Melatonin for Delirium

(DELIRE-ICU Trial)

Recruiting at 1 trial location

Overseen By Johannie Beaucage-Charron, Pharm.D., M.Sc.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Ciusss de L'Est de l'Île de Montréal

Must not be taking: Melatonin

Disqualifiers: Severe brain injury, Schizophrenia, Bipolar, Seizures, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 14 days

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether melatonin can help treat delirium in critically ill ICU patients. Delirium causes confusion and impairs clear thinking, particularly in very sick individuals. The trial compares melatonin to a placebo (a harmless pill with no active medicine) to determine its effectiveness. For those who have been in the ICU for more than two days and are experiencing confusion, this trial might be suitable. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, you cannot have used melatonin within 24 hours before joining the trial.

Is there any evidence suggesting that melatonin is likely to be safe for humans?

Research has shown that melatonin is generally safe for people. In past studies, no major problems arose when patients at risk of or experiencing delirium used melatonin. These studies involved doses similar to the 3 mg used to test its effects on delirium.

Although melatonin did not always prevent or lessen delirium, patients tolerated it well. A meta-analysis, which combines results from several studies, also supports melatonin's safety and potential benefits in preventing delirium. This indicates that melatonin has been used safely in similar situations without causing major issues. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about using melatonin for delirium because it offers a unique approach compared to traditional treatments like antipsychotics and sedatives. Unlike these standard medications, melatonin is a natural hormone that regulates sleep-wake cycles, potentially addressing the sleep disturbances often associated with delirium without the heavy sedative effects. Additionally, the enteral administration of melatonin via an oral suspension makes it easy to use, especially for patients who may have difficulty swallowing pills. This innovative approach could provide a gentler and more targeted option for managing delirium symptoms, sparking interest in its potential benefits.

What evidence suggests that melatonin might be an effective treatment for delirium?

This trial will compare enteral melatonin 9 mg with a placebo to assess its effectiveness in treating delirium. Research has shown mixed results for using melatonin to treat delirium. Some studies suggest that melatonin might help reduce the risk of delirium, especially after surgery. However, other studies have not found clear benefits, with some indicating that melatonin doesn't lessen the severity of delirium. One study found that a lower dose of melatonin worked better than a higher dose. Overall, while some signs are hopeful, more research is needed to confirm melatonin's effectiveness for delirium. ^{2 3 5 6 7}

Who Is on the Research Team?

François Marquis, M.D., M.A.

Principal Investigator

Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Est-de-l'Île-de-Montréal

Are You a Good Fit for This Trial?

Adults over 18 in the ICU with a recent delirium score of at least 4, expected to stay in the ICU for more than 48 hours. Not eligible if they have severe brain injuries, major cognitive disorders, certain psychiatric diagnoses, seizures, coma, are pregnant or breastfeeding, took melatonin recently or can't take oral meds.

Inclusion Criteria

I am 18 or older and have been admitted to the ICU.

Your ICDSC score is 4 or higher for up to 48 hours before being chosen by chance to be in the study.

I expect to stay in the ICU for more than 48 hours.

Exclusion Criteria

My doctor expects my illness to significantly impact my life expectancy in the short term.

I was diagnosed with delirium before being admitted to the ICU.

I do not have active seizures, coma, aphasia, or severe intellectual disability.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive melatonin 9 mg or placebo daily at 21:00 to treat delirium in the ICU

14 days

Daily monitoring in ICU

Follow-up

Participants are monitored for safety and effectiveness after treatment during their stay in the ICU and after transfer to another unit

14 days

What Are the Treatments Tested in This Trial?

Interventions

• Melatonin
• Placebo

Trial Overview The trial is testing whether giving melatonin to critically ill adults helps treat delirium compared to a placebo. It's set up as a small-scale study first to see if it's possible to do a larger one later.

How Is the Trial Designed?

Group I: Enteral melatonin 9 mg Experimental Treatment 1 Intervention

Melatonin 9 mg from a 1 mg/mL oral suspension of melatonin in ORA-BLEND SF® (sugar-free flavoured suspending vehicle). Final volume in the oral syringe will be 9 mL.

Group II: Enteral placebo Placebo Group 1 Intervention

ORA-BLEND SF® (sugar-free flavoured suspending vehicle). Final volume in the oral syringe will be 9 mL.

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

Approved in European Union as Circadin for:

• Insomnia in adults aged 55 and over
• Sleep disorders in children with autism spectrum disorder

Approved in European Union as Slenyto for:

• Insomnia in children and adolescents aged 2-18 with autism spectrum disorder

Approved in United States as Melatonin for:

• Sleep disorders in children with autism spectrum disorder
• Insomnia in adults

Who Is Running the Clinical Trial?

Ciusss de L'Est de l'Île de Montréal

Lead Sponsor

Trials

81

Recruited

6,400+

Maisonneuve-Rosemont Hospital

Collaborator

Trials

102

Recruited

38,300+

Published Research Related to This Trial

A review of six clinical trials on melatonin receptor agonists for preventing delirium showed mixed results, with some trials indicating a reduction in delirium incidence by 12% to 30%, while the largest trial found no benefit.

Due to the conflicting evidence and limited safety evaluations, the routine use of melatonin receptor agonists for delirium prevention is not currently recommended.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin Receptor Agonists for Delirium Prevention. Walker, CK., Gales, MA.[2022]

Melatonin and ramelteon have been found to significantly reduce the incidence of delirium in hospitalized older adults, particularly in medical units, based on an umbrella review of three meta-analyses.

