<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03235531</url>
  </required_header>
  <id_info>
    <org_study_id>17-336</org_study_id>
    <nct_id>NCT03235531</nct_id>
  </id_info>
  <brief_title>Assessment of Valproate on Ethanol Withdrawal</brief_title>
  <acronym>PAVE</acronym>
  <official_title>Prospective Assessment of Valproate on Ethanol Withdrawal</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>CAMC Health System</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>CAMC Health System</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Alcohol use disorder, or heavy drinking, is commonly seen in patients who present to trauma&#xD;
      centers. These patients are at risk for Alcohol Withdrawal Syndrome (AWS), which is&#xD;
      collection of symptoms that can range from anxiety and restlessness to seizures, delirium and&#xD;
      even death. The Clinical Institute Withdrawal Assessment (CIWA) tool is routinely used to&#xD;
      assess alcohol withdrawal symptoms. Benzodiazepines (BZD) are commonly administered to trauma&#xD;
      patients who exhibit symptoms of AWS based on the CIWA scoring system. Although these&#xD;
      medications have proven efficacy, they can also have negative side effects which may affect&#xD;
      recovery. Valprate (VPA) is a medication which may have efficacy in management of AWS&#xD;
      symptoms, thus ameliorating or preventing the need for BZD administration. This trial will&#xD;
      study the effectiveness of VPA in the prevention of AWS symptoms by comparing the amount of&#xD;
      BZD use in trauma patients who receive BZD treatment as indicated by CIWA scores with&#xD;
      patients who receive prophylactic VPA therapy in addition to BZD as indicated by CIWA scores.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Alcohol use disorder is a common comorbidity among trauma patients. This pre-existing&#xD;
      condition is associated with Alcohol Withdrawal Syndrome (AWS) and frequently complicates the&#xD;
      management of this patient population. Current treatment and/or prevention of AWS includes&#xD;
      the administration of sedatives (benzodiazepines [BZD]) in response to the manifestation AWS&#xD;
      symptoms. This manifestation is indicated by monitoring patients using the Clinical Institute&#xD;
      Withdrawal Assessment (CIWA) tool. Benzodiazepines elicit an effect on AWS via mediation of&#xD;
      the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Benzodiazepines, however,&#xD;
      have the potential to promote multiple negative effects in the acute care setting, including&#xD;
      increased incidence of delirium, hospital stay, mortality, and the potential for decreased&#xD;
      long-term cognitive function. The antiepileptic medication valproate (VPA) also has GABA&#xD;
      activity in the brain, but may be less likely to promote the negative effects associated with&#xD;
      BZDs. Currently, previous experience with this agent for the prevention of AWS is limited to&#xD;
      two small studies. In these studies VPA was shown to decrease symptoms of AWS as indicated by&#xD;
      patients' CIWA scores. Therefore, VPA could serve as an efficacious adjuvant therapy for the&#xD;
      prevention of AWS. The aim of this study is to determine whether VPA will decrease the use of&#xD;
      BZD in patients who are receiving symptom-based preventative therapy via CIWA monitoring. The&#xD;
      hypothesis is that VPA will decrease the utilization of symptom-based lorazepam&#xD;
      administration in patients who are determined to be at risk of alcohol withdrawal due to&#xD;
      routine consumption of alcohol.&#xD;
&#xD;
      The purpose of this study is to determine if prophylactic VPA for the prevention of alcohol&#xD;
      withdrawal syndrome can decrease symptom-triggered use of benzodiazepines in patients&#xD;
      monitored for alcohol withdrawal syndrome with the CIWA.&#xD;
&#xD;
      The Primary objective of this study is to determine if prophylactic VPA acid is associated&#xD;
      with decreased lorazepam use in patients monitored for alcohol withdrawal syndrome with the&#xD;
      CIWA.&#xD;
&#xD;
      Secondary objectives are:&#xD;
&#xD;
      To evaluate the difference between comparator arms with respect to:&#xD;
&#xD;
        -  CIWA scores between patients with and without VPA prophylaxis&#xD;
&#xD;
        -  Hospital and Intensive Care Unit (ICU) length of stay&#xD;
&#xD;
        -  In-hospital mortality&#xD;
&#xD;
        -  VPA acid associated side effects (e.g. thrombocytopenia, transaminitis, pancreatitis)&#xD;
&#xD;
      This will be single-center prospective, randomized study, enrolling trauma patients with a&#xD;
      history of alcohol consumption admitted to a Level 1 trauma center. Patients included in this&#xD;
      study will receive standard therapies for AWS practiced at study institution which include&#xD;
      monitoring of withdrawal symptoms and the administration of BZDs (lorazepam) based on CIWA&#xD;
      monitoring.&#xD;
&#xD;
      Following informed consent, patients will be randomized to receive CIWA protocol&#xD;
      monitoring/BZD or CIWA protocol monitoring/BZD and VPA. Therefore, patients that meet the&#xD;
      inclusion criteria will be separated into two study groups to compare outcomes:&#xD;
&#xD;
        1. Treatment Group: Patients treated with CIWA protocol/BZD and VPA&#xD;
&#xD;
        2. Control Group: Patients treated with CIWA protocol/BZD only.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">July 11, 2017</start_date>
  <completion_date type="Anticipated">January 1, 2020</completion_date>
  <primary_completion_date type="Anticipated">July 11, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Lorazepam use in patient monitored with CIWA</measure>
    <time_frame>Time between CIWA initiation and discontinuation for up to 3 weeks</time_frame>
    <description>Amount of lorazepam administration in response to CIWA score</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>CIWA score</measure>
    <time_frame>During patient hospital stay for up to 6 months</time_frame>
    <description>CIWA is a ten item scale used in the assessment and management of alcohol withdrawal.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital Length of Stay</measure>
