Clinical trial NCT06648681: Lemborexant to Prevent Post-operative Delirium in Cardiac Surgery Patients
Official title: A Randomized Trial of Lemborexant for the Prevention of Delirium After Cardiac Surgery (PROTEX): A Pilot Study
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Delirium - Postoperative
Cardiac Surgery
Cardiac Surgery Subjects
Orexin Antagonist
Feasibility Studies
Sleep
In-hospital Mortality
Keywords: lemborexant
Postoperative Delirium
sleep medication
ICDSC
CAM
cardiac surgery
sleep aid
open heart surgery
delirium
sleep quality
Richards-Campbell Sleep Questionnaire
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: Eisai Inc.
name: Providence Health Care, British Columbia
name: St. Paul's Hospital, Vancouver (Providence Health Care)
First posted: 2024-10-18
Enrollment: 60
Sex: ALL
Minimum age (years): 61
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a single centre, randomized, double blinded, placebo-controlled pilot trial, with 1:1 allocation of study drug to placebo.
Primary purpose: PREVENTION

Brief summary: Post-operative delirium is a common complication following cardiac surgery and is associated with increased 1 year mortality. Currently there are no drug therapies to prevent delirium. Orexin is a neuromodulator thought to play an important role in disordered sleep, one of the instigators of delirium. Lembrorexant is an orexin antagonist, originally approved for sleep, that may also reduce the incidence of delirium. The Investigators propose a pilot study to determine the feasibility of a randomized controlled trial comparing Lembrorexant to placebo in patients following cardiac surgery in reducing the incidence of delirium, and improving sleep.

Detailed description: Purpose:

This is a pilot study to determine the feasibility of a larger randomized controlled trial comparing lemborexant to placebo in patients following cardiac surgery. The primary outcome of this feasibility study is to determine the rate of enrolment, adherence and retention of patients. Secondary outcomes will include incidence of postoperative delirium, delirium days, quality of sleep, hospital length of stay, and the safety and adverse side effect profile of Lemborexant.

Hypothesis:

1) Primary outcome: It is feasible to perform a study of lembrorexant versus placebo in patients after cardiac surgery, as defined by achieving a recruitment rate of at least 70% and adherence rate of 80% to the study protocol and drug administration schedule.

Justification:

Postoperative delirium is a frequent complication after cardiac surgery, with an incidence estimated at 20-52%. It is associated with increased 1 year mortality, longer ICU and hospital length of stay, and declines in functional and cognitive status that may persist for up to one year. Orexin, a neuromodulator regulating sleep and wakefulness, is believed to significantly influence the pathophysiology of delirium through its association with disordered sleep. Thus far, there are no promising therapies in prevention or treatment of post cardiac surgery delirium.

Lemborexant is a novel orexin antagonist that has been approved for treating insomnia, and has shown promising results in some studies in reducing incidence of delirium post-cardiac surgery. However, the generalizability of these studies is limited by small numbers of patients, an exclusively Asian population, variability in clinical settings, use of different clinical delirium assessment tools, and variability in comparator groups. In addition, the safety profile of lembrorexant has not been well established in the cardiac surgery population.

Objectives:

Primary Objective: to determine the rate of enrolment, adherence and retention of patients in a randomized controlled trial comparing Lemborexant to placebo early after cardiac surgery.

Secondary Objective: to compare the incidence of postoperative delirium, quality of sleep as measured by Richard Campbell's Sleep Questionnaire (RCSQ), delirium days, hospital length of stay between Lembrorexant and placebo. To determine the safety and adverse side effect profile of Lemborexant.

Research Design:

This will be a single centre, randomized, double blinded, placebo-controlled pilot trial, with 1:1 allocation of study drug to placebo. Local enrollment local is 60 patients (30 control, 30 experimental).

Statistical Analysis plan:

Patient characteristics will be described using means and standard deviations for continuous data and proportions (%) for categorical data. All analyses will be conducted on the intention-to-treat population. For the primary feasibility outcomes, the investigators will calculate 95% confidence intervals using the whole trial sample. For the secondary outcomes, the investigators will compare proportions with Lembrorexant vs placebo two-sample t-test for parametric data and Wilcoxon Rank Sum test for non parametric data. Analyses will be conducted using R 4.0.5.

Sample Size Calculation: To assess feasibility outcomes, the sample size was calculated to estimate an adherence rate of 80% with a 95% confidence interval of +/- 10%. From this calculation, the sample size will be set at 60 participants, or 10% of the sample size of a definitive trial.

Eligibility criteria: Inclusion Criteria:

* Admitted to hospital following open cardiac surgery through midline sternotomy

Exclusion Criteria:

* ● Known severe obstructive sleep apnea diagnosed by polysomnography or STOPBANG score \> 5

  * Periodic limb movement disorder or restless legs syndrome
  * Narcolepsy
  * Somnolence (Pasero Opioid Sedation Scale (POSS) \>2)
  * Current alcohol or substance use disorder as defined by the DSM-V
  * Patient already taking moderate or strong CYP3A inhibitors
  * Frequent use of medications for insomnia defined as \>4 days per week.
  * Liver failure (Child-Pugh score B or C)
  * Renal failure (eGFR\<30 ml/min/1.73 m2)
  * Pre-existing delirium (ICDSC score \>3 or CAM/CAM-ICU positive) at time of consent
  * BMI\>40 kg/m2
  * Known allergy or hypersensitivity to study drug
  * Inability to communicate in English

Primary outcomes:
measure: Recruitment Feasibility
timeFrame: Prior to Surgery, for the duration of the study recruitment period, estimated to be approximately 2 years
measure: Data Collection Adherence
timeFrame: Post-operative day 0 to 7
Secondary outcomes:
measure: Incidence of Postoperative Delirium
timeFrame: Post-operative day 0 at baseline (immediately before administration of the drug/placebo) and every 12 hours following drug/placebo administration until end of the 7 day follow-up
measure: Delirium Days
timeFrame: Post-operative day 0 to 7
measure: Adverse side effects
timeFrame: At the time of study drug initiation (T0) and daily following drug/placebo administration (T1 onwards) until end of the 7 day study follow-up.
measure: Sleep Quality
timeFrame: Preoperative baseline (time of recruitment/consent T -1), and daily following drug/placebo administration (T1 onwards) until end of the 7 day follow-up.
measure: Incidence of Additional Sleep Medications
timeFrame: Post-operative day 0 to 7
measure: Postoperative Hospital Length of Stay
timeFrame: Postoperative day 0 until hospital discharge, usually about 5-7 days postoperatively
measure: In-Hospital Mortality
timeFrame: from postoperative day 0 to hospital discharge, usually 5-7 days postoperatively
Other outcomes:
Locations:
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
Study officials:
References: