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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04513314
Recruitment Status : Not yet recruiting
First Posted : August 14, 2020
Last Update Posted : November 10, 2020
Sponsor:
Information provided by (Responsible Party):
Dominique Musselman, University of Miami

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.

Condition or disease Intervention/treatment Phase
Covid19 Hyperactive Delirium Pneumonia, Viral Drug: Valproate Drug: Quetiapine Other: Standard of Care Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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
Primary Purpose: Treatment
Official Title: A Practical, Pilot, Randomized, Controlled Trial of Valproate Alone or in Combination With Quetiapine for Severe COVID-19 Pneumonia With Agitated Delirium
Estimated Study Start Date : November 1, 2021
Estimated Primary Completion Date : November 1, 2022
Estimated Study Completion Date : November 1, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Delirium Pneumonia

Arm Intervention/treatment
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 Name: 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 Name: 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 Name: 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 Name: Hospital Protocol




Primary Outcome Measures :
  1. Change from baseline RASS score of +3 or greater [ Time Frame: Baseline, Day 7 ]
    Richmond Agitation Sedation Scale (RASS) score ranges from +4 (combative) to 0 (alert & calm) to -5 (unarousable).


Secondary Outcome Measures :
  1. Total dose of dexmedetomidine administered [ Time Frame: Day 7 ]
    Total dose of dexmedetomidine administered will be reported from baseline RASS score of +3 or greater.

  2. Incidence of Treatment Emergent Adverse Events [ Time Frame: Day 7 ]

    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04513314


Contacts
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Contact: Dominique L Musselman, MD 404-723-8361 dmusselman@med.miami.edu
Contact: Sergey Gerasim, MD 646-220-1670 sxg894@miami.edu

Locations
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United States, Florida
Jackson Memorial Hospital
Miami, Florida, United States, 33136
Contact: Dominique L Musselman    404-723-8361    dmusselman@med.miami.edu   
Sub-Investigator: Sergey Gerasim, MD         
Principal Investigator: Dominique Musselman, MD         
Sponsors and Collaborators
University of Miami
Investigators
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Principal Investigator: Dominique L Musselman, MD University of Miami
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Responsible Party: Dominique Musselman, Associate Professor, University of Miami
ClinicalTrials.gov Identifier: NCT04513314    
Other Study ID Numbers: 20200851
First Posted: August 14, 2020    Key Record Dates
Last Update Posted: November 10, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Pneumonia, Viral
Pneumonia
Delirium
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Confusion
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Virus Diseases
Valproic Acid
Quetiapine Fumarate
Antidepressive Agents
Psychotropic Drugs
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Anticonvulsants
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Antimanic Agents