Neuroleptics + Anti-Epileptics for Delirium

Overseen By David Hui, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Lamotrigine, Phenobarbital, Carbamazepine

Disqualifiers: Myasthenia gravis, Hepatic dysfunction, Seizure disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 1 week

42 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how different medications—haloperidol (a neuroleptic), chlorpromazine (a neuroleptic), valproate (an anti-epileptic), and a placebo—can help manage agitated delirium in hospitalized cancer patients. The goal is to determine which treatment, combined with non-drug strategies, best eases the distress caused by delirium. Ideal candidates for this trial have advanced cancer, are experiencing agitated delirium, and have tried non-medication methods like a sitter or restraints. As a Phase 2, Phase 3 trial, this research measures the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval. Participants have the opportunity to contribute to potentially groundbreaking advancements in cancer care.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently taking lamotrigine, phenobarbital, or carbamazepine.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that chlorpromazine is generally safe for short-term use in treating delirium, with most patients experiencing symptom improvement. Studies have found that haloperidol lowers the risk of death in patients with delirium and is considered safe, with a low chance of causing serious side effects. Valproic acid may help reduce agitation and delirium, though some people have reported side effects like liver problems and skin rash, but these are uncommon.

These treatments have been studied in different settings, and their safety has been confirmed over time. They are usually well-tolerated, although individual reactions can differ. Participants should discuss any concerns with their healthcare provider before joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for delirium because they explore combinations of neuroleptics and anti-epileptics, possibly offering new angles for managing the condition. Unlike typical treatments such as antipsychotics like haloperidol alone or benzodiazepines, this trial includes valproate, an anti-epileptic that may stabilize mood and reduce agitation differently from standard options. Additionally, the use of chlorpromazine offers a distinct profile of sedation and calming effects, potentially beneficial in acute settings. These combinations and delivery methods by vein could lead to faster and more effective management of delirium symptoms, providing alternatives to the current standard of care.

What evidence suggests that this trial's treatments could be effective for agitated delirium in cancer patients?

Research has shown that chlorpromazine, which participants in this trial may receive, can help treat symptoms of agitation and confusion. In one study, 80% of patients experienced lasting improvement in their confusion symptoms. Another study found that chlorpromazine helped reduce confusion in patients with terminal cancer.

Haloperidol, another treatment option in this trial, has mixed results in studies. Some research suggests it doesn't reduce confusion but can help lower the need for extra medication and manage agitation. Evidence also indicates that using it in ICU settings reduced death rates over a year.

Valproic acid, also being tested in this trial, has shown promise in reducing agitation and confusion. Research noted a decrease in agitation from 47.8% to 16.7% and in confusion from 84.8% to 63.3% when using valproic acid. It appears to be a helpful option, especially for younger adults experiencing confusion. ^{1 2 4 6 7}

Who Is on the Research Team?

David Hui

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced cancer experiencing agitated delirium. They must be seen by a palliative care team and have permission from their primary clinician to enroll. Exclusions include certain pre-existing conditions like myasthenia gravis, glaucoma, or hepatic encephalopathy; high doses of specific medications; active seizure disorders; Parkinson's disease or dementia; pregnancy; COVID-19 infection; and hypersensitivity to the drugs being tested.

Inclusion Criteria

I have been seen by a palliative care team in the hospital.

Permission from clinician from primary team to enroll

I have delirium and need medication or special care for agitation.

Exclusion Criteria

I am taking more than 4 mg of haloperidol, 100 mg of chlorpromazine, or 750 mg of valproate daily.

You are pregnant, as shown in your medical records.

I am currently taking lamotrigine, phenobarbital, or carbamazepine.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive haloperidol, chlorpromazine, valproate, or placebo every 12 hours for 72 hours to manage agitated delirium

1 week

Daily monitoring (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Chlorpromazine
• Haloperidol
• Placebo
• Valproate

Trial Overview The study tests haloperidol, chlorpromazine, valproic acid (an anti-epileptic), and placebo in treating agitated delirium in hospitalized cancer patients. It's a double-blind trial where neither doctors nor patients know who gets which treatment, aiming to find better ways to ease delirium-related distress without over-relying on neuroleptics.

How Is the Trial Designed?

Group I: Group 4 Experimental Treatment 1 Intervention

Participants will receive placebo every by vein every 12 hours.

Group II: Group 3 Experimental Treatment 1 Intervention

Participants will receive valproate by vein every 12 hours.