The studies showed a moderate effect size in preventing delirium, with odds ratios indicating a notable reduction, although the overall quality of the studies was low-to-moderate and there was high heterogeneity in the results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin and melatonin-receptor agonists to prevent delirium in hospitalized older adults: An umbrella review. Blodgett, TJ., Blodgett, NP.[2022]

Melatonin and its agonist ramelteon may effectively reduce the duration of delirium in hospitalized patients, with a meta-analysis showing a significant decrease of about 1.72 days compared to placebo across three randomized controlled trials involving 1211 participants.

Despite these promising results, the overall quality and quantity of the current studies are limited, suggesting that clinicians should await more robust data from ongoing trials before widely recommending melatonin for delirium treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin and Ramelteon for the treatment of delirium: A systematic review and meta-analysis. Beaucage-Charron, J., Rinfret, J., Coveney, R., et al.[2023]

Melatonin may help prevent and manage delirium in elderly patients, as suggested by two randomized controlled trials, although it does not reduce the severity of delirium or improve behaviors and functions.

Ramelteon, a melatonin agonist, showed benefits in preventing delirium in medically ill older adults compared to placebo, and both melatonin and ramelteon were well tolerated in the studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin and melatonin agonist for delirium in the elderly patients. Chakraborti, D., Tampi, DJ., Tampi, RR.[2022]

Ramelteon, a selective melatonin receptor agonist, was successfully used to treat five cases of delirium within just one day, indicating its potential effectiveness.

The treatment suggests that addressing circadian rhythm disturbances, a key symptom of delirium, may be an important strategy in managing this serious condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Marked improvement in delirium with ramelteon: five case reports. Furuya, M., Miyaoka, T., Yasuda, H., et al.[2022]

A meta-analysis of 18 randomized controlled trials found that melatonin significantly reduces the incidence of delirium in hospitalized patients, with a relative risk of 0.69, indicating a 31% reduction in risk.

The study suggests that while melatonin is effective in preventing delirium in medical patients, further research is needed to explore its effects in surgical and critical care unit patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin intervention to prevent delirium in hospitalized patients: A meta-analysis. You, W., Fan, XY., Lei, C., et al.[2022]

In a postmarketing surveillance study of 653 patients aged 55 and older, prolonged-release melatonin (PRM) significantly improved sleep quality from an average score of 4.2 to 2.6 and morning alertness from 4.0 to 2.5 over three weeks of treatment.

PRM demonstrated a low incidence of rebound insomnia (3.2% early withdrawal, 2.0% late withdrawal) and was well tolerated, with minimal adverse effects, suggesting it is a safe and effective alternative to traditional hypnotics for managing insomnia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lasting treatment effects in a postmarketing surveillance study of prolonged-release melatonin. Hajak, G., Lemme, K., Zisapel, N.[2021]

In a small study of 10 elderly patients with delirium, ramelteon was found to be effective, with six patients showing improvement and no significant adverse effects reported.

Ramelteon may serve as a safe and beneficial alternative to melatonin for treating delirium in older adults, but further randomized controlled trials are needed to validate these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramelteon for the treatment of delirium in elderly patients: a consecutive case series study. Tsuda, A., Nishimura, K., Naganawa, E., et al.[2022]

A systematic review and meta-analysis of five randomized placebo-controlled trials involving 443 hospitalized patients found that ramelteon did not significantly reduce the risk of developing delirium, with an odds ratio of 0.49, indicating no protective effect.

Despite previous smaller studies suggesting potential benefits, the current evidence indicates that ramelteon is ineffective as a preventive treatment for delirium in hospitalized patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prophylactic Use of Ramelteon for Delirium in Hospitalized Patients: A Systematic Review and Meta-Analyses. Dang, V., Mansukhani, MP., Wang, Z., et al.[2023]

Melatonin and its analog ramelteon have shown effectiveness in preventing delirium, as demonstrated in three controlled studies, suggesting their potential as therapeutic options.

Delirium is linked to disruptions in brain activity and circadian rhythms, indicating that melatonergic drugs may help restore normal brain function and improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delirium and its prevention with melatonergic drugs. Howland, RH.[2014]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11587658/

Effects of melatonin on the prevention of delirium in ... The data indicate that melatonin may reduce the incidence of delirium, particularly in postoperative patients. However, further studies are ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12083333/

Effect of melatonin versus placebo for prevention ... Delirium severity showed mixed results; melatonin improved the BPRS score in one RCT, while other studies found no benefit.

3. link.springer.com link.springer.com/article/10.1007/s00134-025-08002-z

Melatonin for prevention of delirium in patients receiving ... This randomized clinical trial found that the low-dose of melatonin (0.3 mg nightly) achieved a better pharmacokinetic profile than the high-dose (3 mg nightly ...

4. agsjournals.onlinelibrary.wiley.com agsjournals.onlinelibrary.wiley.com/doi/10.1111/jgs.18825

Melatonin does not reduce delirium severity in hospitalized ... Our pilot trial found 120 participants would have 90% power to demonstrate a statistically significant outcome.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06509191

The Use of Melatonin for Delirium Prevention in Medically ... The study concluded that the nightly use of 3 mg melatonin did not reduce the incidence of delirium. 29 Overall, the trial conducted on hospitalized patients in ...

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK605079/

Melatonin for the Treatment or Prevention of Delirium - NCBI There were no statistically or clinically significant harms reported from the use of melatonin in the treatment of patients at risk from or experiencing ...

7. chestphysician.org chestphysician.org/oral-medications-for-sleep-in-nonintubated-icu-patients-and-their-impact-on-delirium/

Oral medications for sleep in nonintubated ICU patients and ... A meta-analysis also supports melatonin's safety and possible benefit in delirium prevention. ... ICU studies show mixed results: Some suggest ...