Covid19Phase 4NCT04513314
Valproate Alone or in Combination With Quetiapine for Severe COVID-19 Pneumonia With Agitated Delirium
A Phase 4 study testing Valproate and Quetiapine in people with Covid19 and Hyperactive Delirium, run by University of Miami.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Covid19, Hyperactive Delirium, Pneumonia, Viral
- What is being tested?
- Valproate and Quetiapine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- 28 Mar 2023to 28 Mar 2023
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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.
About this study
Official title: 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.
Read the 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.
- Conditions
- Covid19, Hyperactive Delirium, Pneumonia, Viral
- Being tested
- Valproate, Quetiapine, Standard of Care
- Medical subject headings
- COVID-19, Pneumonia, Viral
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ValproateDrug
Also called Depakote, Valproic acid
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.
QuetiapineDrug
Also called seroquel
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.
Standard of CareOther
Also called Hospital Protocol
Standard of Care is a combination of IV dexmedetomidine (D), midazolam (M), ketamine (K) and propofol (P), at the discretion of treating physician.
| Study group | Role | What they receive |
|---|---|---|
| Standard of Care Only Group | Active comparator | Patients maintained with mechanical ventilation will be treated with standard of care after cessation of paralytic agents. Receives: 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. Receives: Drug: Valproate; Drug: Quetiapine; Other: Standard of Care |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Baseline, Day 7
Secondary outcomes (2)
Total dose of dexmedetomidine administered
Total dose of dexmedetomidine administered will be reported from baseline RASS score of +3 or greater.
Measured: 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.
Measured: Day 7
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Aug 2020
- Study start28 Mar 2023 (estimated)
- Primary completion28 Mar 2023
- Study completion28 Mar 2023
Why it stopped: coronavirus omicron variant infection typically not associated with delirium and agitation severely hampered recruitment.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Covid19Studies of the same condition, open and under way.
- More trials run by University of MiamiThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Miami
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dominique Musselman, University of Miami
- Investigators
- Dominique L Musselman, MD, Principal investigator, University of Miami
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04513314
- Sponsor's protocol ID
- 20200851
- Status last verified
- Mar 2023
- First submitted
- 12 Aug 2020
- Last updated
- 31 Mar 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
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.
PubMed 34645381
Study at a glance
From the registry record, last updated by the sponsor on 31 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Practical, Pilot, Randomized, Controlled Trial of Valproate Alone or in Combination With Quetiapine for Severe COVID-19 Pneumonia With Agitated Delirium
- ClinicalTrials.gov ID
- NCT04513314
- Acronym / sponsor ID
- 20200851
- Conditions
- Covid19, Hyperactive Delirium, Pneumonia, Viral
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: coronavirus omicron variant infection typically not associated with delirium and agitation severely hampered recruitment.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- University of MiamiUniversity, hospital or other
- Study start
- 28 Mar 2023 (estimated)
- Primary completion
- 28 Mar 2023 (actual)
- Study completion
- 28 Mar 2023 (actual)
- First posted
- 14 Aug 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Standard of Care Only Group | Active comparator | Other: Standard of CarePatients maintained with mechanical ventilation will be treated with standard of care after cessation of paralytic agents. |
| Treatment Arm Group | Active comparator | Drug: Valproate, Drug: Quetiapine, Other: Standard of CarePatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 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
Key exclusion criteria (15 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ValproateAlso: Depakote, Valproic acidValproate 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. | Drug | Treatment Arm Group |
| QuetiapineAlso: seroquelEnteral 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. | Drug | Treatment Arm Group |
| Standard of CareAlso: Hospital ProtocolStandard of Care is a combination of IV dexmedetomidine (D), midazolam (M), ketamine (K) and propofol (P), at the discretion of treating physician. | Other | Standard of Care Only Group, Treatment Arm Group |
Primary outcome
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).
2 secondary outcomes
Total dose of dexmedetomidine administered
Time frame: Day 7
Incidence of Treatment Emergent Adverse Events
Time frame: Day 7
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Mar 2023.
- Derived from this study: PubMed 34645381Goel 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Dominique L Musselman, MD principal investigator
University of Miami
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Valproate and Quetiapine in people with Covid19 and Hyperactive Delirium, run by University of Miami.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 31 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change from baseline RASS score of +3 or greater (time frame: Baseline, Day 7). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04513314, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Mar 2023.