    <time_frame>During patient hospital stay for up to 6 months</time_frame>
    <description>Date of admission to date of discharge from the hospital</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intensive Care Unit Length of Stay</measure>
    <time_frame>During patient Intensive Care Unit stay for up to 6 months</time_frame>
    <description>Date of admission to date of discharge from the Intensive Care Unit</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>In-hospital Mortality</measure>
    <time_frame>During patient hospital stay for up to 6 months</time_frame>
    <description>Number of deaths</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Valproate associated side effects</measure>
    <time_frame>During patient hospital stay for up to 6 months</time_frame>
    <description>Known side effects associated with valproate use, such as thrombocytopenia, transaminitis, pancreatitis, and hyperammonemia</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">210</enrollment>
  <condition>Alcohol Dependence</condition>
  <condition>Alcohol Withdrawal Syndrome</condition>
  <condition>Trauma</condition>
  <condition>Heavy Drinking</condition>
  <condition>Alcohol Use Disorder</condition>
  <arm_group>
    <arm_group_label>CIWA Protocol/BZD and Valproate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Interventions to decrease symptoms of AWS will be made based on the CIWA tool.&#xD;
CIWA Score 9-14: 1 mg IV push lorazepam&#xD;
CIWA Score &gt;15: 2 mg IV push lorazepam&#xD;
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.&#xD;
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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CIWA Protocol Only</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Interventions to decrease symptoms of AWS will be made based on the CIWA tool&#xD;
CIWA Score 9-14: 1 mg IV push lorazepam&#xD;
CIWA Score &gt;15: 2 mg IV push lorazepam&#xD;
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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Valproate</intervention_name>
    <description>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.</description>
    <arm_group_label>CIWA Protocol/BZD and Valproate</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lorazepam</intervention_name>
    <description>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.</description>
    <arm_group_label>CIWA Protocol Only</arm_group_label>
    <arm_group_label>CIWA Protocol/BZD and Valproate</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Admission to Trauma Services&#xD;
&#xD;
          -  Heavy drinkers based on social history&#xD;
&#xD;
               -  Men &lt;65 years: &gt; 4 drinks per day or 14 per week&#xD;
&#xD;
               -  Women: &gt; 3 drinks per day or 7 drinks per week&#xD;
&#xD;
               -  All adults &gt;65 years: &gt; 3 drinks per day or 7 drinks per week&#xD;
&#xD;
          -  Moderate or severe alcohol use disorder based on social history and DSM-5 criteria&#xD;
&#xD;
               -  Moderate: Presence of 4-5 symptoms based on social history&#xD;
&#xD;
               -  Severe: Presence of 6 symptoms based on social history&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Intubated patients&#xD;
&#xD;
          -  Glasgow Coma Score &lt;8&#xD;
&#xD;
          -  Grade IV liver laceration or greater&#xD;
&#xD;
          -  Child-Pugh Class B or greater, history of cirrhosis, or cirrhosis identified by&#xD;
             radiographic imaging upon admission&#xD;
&#xD;
          -  Transaminase (AST/ALT) elevation of ≥ 2x normal&#xD;
&#xD;
          -  Anticipated admission less than 72 hours&#xD;
&#xD;
          -  Levetiracetam administration for seizure prophylaxis secondary to a traumatic brain&#xD;
             injury&#xD;
&#xD;
          -  Patient with VPA as home medication&#xD;
&#xD;
          -  Known allergy to VPA&#xD;
&#xD;
          -  Patients with pre-existing blood dyscrasias, i.e. thrombocytopenia (platelet count &lt;&#xD;
             50,000, etc)&#xD;
&#xD;
          -  Inability to obtain social history from patient, surrogate, family member or an&#xD;
             individual deemed to be knowledgeable about the patient's social history&#xD;
&#xD;
          -  Pregnancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Audis Bethea, PharmD, BCPS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Charleston Area Medical Center Health System</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Audis Bethea, PharmD, BCPS</last_name>
    <phone>304-388-6260</phone>
    <email>audis.bethea@camc.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>Charleston Area Medical Center, General Hospital, Level 1 Trauma Center</name>
      <address>
        <city>Charleston</city>
        <state>West Virginia</state>
        <zip>25301</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Audis Bethea, PharmD, BCPS</last_name>
      <phone>304-388-3653</phone>
      <email>audis.bethea@camc.org</email>
    </contact>
    <investigator>
      <last_name>Audis Bethea, PharmD, BCPS</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Richard Umstot, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Chelsea Knotts, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Brent Stover, MA, LPC, ADC</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Damayanti Samanta, MS</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Julton Tomanguillo Chumbe, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Charleston Area Medical Center</name>
      <address>
        <city>Charleston</city>
        <state>West Virginia</state>
        <zip>25304</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Audis Bethea, PharmD, BCPS</last_name>
      <phone>304-388-3653</phone>
      <email>audis.bethea@camc.org</email>
    </contact>
    <investigator>
      <last_name>Audis Bethea, PharmD, BCPS</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Richard Umstot, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Chelsea Knotts, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Brent Stover, MA, LPC, ADC</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Damayanti Samanta, MS</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Julton Tomanguillo Chumbe, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <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. No abstract available.</citation>
