Valproic Acid for Treatment of Hyperactive or Mixed Delirium in ICU

• Sponsor: Stanford University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02343575
• Collaborator: (none)
• Enrollment: 3
• Location: 1
• Arms: 2
• Duration (Months): 36
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Delirium is the most often encountered psychiatric diagnosis in the general hospital, with incidence up to 85% in the intensive care unit (ICU) setting and with significant consequences on patients' morbidity and mortality. Currently, although not FDA approved, antipsychotics are often considered the first-line pharmacological treatment. However, there can be limitations to their use, including side effects or lack of efficacy. Valproic acid (VPA) is one of the alternatives at times used in such patients which from limited case series data appears to be helpful and tolerated. VPA can provide relief from agitation that poses a threat to the safety and recovery of the patient. Moreover, mechanistically it addresses the neurochemical and cellular abnormalities inherent in delirium (it has NMDA-antagonist, anti-dopaminergic, GABAergic,anti-inflammatory, anti-apoptotic, and histone deacetylase inhibitor properties, among others). The purpose of this study is to evaluate the efficacy and tolerability of the VPA in the first known to us randomized controlled trial.

Condition or Disease	Intervention/Treatment	Phase
Hyperactive Delirium; Mixed Delirium	Drug: Valproic Acid; Drug: Placebo; Drug: Haloperidol	Phase 4

Detailed Description

The investigators plan to investigate the efficacy and tolerability of scheduled VPA as compared to placebo with as needed basis (PRN) haloperidol (as a back-up in both arms) for treatment of hyperactive or mixed delirium. Patients will be randomized to scheduled VPA or placebo (normal saline) and both arms will have flexible PRN dosing of haloperidol. Thus, the investigators plan to learn the time to delirium resolution in patients treated with VPA versus placebo; percentage of patients responding to VPA versus placebo; tolerability of VPA versus placebo. If addition of scheduled VPA proves to shorten time to delirium resolution as compared to placebo, lead to less use of haloperidol, and/or have fewer side effects, it would provide a very important addition to our limited evidence-based repertoire of delirium treatment. Moreover, this pilot study would then pave the way for the bigger randomized control trial powered to detect its effect size.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Valproic Acid for Treatment of Hyperactive or Mixed Delirium in ICU
• Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Jan 1, 2018
• Actual Study Completion Date: Jan 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Valproic Acid Start: VPA PO/NGT 500 mg BID If need to increase in 24 or more hours: VPA 500 mg PO/NGT q am, 1000 mg PO/NGT QHS If need to increase in 24 or more hours: VPA 500 mg PO/NGT q am, 1500 mg PO/NGT QHS If need to increase in 24 or more hours: VPA 500 mg PO/NGT Q am, 2000 mg PO/NGT QHS Rescue at all stages: HAL IV 2-5 mg Q4hr PRN	Drug: Valproic Acid; 1. Start: VPA PO/NGT 500 mg BID 2. If need to increase in 24 or more hours: VPA 500 mg PO/NGT q am, 1000 mg PO/NGT QHS 3. If need to increase in 24 or more hours: VPA 500 mg PO/NGT q am, 1500 mg PO/NGT QHS 4.If need to increase in 24 or more hours: VPA 500 mg PO/NGT Q am, 2000 mg PO/NGT QHS; Other Names: VPA Valproate Depakote ; Drug: Haloperidol; Both arms (intervention VPA and placebo) will receive flexible as needed haloperidol: Rescue: HAL IV 2-5 mg Q4hr PRN; Other Names: Haldol
Placebo Comparator: Placebo Placebo: PO/NGT BID Rescue: HAL IV 2-5 mg Q4hr PRN	Drug: Placebo; Placebo 500 mg matched to VPA BID PO/NGT; Drug: Haloperidol; Both arms (intervention VPA and placebo) will receive flexible as needed haloperidol: Rescue: HAL IV 2-5 mg Q4hr PRN; Other Names: Haldol

Outcome Measures

Primary Outcome Measures

1. Time to Delirium Resolution [Up to 5 days]

   Delirium resolution was defined as three negative Confusion Assessment Method (CAM) assessments, performed by nurses every 12 hours.

