PAVE: Assessment of Valproate on Ethanol Withdrawal

Sponsor

CAMC Health System (Other)

Overall Status

Unknown status

CT.gov ID

NCT03235531

Collaborator

(none)

210

Enrollment

Locations

Arms

29.7

Anticipated Duration (Months)

105

Patients Per Site

3.5

Patients Per Site Per Month

Study Details

Study Description

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:

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

Study Design

Study Type:

Interventional

Anticipated 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 :

Jul 11, 2017

Anticipated Primary Completion Date :

Jul 11, 2019

Anticipated Study Completion Date :

Jan 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CIWA Protocol/BZD and Valproate 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 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. 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 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 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.

Arm

Intervention/Treatment

Experimental: CIWA Protocol/BZD and Valproate

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 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. 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

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 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.

Outcome Measures

Primary Outcome Measures

Lorazepam use in patient monitored with CIWA [Time between CIWA initiation and discontinuation for up to 3 weeks]
Amount of lorazepam administration in response to CIWA score

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Charleston Area Medical Center, General Hospital, Level 1 Trauma Center	Charleston	West Virginia	United States	25301
2	Charleston Area Medical Center	Charleston	West Virginia	United States	25304