Melatonin for Delirium

(DELIRE-ICU Trial)

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

Trial Summary

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.

What data supports the effectiveness of the drug melatonin for delirium?

Research indicates that melatonin may help prevent and manage delirium in older adults, although it doesn't seem to reduce the severity of delirium. Additionally, a similar drug, ramelteon, has shown benefits in preventing delirium, suggesting that melatonin might also be effective. ^{1 2 3 4 5}

Is melatonin safe for humans?

Melatonin and its agonists, like ramelteon, have been well tolerated in studies, with few adverse effects reported. In trials for conditions like delirium and insomnia, melatonin was generally safe, with mild side effects such as nausea and dizziness occurring in a small number of cases. ^{1 2 6 7 8}

How does melatonin differ from other drugs for delirium?

Melatonin is unique in its use for delirium because it is a natural hormone that helps regulate sleep-wake cycles, and it is well-tolerated with few side effects. Unlike other drugs, melatonin focuses on correcting circadian rhythm disruptions, which are thought to contribute to delirium, rather than directly targeting symptoms or behaviors. ^{1 2 8 9 10}

What is the purpose of this trial?

This trial aims to test if melatonin can help reduce delirium in critically ill ICU patients by improving their sleep. Delirium is common in these patients, and there are no effective drug treatments currently available. By regulating sleep, melatonin might shorten the duration of delirium episodes. Melatonin is a natural hormone secreted by the pineal gland which helps in the regulation of the sleep-wake cycle.

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

Eligibility Criteria

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

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

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Melatonin and melatonin agonist for delirium in the elderly patients. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Melatonin Receptor Agonists for Delirium Prevention. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Marked improvement in delirium with ramelteon: five case reports. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

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

5. England pubmed.ncbi.nlm.nih.gov

Melatonin and Ramelteon for the treatment of delirium: A systematic review and meta-analysis. [2023]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Prophylactic Use of Ramelteon for Delirium in Hospitalized Patients: A Systematic Review and Meta-Analyses. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Lasting treatment effects in a postmarketing surveillance study of prolonged-release melatonin. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Ramelteon for the treatment of delirium in elderly patients: a consecutive case series study. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Delirium and its prevention with melatonergic drugs. [2014]

10. United States pubmed.ncbi.nlm.nih.gov

Melatonin intervention to prevent delirium in hospitalized patients: A meta-analysis. [2022]