The Role of Circadian Factors in Regulation of Neuroplasticity in Ischemic Stroke (Interventional)

There is a lack of complex studies which could establish the association between genetic circadian factors with the features and short-term outcomes of ischemic stroke, as well as the effects of various auxiliary therapies for circadian rhythm modulation for neuroplasticity enhancement and improvement of short-term outcomes in ischemic stroke.

The main research hypothesis is that circadian factors influence the recovery from ischemic stroke via sleep-mediated regulation of synaptic plasticity.

The project aims at the investigation of the influence of combined melatonin therapy and blue light exposure on molecular circadian biomarkers, sleep characteristics, neuroplasticity markers and stroke outcome in acute stroke patients.

This study is a prospective, interventional, randomized placebo-controlled trial.

Study Overview

• Status: Recruiting
• Conditions: Sleep Disorders, Circadian Rhythm; Ischemic Stroke, Acute
• Intervention / Treatment: Combination product: Blue light exposure + Melatonin treatment; Drug: Melatonin treatment; Device: Blue light exposure; Combination product: Placebo

Detailed Description

The study will investigate the influence of combined blue light exposure and melatonin therapy on molecular biomarkers of circadian rhythms, sleep characteristics and stroke outcome in acute stroke patients This study is designed as a prospective study in acute stroke patients (approx 80 patients) admitted to the Stroke Unit. After initial assessment, the participants will be randomly assigned in 4 groups (the treatment or control) with approx.20 participants in each group.

In all participants, the following parameters will be assessed: medical records, stroke characteristics, sleep characteristics, cardiovascular circadian rhythms and blood samples for the evaluation of circadian molecular biomarkers at baseline and 14 days after inclusion. Stroke outcomes will be reassessed at 3-month follow-up.

The following associations will be assessed:

• the role of blue light exposure and melatonin treatment for stroke outcome
• the role of blue light exposure and melatonin treatment in the modulation of sleep parameters in acute stroke
• the association of molecular biomarkers of circadian rhythms with stroke outcome (the difference in neurological and functional deficit from admission to 14 and 90 days after study inclusion), with stroke characteristics (stroke subtype and neuroimaging stroke parameters, routine protocol) and with sleep characteristics.
• the association of sleep characteristics with stroke outcome (the difference in neurological and functional deficit from admission to 14 and 90 days after stroke) and with stroke characteristics (stroke subtype and neuroimaging stroke parameters, routine protocol).

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Lyudmila Korostovtseva; Phone Number: +79217873548; Email: lyudmila_korosto@mail.ru

Study Locations

• Russian Federation
  • St Petersburg, Russian Federation, 197341
    • Recruiting
    • Almazov National Medical Research Centre
    • Contact: Lyudmila Korostovtseva; Phone Number: 89217873548; Email: lyudmila_korosto@mail.ru

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• acute (symptom onset to admission <1 days) ischemic stroke
• ischemic stroke affecting the branches of anterior cerebral artery, middle cerebral artery and posterior cerebral artery
• age 18-80 years
• moderate or severe stroke (National Institutes of Health Stroke Scale, NIHSS>=5)
• intravascular stroke treatment with thrombolysis or thrombectomy leading to satisfactory reperfusion (if applicable)
• informed consent

Exclusion Criteria:

• secondary parenchymal hemorrhage (>hemorrhage index (HI)-2)
• clinically unstable or life-threatening conditions
• previous stroke in the last 6 months
• known progressive neurological diseases
• known psychiatric diseases
• concomitant benzodiazepine medication
• drug or alcohol abuse
• pregnancy
• inability to participate in the study
• severe sensory aphasia
• melatonin intake at/before admission
• light therapy use at/before admission
• blindness
• severe sleep-disordered breathing (apnea-hypopnea index >=30/h)
• contraindications to light therapy (severe retinopathy, epilepsy, porphyria, intake of drugs with photosensitizing effects)
• contraindications to melatonin intake (severe bronchial asthma, severe autoimmune disorders, chronic kidney disease 3b stage and higher, leukosis)
• congestive heart failure with reduced ejection fraction (<=45%) or New York Heart Association (NYHA) classification III-IV functional class.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Blue light exposure + Melatonin treatment; The participants will receive the combination of blue light exposure according to the protocol described by Killgore et al. (2020) and 3 mg of melatonin 1 hour before going to sleep (approximately at 20:00) (Ramos et al 2020) for 14 days	Combination product: Blue light exposure + Melatonin treatment; 3 mg Melatonin pill will be given 1 hour before going to bed. Blue light exposure will be performed during 30-minute sessions with the use of the lamps (Lumie/Vitamin L) in the morning.
Experimental: Melatonin treatment; The participants will receive 3 mg of melatonin 1 hour before going to sleep (approximately at 20:00) (Ramos et al 2020) and the morning placebo-light exposure according to the protocol described by Killgore et al. (2020) for 14 days	Drug: Melatonin treatment; 3 mg Melatonin pill will be given 1 hour before going to bed.; Other Names: Melaxen
Experimental: Blue light exposure; The participants will receive the morning blue light exposure according to the protocol described by Killgore et al. (2020) for 14 days and placebo pill 1 hour before going to sleep (approximately at 20:00)	Device: Blue light exposure; Blue light exposure will be performed during 30-minute sessions with the use of the lamps (Lumie/Vitamin L) in the morning.; Other Names: Lamps Lumie/Vitamin L
Placebo Comparator: Placebo group; The participants will receive placebo light exposure in the morning (lamp turned off) and placebo pill treatment in the evening for 14 days	Combination product: Placebo; Placebo light exposure will be performed by using lamp turned off; and placebo pill will be given in the evening

