Suvorexant for Postoperative Delirium

(REPOSE Trial)

Overseen By Kelly Rodden, RN, BSN

Age: 65+

Sex: Any

Trial Phase: Phase 2

Sponsor: Duke University

Must not be taking: CYP3A inhibitors, CYP3A inducers, Sedating sleep aids

Disqualifiers: Obesity, Psychotic disorders, Liver failure, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 3 days

130 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires you to stop taking certain medications, such as sedating sleep aids and moderate or strong CYP3A inhibitors or inducers, at least one week before surgery. If you are taking any of these, you may need to stop or adjust them to participate.

What data supports the effectiveness of the drug suvorexant for preventing postoperative delirium?

Suvorexant, known for treating insomnia, is being studied for its potential to prevent delirium, a common complication after surgery. Some studies suggest it might help reduce the incidence of delirium, but there is not yet a consensus on its effectiveness. ^{1 2 3 4 5}

Is suvorexant generally safe for humans?

Suvorexant, also known as Belsomra, is approved by the FDA for treating insomnia in adults and has been studied for its safety and metabolism in humans. It is primarily processed by the liver and excreted in urine and feces, with no significant drug interactions expected at clinical doses. ^{1 2 5 6 7}

How is the drug Suvorexant unique for treating postoperative delirium?

Suvorexant is unique because it is a dual orexin receptor antagonist, which means it works by blocking the action of orexin, a chemical in the brain that promotes wakefulness. This mechanism is different from other sleep-promoting drugs that often reduce rapid eye movement sleep and can cause delirium, making Suvorexant potentially beneficial for reducing postoperative delirium by improving sleep without these side effects. ^{1 5 6 7 8}

What is the purpose of this trial?

This research study will evaluate the effectiveness of postoperative administration of a drug called suvorexant, to improve postoperative sleep and decrease the severity of delirium (serious confusion) in adults 65 years and older undergoing non-cardiac surgery.

Research Team

Michael Devinney Jr, MD, PhD

Principal Investigator

Duke University

Eligibility Criteria

This trial is for adults aged 65 and older who are English-speaking, scheduled for non-cardiac surgery with an overnight stay, and can consent to participate. Excluded are those with a BMI over 40, severe sleep apnea, certain psychotic disorders, liver failure, or using specific medications that affect suvorexant.

Inclusion Criteria

Able to give informed consent or has legally authorized representative able to give informed consent on their behalf

I am having surgery that does not involve my heart or brain.

English-speaking

Exclusion Criteria

I am having surgery that needs strict bowel rest afterwards, like stomach or pancreas surgery.

You have a very high body mass index.

I will have surgery that stops me from taking pills by mouth.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Preoperative Assessment

Participants complete questionnaires, thinking and memory tests, attention tests, and pupil size measurements. A blood sample is collected.

1 day

1 visit (in-person)

Treatment

Participants receive either suvorexant or placebo for the first three nights after surgery. Sleep quality and delirium tests are conducted.

3 days

Daily monitoring (in-hospital)

Postoperative Monitoring

Participants' sleep quality and delirium severity are assessed daily until postoperative day 5 or hospital discharge.

5 days

Daily monitoring (in-hospital)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including hospital length of stay and follow-up visit.

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Placebo
• Suvorexant

Trial Overview The REPOSE Study is testing if suvorexant (20 mg), a drug given after surgery can improve sleep quality and reduce delirium severity compared to a placebo in older adults following non-cardiac surgery.

Participant Groups

Group I: Suvorexant Arm Active Control 1 Intervention

Group II: Placebo Arm Placebo Group 1 Intervention

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

Approved in United States as Belsomra for:

• Insomnia characterized by difficulties with sleep onset and/or sleep maintenance

Approved in Japan as Belsomra for:

• Insomnia characterized by difficulties with sleep onset and/or sleep maintenance

Who Is Running the Clinical Trial?

Duke University

Lead Sponsor

Trials

2,495

Recruited

5,912,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

This trial will assess the efficacy of suvorexant, an FDA-approved sleep aid, in reducing nighttime wakefulness and delirium in 120 older cardiac surgery patients in the ICU.

The study aims to determine if suvorexant can improve sleep quality and reduce the incidence of postoperative delirium, which is important for recovery in this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study protocol for a randomised controlled trial evaluating the effects of the orexin receptor antagonist suvorexant on sleep architecture and delirium in the intensive care unit. Azimaraghi, O., Hammer, M., Santer, P., et al.[2021]

Suvorexant, administered at doses of 15 to 20 mg, effectively reduces the incidence and onset time of delirium in acutely hospitalized patients, potentially leading to shorter hospital stays.

