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Assessment of Valproate on Ethanol Withdrawal (PAVE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03235531
Recruitment Status : Unknown
Verified July 2017 by Audis Bethea, Pharm.D., CAMC Health System.
Recruitment status was:  Recruiting
First Posted : August 1, 2017
Last Update Posted : August 1, 2017
Sponsor:
Information provided by (Responsible Party):
Audis Bethea, Pharm.D., CAMC Health System

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Alcohol Dependence Alcohol Withdrawal Syndrome Trauma Heavy Drinking Alcohol Use Disorder Drug: Valproate Drug: Lorazepam Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Prospective Assessment of Valproate on Ethanol Withdrawal
Actual Study Start Date : July 11, 2017
Estimated Primary Completion Date : July 11, 2019
Estimated Study Completion Date : January 1, 2020

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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.

  2. 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

  3. 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

  4. In-hospital Mortality [ Time Frame: During patient hospital stay for up to 6 months ]
    Number of deaths

  5. 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03235531


Contacts
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Contact: Audis Bethea, PharmD, BCPS 304-388-6260 audis.bethea@camc.org

Locations
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United States, West Virginia
Charleston Area Medical Center, General Hospital, Level 1 Trauma Center Recruiting
Charleston, West Virginia, United States, 25301
Contact: Audis Bethea, PharmD, BCPS    304-388-3653    audis.bethea@camc.org   
Principal Investigator: Audis Bethea, PharmD, BCPS         
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 Area Medical Center Recruiting
Charleston, West Virginia, United States, 25304
Contact: Audis Bethea, PharmD, BCPS    304-388-3653    audis.bethea@camc.org   
Principal Investigator: Audis Bethea, PharmD, BCPS         
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         
Sponsors and Collaborators
CAMC Health System
Investigators
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Principal Investigator: Audis Bethea, PharmD, BCPS Charleston Area Medical Center Health System
Publications:

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Responsible Party: Audis Bethea, Pharm.D., Clinical Pharmacy Specialist, Clinical Research Scientist, CAMC Health System
ClinicalTrials.gov Identifier: NCT03235531    
Other Study ID Numbers: 17-336
First Posted: August 1, 2017    Key Record Dates
Last Update Posted: August 1, 2017
Last Verified: July 2017

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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
Keywords provided by Audis Bethea, Pharm.D., CAMC Health System:
alcohol withdrawal syndrome
trauma
alcohol use disorder
alcohol
lorazepam
benzodiazepine
valproate
Additional relevant MeSH terms:
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Alcoholism
Substance Withdrawal Syndrome
Alcohol Drinking
Drinking Behavior
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Valproic Acid
Lorazepam
Anticonvulsants
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Hypnotics and Sedatives
Anti-Anxiety Agents
GABA Modulators