Ignite Creation Date:
2025-12-24 @ 5:44 PM
Ignite Modification Date:
2025-12-25 @ 3:12 PM
Study NCT ID:
NCT04335968
Status:
COMPLETED
Last Update Posted:
2025-09-08
First Post:
2020-02-28
Is NOT Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
Melatonin for Prevention of Postoperative Delirium After Lower Limb Fracture Surgery in Elderly Patients
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'conditionBrowseModule': {'meshes': [{'id': 'D003693', 'term': 'Delirium'}], 'ancestors': [{'id': 'D003221', 'term': 'Confusion'}, {'id': 'D019954', 'term': 'Neurobehavioral Manifestations'}, {'id': 'D009461', 'term': 'Neurologic Manifestations'}, {'id': 'D009422', 'term': 'Nervous System Diseases'}, {'id': 'D012816', 'term': 'Signs and Symptoms'}, {'id': 'D013568', 'term': 'Pathological Conditions, Signs and Symptoms'}, {'id': 'D019965', 'term': 'Neurocognitive Disorders'}, {'id': 'D001523', 'term': 'Mental Disorders'}]}, 'interventionBrowseModule': {'meshes': [{'id': 'D008550', 'term': 'Melatonin'}], 'ancestors': [{'id': 'D014363', 'term': 'Tryptamines'}, {'id': 'D007211', 'term': 'Indoles'}, {'id': 'D006574', 'term': 'Heterocyclic Compounds, 2-Ring'}, {'id': 'D000072471', 'term': 'Heterocyclic Compounds, Fused-Ring'}, {'id': 'D006571', 'term': 'Heterocyclic Compounds'}, {'id': 'D006728', 'term': 'Hormones'}, {'id': 'D006730', 'term': 'Hormones, Hormone Substitutes, and Hormone Antagonists'}]}}, 'protocolSection': {'designModule': {'phases': ['PHASE3'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'RANDOMIZED', 'maskingInfo': {'masking': 'QUADRUPLE', 'whoMasked': ['PARTICIPANT', 'CARE_PROVIDER', 'INVESTIGATOR', 'OUTCOMES_ASSESSOR']}, 'primaryPurpose': 'PREVENTION', 'interventionModel': 'PARALLEL', 'interventionModelDescription': 'Prospective, national multicentric (21 centers), phase III, superiority, comparative randomized (1:1) double-blinded clinical trial with two parallel arms'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 357}}, 'statusModule': {'overallStatus': 'COMPLETED', 'startDateStruct': {'date': '2021-01-23', 'type': 'ACTUAL'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2025-05', 'completionDateStruct': {'date': '2025-04-18', 'type': 'ACTUAL'}, 'lastUpdateSubmitDate': '2025-09-01', 'studyFirstSubmitDate': '2020-02-28', 'studyFirstSubmitQcDate': '2020-04-02', 'lastUpdatePostDateStruct': {'date': '2025-09-08', 'type': 'ESTIMATED'}, 'studyFirstPostDateStruct': {'date': '2020-04-07', 'type': 'ACTUAL'}, 'primaryCompletionDateStruct': {'date': '2025-04-18', 'type': 'ACTUAL'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Postoperative delirium incidence', 'timeFrame': '10 days after surgery', 'description': 'The Confusion Assessment Method (CAM) score, for patients hospitalized in surgery, or CAM-ICU score, for patients hospitalized in ICU will be applied daily during the first 10 days after surgery or end of hospital stay if shorter'}], 'secondaryOutcomes': [{'measure': 'Number of days CAM positive', 'timeFrame': '10 days after surgery', 'description': 'CAM will be applied daily during the first 10 days. the minimum 0 and maximum 4 values, and higher scores mean a worse outcome.'}, {'measure': 'Incidence of postoperative sedative or antipsychotic drugs administration from', 'timeFrame': '10 days after surgery', 'description': 'Daily review of the medical chart and prescriptions looking for any sedative or antipsychotic drug administration'}, {'measure': 'Incidence of postoperative physical restrain prescription', 'timeFrame': '10 days after surgery', 'description': 'Daily review of the medical chart and prescriptions looking for physical restraint prescription.'}, {'measure': 'Incidence of postoperative falls', 'timeFrame': '10 days after surgery', 'description': 'Daily review of the medical chart and prescriptions looking for falls, whichever the gravity'}, {'measure': 'Mini Mental State Examination', 'timeFrame': '10 days (or end of hospital stay if shorter)', 'description': 'Cognitive testing interview at bedside using the widely used French validated translation of the Mini Mental State Examination.\n\nthe minimum 0 and maximum 30 values, and higher scores mean a better outcome.'