Ramelteon for Delirium

(DREAM Trial)

Overseen By Chelsea Mitchell, PharmD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Centennial Medical Center

Must not be taking: Fluvoxamine

Disqualifiers: Cirrhosis, Alcohol withdrawal, Pregnancy, 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

506 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether ramelteon, a drug typically used for insomnia, can prevent or treat delirium (sudden confusion) in ICU patients. Delirium poses a significant challenge for those in intensive care, and no proven medication currently exists to prevent or treat it. The trial compares ramelteon to a placebo (a harmless pill with no active drug) to assess its effectiveness. Participants must be in a medical or surgical ICU and able to take medicine by mouth or tube shortly after arrival. As a Phase 4 trial, this research aims to understand how the already FDA-approved treatment benefits more patients.

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 taking fluvoxamine.

What is the safety track record for Ramelteon?

Research has shown that ramelteon, a medication approved for treating insomnia, could be beneficial in hospitals. Studies have found that ramelteon may reduce the duration of delirium and shorten ICU stays. It appears to improve sleep quality, which is crucial for recovery.

In another study, ramelteon was linked to a lower risk of delirium. Only 3% of patients taking ramelteon developed delirium, compared to 32% in a comparison group. This suggests that ramelteon is generally well-tolerated and might be safer than traditional treatments.

These findings indicate that ramelteon is safe for patients, especially since it is already used for sleep issues. It could be an effective option for managing or preventing delirium in the ICU. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Most treatments for delirium, like antipsychotics or sedatives, work by calming the nervous system. But Ramelteon works differently, targeting the body’s natural sleep-wake cycle. Ramelteon is a melatonin receptor agonist, meaning it helps regulate sleep without the sedative effects that can sometimes worsen delirium. Researchers are excited about Ramelteon because it might offer a safer and more natural approach to managing delirium, potentially reducing the risk of side effects associated with traditional medications.

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

Research has shown that ramelteon, a medication for insomnia, might also reduce confusion (delirium) in ICU patients. One study found that patients taking ramelteon had shorter ICU stays, experienced less delirium, and slept better. Another review indicated that ramelteon significantly lowered the chances of delirium, though confidence in this finding is low. However, some studies suggest ramelteon might not effectively prevent delirium in hospitalized patients. In this trial, participants will receive either ramelteon or a placebo to further investigate its effectiveness for delirium. While some evidence suggests ramelteon could be helpful, results are mixed, and more research is needed to confirm its effectiveness for delirium. ^{1 3 6 7 8}

Who Is on the Research Team?

Jennifer Johnson, MD

Principal Investigator

Centennial Medical Center

Are You a Good Fit for This Trial?

This trial is for ICU patients who can take oral or tube medication within 48 hours of admission, expected to stay in the ICU and live at least another 48 hours. They must be able to consent. It's not for those with cirrhosis, alcohol withdrawal, certain drug use, ramelteon allergy, incarceration, pregnancy, acute brain conditions or non-English speakers.

Inclusion Criteria

I can take medicine by mouth or through a tube within 2 days of ICU admission.

I am expected to stay in the ICU for at least 48 hours and live beyond that.

I am currently a patient in the ICU.

Exclusion Criteria

You have reported being very sensitive or allergic to ramelteon.

I was taking fluvoxamine before I was admitted.

I have a current acute brain condition like an abscess, bleed, or meningitis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either ramelteon 8 mg or placebo daily at 20:30 for delirium prevention and treatment

14 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ramelteon

Trial Overview The study tests if Ramelteon (an insomnia drug) can treat or prevent delirium by helping regulate sleep cycles in ICU patients. Participants will receive an 8mg dose of Ramelteon with the aim to see if it reduces instances of delirium.

How Is the Trial Designed?

Group I: ramelteon Experimental Treatment 1 Intervention

ramelteon 8 mg crushed tablet daily at 20:30

Group II: placebo Placebo Group 1 Intervention

placebo powder equivalent grams at 20:30

Ramelteon is already approved in United States, Japan for the following indications:

Approved in United States as Rozerem for:

• Insomnia characterized by difficulty with sleep onset

Approved in Japan as Rozerem for:

• Insomnia

Who Is Running the Clinical Trial?

Centennial Medical Center

Lead Sponsor

Trials

1

Recruited

510+

Published Research Related to This Trial

Ramelteon, a selective melatonin receptor agonist, has potential as a safe and effective prophylactic treatment for preventing delirium in frail older patients, particularly those at high risk.

Despite its promise, current evidence is insufficient to confirm the effectiveness of ramelteon and exogenous melatonin in preventing or treating postoperative delirium and sleep disorders in critically ill patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Delirium, insomnia in hospitalization and ramelteon]. Ito, T.[2014]

Ramelteon 8 mg significantly reduced the time it took for older adults with severe sleep-onset difficulties to fall asleep, showing a mean reduction of 23.2 minutes in the first week and sustained improvements over 5 weeks.

The treatment was well-tolerated, with low incidence of adverse events, suggesting that ramelteon is a safe option for managing insomnia in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Self-reported efficacy and tolerability of ramelteon 8 mg in older adults experiencing severe sleep-onset difficulty. Mini, LJ., Wang-Weigand, S., Zhang, J.[2014]

In a study involving 120 patients undergoing elective pulmonary thromboendarterectomy, ramelteon did not significantly reduce the incidence of postoperative delirium compared to placebo, with 22 cases in the placebo group and 19 in the ramelteon group.

