Clinical trial NCT04335968: Melatonin for Prevention of Postoperative Delirium After Lower Limb Fracture Surgery in Elderly Patients
Official title: Melatonin for Prevention of Postoperative Delirium After Lower Limb Fracture Surgery in Elderly Patients: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Orthopedic Surgery
Keywords: delirium
aging
Perioperative neurocognitive disorders
melatonine
orthopedic surgery
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2020-04-07
Enrollment: 357
Sex: ALL
Minimum age (years): 70
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, national multicentric (21 centers), phase III, superiority, comparative randomized (1:1) double-blinded clinical trial with two parallel arms
Primary purpose: PREVENTION

Brief summary: Postoperative delirium (POD) is one of the most frequent complications after surgery in elderly patients, affecting between 20 and 40% of patients older than 60 after major surgery. This complication has huge consequences for the patients, families and society: increase of morbidity and mortality, prolonged length of stay, cognitive and functional decline leading to loss of autonomy, and important additional healthcare costs.

Among numerous risk factors identified, perioperative inflammatory stress is a key element in delirium genesis: surgical trauma releases danger signals in systemic circulation, activating immune cells and leading to neuroinflammation.

Melatonin is a neurohormone regulating circadian rhythm. But it also exhibits antioxidant and free radical scavenger properties, and regulates energy metabolism and immune function. It has already demonstrated a neuroprotective potential in various animal models. Its use against delirium is promising: it decreases delirium incidence in elderly patients hospitalized in medical ward, and several studies are now recruiting in ICU.

The hypothesis of the trial is that in a high-risk population, perioperative melatonin can reduce the incidence of POD.

The main objective is to evaluate the effect of perioperative melatonin administration on postoperative delirium incidence in the first 10 days after surgery, in elderly patients (over 70 years old) being hospitalized and scheduled for acute surgery of fractured lower limb (from femoral head to tibial plateau).

This is a prospective, national multicentric (24 centers), phase III, superiority, comparative randomized (1:1) double-blinded clinical trial with two parallel arms:

Experimental group: melatonin 4mg per os every night, starting the evening before surgery (or 2 hours before emergency surgery) and until day 5 after surgery.

Control group: placebo of this drug with the same schedule, during the same period of time.

The patients are aged 70 or older, hospitalized and scheduled for surgery of a severe fracture of a lower limb (from femoral head to tibial plateau).

Detailed description: Postoperative delirium (POD) is one of the most frequent complications after surgery in elderly patients, affecting between 20 and 40% of patients older than 60 after major surgery. This complication has huge consequences for the patients, families and society: increase of morbidity and mortality, prolonged length of stay, cognitive and functional decline leading to loss of autonomy, and important additional healthcare costs.

Among numerous risk factors identified, perioperative inflammatory stress is a key element in delirium genesis: surgical trauma releases danger signals in systemic circulation, activating immune cells and leading to neuroinflammation. In the brain, especially in hippocampus, proinflammatory cytokines, immune cells recruitment and microglial activation alter synaptic plasticity and lead to acute cognitive dysfunction. Moreover, with aging, an increase in initial neuroinflammatory response and a decrease in subsequent resolution phase are observed.

Melatonin is a neurohormone regulating circadian rhythm. But it also exhibits antioxidant and free radical scavenger properties, and regulates energy metabolism and immune function. It has already demonstrated a neuroprotective potential in various animal models. Its use against delirium is promising: it decreases delirium incidence in elderly patients hospitalized in medical ward, and several studies are now recruiting in ICU. Concerning the perioperative period, only two studies with conflicting results are available. The first one (Sultan, 2010), that has shown that melatonin decreases POD incidence, has strong methodological limitations (no calculated sample size, only 53 patients in melatonin group, all patients, even in the control group received melatonin if they developed POD, etc). In the second one (deJonghe, 2014), melatonin had no effect on POD incidence, but showed a reduction in the proportion of patients with POD exceeding 2 days. These conflicting results emphasize the need for a third RCT, with optimized methodology.

The hypothesis of the trial is that in a high-risk population, perioperative melatonin can reduce the incidence of POD.

The main objective is to evaluate the effect of perioperative melatonin administration on postoperative delirium incidence in the first 10 days after surgery, in elderly patients (over 70 years old) being hospitalized and scheduled for acute surgery of fractured lower limb (from femoral head to tibial plateau).

This is a prospective, national multicentric (24 centers), phase III, superiority, comparative randomized (1:1) double-blinded clinical trial with two parallel arms:

Experimental group: melatonin 4mg per os every night, starting the evening before surgery (or 2 hours before emergency surgery) and until day 5 after surgery.

