Assessment of Valproate on Ethanol Withdrawal

Alcohol Use Disorder Clinical Trial

— PAVE  

Official title:

Prospective Assessment of Valproate on Ethanol Withdrawal

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03235531
• Other study ID #: 17-336
• Status: Recruiting
• Phase: Phase 4
• First received: July 14, 2017
• Last updated: July 27, 2017
• Start date: July 11, 2017
• Est. completion date: January 1, 2020

Study information

• Verified date: July 2017
• Source: CAMC Health System
• Contact: Audis Bethea, PharmD, BCPS
• Phone: 304-388-6260
• Email: audis.bethea[@]camc.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 210
• Est. completion date: January 1, 2020
• Est. primary completion date: July 11, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Alcohol Dependence
• Alcohol Drinking
• Alcohol Use Disorder
• Alcohol Withdrawal Syndrome
• Alcoholism
• Heavy Drinking
• Substance Withdrawal Syndrome
• Trauma

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Charleston Area Medical Center	Charleston	West Virginia
United States	Charleston Area Medical Center, General Hospital, Level 1 Trauma Center	Charleston	West Virginia

Sponsors (1)

Lead Sponsor	Collaborator
CAMC Health System

Country where clinical trial is conducted

United States, 

References & Publications (18)

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Craft PP, Foil MB, Cunningham PR, Patselas PC, Long-Snyder BM, Collier MS. Intravenous ethanol for alcohol detoxification in trauma patients. South Med J. 1994 Jan;87(1):47-54. — View Citation

Eastes LE. Alcohol withdrawal syndrome in trauma patients: a review. J Emerg Nurs. 2010 Sep;36(5):507-9. doi: 10.1016/j.jen.2010.05.011. Epub 2010 Aug 5. Review. — View Citation

Eyer F, Schreckenberg M, Hecht D, Adorjan K, Schuster T, Felgenhauer N, Pfab R, Strubel T, Zilker T. Carbamazepine and valproate as adjuncts in the treatment of alcohol withdrawal syndrome: a retrospective cohort study. Alcohol Alcohol. 2011 Mar-Apr;46(2):177-84. doi: 10.1093/alcalc/agr005. — View Citation

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Girard TD, Pandharipande PP, Ely EW. Delirium in the intensive care unit. Crit Care. 2008;12 Suppl 3:S3. doi: 10.1186/cc6149. Epub 2008 May 14. Review. — View Citation

Kosten TR, O'Connor PG. Management of drug and alcohol withdrawal. N Engl J Med. 2003 May 1;348(18):1786-95. Review. — View Citation

Lum E, Gorman SK, Slavik RS. Valproic acid management of acute alcohol withdrawal. Ann Pharmacother. 2006 Mar;40(3):441-8. Epub 2006 Feb 28. Review. — View Citation

Makic MB. Alcohol Withdrawal Syndrome. J Perianesth Nurs. 2017 Apr;32(2):140-141. doi: 10.1016/j.jopan.2017.01.007. — View Citation

Maldonado JR. Delirium in the acute care setting: characteristics, diagnosis and treatment. Crit Care Clin. 2008 Oct;24(4):657-722, vii. doi: 10.1016/j.ccc.2008.05.008. Review. — View Citation

McKeon A, Frye MA, Delanty N. The alcohol withdrawal syndrome. J Neurol Neurosurg Psychiatry. 2008 Aug;79(8):854-62. Epub 2007 Nov 6. Review. — View Citation

Reoux JP, Saxon AJ, Malte CA, Baer JS, Sloan KL. Divalproex sodium in alcohol withdrawal: a randomized double-blind placebo-controlled clinical trial. Alcohol Clin Exp Res. 2001 Sep;25(9):1324-9. — View Citation

Saitz R, Mayo-Smith MF, Roberts MS, Redmond HA, Bernard DR, Calkins DR. Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial. JAMA. 1994 Aug 17;272(7):519-23. — View Citation

Sher Y, Miller Cramer AC, Ament A, Lolak S, Maldonado JR. Valproic Acid for Treatment of Hyperactive or Mixed Delirium: Rationale and Literature Review. Psychosomatics. 2015 Nov-Dec;56(6):615-25. doi: 10.1016/j.psym.2015.09.008. Epub 2015 Oct 3. Review. — View Citation

Spies C, Tønnesen H, Andreasson S, Helander A, Conigrave K. Perioperative morbidity and mortality in chronic alcoholic patients. Alcohol Clin Exp Res. 2001 May;25(5 Suppl ISBRA):164S-170S. Review. — View Citation

Tsai G, Coyle JT. The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. Annu Rev Med. 1998;49:173-84. Review. — View Citation

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* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Lorazepam use in patient monitored with CIWA	Amount of lorazepam administration in response to CIWA score	Time between CIWA initiation and discontinuation for up to 3 weeks
Secondary	CIWA score	CIWA is a ten item scale used in the assessment and management of alcohol withdrawal.	During patient hospital stay for up to 6 months
Secondary	Hospital Length of Stay	Date of admission to date of discharge from the hospital	During patient hospital stay for up to 6 months
Secondary	Intensive Care Unit Length of Stay	Date of admission to date of discharge from the Intensive Care Unit	During patient Intensive Care Unit stay for up to 6 months
Secondary	In-hospital Mortality	Number of deaths	During patient hospital stay for up to 6 months
Secondary	Valproate associated side effects	Known side effects associated with valproate use, such as thrombocytopenia, transaminitis, pancreatitis, and hyperammonemia	During patient hospital stay for up to 6 months