Secondary Outcome Measures

1. Use of as Needed Anti-psychotic Agent [Up to 5 days]

   Amount of Haldol administered.

2. Side Effects From Medications [Up to 5 days]

   Side effects may have included liver function test (LFT) increase, platelet decrease, bleeding, or QTc prolongation.

3. Intensity of Delirium as Measured by the Intensive Care Delirium Screening Checklist (ICDSC) Delirium Severity Scale [Up to 5 days]

   The items include the assessment of: (1) consciousness ( deep sedation/coma, agitation, normal wakefulness, or light sedation); (2) inattention; (3) disorientation; (4) hallucination, delusion, or psychosis; (5) psychomotor agitation or retardation; (6) inappropriate speech or mood; (7) sleep-wake cycle disturbances; and (8) fluctuation of symptomatology. The maximum score is eight; scores of ≥4 indicate the presence of delirium and score zero is indicate not in delirium. Each item is scored 0-8.

4. Length of ICU Stay [During expected average hospitalization (of 1 month)]

5. Length of Hospital Stay [During expected average hospitalization (of 1 month)]

   Participation in the study ended once delirium was resolved and the patient was off study drug. This outcome presents the total length of hospital stay, which may have been longer than participation in the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• patients 18 years of age and older

• admitted to surgical ICU

• diagnosed with hyperactive or mixed delirium

Exclusion Criteria:

• hypoactive delirium

• primary team does not think patient is appropriate to participate

• no oral access (PO or NGT)

• non-English speaking

• contraindication to study medications

• pregnant women or woman of child-bearing age not on documented contraception

• QTc = or greater than 480

• hepatic dysfunction

• decreased platelets or platelet dysfunction

• bleeding disorder, current major bleeding

• history of NMS, epilepsy, or PD

• diagnosis of schizophrenia, bipolar disorder or schizoaffective disorder

• on warfarin or carbapenems

• delirium due to alcohol withdrawal

• treated with antipsychotics for more than 48 hours prior to study enrollment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford Hospital and Clinics	Stanford	California	United States	94305

Sponsors and Collaborators

• Stanford University

Investigators

• Principal Investigator: Yelizaveta Sher, M.D., Stanford University
• Study Director: Jose R Maldonado, M.D., Stanford University

Study Documents (Full-Text)

• Study Protocol - Mar 12, 2014

More Information

Publications

None provided.

• Responsible Party: Yelizaveta Sher, Clinical Assistant Professor, Stanford University
• ClinicalTrials.gov Identifier: NCT02343575
• Other Study ID Numbers: 28330
• First Posted: Jan 22, 2015
• Last Update Posted: Jun 26, 2019
• Last Verified: May 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Yelizaveta Sher, Clinical Assistant Professor, Stanford University: Hyperactive delirium; Mixed delirium; Anti-psychotic; Haldol; Valproic Acid
• Additional relevant MeSH terms: Delirium; Hyperkinesis; Psychomotor Agitation; Valproic Acid; Haloperidol; Haloperidol decanoate

Study Results

Participant Flow

Arm/Group Title	Valproic Acid	Placebo
Arm/Group Description	Participants received Valproic Acid (VPA) and flexible haloperidol as needed.	Participants received VPA placebo and flexible haloperidol as needed.
Period Title: Overall Study
STARTED	1	2
COMPLETED	1	2
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Valproic Acid	Placebo	Total
Arm/Group Description	Participants received VPA and flexible haloperidol as needed.	Participants received VPA placebo and flexible haloperidol as needed.	Total of all reporting groups
Overall Participants	1	2	3
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	0 0%	1 50%	1 33.3%
>=65 years	1 100%	1 50%	2 66.7%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	1 100%	2 100%	3 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	1 50%	1 33.3%
Black or African American	0 0%	1 50%	1 33.3%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 100%	0 0%	1 33.3%

