Back to resultsValproate 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Withdrawn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
About this trial
This is an interventional treatment trial for Covid19
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.
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
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
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Valproate Alone or in Combination With Quetiapine for Severe COVID-19 Pneumonia With Agitated Delirium
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