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

NCT04513314 | Withdrawn Phase 4 FDA Drug

• 1 other identifier: 20200851
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Covid19; Hyperactive Delirium; Pneumonia, Viral

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Total dose of dexmedetomidine administered

  Day 7

• Incidence of Treatment Emergent Adverse Events

  Day 7

Study Arms (2)

Standard of Care Only Group

ACTIVE COMPARATOR

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

Other: Standard of Care

Treatment Arm Group

ACTIVE COMPARATOR

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; Drug: Quetiapine; Other: Standard of Care

Interventions

Valproate DRUG

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.

Also known as: Depakote, Valproic acid

Treatment Arm Group

Quetiapine DRUG

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.

Also known as: seroquel

Treatment Arm Group

Standard of Care OTHER

Standard of Care is a combination of IV dexmedetomidine (D), midazolam (M), ketamine (K) and propofol (P), at the discretion of treating physician.

Also known as: Hospital Protocol

Standard of Care Only Group; Treatment Arm Group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Miami: lead

Related Publications (1)

• 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.

  PMID: 34645381 DERIVED

MeSH Terms

Conditions

COVID-19; Pneumonia, Viral

Interventions

Valproic Acid; Quetiapine Fumarate; Standard of Care

Condition Hierarchy (Ancestors)

Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids; Dibenzothiazepines; Thiazepines; Thiepins; Sulfur Compounds; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Dominique L Musselman, MD

  University of Miami

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: study rater/outcomes assessor and participant will be ignorant of the treatment arm pharmacist and investigator will be aware of the treatment arm
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: August 12, 2020
• First Posted: August 14, 2020
• Study Start: March 28, 2023
• Primary Completion: March 28, 2023
• Study Completion: March 28, 2023
• Last Updated: March 31, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share