Outcome Measures

1. Primary Outcome

Title	Time to Delirium Resolution
Description	Delirium resolution was defined as three negative Confusion Assessment Method (CAM) assessments, performed by nurses every 12 hours.
Time Frame	Up to 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Valproic Acid	Placebo
Arm/Group Description	Participants received VPA and flexible haloperidol as needed.	Participants received VPA placebo and flexible haloperidol as needed.
Measure Participants	1	2
Mean (Standard Deviation) [days]	2	1.5 (0.7)

2. Secondary Outcome

Title	Use of as Needed Anti-psychotic Agent
Description	Amount of Haldol administered.
Time Frame	Up to 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Valproic Acid	Placebo
Arm/Group Description	Participants received VPA and flexible haloperidol as needed.	Participants received VPA placebo and flexible haloperidol as needed.
Measure Participants	1	2
Mean (Standard Deviation) [mg]	0	1 (1.2)

3. Secondary Outcome

Title	Side Effects From Medications
Description	Side effects may have included liver function test (LFT) increase, platelet decrease, bleeding, or QTc prolongation.
Time Frame	Up to 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Valproic Acid	Placebo
Arm/Group Description	Participants received VPA and flexible haloperidol as needed.	Participants received VPA placebo and flexible haloperidol as needed.
Measure Participants	1	2
LFT increase	0 0%	0 0%
Platelet decrease	0 0%	0 0%
Bleeding	0 0%	0 0%
QTc prolongation	0 0%	1 50%

4. Secondary Outcome

Title	Intensity of Delirium as Measured by the Intensive Care Delirium Screening Checklist (ICDSC) Delirium Severity Scale
Description	The items include the assessment of: (1) consciousness ( deep sedation/coma, agitation, normal wakefulness, or light sedation); (2) inattention; (3) disorientation; (4) hallucination, delusion, or psychosis; (5) psychomotor agitation or retardation; (6) inappropriate speech or mood; (7) sleep-wake cycle disturbances; and (8) fluctuation of symptomatology. The maximum score is eight; scores of ≥4 indicate the presence of delirium and score zero is indicate not in delirium. Each item is scored 0-8.
Time Frame	Up to 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Valproic Acid	Placebo
Arm/Group Description	Participants received VPA and flexible haloperidol as needed.	Participants received VPA placebo and flexible haloperidol as needed.
Measure Participants	1	2
Mean (Standard Deviation) [score on a scale]	5	4 (2.7)

5. Secondary Outcome

Title	Length of ICU Stay
Time Frame	During expected average hospitalization (of 1 month)

Outcome Measure Data

Analysis Population Description

Data were not collected for this outcome

Arm/Group Title	Valproic Acid	Placebo
Arm/Group Description	Participants received VPA and flexible haloperidol as needed.	Participants received VPA placebo and flexible haloperidol as needed.
Measure Participants	0	0

6. Secondary Outcome

Title	Length of Hospital Stay
Description	Participation in the study ended once delirium was resolved and the patient was off study drug. This outcome presents the total length of hospital stay, which may have been longer than participation in the study.
Time Frame	During expected average hospitalization (of 1 month)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Valproic Acid	Placebo
Arm/Group Description	Participants received VPA and flexible haloperidol as needed.	Participants received VPA placebo and flexible haloperidol as needed.
Measure Participants	1	2
Mean (Standard Deviation) [days]	4	8 (8.5)

Adverse Events

Time Frame	Up to 5 days
Arm/Group Title	Valproic Acid		Placebo
Arm/Group Description	Participants received VPA and flexible haloperidol as needed.		Participants received VPA placebo and flexible haloperidol as needed.
All Cause Mortality
	Valproic Acid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/2 (0%)
Serious Adverse Events
	Valproic Acid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Valproic Acid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		1/2 (50%)
Cardiac disorders
QTc prolongation	0/1 (0%)		1/2 (50%)

Limitations/Caveats

The study terminated early and did not meet its planned sample size of 30 participants, leading to a small number of subjects analyzed.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.