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Purpose

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.

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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.

Study Design

Phase
Phase 4
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
Double (Participant, Outcomes 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

Arm Groups

ArmDescriptionAssigned Intervention
Active Comparator
Standard of Care Only Group 		Patients maintained with mechanical ventilation will be treated with standard of care after cessation of paralytic agents.
  • Other: Standard of Care
    Standard of Care is a combination of IV dexmedetomidine (D), midazolam (M), ketamine (K) and propofol (P), at the discretion of treating physician.
    Other names:
    • Hospital Protocol
Active Comparator
Treatment Arm Group 		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.
  • Drug: Valproate
    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.
    Other names:
    • Depakote, Valproic acid
  • Drug: Quetiapine
    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.
    Other names:
    • seroquel
  • Other: Standard of Care
    Standard of Care is a combination of IV dexmedetomidine (D), midazolam (M), ketamine (K) and propofol (P), at the discretion of treating physician.
    Other names:
    • Hospital Protocol

More Details

NCT ID
NCT04513314
Status
Withdrawn
Sponsor
University of Miami

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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.