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the value of National Institutes of Health Stroke Scale from baseline to 14 days after inclusion	National Institutes of Health Stroke Scale (NIHSS) is a tool used to objectively quantify the impairment caused by a stroke, 0-42 scores, higher scores characterize worse impairment	From baseline to 14 days after treatment initiation
Stroke-related disability assessed by the change in modified Rankin scale from baseline to 14 days after treatment initiation	values of modified Rankin scale (scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke, from 0 (no symptoms) to 6 (dead) points)	From baseline to 14 days after treatment initiation
Stroke-related disability assessed by the change in Rivermead Mobility Index from baseline to 14 days after treatment initiation	Rivermead Mobility Index (a standardized scale used to assess mobility in patients with neurological deficits, a maximum of 15 points is possible; higher scores indicate better mobility performance)	From baseline to 14 days after treatment initiation
Stroke-related disability assessed by the change in Barthel Index from baseline to 14 days after treatment initiation	Barthel Index (a common scale used to measure performance in activities of daily living, 0-100 scores, higher scores define better performance)	From baseline to 14 days after treatment initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Psychomotor vigilance task (mean reaction time) from baseline to 14 days after treatment initiation	The psychomotor vigilance task is a sustained-attention, reaction-timed task that measures the speed with which subjects respond to a visual stimulus, the outcome (mean reaction time) is measured in msec	From baseline to 14 days after treatment initiation
Change in Psychomotor vigilance task (mean reaction time) from baseline to 90 days after inclusion	The psychomotor vigilance task is a sustained-attention, reaction-timed task that measures the speed with which subjects respond to a visual stimulus, the outcome (mean reaction time) is measured in msec	From baseline to 90±7 days after inclusion
Change in Kraepelin test from baseline to 14 days after treatment initiation	Kraepelin test is the test in which the examinee performs a simple single-digit addition. The outcome is the number of correct and incorrect addition operations per each 30 sec and during the whole task, performance index (number of correct addition operations during second part of task / number of correct addition operations during first part of task)	From baseline to 14 days after treatment initiation
Change in Kraepelin test from baseline to 90 days after inclusion	Kraepelin test is the test in which the examinee performs a simple single-digit addition. The outcome is the number of correct and incorrect addition operations per each 30 sec and during the whole task, performance index (number of correct addition operations during second part of task / number of correct addition operations during first part of task)	From baseline to 90±7 days after inclusion
Change in Trail Making test from baseline to 14 days after treatment initiation	Trails Making Test (Trails) is a neuropsychological test of visual attention and task switching. It can provide information about visual search speed, scanning, speed of processing, mental flexibility, as well as executive functioning	From baseline to 14 days after treatment initiation
Change in Trail Making test from baseline to 90 days after inclusion	Trails Making Test (Trails) is a neuropsychological test of visual attention and task switching. It can provide information about visual search speed, scanning, speed of processing, mental flexibility, as well as executive functioning. Execution time will be assessed (in msec)	From baseline to 90±7 days after inclusion
Change in Victoria Stroop test from baseline to 14 days after treatment initiation	Victoria Stroop is a neuropsychological test extensively used to assess the ability to inhibit cognitive interference. Execution time will be measured. (in msec)	From baseline to 14 days after treatment initiation
Change in Victoria Stroop test from baseline to 90 days after inclusion	Victoria Stroop is a neuropsychological test extensively used to assess the ability to inhibit cognitive interference. Execution time will be measured. (in msec)	From baseline to 90±7 day after inclusion
Change in Hopkins Verbal Learning Test (Revised) from baseline to 14 days after treatment initiation	Hopkins Verbal Learning Test - Revised brief assessment of immediate recall, delayed recall and delayed recognition. The number of words recalled will be assessed.	From baseline to 14 days after treatment initiation
Change in Hopkins Verbal Learning Test (Revised) from baseline to 90 days after inclusion	Hopkins Verbal Learning Test - Revised brief assessment of immediate recall, delayed recall and delayed recognition. The number of words recalled will be assessed.	From baseline to 90±7 days after inclusion
Change in Brief Visuospatial Memory Test (Revised) from baseline to 14 days after treatment initiation	Brief Visuospatial Memory Test (Revised)is a commonly used, commercialized, assessment tool to measure visuospatial learning and memory abilities across research and clinical settings. The number of figures will be assessed.	From baseline to 14 days after treatment initiation
Change in Brief Visuospatial Memory Test (Revised) from baseline to 90 days after inclusion	Brief Visuospatial Memory Test (Revised)is a commonly used, commercialized, assessment tool to measure visuospatial learning and memory abilities across research and clinical settings. The number of figures will be assessed.	From baseline to 90±7 days after inclusion
Change in Wechsler Memory Scale (Revised) from baseline to 14 days after treatment initiation	Wechsler Memory Scale - Revised is a neuropsychological test designed to measure different memory functions in a person. A composite score will be assessed.	From baseline to 14 days after treatment initiation
