.1186/s40814-021-00963-4.

  PMID: 35065662 DERIVED

MeSH Terms

Conditions

Alcohol Withdrawal Delirium; Alcohol Withdrawal Seizures

Interventions

Phenobarbital; Diazepam

Condition Hierarchy (Ancestors)

Alcohol-Induced Disorders, Nervous System; Neurotoxicity Syndromes; Nervous System Diseases; Poisoning; Chemically-Induced Disorders; Alcohol-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Substance Withdrawal Syndrome; Mental Disorders; Seizures; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Barbiturates; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzodiazepinones; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Karen Burns

  Unity Health Toronto

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: To conceal allocation, central randomization will be conducted by the Pharmacy Department of Unity Health Toronto - St. Michael's Hospital using a list of random treatment assignments created on www.randomize.net.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: As soon as possible after randomization, patients will receive either a single IV dose of phenobarbital (7.5 mg per kg of ideal body weight, prepared in 250 ml D5W; n=26) or placebo (250 ml D5W; n=13)

Study Record Dates

• First Submitted: June 21, 2018
• First Posted: July 13, 2018
• Study Start: June 11, 2021
• Primary Completion: July 17, 2023
• Study Completion: July 17, 2023
• Last Updated: November 2, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)