search
Back to results

Valproate Alone or in Combination With Quetiapine for Severe COVID-19 Pneumonia With Agitated Delirium

Primary Purpose

Covid19, Hyperactive Delirium, Pneumonia, Viral

Status
Withdrawn
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
Valproate
Quetiapine
Standard of Care
Sponsored by
University of Miami
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Covid19

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Signed Informed Consent Form by his or her legal/authorized representative
  • Age ≥ 18 years at time of signing Informed Consent Form
  • Ability to comply with the study protocol, in the investigator's judgement
  • Hospitalized with COVID-19 pneumonia confirmed with World Health Organization (WHO) criteria (including an RNA test of any specimen, e.g. respiratory, blood, urine, stool, other bodily fluid) and evidence by chest X-ray or CT scan
  • Fraction of inspired oxygen (Fi02) ≤ 0.40 and positive end-expiratory pressure (PEEP) ≤8 OR Fi02 ≤ 0.50 and PEEP ≤5
  • Fi02 and PEEP ≤ values of previous day
  • Patient has acceptable spontaneous breathing efforts (may decrease vent rate by 50% for 5 minutes to detect effort.)
  • No neuromuscular blocking agents or blockade.
  • RASS score initially at -3 ≤, rising to 3+ after initial attempt to wean from standard of care sedating medications
  • Other investigational interventions may be permitted

Exclusion Criteria:

  • Known severe allergic reactions to valproate or quetiapine
  • History of hepatic encephalopathy or end-stage liver disease (Childs-Pugh class B or worse)
  • Alcohol, or history of alcohol/substance dependence prior to admission
  • Hx of dementia
  • Treatment with an antipsychotic agent in the 30 days before ICU admission
  • Baseline QT duration corrected (QTc) interval ≥ 500 msecs
  • Pregnancy
  • Suspected active bacterial, fungal, viral, or other infection (besides COVID-19)
  • In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 X upper limit of normal (ULN) detected within 24 hours at screening or at baseline
  • Absolute neutrophil count (ANC) < 1000/microliter (uL) at screening and baseline
  • Platelet count < 50,000/uL at screening and baseline
  • Individuals < 18 (infants, children, teenagers)
  • Any serious medical condition or abnormality of clinical laboratory tests that, in the investigator's judgement, precludes the patient's safe participation in and completion of the study, e.g. active seizure disorder already receiving treatment with lamotrigine
  • Informed consent could not be obtained from the legally authorized representative.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Active Comparator

    Arm Label

    Standard of Care Only Group

    Treatment Arm Group

    Arm Description

    Patients maintained with mechanical ventilation will be treated with standard of care after cessation of paralytic agents.

    Patients maintained with mechanical ventilation will be treated with standard of care, plus Valproate on Days 1-7 after cessation of paralytic agents, and then augmented by the addition of Quetiapine beginning Days 3-7 if there are no improvement in RASS score.

    Outcomes

    Primary Outcome Measures

    Change from baseline RASS score of +3 or greater
    Richmond Agitation Sedation Scale (RASS) score ranges from +4 (combative) to 0 (alert & calm) to -5 (unarousable).

    Secondary Outcome Measures

    Total dose of dexmedetomidine administered
    Total dose of dexmedetomidine administered will be reported from baseline RASS score of +3 or greater.
    Incidence of Treatment Emergent Adverse Events
    Incidence of Treatment Emergent Adverse Events will include: QTc duration > 470 msecs. Increase in Liver Function Tests to a Grade 3 or higher using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Suicidality reported as having a score of moderate or high risk using the Columbia-Suicide Severity Rating Scale Screening (C-SSRS). C-SSRS is a calculated risk assessment tool that scores suicidality from no risk to high risk.

    Full Information

    First Posted
    August 12, 2020
    Last Updated
    March 29, 2023
    Sponsor
    University of Miami
    search

    1. Study Identification

    Unique Protocol Identification Number
    NCT04513314
    Brief Title
    Valproate Alone or in Combination With Quetiapine for Severe COVID-19 Pneumonia With Agitated Delirium
    Official Title
    A Practical, Pilot, Randomized, Controlled Trial of Valproate Alone or in Combination With Quetiapine for Severe COVID-19 Pneumonia With Agitated Delirium
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    March 2023
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    coronavirus omicron variant infection typically not associated with delirium and agitation severely hampered recruitment.
    Study Start Date
    March 28, 2023 (Anticipated)
    Primary Completion Date
    March 28, 2023 (Actual)
    Study Completion Date
    March 28, 2023 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    University of Miami

    4. Oversight

    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.
    No
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    The primary purpose of this research is to determine whether Valproate alone, and in combination with Quetiapine, lowers confusion and agitation in persons with severe Corona Virus Disease (COVID)19 pneumonia during weaning from the breathing machine (ventilator). Though Valproate and Quetiapine are often given to persons with severe confusion with agitation, the purpose of this small research study is specifically for: a) persons infected with COVID 2019 on a ventilator whose agitation is not responding to the usual medications (like dexmedetomidine), and b) to reduce the time persons are treated with dexmedetomidine, which requires continuous close monitoring in an ICU.
    Detailed Description
    This is a pilot feasibility study involving a randomized, single-blind, controlled comparison scheme examining the efficacy and safety of standard of care (n=10) combined with valproate alone, and in combination with quetiapine (N=10) , in order to reduce the magnitude of agitation associated with COVID 19 delirium as assessed by the RASS scale when weaning from a ventilator, and reduce need for dexmedetomidine as assessed by number of doses of dexmedetomidine administered.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Covid19, Hyperactive Delirium, Pneumonia, Viral