The treatment was well tolerated, with adverse effects comparable to those of a placebo, indicating a favorable safety profile for suvorexant in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of suvorexant in the prevention of delirium during acute hospitalization: A systematic review. Adams, AD., Pepin, MJ., Brown, JN.[2021]

A meta-analysis of seven studies involving 402 patients treated with suvorexant showed a significant reduction in the incidence of delirium (odds ratio of 0.30) and a delay in the onset of delirium (standardized mean difference of 0.44) compared to control treatments.

Suvorexant did not show significant benefits on secondary outcomes such as length of hospital stay, time on ventilation, or mortality, indicating its primary effectiveness lies in preventing delirium rather than improving overall hospital metrics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Suvorexant for the prevention of delirium: A meta-analysis. Xu, S., Cui, Y., Shen, J., et al.[2021]

In a clinical trial involving 72 elderly patients (ages 65-89) admitted for acute care, suvorexant significantly reduced the incidence of delirium compared to placebo, with 0% of patients on suvorexant developing delirium versus 17% on placebo (P = .025).

The study suggests that suvorexant may help improve sleep-wake cycle disturbances associated with delirium, although further research with larger sample sizes is needed to confirm its efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preventive Effects of Suvorexant on Delirium: A Randomized Placebo-Controlled Trial. Hatta, K., Kishi, Y., Wada, K., et al.[2022]

Suvorexant, a dual orexin receptor antagonist used for treating insomnia, promotes sleep by blocking orexin receptors, and has been available since 2014 in the USA and Japan.

This report presents the first quantitation of suvorexant in postmortem specimens from three autopsy cases, indicating its potential relevance in forensic toxicology as its use may increase.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tissue Distribution of Suvorexant in Three Forensic Autopsy Cases. Waters, B., Hara, K., Ikematsu, N., et al.[2018]

Suvorexant (Belsomra®) is a new sleep medication that works by blocking orexin neurons, leading to a rapid onset of sleep, and is effective at a prescribed dose of 10 mg before bedtime.

A highly sensitive urine assay was developed to accurately identify and quantify suvorexant, demonstrating excellent precision and stability, which is crucial for monitoring its use due to potential misuse and interactions with other sedatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of Suvorexant in Urine Using Liquid Chromatography-Quadrupole/Time-of-Flight Mass Spectrometry (LC-Q/TOF-MS). Sullinger, S., Bryand, K., Kerrigan, S.[2017]

Suvorexant, a dual orexin receptor antagonist approved for insomnia, is primarily metabolized in the body with 90% of its radioactivity recovered after administration, indicating effective absorption and elimination.

The drug mainly inhibits CYP3A4 and CYP2C19 enzymes but is unlikely to cause significant drug interactions at clinical doses due to low plasma concentrations, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro and in vivo characterisation of the metabolism and disposition of suvorexant in humans. Cui, D., Cabalu, T., Yee, KL., et al.[2017]

A reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to measure suvorexant levels in human plasma, demonstrating high precision and accuracy across a wide concentration range (1-1000 ng/mL).

The method has been validated for stability and can support clinical studies for suvorexant, showing that plasma samples remain stable for up to 25 months at -20°C, which is crucial for long-term studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of suvorexant in human plasma using 96-well liquid-liquid extraction and HPLC with tandem mass spectrometric detection. Breidinger, SA., Simpson, RC., Mangin, E., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Study protocol for a randomised controlled trial evaluating the effects of the orexin receptor antagonist suvorexant on sleep architecture and delirium in the intensive care unit. [2021]

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

The role of suvorexant in the prevention of delirium during acute hospitalization: A systematic review. [2021]

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

Suvorexant for the prevention of delirium: A meta-analysis. [2021]

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

Preventive Effects of Suvorexant on Delirium: A Randomized Placebo-Controlled Trial. [2022]

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

Tissue Distribution of Suvorexant in Three Forensic Autopsy Cases. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Identification of Suvorexant in Urine Using Liquid Chromatography-Quadrupole/Time-of-Flight Mass Spectrometry (LC-Q/TOF-MS). [2017]

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

In vitro and in vivo characterisation of the metabolism and disposition of suvorexant in humans. [2017]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Determination of suvorexant in human plasma using 96-well liquid-liquid extraction and HPLC with tandem mass spectrometric detection. [2019]