Change in Wechsler Memory Scale (Revised) from baseline to 90 days after inclusion	Wechsler Memory Scale - Revised is a neuropsychological test designed to measure different memory functions in a person. A composite score will be assessed.	From baseline to 90±7 days after inclusion
Change in Corsi block-tapping test from baseline to 14 days after treatment initiation	The Corsi block-tapping test is a psychological test that assesses visuo-spatial short term working memory. The visual span raw score will be assessed.	From baseline to 14 days after treatment initiation
Change in Corsi block-tapping test from baseline to 90 days after inclusion	The Corsi block-tapping test is a psychological test that assesses visuo-spatial short term working memory. The visual span raw score will be assessed.	From baseline to 90±7 days after inclusion
Change from baseline in objective sleep duration assessed by polysomnography	Sleep duration (minutes)	From baseline to 14 days after treatment initiation
Change from baseline in objective sleep efficiency assessed by polysomnography	sleep efficiency (%)	From baseline to 14 days after treatment initiation
Change from baseline in objective sleep latency assessed by polysomnography	sleep latency (minutes)	From baseline to 14 days after treatment initiation
Change from baseline in sleep S1 stage duration assessed by polysomnography	S1 sleep stage percentage of total sleep time (%)	From baseline to 14 days after treatment initiation
Change from baseline in sleep S2 stage duration assessed by polysomnography	S2 sleep stage percentage of total sleep time (%)	From baseline to 14 days after treatment initiation
Change from baseline in sleep S3 stage duration assessed by polysomnography	S3 sleep stage percentage of total sleep time (%)	From baseline to 14 days after treatment initiation
Change from baseline in rapid eye movement (REM) sleep stage duration assessed by polysomnography	Rapid eye movement (REM) sleep stage percentage of total sleep time (%)	From baseline to 14 days after treatment initiation
Change from baseline in wake-after-sleep-onset time assessed by polysomnography	wake after sleep onset time (minutes)	From baseline to 14 days after treatment initiation
Change from baseline in arousal index assessed by polysomnography	Arousal index (episodes/hour of sleep)	From baseline to 14 days after treatment initiation
Change in emotional outcome assessed by Hospital anxiety and depression scale from baseline to 90 days after inclusion	Hospital anxiety and depression scale is used to determine the levels of anxiety and depression. It is a 14-item scale; Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression, higher scores indicate worse situation	from baseline to 14 days after treatment initiation
Change in emotional outcome assessed by Hospital anxiety and depression scale from baseline to 14 days after treatment initiation	Hospital anxiety and depression scale is used to determine the levels of anxiety and depression. It is a 14-item scale; Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression, higher scores indicate worse situation	From baseline to 90±7 days after inclusion
Assessment of mood by change in Visual Analogue Mood Scale from baseline to 14 days after treatment initiation	Visual Analogue Mood Scale is a reliable and valid measure of eight specific mood states: Afraid, Confused, Sad, Angry, Energetic, Tired, Happy, and Tense. The score for each mood ranges from 0 to 100 (100 mm vertical line), with 100 representing a maximal level of that mood and zero representing a minimal level (or absence) of that mood	from baseline to 14 days after treatment initiation
Assessment of mood by change in Visual Analogue Mood Scale from baseline to 90 days after inclusion	Visual Analogue Mood Scale is a reliable and valid measure of eight specific mood states: Afraid, Confused, Sad, Angry, Energetic, Tired, Happy, and Tense. The score for each mood ranges from 0 to 100 (100 mm vertical line), with 100 representing a maximal level of that mood and zero representing a minimal level (or absence) of that mood	From baseline to 90±7 days after inclusion
Change in the value of National Institutes of Health Stroke Scale from baseline to 90 days after inclusion	National Institutes of Health Stroke Scale (NIHSS) is a tool used to objectively quantify the impairment caused by a stroke, 0-42 scores, higher scores characterize worse impairment	From baseline to 90±7 days after inclusion
Change in modified Rankin scale from baseline to 90 days after inclusion	values of modified Rankin scale (scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke, from 0 (no symptoms) to 6 (dead) points)	From baseline to 90±7 days after inclusion
Change in Rivermead Mobility Index from baseline to 90 days after inclusion	Rivermead Mobility Index (a standardized scale used to assess mobility in patients with neurological deficits, a maximum of 15 points is possible; higher scores indicate better mobility performance)	From baseline to 90±7 days after inclusion
Change in Barthel Index from baseline to 90 days after inclusion	Barthel Index (a common scale used to measure performance in activities of daily living, 0-100 scores, higher scores define better performance)	From baseline to 90±7 days after inclusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in time in bed assessed by actigraphy	time in bed (minutes)	from baseline to 14 days after treatment initiation
Change from baseline in total sleep time assessed by actigraphy	total sleep time (minutes)	from baseline to 14 days after treatment initiation
Change from baseline in sleep efficiency assessed by actigraphy	sleep efficiency (%)	from baseline to 14 days after treatment initiation
Change from baseline in sleep onset latency assessed by actigraphy	sleep onset latency (min)	from baseline to 14 days after treatment initiation
Change from baseline in number of awakenings assessed by actigraphy	number of awakenings	from baseline to 14 days after treatment initiation