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 4
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantOutcomes Assessor
    Masking Description
    study rater/outcomes assessor and participant will be ignorant of the treatment arm pharmacist and investigator will be aware of the treatment arm
    Allocation
    Randomized
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Standard of Care Only Group
    Arm Type
    Active Comparator
    Arm Description
    Patients maintained with mechanical ventilation will be treated with standard of care after cessation of paralytic agents.
    Arm Title
    Treatment Arm Group
    Arm Type
    Active Comparator
    Arm Description
    Patients maintained with mechanical ventilation will be treated with standard of care, plus Valproate on Days 1-7 after cessation of paralytic agents, and then augmented by the addition of Quetiapine beginning Days 3-7 if there are no improvement in RASS score.
    Intervention Type
    Drug
    Intervention Name(s)
    Valproate
    Other Intervention Name(s)
    Depakote, Valproic acid
    Intervention Description
    Valproate sodium (enteral or intravenous) will be administered at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day.
    Intervention Type
    Drug
    Intervention Name(s)
    Quetiapine
    Other Intervention Name(s)
    seroquel
    Intervention Description
    Enteral quetiapine dosing on Day 3: 25 mg to 50 mg twice daily. Increase in increments of 50 mg/day to 100 mg/day divided two on Days 4 and 5 to range of 50-400 mg/day by Day 7. Further adjustments can be made in increments of 25-50 mg twice a day, in intervals of not less than 2 days. Recommended dose range is 150-750 mg/day.
    Intervention Type
    Other
    Intervention Name(s)
    Standard of Care
    Other Intervention Name(s)
    Hospital Protocol
    Intervention Description
    Standard of Care is a combination of IV dexmedetomidine (D), midazolam (M), ketamine (K) and propofol (P), at the discretion of treating physician.
    Primary Outcome Measure Information:
    Title
    Change from baseline RASS score of +3 or greater
    Description
    Richmond Agitation Sedation Scale (RASS) score ranges from +4 (combative) to 0 (alert & calm) to -5 (unarousable).
    Time Frame
    Baseline, Day 7
    Secondary Outcome Measure Information:
    Title
    Total dose of dexmedetomidine administered
    Description
    Total dose of dexmedetomidine administered will be reported from baseline RASS score of +3 or greater.
    Time Frame
    Day 7
    Title
    Incidence of Treatment Emergent Adverse Events
    Description
    Incidence of Treatment Emergent Adverse Events will include: QTc duration > 470 msecs. Increase in Liver Function Tests to a Grade 3 or higher using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Suicidality reported as having a score of moderate or high risk using the Columbia-Suicide Severity Rating Scale Screening (C-SSRS). C-SSRS is a calculated risk assessment tool that scores suicidality from no risk to high risk.
    Time Frame
    Day 7

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Signed Informed Consent Form by his or her legal/authorized representative Age ≥ 18 years at time of signing Informed Consent Form Ability to comply with the study protocol, in the investigator's judgement Hospitalized with COVID-19 pneumonia confirmed with World Health Organization (WHO) criteria (including an RNA test of any specimen, e.g. respiratory, blood, urine, stool, other bodily fluid) and evidence by chest X-ray or CT scan Fraction of inspired oxygen (Fi02) ≤ 0.40 and positive end-expiratory pressure (PEEP) ≤8 OR Fi02 ≤ 0.50 and PEEP ≤5 Fi02 and PEEP ≤ values of previous day Patient has acceptable spontaneous breathing efforts (may decrease vent rate by 50% for 5 minutes to detect effort.) No neuromuscular blocking agents or blockade. RASS score initially at -3 ≤, rising to 3+ after initial attempt to wean from standard of care sedating medications Other investigational interventions may be permitted Exclusion Criteria: Known severe allergic reactions to valproate or quetiapine History of hepatic encephalopathy or end-stage liver disease (Childs-Pugh class B or worse) Alcohol, or history of alcohol/substance dependence prior to admission Hx of dementia Treatment with an antipsychotic agent in the 30 days before ICU admission Baseline QT duration corrected (QTc) interval ≥ 500 msecs Pregnancy Suspected active bacterial, fungal, viral, or other infection (besides COVID-19) In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 X upper limit of normal (ULN) detected within 24 hours at screening or at baseline Absolute neutrophil count (ANC) < 1000/microliter (uL) at screening and baseline Platelet count < 50,000/uL at screening and baseline Individuals < 18 (infants, children, teenagers) Any serious medical condition or abnormality of clinical laboratory tests that, in the investigator's judgement, precludes the patient's safe participation in and completion of the study, e.g. active seizure disorder already receiving treatment with lamotrigine Informed consent could not be obtained from the legally authorized representative.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Dominique L Musselman, MD
    Organizational Affiliation
    University of Miami
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    Citations:
    PubMed Identifier
    34645381
    Citation
    Goel D, Srivastava A, Aledo-Serrano A, Krishnan A, Vohora D. Pharmacotherapy for SARS-CoV-2 and Seizures for Drug Repurposing Presumed on Mechanistic Targets. Curr Mol Pharmacol. 2022;15(6):832-845. doi: 10.2174/1874467214666211013122528.
    Results Reference
    derived

    Learn more about this trial

    Valproate Alone or in Combination With Quetiapine for Severe COVID-19 Pneumonia With Agitated Delirium

    We'll reach out to this number within 24 hrs