Assessment of Valproate on Ethanol Withdrawal (PAVE)

July 27, 2017 updated by: Audis Bethea, Pharm.D., CAMC Health System

Prospective Assessment of Valproate on Ethanol Withdrawal

Alcohol use disorder, or heavy drinking, is commonly seen in patients who present to trauma centers. These patients are at risk for Alcohol Withdrawal Syndrome (AWS), which is collection of symptoms that can range from anxiety and restlessness to seizures, delirium and even death. The Clinical Institute Withdrawal Assessment (CIWA) tool is routinely used to assess alcohol withdrawal symptoms. Benzodiazepines (BZD) are commonly administered to trauma patients who exhibit symptoms of AWS based on the CIWA scoring system. Although these medications have proven efficacy, they can also have negative side effects which may affect recovery. Valprate (VPA) is a medication which may have efficacy in management of AWS symptoms, thus ameliorating or preventing the need for BZD administration. This trial will study the effectiveness of VPA in the prevention of AWS symptoms by comparing the amount of BZD use in trauma patients who receive BZD treatment as indicated by CIWA scores with patients who receive prophylactic VPA therapy in addition to BZD as indicated by CIWA scores.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Alcohol use disorder is a common comorbidity among trauma patients. This pre-existing condition is associated with Alcohol Withdrawal Syndrome (AWS) and frequently complicates the management of this patient population. Current treatment and/or prevention of AWS includes the administration of sedatives (benzodiazepines [BZD]) in response to the manifestation AWS symptoms. This manifestation is indicated by monitoring patients using the Clinical Institute Withdrawal Assessment (CIWA) tool. Benzodiazepines elicit an effect on AWS via mediation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Benzodiazepines, however, have the potential to promote multiple negative effects in the acute care setting, including increased incidence of delirium, hospital stay, mortality, and the potential for decreased long-term cognitive function. The antiepileptic medication valproate (VPA) also has GABA activity in the brain, but may be less likely to promote the negative effects associated with BZDs. Currently, previous experience with this agent for the prevention of AWS is limited to two small studies. In these studies VPA was shown to decrease symptoms of AWS as indicated by patients' CIWA scores. Therefore, VPA could serve as an efficacious adjuvant therapy for the prevention of AWS. The aim of this study is to determine whether VPA will decrease the use of BZD in patients who are receiving symptom-based preventative therapy via CIWA monitoring. The hypothesis is that VPA will decrease the utilization of symptom-based lorazepam administration in patients who are determined to be at risk of alcohol withdrawal due to routine consumption of alcohol.

The purpose of this study is to determine if prophylactic VPA for the prevention of alcohol withdrawal syndrome can decrease symptom-triggered use of benzodiazepines in patients monitored for alcohol withdrawal syndrome with the CIWA.

The Primary objective of this study is to determine if prophylactic VPA acid is associated with decreased lorazepam use in patients monitored for alcohol withdrawal syndrome with the CIWA.

Secondary objectives are:

To evaluate the difference between comparator arms with respect to:

  • CIWA scores between patients with and without VPA prophylaxis
  • Hospital and Intensive Care Unit (ICU) length of stay
  • In-hospital mortality
  • VPA acid associated side effects (e.g. thrombocytopenia, transaminitis, pancreatitis)

This will be single-center prospective, randomized study, enrolling trauma patients with a history of alcohol consumption admitted to a Level 1 trauma center. Patients included in this study will receive standard therapies for AWS practiced at study institution which include monitoring of withdrawal symptoms and the administration of BZDs (lorazepam) based on CIWA monitoring.

Following informed consent, patients will be randomized to receive CIWA protocol monitoring/BZD or CIWA protocol monitoring/BZD and VPA. Therefore, patients that meet the inclusion criteria will be separated into two study groups to compare outcomes:

  1. Treatment Group: Patients treated with CIWA protocol/BZD and VPA
  2. Control Group: Patients treated with CIWA protocol/BZD only.

Study Type

Interventional

Enrollment (Anticipated)

210

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • West Virginia
      • Charleston, West Virginia, United States, 25304
        • Recruiting
        • Charleston Area Medical Center
        • Sub-Investigator:
          • Richard Umstot, MD
        • Sub-Investigator:
          • Chelsea Knotts, MD
        • Sub-Investigator:
          • Brent Stover, MA, LPC, ADC
        • Sub-Investigator:
          • Damayanti Samanta, MS
        • Sub-Investigator:
          • Julton Tomanguillo Chumbe, MD
      • Charleston, West Virginia, United States, 25301
        • Recruiting
        • Charleston Area Medical Center, General Hospital, Level 1 Trauma Center
        • Sub-Investigator:
          • Richard Umstot, MD
        • Sub-Investigator:
          • Chelsea Knotts, MD
        • Sub-Investigator:
          • Brent Stover, MA, LPC, ADC
        • Sub-Investigator:
          • Damayanti Samanta, MS
        • Sub-Investigator:
          • Julton Tomanguillo Chumbe, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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:

  • Admission to Trauma Services

  • Heavy drinkers based on social history

    • Men <65 years: > 4 drinks per day or 14 per week
    • Women: > 3 drinks per day or 7 drinks per week
    • All adults >65 years: > 3 drinks per day or 7 drinks per week

