Suvorexant for Postoperative Delirium

(REPOSE Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Michael Devinney Jr, MD, PhD

Age: 65+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Duke University

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

Disqualifiers: Obesity, Psychotic disorders, Liver failure, others

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

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.

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}

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.

Trial 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 (Other)
• Suvorexant (Orexin Antagonist)

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, Australia, 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 Australia 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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Duke University Medical Center Durham, NC

Who Is Running the Clinical Trial?

Duke University Lead Sponsor

Merck Sharp & Dohme LLC Industry Sponsor

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] Insomnia frequently occurs in patients admitted to an intensive care unit (ICU). Sleep-promoting agents may reduce rapid eye movement sleep and have deliriogenic effects. Suvorexant (Belsomra) is an orexin receptor antagonist with Food and Drug Administration (FDA) approval for the treatment of adult insomnia, which improves sleep onset and maintenance as well as subjective measures of quality of sleep. This trial will evaluate the efficacy of postoperative oral suvorexant treatment on night-time wakefulness after persistent sleep onset as well as the incidence and duration of delirium among adult cardiac surgical patients.

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

The role of suvorexant in the prevention of delirium during acute hospitalization: A systematic review. [2021] To assess the efficacy and safety of suvorexant for the prevention of delirium during acute hospitalization.

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

Suvorexant for the prevention of delirium: A meta-analysis. [2021] Delirium is a frequently encountered complication, which is associated with increased mortality. Suvorexant, an approved agent for the treatment of insomnia, is recently suggested to be also effective for prevention of delirium by some authors. However, a consensus has yet to be reached. The goal of this study was to perform a meta-analysis to overall estimate the effectiveness of suvorexant in preventing delirium and its related consequences.

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

Preventive Effects of Suvorexant on Delirium: A Randomized Placebo-Controlled Trial. [2022] No highly effective pharmacologic interventions to prevent delirium have been identified. We examined whether suvorexant, a potent and selective orexin receptor antagonist, is effective for the prevention of delirium.

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

Tissue Distribution of Suvorexant in Three Forensic Autopsy Cases. [2018] Suvorexant (Belsomra®) is a relatively new insomnia medication that has been available in USA and Japan since 2014. It is a dual orexin receptor antagonist that promotes sleep by inhibiting the binding of orexin neurons to the OX1R and OX2R receptors. In this report, we describe the detection and quantitation of suvorexant from the postmortem specimens of three separate autopsy cases handled by our department. Suvorexant was identified by fast gas chromatography/mass spectrometry during routine screening, and quantitated by a fully validated liquid chromatography-tandem mass spectroscopy method. Quantitation was achieved by positive electrospray ionization in the selected reaction monitoring mode. Monitored transitions were m/z 451 > 186 for quantitation and m/z 451 > 104 for qualification. To our knowledge, this is the first instance of suvorexant being quantitated from actual autopsy cases. It is likely that this compound will be encountered more often by the forensic toxicology community going forward.

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] Suvorexant (Belsomra®) is a new hypnotic drug with a novel mechanism of action. In prescribed doses of 10 mg before bedtime, the drug produces rapid onset of sleep by inhibiting the orexin neurons of the arousal system, promoting decreased wakefulness. Suvorexant is a potent and highly selective dual orexin receptor antagonist. Sedative hypnotics are of forensic importance due to their widespread use, potential for additive effects with other central nervous system depressants, impairing effects and potential for misuse. In this report we describe a highly sensitive assay for the identification and quantification of suvorexant in urine. Suvorexant was isolated using liquid/liquid extraction (LLE) and identified using liquid chromatography-quadrupole/time-of-flight mass spectrometry. Suvorexant was quantified using a quadratic calibration model between 5 and 250 ng/mL (R2 = 1.000, n = 6). Processed sample stability was demonstrated for up to 24 h. The limit of detection was 0.5 ng/mL and the limit of quantification (LOQ) was 5 ng/mL. The accuracy, bias and precision of the assay at the LOQ were 99% (81-117%), -1% and 12% (n = 18). Intraassay (n = 5) and interassay (n = 15) precision (% CV) at 10, 50 and 200 ng/mL were ≤8%, and bias ranged from -2% to 4% (98-104% accuracy). No qualitative interferences were detected from matrix, internal standard or 50 common drugs. Matrix effects evaluated at low and high concentrations were -16% and -9%, respectively, and produced CVs of 11% and 5% (n = 20). Suvorexant is a new drug of forensic importance. In this report we describe how a simple acidic/neutral LLE can be used to isolate this lipophilic drug with high recoveries and sound analytical performance.

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

In vitro and in vivo characterisation of the metabolism and disposition of suvorexant in humans. [2017] 1. Suvorexant (MK-4305, Belsomra®) is a first-in-class dual orexin receptor antagonist approved in the USA and Japan for the treatment of insomnia. The current studies describe suvorexant's absorption, disposition and potential for CYP-mediated drug interactions in humans. 2. Following single oral administration of [(14)C]suvorexant to healthy human subjects, 90% of the radioactivity was recovered (66% in faeces, 23% in urine), primarily as oxidative metabolites. 3. In plasma, suvorexant and M9 were predominant, accounting for 30 and 37% of the total radioactivity, respectively. Metabolite M17 became more prominent (approaching 10%) following multiple daily doses of unlabelled suvorexant. M9 and M17 are not expected to contribute to the pharmacological activity of suvorexant due to reduced orexin receptor binding affinity and limited brain penetration. 4. CYP3A was determined to be the predominant enzyme mediating suvorexant oxidation. In vitro, suvorexant demonstrated reversible inhibition of CYP3A4 and 2C19 (IC50 ∼ 4-5 μM), and weak time-dependent inhibition of CYP3A4 (KI = 12 μM, kinact = 0.14 min(-1)). Suvorexant was also a weak inducer of CYP3A4, 1A2 and 2B6. Given the low plasma concentrations at clinical doses, suvorexant was not anticipated to cause significant drug interactions via inhibition and/or induction of major CYPs in vivo.

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] A method, using liquid chromatography with tandem mass spectrometric detection (LC-MS/MS), was developed for the determination of suvorexant (MK-4305, Belsomra(®)), a selective dual orexin receptor antagonist for the treatment insomnia, in human plasma over the concentration range of 1-1000ng/mL. Stable isotope labeled (13)C(2)H3-suvorexant was used as an internal standard. The sample preparation procedure utilized liquid-liquid extraction, in the 96-well format, of a 100μL plasma sample with methyl t-butyl ether. The compounds were chromatographed under isocratic conditions on a Waters dC18 (50×2.1mm, 3μm) column with a mobile phase consisting of 30/70 (v/v %) 10mM ammonium formate, pH3/acetonitrile at a flow rate of 0.3mL/min. Multiple reaction monitoring of the precursor-to-product ion pairs for suvorexant (m/z 451→186) and (13)C(2)H3-suvorexant (m/z 455→190) on an Applied Biosystems API 4000 tandem mass spectrometer was used for quantitation. Intraday assay precision, assessed in six different lots of control plasma, was within 10% CV at all concentrations, while assay accuracy ranged from 95.6 to 105.0% of nominal. Quality control (QC) samples in plasma were stored at -20°C. Initial within day analysis of QCs after one freeze-thaw cycle showed accuracy within 9.5% of nominal with precision (CV) of 6.7% or less. The plasma QC samples were demonstrated to be stable for up to 25 months at -20°C. The method described has been used to support clinical studies during Phase I through III of clinical development.