Change from baseline in mean motor activity assessed by actigraphy	mean motor activity (units)	from baseline to 14 days after treatment initiation
Change from baseline in Sleep Quality Score assessed by questionnaire Pittsburgh Sleep Quality Index	Pittsburgh Sleep Quality Index is a self-rated questionnaire which assesses subjective sleep quality and disturbances over a 1-month time interval, Each of the sleep components yields a score ranging from 0 to 3, with 3 indicating the greatest dysfunction. The sleep component scores are summed to yield a total score ranging from 0 to 21 with the higher total score indicating worse sleep quality	from baseline to 14 days after treatment initiation
Change from baseline in daytime sleepiness assessed by Epworth Sleepiness Scale	Epworth Sleepiness Scale is a common tool to assess sleepiness; 0-24 points, higher score indicate greater sleepiness	from baseline to 14 days after treatment initiation
Change from baseline in fatigue severity assessed by Fatigue severity Scale	Fatigue severity Scale is a common 9-item tool used to determine and quantify fatigue as subjective feeling of exhaustion, persisting lack of energy and rapid inanition, 9-63 points, higher score indicates more severe fatigue	from baseline to 14 days after treatment initiation
Change from baseline in Insomnia severity index	Insomnia severity index is a 7-item tool to assess the severity of insomnia, 0-5 points per each item, higher score indicates more severe insomnia	from baseline to 14 days after treatment initiation
Change from baseline in sensorimotor assessment of upper limbs	Sensorimotor assessment of upper limbs by Fugl-Meyer is a stroke-specific, performance-based impairment index. The total possible scale score is 226	from baseline to 14 days after treatment initiation
Change from baseline in melatonin curve secretion	salivary melatonin levels samples collected every 3 hours for 24 hours at study inclusion and at 14 days after study inclusion	from baseline to 14 days after treatment initiation
Change from baseline in cortisol curve secretion	salivary cortisol sampled every 3 hours for 24 hours at study inclusion and at 14 days after study inclusion	from baseline to 14 days after treatment initiation
Change from baseline in circadian brain-derived neurotrophic factor messenger ribonucleic acid (mRNA) expression	Brain-derived neurotrophic factor messenger ribonucleic acid (mRNA) expression will be measured in blood samples taken every 4 hours for 24 hours at study inclusion and at 14 days after study inclusion	from baseline to 14 days after treatment initiation
Change from baseline in circadian clock gene CLOCK messenger ribonucleic acid (mRNA) expression	clock gene CLOCK messenger ribonucleic acid (mRNA) expression will be measured in blood samples taken every 4 hours for 24 hours at study inclusion and at 14 days after study inclusion	from baseline to 14 days after treatment initiation
Change from baseline in circadian clock gene Bmal1 messenger ribonucleic acid (mRNA) expression	clock gene Bmal1 messenger ribonucleic acid (mRNA) expression will be measured in blood samples taken every 4 hours for 24 hours at study inclusion and at 14 days after study inclusion	from baseline to 14 days after treatment initiation
Change from baseline in circadian Melatonin receptor messenger ribonucleic acid (mRNA) expression	Melatonin receptor messenger ribonucleic acid (mRNA) expression will be measured in blood samples taken every 4 hours for 24 hours at study inclusion and at 14 days after study inclusion	from baseline to 14 days after treatment initiation
Change in psychophysiological state: heart rate variability assessed by biofeedback method from baseline to 14 days	heart rate variability assessed by electrocardiogram (maximum heart rate - minimum heart rate, beats per minute)	from baseline to 14 days after treatment initiation
Change in psychophysiological state: heart rate variability assessed by biofeedback method from baseline to 90 days after inclusion	heart rate variability assessed by electrocardiogram (maximum heart rate - minimum heart rate, beats per minute)	from baseline to 90±7 days after inclusion
Change in psychophysiological state: respiratory movement amplitude assessed by biofeedback method - from baseline to 14 days	respiratory movement amplitude assessed by respiratory rate abdominal and thoracic sensors (units)	from baseline to 90±7 days after treatment initiation
Change in psychophysiological state: respiratory movement amplitude assessed by biofeedback method- from baseline to 90 days	respiratory movement amplitude assessed by respiratory rate abdominal and thoracic sensors (units)	from baseline to 90±7 days after inclusion
Change in psychophysiological state: alpha-rhythm index assessed by biofeedback method - from baseline to 14 days after treatment initiation	alpha rhythm index (%) assessed by electroencephalogram	from baseline to 14 days after treatment initiation
Change in psychophysiological state: beta-rhythm index assessed by biofeedback method - from baseline to 14 days after treatment initiation	beta rhythm index (%) assessed by electroencephalogram	from baseline to 14 days after treatment initiation
Change in psychophysiological state: alpha-rhythm index assessed by biofeedback method - from baseline to 90 days after inclusion	alpha rhythm index (%) assessed by electroencephalogram	from baseline to 90±7 days after inclusion
Change in psychophysiological state: beta-rhythm index assessed by biofeedback method - from baseline to 90 days after inclusion	beta rhythm index (%) assessed by electroencephalogram	from baseline to 90±7 days after inclusion
Number of participants with treatment-related adverse events assessed according to the protocol-specified adverse effects	Number of participants with treatment-related adverse events assessed according to the Toronto Side Effects Scale	14 days after treatment initiation