  • Moderate or severe alcohol use disorder based on social history and DSM-5 criteria

    • Moderate: Presence of 4-5 symptoms based on social history
    • Severe: Presence of 6 symptoms based on social history

Exclusion Criteria:

  • Intubated patients
  • Glasgow Coma Score <8
  • Grade IV liver laceration or greater
  • Child-Pugh Class B or greater, history of cirrhosis, or cirrhosis identified by radiographic imaging upon admission
  • Transaminase (AST/ALT) elevation of ≥ 2x normal
  • Anticipated admission less than 72 hours
  • Levetiracetam administration for seizure prophylaxis secondary to a traumatic brain injury
  • Patient with VPA as home medication
  • Known allergy to VPA
  • Patients with pre-existing blood dyscrasias, i.e. thrombocytopenia (platelet count < 50,000, etc)
  • Inability to obtain social history from patient, surrogate, family member or an individual deemed to be knowledgeable about the patient's social history
  • Pregnancy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: CIWA Protocol/BZD and Valproate

  1. Interventions to decrease symptoms of AWS will be made based on the CIWA tool.

    • CIWA Score 9-14: 1 mg IV push lorazepam
    • CIWA Score >15: 2 mg IV push lorazepam
  2. Patients who have a known history of alcohol withdrawal seizures or who have received greater than 4 mg IV lorazepam per CIWA protocol will be placed on a scheduled lorazepam regimen, 1 mg every 6 hours. The primary managing service may increase the scheduled lorazepam regimen above 1mg every 6 hours if needed to control withdrawal symptoms. Scheduled lorazepam will be discontinued or de-escalated following a 24-hour period in which no additional lorazepam was received per CIWA protocol.
  3. The treatment group will also receive scheduled valproate (VPA), 15 mg/kg divided over 4 doses, rounded up to the nearest increment of 50mg (i.e. a 70 kg person would be administered 300 mg IV VPA every 6 hours) for 96 hours.
Drug: Valproate
Valproate is an anti-epileptic medication that can influence the chemical changes in the brain that result from alcohol withdrawal syndrome (AWS) via three mechanisms of action: (1) an increase in GABA activity, (2) inhibition of glutamate binding to NMDA, and (3) restoration of the balance between dopamine and acetylcholine activity. VPA may be effective in the prevention of AWS, and could serve as efficacious adjuvant to traditional benzodiazepine (BZD) therapy for AWS, both decreasing symptoms of AWS and decreasing the use of BZDs.
Drug: Lorazepam
Lorazepam is a benzodiazepine used to treat symptoms of AWS. Standard of care at CAMC is monitoring by CIWA tool and administration of lorazepam according to CIWA score.
Active Comparator: CIWA Protocol Only

  1. Interventions to decrease symptoms of AWS will be made based on the CIWA tool

    • CIWA Score 9-14: 1 mg IV push lorazepam
    • CIWA Score >15: 2 mg IV push lorazepam
  2. Patients who have a known history of alcohol withdrawal seizures or who have received greater than 4 mg IV lorazepam per CIWA protocol will be placed on a scheduled lorazepam regimen, 1 mg every 6 hours. The primary managing service may increase the scheduled lorazepam regimen above 1mg every 6 hours if needed to control withdrawal symptoms. Scheduled lorazepam will be discontinued or de-escalated following a 24-hour period in which no additional lorazepam was received per CIWA protocol.
Drug: Lorazepam
Lorazepam is a benzodiazepine used to treat symptoms of AWS. Standard of care at CAMC is monitoring by CIWA tool and administration of lorazepam according to CIWA score.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Lorazepam use in patient monitored with CIWA
Time Frame: Time between CIWA initiation and discontinuation for up to 3 weeks
Amount of lorazepam administration in response to CIWA score
Time between CIWA initiation and discontinuation for up to 3 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
CIWA score
Time Frame: During patient hospital stay for up to 6 months
CIWA is a ten item scale used in the assessment and management of alcohol withdrawal.
During patient hospital stay for up to 6 months
Hospital Length of Stay
Time Frame: During patient hospital stay for up to 6 months
Date of admission to date of discharge from the hospital
During patient hospital stay for up to 6 months
Intensive Care Unit Length of Stay
Time Frame: During patient Intensive Care Unit stay for up to 6 months
Date of admission to date of discharge from the Intensive Care Unit
During patient Intensive Care Unit stay for up to 6 months
In-hospital Mortality
Time Frame: During patient hospital stay for up to 6 months
Number of deaths
During patient hospital stay for up to 6 months
Valproate associated side effects
Time Frame: During patient hospital stay for up to 6 months
Known side effects associated with valproate use, such as thrombocytopenia, transaminitis, pancreatitis, and hyperammonemia
During patient hospital stay for up to 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

CAMC Health System

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 11, 2017

Primary Completion (Anticipated)

July 11, 2019

Study Completion (Anticipated)

January 1, 2020

Study Registration Dates

First Submitted

July 14, 2017

First Submitted That Met QC Criteria

July 27, 2017

First Posted (Actual)

August 1, 2017

Study Record Updates

Last Update Posted (Actual)

August 1, 2017

Last Update Submitted That Met QC Criteria

July 27, 2017

Last Verified

July 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 17-336

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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