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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

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

Conditions
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Ischemic Stroke, Acute, Sleep Disorders, Circadian Rhythm

Intervention / Treatment
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* Combination Product: Blue light exposure + Melatonin treatment
* Drug: Melatonin treatment
* Device: Blue light exposure
* Combination Product: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: patients will be randomized into 4 parallel groups
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blue light exposure + Melatonin treatment<br>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<br>* 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.<br>|
| Experimental: Melatonin treatment<br>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<br>* 3 mg Melatonin pill will be given 1 hour before going to bed.<br>* Other names: Melaxen;|
| Experimental: Blue light exposure<br>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<br>* Blue light exposure will be performed during 30-minute sessions with the use of the lamps (Lumie/Vitamin L) in the morning.<br>* Other names: Lamps Lumie/Vitamin L;|
| Placebo Comparator: Placebo group<br>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<br>* Placebo light exposure will be performed by using lamp turned off; and placebo pill will be given in the evening<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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circadian misalignment, neuroplasticity, melatonin, light therapy, circadian disorder