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

A Practical, Pilot, Randomized, Controlled Trial of Valproate Alone or in Combination With Quetiapine for Severe COVID-19 Pneumonia With Agitated Delirium

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.

Study Overview

• Status: Withdrawn
• Conditions: Pneumonia, Viral; Covid19; Hyperactive Delirium
• Intervention / Treatment: Other: Standard of Care; Drug: Valproate; Drug: Quetiapine

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.

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Dominique L Musselman, MD; Phone Number: 404-723-8361; Email: dmusselman@med.miami.edu
• Study Contact Backup: Name: Sergey Gerasim, MD; Phone Number: 646-220-1670; Email: sxg894@miami.edu

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Jackson Memorial Hospital
      • Contact: Dominique L Musselman; Phone Number: 404-723-8361; Email: dmusselman@med.miami.edu
      • Sub-Investigator: Sergey Gerasim, MD
      • Principal Investigator: Dominique Musselman, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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 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.	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; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Baseline, Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total dose of dexmedetomidine administered	Total dose of dexmedetomidine administered will be reported from baseline RASS score of +3 or greater.	Day 7
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.	Day 7

Collaborators and Investigators

• Sponsor: University of Miami
• Investigators: Principal Investigator: Dominique L Musselman, MD, University of Miami

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Anticipated): March 28, 2023
• Primary Completion (Actual): March 28, 2023
• Study Completion (Actual): March 28, 2023

Study Registration Dates

• First Submitted: August 12, 2020
• First Submitted That Met QC Criteria: August 13, 2020
• First Posted (Actual): August 14, 2020

Study Record Updates

• Last Update Posted (Actual): March 31, 2023
• Last Update Submitted That Met QC Criteria: March 29, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; COVID-19; Delirium; Pneumonia; Pneumonia, Viral; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; GABA Agents; Anticonvulsants; Antimanic Agents; Valproic Acid; Quetiapine Fumarate
• Other Study ID Numbers: 20200851

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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