Clinical trial NCT02343575
Conditions: Hyperactive Delirium Mixed Delirium
Keywords: Hyperactive delirium Mixed delirium Anti-psychotic Haldol Valproic Acid
Sponsor: Stanford University
Start date: 2015-01-01; Completion date: 2018-01-01
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

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.

Arms: arm 1: 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

Rescue at all stages: HAL IV 2-5 mg Q4hr PRN arm 2: Placebo: PO/NGT BID

Rescue: HAL IV 2-5 mg Q4hr PRN
Interventions: intervention 1: Valproic Acid intervention 2: Placebo intervention 3: Haloperidol
Intervention descriptions: intervention 1: 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 intervention 2: Placebo 500 mg matched to VPA BID PO/NGT intervention 3: Both arms (intervention VPA and placebo) will receive flexible as needed haloperidol: Rescue: HAL IV 2-5 mg Q4hr PRN

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
Valproic Acid for Treatment of Hyperactive or Mixed Delirium in ICU 
Study Protocol 
NCT02343575 
Document Date: March 12, 2014 


VPA as an Adjunct Treatment for Hyperactive/Mixed Delirium Study 
 
1 
 
Medication adjustment protocol: 
Adjustments can take place every 24 hours according to the below schedule: 
If study physician decides based on the below criteria that medications need to change, they notify 
RA/pharmacy 
 
Placebo arm 
VPA arm 
1. start 
 Placebo PO BID 
 Rescue: HAL IV 1-5 mg 
Q4hr PRN 
 
 VPA PO 500 mg BID 
 Rescue: HAL IV 1-5 mg 
Q4hr PRN 
 
2. If ICDCS = or > 4, RASS = 
or > 1 and patient cont 
to meet criteria for 
hyperactive/mixed 
delirium, consider 
increasing meds 
according to protocol 
 Placebo PO BID 
 Rescue: HAL IV 1-5 mg 
Q4hr PRN 
 
 VPA 500 mg PO q am, 1000 
mg PO QHS 
 Rescue: HAL IV 1-5 mg 
Q4hr PRN 
3. If need to increase 
 Placebo PO BID 
 Rescue: HAL IV 1-5 mg 
Q4hr PRN 
 VPA 500 mg PO q am, 1500 
mg PO QHS 
 Rescue: HAL IV 1-5 mg 
Q4hr PRN 
 
4. If need to increase 
 
 Placebo PO BID 
 Rescue: HAL IV 1-5 mg 
Q4hr PRN 
 VPA 500 mg PO Q am, 2000 
mg PO QHS 
 Rescue: HAL IV 1-5 mg 
Q4hr PRN  
 
 
Blinded physician evaluates patient daily: clinical exam, ICDSC, DSM V criteria for delirium, 
EPS, primitive reflexes 
 
Research Assistant daily collects CBC (esp platelets), CMP (esp LFTs), INR, QTc, EPS side effects 
 
If QTC increases by 20% from initiation of medication or equals 500 or above, LFTs increase 
(ALT > 150, AST> 80) or platelets decrease by 30% or are below 150, research assistant 
consults with affiliated physician (#2). Physician #2 carefully examines situation and decides 
whether any of these changes can be due to study medication. 
o  If No  note is taken, study continues as designed, no unblinding necessary.  
o If Yes study physician #1 is informed and unblinded and the best clinical decision for 
the patient is taken 
 
Patients will be in the study for total of 7 days or until resolution of delirium (ICDSC < 4 plus 24 
hours), whichever is shorter time. If patients need continued treatment after the study 
resolution, they will be followed by the regular psychiatry consult team.