Group III: Group 2 Experimental Treatment 1 Intervention

Participants will receive chlorpromazine by vein every 12 hours (or more often, as needed).

Group IV: Group 1 Experimental Treatment 1 Intervention

Participants will receive haloperidol by vein every 12 hours (or more often, as needed).

Chlorpromazine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Thorazine for:

• Schizophrenia
• Nausea and vomiting
• Hiccups
• Acute intermittent porphyria
• Tetanus
• Severe behavioral problems in children

Approved in European Union as Largactil for:

• Schizophrenia and other psychoses
• Nausea and vomiting
• Hiccups
• Acute intermittent porphyria
• Tetanus

Approved in Canada as Chlorpromazine Hydrochloride for:

• Schizophrenia and other psychoses
• Nausea and vomiting
• Hiccups
• Acute intermittent porphyria
• Tetanus

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Cancer Prevention Research Institute of Texas

Collaborator

Trials

55

Recruited

98,900+

Published Research Related to This Trial

Neuroleptics, particularly haloperidol, are commonly used as first-line treatments for delirium in cancer patients, with alternatives like olanzapine, risperidone, and quetiapine available for those who do not respond adequately.

There is a critical need for well-designed, randomized controlled trials to establish effective treatment strategies for managing delirium in patients with advanced cancer, as current evidence is limited and often lacks high-quality studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuroleptics in the management of delirium in patients with advanced cancer. Hui, D., Dev, R., Bruera, E.[2018]

In a study of four cases of treatment-resistant schizophrenia, the combination of valproate with neuroleptic drugs (thioridazine or loxapine) led to significant clinical improvement, including reduced positive symptoms and normalization of disruptive behavior after an average of three months.

The positive effects of this treatment persisted for 4 to 24 months post-treatment, suggesting that valproate may play a beneficial role in managing resistant schizophrenia, potentially due to its GABAergic properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of resistant schizophrenia with valproate and neuroleptic drugs. Moriñigo, A., Martin, J., Gonzalez, S., et al.[2013]

Clozapine was found to be more effective than chlorpromazine in treating newly admitted, acutely psychotic schizophrenic patients, showing better overall improvement and higher discharge rates.

Unlike chlorpromazine, clozapine did not cause extrapyramidal side effects, making it a safer option for patients, although it did have side effects like sedation and hypotension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clozapine, chlorpromazine, and placebo in newly hospitalized, acutely schizophrenic patients: a controlled, double-blind comparison. Shopsin, B., Klein, H., Aaronsom, M., et al.[2019]

In a study of 68 critically ill patients with subsyndromal delirium, low-dose haloperidol did not significantly prevent the development of delirium compared to placebo, with similar rates of delirium occurrence in both groups (35% vs. 23%).

While haloperidol reduced agitation during ICU stays, it did not improve overall outcomes such as time spent without delirium or coma, duration of delirium, or ICU mortality, indicating limited therapeutic benefit for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preventing ICU Subsyndromal Delirium Conversion to Delirium With Low-Dose IV Haloperidol: A Double-Blind, Placebo-Controlled Pilot Study. Al-Qadheeb, NS., Skrobik, Y., Schumaker, G., et al.[2018]

In a study involving 21 matched cases, haloperidol, risperidone, olanzapine, and aripiprazole were found to be equally effective in managing delirium, with no significant differences in delirium resolution rates over one week.

However, the side-effect profiles varied: haloperidol was associated with the highest rate of extrapyramidal symptoms, while olanzapine led to the most sedation, highlighting the importance of considering side effects when choosing a treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haloperidol, risperidone, olanzapine and aripiprazole in the management of delirium: A comparison of efficacy, safety, and side effects. Boettger, S., Jenewein, J., Breitbart, W.[2018]

In a study of 30 adult AIDS patients with delirium, treatment with low doses of haloperidol or chlorpromazine significantly improved delirium symptoms, while lorazepam showed no improvement and caused adverse effects.

Haloperidol and chlorpromazine were associated with a low prevalence of extrapyramidal side effects, making them safer options for treating delirium in this patient population compared to lorazepam, which was terminated early due to treatment-limiting side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Breitbart, W., Marotta, R., Platt, MM., et al.[2022]

Haloperidol is often the first choice among classic antipsychotics due to its various routes of administration, making it suitable for patients who cannot take oral medications.