    <PMID>20837230</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>8284718</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>28343640</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>16203295</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>11391067</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>7864257</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>9509257</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>17986499</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>21678378</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>12724485</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>18929939</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>21068014</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>18495054</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>8046805</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>21339186</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>11584152</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>16507623</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>26674479</PMID>
  </reference>
  <verification_date>July 2017</verification_date>
  <study_first_submitted>July 14, 2017</study_first_submitted>
  <study_first_submitted_qc>July 27, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 1, 2017</study_first_posted>
  <last_update_submitted>July 27, 2017</last_update_submitted>
  <last_update_submitted_qc>July 27, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 1, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>CAMC Health System</investigator_affiliation>
    <investigator_full_name>Audis Bethea, Pharm.D.</investigator_full_name>
    <investigator_title>Clinical Pharmacy Specialist, Clinical Research Scientist</investigator_title>
  </responsible_party>
  <keyword>alcohol withdrawal syndrome</keyword>
  <keyword>trauma</keyword>
  <keyword>alcohol use disorder</keyword>
  <keyword>alcohol</keyword>
  <keyword>lorazepam</keyword>
  <keyword>benzodiazepine</keyword>
  <keyword>valproate</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alcoholism</mesh_term>
    <mesh_term>Substance Withdrawal Syndrome</mesh_term>
    <mesh_term>Alcohol Drinking</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Valproic Acid</mesh_term>
    <mesh_term>Lorazepam</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03235531
org study id: 17-336
nct id: NCT03235531
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Lorazepam use in patient monitored with CIWA
time frame: Time between CIWA initiation and discontinuation for up to 3 weeks
description: Amount of lorazepam administration in response to CIWA score
measure: CIWA score
time frame: During patient hospital stay for up to 6 months
description: CIWA is a ten item scale used in the assessment and management of alcohol withdrawal.
measure: Hospital Length of Stay
time frame: During patient hospital stay for up to 6 months
description: Date of admission to date of discharge from the hospital
measure: Intensive Care Unit Length of Stay
time frame: During patient Intensive Care Unit stay for up to 6 months
description: Date of admission to date of discharge from the Intensive Care Unit
measure: In-hospital Mortality
time frame: During patient hospital stay for up to 6 months
description: Number of deaths
measure: Valproate associated side effects
time frame: During patient hospital stay for up to 6 months
description: Known side effects associated with valproate use, such as thrombocytopenia, transaminitis, pancreatitis, and hyperammonemia
arm group label: CIWA Protocol/BZD and Valproate
arm group type: Experimental
description: 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.
arm group label: CIWA Protocol Only
arm group type: Active Comparator
description: 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.
intervention type: Drug
intervention name: Valproate
description: 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.
arm group label: CIWA Protocol/BZD and Valproate
intervention type: Drug
intervention name: Lorazepam
description: 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 group label: CIWA Protocol Only
arm group label: CIWA Protocol/BZD and Valproate
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Audis Bethea, PharmD, BCPS
role: Principal Investigator
affiliation: Charleston Area Medical Center Health System
last name: Audis Bethea, PharmD, BCPS
phone: 304-388-6260
email: audis.bethea@camc.org
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
country: United States
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. No abstract available.
PMID: 20837230
citation: 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
citation: 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
citation: 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
citation: 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
citation: 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
citation: 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
citation: 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
citation: 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
citation: 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
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.
PMID: 18929939
citation: 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
citation: 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
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.
PMID: 8046805
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.
PMID: 21339186
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.
PMID: 11584152
citation: 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
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.
PMID: 26674479
responsible party type: Principal Investigator
investigator affiliation: CAMC Health System
investigator full name: Audis Bethea, Pharm.D.
investigator title: Clinical Pharmacy Specialist, Clinical Research Scientist
mesh term: Alcoholism
mesh term: Substance Withdrawal Syndrome
mesh term: Alcohol Drinking
mesh term: Valproic Acid
mesh term: Lorazepam