Assessment of Valproate on Ethanol Withdrawal

NCT03235531 | Unknown Phase 4 FDA Drug

• 1 other identifier: 17-336
• Study Type: interventional
• Target: 210
• Locations: 1 country
• Sites: 2

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.

Conditions

Alcohol Dependence; Alcohol Withdrawal Syndrome; Trauma; Heavy Drinking; Alcohol Use Disorder

Keywords

alcohol withdrawal syndrome; trauma; alcohol use disorder; alcohol; lorazepam; benzodiazepine; valproate

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• CIWA score

  During patient hospital stay for up to 6 months

• Hospital Length of Stay

  During patient hospital stay for up to 6 months

• Intensive Care Unit Length of Stay

  During patient Intensive Care Unit stay for up to 6 months

• In-hospital Mortality

  During patient hospital stay for up to 6 months

• Valproate associated side effects

  During patient hospital stay for up to 6 months

Study Arms (2)

CIWA Protocol/BZD and Valproate

EXPERIMENTAL

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; Drug: Lorazepam

CIWA Protocol Only

ACTIVE COMPARATOR

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

Interventions

Valproate DRUG

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.

CIWA Protocol/BZD and Valproate

Lorazepam DRUG

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.

CIWA Protocol Only; CIWA Protocol/BZD and Valproate

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• CAMC Health System: lead

Study Sites (2)

Charleston Area Medical Center, General Hospital, Level 1 Trauma Center

Charleston, West Virginia, 25301, United States

RECRUITING

Charleston Area Medical Center

Charleston, West Virginia, 25304, United States

RECRUITING

Related Publications (18)

• 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. No abstract available.

  PMID: 20837230 BACKGROUND

• 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. doi: 10.1097/00007611-199401000-00011.

  PMID: 8284718 BACKGROUND

• Makic MB. Alcohol Withdrawal Syndrome. J Perianesth Nurs. 2017 Apr;32(2):140-141. doi: 10.1016/j.jopan.2017.01.007. No abstract available.

  PMID: 28343640 BACKGROUND

• Foy A, Kay J. The incidence of alcohol-related problems and the risk of alcohol withdrawal in a general hospital population. Drug Alcohol Rev. 1995;14(1):49-54. doi: 10.1080/09595239500185051.

  PMID: 16203295 BACKGROUND

• Spies C, Tonnesen 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. doi: 10.1097/00000374-200105051-00028.

  PMID: 11391067 BACKGROUND

• Tsai G, Gastfriend DR, Coyle JT. The glutamatergic basis of human alcoholism. Am J Psychiatry. 1995 Mar;152(3):332-40. doi: 10.1176/ajp.152.3.332.

  PMID: 7864257 BACKGROUND

• Tsai G, Coyle JT. The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. Annu Rev Med. 1998;49:173-84. doi: 10.1146/annurev.med.49.1.173.

  PMID: 9509257 BACKGROUND

• McKeon A, Frye MA, Delanty N. The alcohol withdrawal syndrome. J Neurol Neurosurg Psychiatry. 2008 Aug;79(8):854-62. doi: 10.1136/jnnp.2007.128322. Epub 2007 Nov 6.

  PMID: 17986499 BACKGROUND

• Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome. Cochrane Database Syst Rev. 2011 Jun 15;2011(6):CD008537. doi: 10.1002/14651858.CD008537.pub2.

  PMID: 21678378 BACKGROUND

• Kosten TR, O'Connor PG. Management of drug and alcohol withdrawal. N Engl J Med. 2003 May 1;348(18):1786-95. doi: 10.1056/NEJMra020617. No abstract available.

  PMID: 12724485 BACKGROUND

• 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.

  PMID: 18929939 BACKGROUND

• Clegg A, Young JB. Which medications to avoid in people at risk of delirium: a systematic review. Age Ageing. 2011 Jan;40(1):23-9. doi: 10.1093/ageing/afq140. Epub 2010 Nov 9.

  PMID: 21068014 BACKGROUND

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

  PMID: 18495054 BACKGROUND

• 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.

  PMID: 8046805 BACKGROUND

• 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.

  PMID: 21339186 BACKGROUND

• 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.

  PMID: 11584152 BACKGROUND

• Lum E, Gorman SK, Slavik RS. Valproic acid management of acute alcohol withdrawal. Ann Pharmacother. 2006 Mar;40(3):441-8. doi: 10.1345/aph.1G243. Epub 2006 Feb 28.

  PMID: 16507623 BACKGROUND

• 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.

  PMID: 26674479 BACKGROUND

MeSH Terms

Conditions

Alcoholism; Wounds and Injuries

Interventions

Valproic Acid; Lorazepam

Condition Hierarchy (Ancestors)

Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids; Benzodiazepinones; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Audis Bethea, PharmD, BCPS

  Charleston Area Medical Center Health System

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Audis Bethea, PharmD, BCPS

CONTACT

304-388-6260; audis.bethea@camc.org

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Pharmacy Specialist, Clinical Research Scientist

Study Record Dates

• First Submitted: July 14, 2017
• First Posted: August 1, 2017
• Study Start: July 11, 2017
• Primary Completion: July 11, 2019
• Study Completion: January 1, 2020
• Last Updated: August 1, 2017

Record last verified: 2017-07

Locations

US (2)