For patients needing non-oral options, medications like clomipramine and amitriptyline are available as parenteral antidepressants, while lorazepam and diazepam can be administered via injection or rectally for anxiety relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Non-oral routes of administration of psychotropic agents]. Sno, HN., Schuitenmaker, MG.[2008]

Haloperidol was associated with significantly fewer participants dropping out of studies compared to chlorpromazine, suggesting it may have better adherence in treatment for schizophrenia (RR 0.26).

However, haloperidol was linked to a higher incidence of movement disorders, while chlorpromazine was more likely to cause hypotension, indicating that while both drugs are effective, their side effect profiles differ significantly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haloperidol versus chlorpromazine for schizophrenia. Leucht, C., Kitzmantel, M., Chua, L., et al.[2018]

In a study of 42 patients with delirium, both aripiprazole and haloperidol showed similar efficacy in reducing delirium symptoms, with resolution rates of 76.2% for both medications.

Aripiprazole was associated with fewer extrapyramidal side effects compared to haloperidol, making it a potentially safer option for managing delirium, especially in patients with hypoactive delirium where it achieved a 100% resolution rate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aripiprazole and haloperidol in the treatment of delirium. Boettger, S., Friedlander, M., Breitbart, W., et al.[2015]

In a study involving 63 patients with delirium, both quetiapine and haloperidol were found to be equally effective in reducing delirium symptoms over a 6-day period, as measured by the Delirium Rating Scale-Revised-98 (DRS-R-98).

At the end of the trial, approximately 68% of patients in both treatment groups achieved significant improvement, with no notable differences in efficacy between the two medications, indicating that quetiapine can be a viable alternative to haloperidol for treating delirium.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of quetiapine and haloperidol in delirium: A single blind randomized controlled study. Grover, S., Mahajan, S., Chakrabarti, S., et al.[2020]

A systematic review of clinical trials for delirium treatment in palliative care identified that haloperidol is recommended as an effective treatment, supported by positive clinical experiences.

While olanzapine and aripiprazole are also somewhat effective, lorazepam should be avoided for treating delirium in this context, highlighting the need for further substantial studies to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological treatment of delirium in palliative care patients. A systematic literature review]. Perrar, KM., Golla, H., Voltz, R.[2021]

In a study monitoring 86,439 patients treated with neuroleptics from 1993 to 2000, severe adverse drug reactions (ADRs) occurred in 1.1% of patients, with atypical neuroleptics causing more severe ADRs than typical ones, primarily due to clozapine-related issues.

When excluding clozapine, typical and atypical neuroleptics showed similar rates of severe ADRs, but their profiles differed, highlighting the importance of considering real-life ADR data for better treatment decisions in psychiatric care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe adverse drug reactions in psychiatric inpatients treated with neuroleptics. Bender, S., Grohmann, R., Engel, RR., et al.[2007]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9674356/

Chlorpromazine as Treatment for Refractory Agitation ... Short-term use of chlorpromazine was safe and effective in treating both hyperactive and mixed delirium symptoms, and its associated refractory ...

2. academic.oup.com academic.oup.com/oncolo/advance-article/doi/10.1093/oncolo/oyaf324/8266772

Intravenous haloperidol or chlorpromazine—which is more ... Intravenous haloperidol or chlorpromazine—which is more effective to improve agitation and communication in agitated delirium at the end of life ...

3. liebertpub.com liebertpub.com/doi/full/10.1089/jpm.2022.0308

Chlorpromazine's Potential Role in Palliating Distressing ... Results: Sustained improvement in symptoms of delirium was seen in 80% of patients as identified in the palliative psychiatrist's progress notes.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29757064/

Factors Associated with the Effectiveness of Intravenous ... Conclusions: Intravenous administration of low-dose chlorpromazine may be an effective and safe treatment option for delirium in patients with terminal cancer ...

5. journals.sagepub.com journals.sagepub.com/doi/full/10.1089/jpm.2022.0308

Chlorpromazine's Potential Role in Palliating Distressing ... Improvement in delirium was also measured as a reduction in the mean daily DOSS scores from baseline (day before CPZ initiation) to a value <3. A patient was ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0885392424000745

Comparison of Pharmacological Treatments for Agitated ... Haloperidol with as-needed benzodiazepine, chlorpromazine, or levomepromazine may be effective and safe for terminal agitation.

7. emcrit.org emcrit.org/ibcc/delirium/

Delirium & antipsychotic pharmacology [1] Chlorpromazine is more sedating. Chlorpromazine might be roughly compared to a combination of haloperidol plus diphenhydramine (anti-H1, ...