}, {'measure': 'Duration of hospital stay', 'timeFrame': '30 days after surgery', 'description': 'Daily review of the medical file'}, {'measure': '30 days postoperative mortality', 'timeFrame': '30 days after surgery', 'description': 'Phone call (or visit for those who had not left the hospital) to the patient or caregivers'}, {'measure': '30 days postoperative patient autonomy', 'timeFrame': '30 days after surgery', 'description': 'Phone call (or visit for those who had not left the hospital) to the patient or caregivers and evaluation by the Katz Index of activities of daily living.\n\nThe minimum and maximum values are respectively 0 and 6, and higher scores mean a better outcome.'}, {'measure': '30 days postoperative Quality of life', 'timeFrame': '30 days after surgery', 'description': 'evaluated by EQ5D5L (standardized instrument for measuring generic health status : MOBILITY, SELF-CARE, USUAL ACTIVITIES, PAIN/DISCOMFORT and ANXIETY/ DEPRESSION),) Questionnaire. the minimum 5 and maximum 125 values, and higher scores mean a better outcome.'}, {'measure': '30 days postoperative QALYs (quality-adjusted life year)', 'timeFrame': '30 days after surgery', 'description': 'QALYs (quality-adjusted life year) are the utility weights for the 30 day period x30/365. the minimum and maximum values are respectively 0 and1, and higher scores mean a better outcome.'}, {'measure': 'Total hospital costs at 30 days', 'timeFrame': '30 days after surgery', 'description': 'calculated as the cumulative costs of all admissions (in- and outpatient, home care, rehabilitation) over a 30 day period'}, {'measure': 'Incremental cost effectiveness', 'timeFrame': '30 days after surgery', 'description': 'The incremental cost effectiveness ratio is the difference in total costs divided by the difference in the incidence rate of delirium between the two arms'}, {'measure': 'cost utility ratios', 'timeFrame': '30 days after surgery', 'description': 'the incremental cost utility ratio is the difference in total costs divided by the difference in QALYs (quality-adjusted life year)'}, {'measure': 'Occurrence of side effects', 'timeFrame': '30 days after surgery', 'description': 'During the follow-up, daily interview of the patient and review of the medical chart will be performed, looking for side effects of melatonin.'}]}, 'oversightModule': {'isUsExport': False, 'oversightHasDmc': False, 'isFdaRegulatedDrug': False, 'isFdaRegulatedDevice': False}, 'conditionsModule': {'keywords': ['delirium', 'aging', 'Perioperative neurocognitive disorders', 'melatonine', 'orthopedic surgery'], 'conditions': ['Orthopedic Surgery']}, 'referencesModule': {'references': [{'pmid': '34952881', 'type': 'DERIVED', '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.'}]}, 'descriptionModule': {'briefSummary': '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.\n\nAmong 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.\n\nMelatonin 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.\n\nThe hypothesis of the trial is that in a high-risk population, perioperative melatonin can reduce the incidence of POD.\n\nThe 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).\n\nThis is a prospective, national multicentric (24 centers), phase III, superiority, comparative randomized (1:1) double-blinded clinical trial with two parallel arms:\n\nExperimental group: melatonin 4mg per os every night, starting the evening before surgery (or 2 hours before emergency surgery) and until day 5 after surgery.\n\nControl group: placebo of this drug with the same schedule, during the same period of time.\n\nThe 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).', 'detailedDescription': '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.\n\nAmong 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.\n\nMelatonin 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.\n\nThe hypothesis of the trial is that in a high-risk population, perioperative melatonin can reduce the incidence of POD.\n\nThe 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).\n\nThis is a prospective, national multicentric (24 centers), phase III, superiority, comparative randomized (1:1) double-blinded clinical trial with two parallel arms:\n\nExperimental group: melatonin 4mg per os every night, starting the evening before surgery (or 2 hours before emergency surgery) and until day 5 after surgery.