Control group: placebo of this drug with the same schedule, during the same period of time.

The patients are aged 70 or older, hospitalized and scheduled for surgery of a severe fracture of a lower limb (from femoral head to tibial plateau).

An ancillary study is also planned in this study with the hypothesise that :

* Patients presenting post-operative delirium may exhibit significant perturbations of phenotypic and transcriptomic features of circulating leukocytes, of plasma levels of cytokines, and of oxidative stress level.
* Administration of melatonin may prevent these perturbations.

Ancillary study concerns Beaujon, Bichat and la Pitié centers.

Eligibility criteria: Inclusion Criteria:

* Demographic criteria: patient 70 years old or older
* Diagnostic criteria: isolated fracture of a lower limb

  * Proximal femoral fractures: head, cervical, or trochanteric fractures
  * Periprosthetic hip fracture
  * Femoral shaft fracture
  * Distal femoral fractures: supracondylar or condylar
  * Periprosthetic knee fracture
  * Tibial plateau fracture
* Treatments/strategies/procedures: scheduled orthopedic surgery (osteosynthesis or arthroplasty)
* proxy or care giver knowing baseline cognitive status of the patient present or reachable by phone for an interview

Exclusion Criteria:

* Patient already taking Melatonin
* Contraindications and precaution for use of Melatonin administration:

  * Hypersensitivity to the active substance or to any of the excipients of Circadin©
  * Liver failure (presence of some of the following clinical and biological symptoms: icterus, asterixis, ascites, known esophageal varices, total bilirubin \>20 micromol/L, FV \<70%),
  * Cirrhosis (known histological liver fibrosis)
  * Renal failure with clearance \<30 ml/min O Autoimmune disease O Hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome
  * Patients taking fluvoxamine, 5- or 8-methoxypsoralen, cimetidine, oestrogenotherapy, quinolones, carbamazepine, rifampicin
* Other concomitant trauma than lower limb fracture(s)
* Surgery scheduled in more than 5 days
* Patient under mechanical ventilation
* Patient refusing to participate
* Patient not talking / understanding French (delirium assessment impossible)
* Patient already participating to another interventional study
* No signed informed consent,
* No affiliation to a social security regime

Secondary Exclusion Criteria:

Secondary exclusion (before randomization): diagnosis of delirium at the CAM assessment at inclusion, or creatinin clearance \<30 ml / min and /or biological signs of hepatocellular insufficiency (bilirubin\> 20 umol/l and factor V \<70%) if samples not available during the anesthesiologist consultation and so performed after inclusion.

Primary outcomes:
measure: Postoperative delirium incidence
timeFrame: 10 days after surgery
Secondary outcomes:
measure: Number of days CAM positive
timeFrame: 10 days after surgery
measure: Incidence of postoperative sedative or antipsychotic drugs administration from
timeFrame: 10 days after surgery
measure: Incidence of postoperative physical restrain prescription
timeFrame: 10 days after surgery
measure: Incidence of postoperative falls
timeFrame: 10 days after surgery
measure: Mini Mental State Examination
timeFrame: 10 days (or end of hospital stay if shorter)
measure: Duration of hospital stay
timeFrame: 30 days after surgery
measure: 30 days postoperative mortality
timeFrame: 30 days after surgery
measure: 30 days postoperative patient autonomy
timeFrame: 30 days after surgery
measure: 30 days postoperative Quality of life
timeFrame: 30 days after surgery
measure: 30 days postoperative QALYs (quality-adjusted life year)
timeFrame: 30 days after surgery
measure: Total hospital costs at 30 days
timeFrame: 30 days after surgery
measure: Incremental cost effectiveness
timeFrame: 30 days after surgery
measure: cost utility ratios
timeFrame: 30 days after surgery
measure: Occurrence of side effects
timeFrame: 30 days after surgery
Other outcomes:
Locations:
city: Clichy-sous-Bois
country: France
facility: hôpital Beaujon
Study officials:
affiliation: APHP
name: Stéphanie Sigaut
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sigaut S, Couffignal C, Esposito-Farese M, Degos V, Molliex S, Boddaert J, Raynaud-Simon A, Durand-Zaleski I, Marcault E, Jacota M, Dahmani S, Paugam-Burtz C, Weiss E. Melatonin for prevention of postoperative delirium after lower limb fracture surgery in elderly patients (DELIRLESS): study protocol for a multicentre randomised controlled trial. BMJ Open. 2021 Dec 24;11(12):e053908. doi: 10.1136/bmjopen-2021-053908.