The duration of delirium and coma-free days were similar between the two groups, indicating that ramelteon 8 mg was ineffective in preventing delirium in the ICU setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramelteon for Prevention of Postoperative Delirium: A Randomized Controlled Trial in Patients Undergoing Elective Pulmonary Thromboendarterectomy. Jaiswal, SJ., Vyas, AD., Heisel, AJ., et al.[2020]

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]

Ramelteon (Rozerem) significantly improves latency to persistent sleep (LPS) in patients with chronic insomnia when taken 30 minutes before bedtime, with effects maintained over 5 weeks and 6 months in clinical studies.

It is generally well tolerated, does not impair next-day performance, and has no withdrawal symptoms or abuse potential, making it a safe option for treating insomnia related to sleep onset difficulties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramelteon: a review of its use in insomnia. Simpson, D., Curran, MP.[2021]

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]

Ramelteon significantly reduces the odds of delirium occurrence in hospitalized patients compared to placebo, with an odds ratio of 0.50 based on a meta-analysis of 8 randomized controlled trials involving 587 participants.

The effectiveness of ramelteon in preventing delirium is particularly notable in elderly patients and those receiving multiple dosages, suggesting it may be a beneficial option for these specific groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramelteon for delirium prevention in hospitalized patients: An updated meta-analysis and trial sequential analysis of randomized controlled trials. Yu, CL., Carvalho, AF., Thompson, T., et al.[2023]

Ramelteon, a melatonin receptor agonist, has shown promise in preventing postoperative delirium in cancer patients, particularly in Japanese studies, with no serious safety concerns reported.

A new phase III trial is being conducted to further evaluate the effectiveness and safety of ramelteon for preventing delirium in cancer patients aged 65 and older, following positive results from a phase II study in patients aged 75 and above.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multi-centre, double-blind, randomized, placebo-controlled trial to evaluate the effectiveness and safety of ramelteon for the prevention of postoperative delirium in elderly cancer patients: a study protocol for JORTC-PON2/J-SUPPORT2103/NCCH2103. Sadahiro, R., Hatta, K., Yamaguchi, T., et al.[2023]

In a study of 125 elderly patients with delirium, those treated with ramelteon showed a significantly lower need for as-needed antipsychotics (60% vs. 80%) compared to those who did not receive ramelteon.

The results suggest that ramelteon may effectively reduce agitation in delirious patients, with an odds ratio of 4.3 indicating a higher likelihood of antipsychotic use in the non-ramelteon group, highlighting its potential as a safer alternative for managing agitation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of Ramelteon in Reduction of As-Needed Antipsychotics in Elderly Patients with Delirium in a General Hospital Setting. Pinkhasov, A., James, SA., Fazzari, M., et al.[2022]

In a small study involving three patients, ramelteon was associated with improved scores on the Memorial Delirium Assessment Scale, indicating a potential benefit in treating delirium.

The results suggest that ramelteon may be effective for delirium, but further randomized controlled studies are necessary to confirm its therapeutic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of delirium with ramelteon: initial experience in three patients. Kimura, R., Mori, K., Kumazaki, H., et al.[2022]

Ramelteon (Rozerem) is a melatonin receptor agonist that promotes sleep without the common side effects associated with traditional hypnotics, such as cognitive impairment and dependence.

Clinical trials have shown that ramelteon effectively improves sleep while having a favorable safety profile, making it a valuable alternative for treating insomnia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A novel therapeutic drug: ramelteon]. Miyamoto, M.[2014]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12415405/

Efficacy and Safety of Ramelteon in the Reduction ... Ramelteon was associated with a reduced ICU stay, shorter delirium duration, and improved sleep quality in critically ill patients. While its ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40511987/

Efficacy of Ramelteon, Suvorexant, and Lemborexant for ... Pooled analyses showed a significant reduction in delirium prevalence in both randomized trials (RR, 0.60; 95% CI, 0.38-0.97; low certainty) and ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03931070

The Effect of Ramelteon on Delirium and Sleep in Patients ... Many pharmacologic agents have been studied to reduce delirium in high risk patients, but the data has not shown significant or clinically important outcomes.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2667296022002786

Prophylactic Use of Ramelteon for Delirium in Hospitalized ... Current evidence suggests that ramelteon is ineffective as a prophylactic drug in reducing the incidence of delirium in hospitalized patients.

5. journals.lww.com journals.lww.com/ccmjournal/fulltext/2025/09000/efficacy_of_ramelteon,_suvorexant,_and_lemborexant.7.aspx

Efficacy of Ramelteon, Suvorexant, and Lemborexant for... Sleep-wake regulating pharmacologic agents were associated with 40%–46% relative risk reductions in delirium prevalence, based on low-certainty evidence.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40926919/

Efficacy and Safety of Ramelteon in the Reduction ... Conclusion Ramelteon was associated with a reduced ICU stay, shorter delirium duration, and improved sleep quality in critically ill patients.

7. jamanetwork.com jamanetwork.com/journals/jamapsychiatry/fullarticle/1831407

Preventive Effects of Ramelteon on Delirium Results Ramelteon was associated with a lower risk of delirium (3% vs 32%; P = .003), with a relative risk of 0.09 (95% CI, 0.01-0.69). Even ...

8. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1111%2Fjpi.12857

Ramelteon for delirium prevention in hospitalized patients ... The results of TSA support that ramelteon may reduce the RR of delirium by 40%−60% than placebo. Second, the subgroup analyses suggested that ...