\n\nControl group: placebo of this drug with the same schedule, during the same period of time.\n\nThe 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).\n\nAn ancillary study is also planned in this study with the hypothesise that :\n\n* 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.\n* Administration of melatonin may prevent these perturbations.\n\nAncillary study concerns Beaujon, Bichat and la Pitié centers.'}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['OLDER_ADULT'], 'minimumAge': '70 Years', 'healthyVolunteers': False, 'eligibilityCriteria': 'Inclusion Criteria:\n\n* Demographic criteria: patient 70 years old or older\n* Diagnostic criteria: isolated fracture of a lower limb\n\n * Proximal femoral fractures: head, cervical, or trochanteric fractures\n * Periprosthetic hip fracture\n * Femoral shaft fracture\n * Distal femoral fractures: supracondylar or condylar\n * Periprosthetic knee fracture\n * Tibial plateau fracture\n* Treatments/strategies/procedures: scheduled orthopedic surgery (osteosynthesis or arthroplasty)\n* proxy or care giver knowing baseline cognitive status of the patient present or reachable by phone for an interview\n\nExclusion Criteria:\n\n* Patient already taking Melatonin\n* Contraindications and precaution for use of Melatonin administration:\n\n * Hypersensitivity to the active substance or to any of the excipients of Circadin©\n * 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%),\n * Cirrhosis (known histological liver fibrosis)\n * Renal failure with clearance \\<30 ml/min O Autoimmune disease O Hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome\n * Patients taking fluvoxamine, 5- or 8-methoxypsoralen, cimetidine, oestrogenotherapy, quinolones, carbamazepine, rifampicin\n* Other concomitant trauma than lower limb fracture(s)\n* Surgery scheduled in more than 5 days\n* Patient under mechanical ventilation\n* Patient refusing to participate\n* Patient not talking / understanding French (delirium assessment impossible)\n* Patient already participating to another interventional study\n* No signed informed consent,\n* No affiliation to a social security regime\n\nSecondary Exclusion Criteria:\n\nSecondary 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.'}, 'identificationModule': {'nctId': 'NCT04335968', 'acronym': 'DELIRLESS', 'briefTitle': 'Melatonin for Prevention of Postoperative Delirium After Lower Limb Fracture Surgery in Elderly Patients', 'organization': {'class': 'OTHER', 'fullName': 'Assistance Publique - Hôpitaux de Paris'}, 'officialTitle': 'Melatonin for Prevention of Postoperative Delirium After Lower Limb Fracture Surgery in Elderly Patients: a Randomized Controlled Trial', 'orgStudyIdInfo': {'id': 'APHP180594'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'EXPERIMENTAL', 'label': 'Experimental group', 'description': 'melatonin 4mg per os every night, starting the evening before surgery (or 2 hours before emergency surgery) and until day 5 after surgery', 'interventionNames': ['Drug: Melatonin 4 mg']}, {'type': 'PLACEBO_COMPARATOR', 'label': 'Control group', 'description': 'placebo of this drug with the same schedule, during the same period of time.', 'interventionNames': ['Drug: Placebo oral tablet']}], 'interventions': [{'name': 'Melatonin 4 mg', 'type': 'DRUG', 'description': 'melatonin 4mg per os every night, starting the evening before surgery (or 2 hours before emergency surgery) and until day 5 after surgery.', 'armGroupLabels': ['Experimental group']}, {'name': 'Placebo oral tablet', 'type': 'DRUG', 'description': 'placebo of this drug with the same schedule, during the same period of time.', 'armGroupLabels': ['Control group']}]}, 'contactsLocationsModule': {'locations': [{'zip': '93390', 'city': 'Clichy-sous-Bois', 'country': 'France', 'facility': 'hôpital Beaujon', 'geoPoint': {'lat': 48.9102, 'lon': 2.55323}}], 'overallOfficials': [{'name': 'Stéphanie Sigaut', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'APHP'}]}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'Assistance Publique - Hôpitaux de Paris', 'class': 'OTHER'}, 'responsibleParty': {'type': 'SPONSOR'}}}}