Collaborators and Investigators

• Sponsor: Federal State Budgetary Institution, V. A. Almazov Federal North-West Medical Research Centre, of the Ministry of Health
• Investigators: Principal Investigator: Lyudmila Korostovtseva, Almazov National Medical Research Centre

Publications and helpful links

General Publications

• Bochkarev MV, Korostovtseva LS, Medvedeva EA, Rotar OP, Sviryaev YV, Zhernakova YV, Shalnova SA, Konradi AO, Chazova IE, Boitsov SA, Shlyakhto EV. [Sleep disorders and stroke: data of the esse-rf study]. Zh Nevrol Psikhiatr Im S S Korsakova. 2019;119(4. Vyp. 2):73-80. doi: 10.17116/jnevro201911904273. Russian.
• Korostovtseva L. Ischemic Stroke and Sleep: The Linking Genetic Factors. Cardiol Ther. 2021 Dec;10(2):349-375. doi: 10.1007/s40119-021-00231-9. Epub 2021 Jun 30.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2022
• Primary Completion (Estimated): January 30, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: January 26, 2022
• First Submitted That Met QC Criteria: February 15, 2022
• First Posted (Actual): February 18, 2022

Study Record Updates

• Last Update Posted (Actual): August 8, 2025
• Last Update Submitted That Met QC Criteria: August 5, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: melatonin; neuroplasticity; light therapy; circadian misalignment; circadian disorder
• Additional Relevant MeSH Terms: Neurologic Manifestations; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Mental Disorders; Pathologic Processes; Brain Infarction; Brain Ischemia; Infarction; Necrosis; Dyssomnias; Chronobiology Disorders; Occupational Diseases; Ischemic Stroke; Stroke; Cerebral Infarction; Ischemia; Sleep Wake Disorders; Sleep Disorders, Circadian Rhythm; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antioxidants; Protective Agents; Melatonin
• Other Study ID Numbers: 21-75-10173-1 (interventional)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No