Enhancement of Stroke Rehabilitation With Levodopa

Study Overview
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Brief Summary
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Trial investigates the benefits and harms of Levodopa /Carbidopa 100/25mg compared to placebo (given in addition to standardized rehabilitation based on the principles of motor learning) and whether there is an association with a patient-relevant enhancement of functional recovery in acute stroke patients. Study participants will be randomized 1:1.

Detailed Description
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Trial investigates whether Levodopa/Carbidopa compared to placebo given in addition to standardized rehabilitative therapy in patients with acute stroke is associated with a) patient relevant improvements of physical function b) improvement in patient-self assessed general health aspects, pain, mood, anxiety, fatigue and social participation c) long-term sustainability of a patient-relevant improvement of motor function d) improvement of selective hand and wrist movement e) a higher rate of patients walking independently of the help of another person. f) less severe impairment g) a higher level of activity of daily living h) improvements of quality of life (i) better cognitive performance (j) no signals of harms (i.e. indications for increased all-cause mortality, recurrent stroke or serious adverse events). Estrel-Longterm: optional prolongation of the observational study phase. To investigate the long-term outcomes of our study population the investigator aim to offer an optional prolongation of the observational phase to the participants through regular structured (once yearly) telephone visits. The telephone visits will be carried out annually for the following 4 years.

Official Title
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Enhancement of Stroke Rehabilitation With Levodopa (ESTREL): a Randomized Placebo-controlled Trial

Conditions
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Acute Stroke, Stroke Rehabilitation

Intervention / Treatment
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* Drug: IMP Levodopa 100mg/Carbidopa 25mg
* Drug: Matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute ischemic or hemorrhagic (i.e. intracerebral hemorrhage excluding subarachnoid hemorrhage and cerebal venous sinus thrombosis) stroke ≤ 7 days prior to randomization Clinically meaningful hemiparesis (i.e. scoring a total of ≥ 3 points on the following NIH stroke scale score items (i) motor arm, (ii) motor leg, (iii) limb ataxia; a distal arm paresis is equivalent to one of the aforementioned (i-iii)) Time of randomization ≥24-hours since thrombolysis or thrombectomy In-hospital rehabilitation required Capable to participate in standardized rehabilitation therapy Informed consent of patient or next of kin Exclusion Criteria: Diagnosis of Parkinson's Disease Use of Levodopa mandatory according to judgement of treating physician Inability or unwillingness to comply with study procedures including adherence to study drug intake (orally, or via nasogastric tube or percutaneous endoscopic gastrostomy tube) Severe aphasia (i.e. unable to follow two-stage-commands) Previously dependent in the basal activities of daily living (defined as modified Ranking Scale prior to stroke > 3) Pre-existing hemiparesis Known hypersensitivity to Levodopa/Carbidopa and other contraindications for Levodopa/Carbidopa as outlined in the summary of product characteristics Women who are pregnant or breast feeding, or who intend to become pregnant during the course of the study. Women of childbearing age must take a pregnancy test to be eligible for the study. Lack of safe contraception, defined as: Female Participants of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the Investigator in individual cases. Female Participants who are surgically sterilized / hysterectomized or post- menopausal for longer than 2 years are not considered as being of child- bearing potential.

Ages Eligible for Study
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Minimum Age: 18 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: Study participants will be randomized 1:1
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Experimental Intervention<br>White Investigational Medicinal Product (IMP)- capsules of a combination of IMP Levodopa 100mg/Carbidopa 25mg. | Drug: IMP Levodopa 100mg/Carbidopa 25mg<br>* Study treatment will comprise 3 phases: Dose escalation phase: On day 1-3, patients will receive IMP solely in the morning; on day 4-6 in the morning and at lunch time; full study treatment phase: from day 7 to day 34, 3 times per day (tid). Treatment will stop with a tapering phase: On day 35-37, patients will receive IMP in the morning and at lunch time; on day 38 and 39 solely in the morning.<br>|
| Placebo Comparator: Control Intervention<br>Matching placebo, identical in aspect, texture, and taste when compared to the IMP. Procedures regarding route of administration, study treatment duration and treatment phases will be identical in the IMP- and the placebo-group. | Drug: Matching placebo<br>* Study treatment will comprise 3 phases: Dose escalation phase: On day 1-3, patients will receive Placebo solely in the morning; on day 4-6 in the morning and at lunch time; full study treatment phase: from day 7 to day 34, Placebo capsules 3 times per day (tid). Treatment will stop with a tapering phase: On day 35-37, patients will receive Placebo in the morning and at lunch time; on day 38 and 39 solely in the morning.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Between-group difference of scores in the Fugl-Meyer-Motor Assessment (FMMA) | FMMA is a stroke-specific impairment index designed to assess motor recovery. Scale items are scored on the basis of ability to complete the item using a 3-point ordinal scale (0=cannot perform; 1=performs partially and 2= performs fully). FMMA total scores range from 0 (no movements) to 100 (normal movements) with 66 points for movements of the upper limbs (FMMA-UE) and 34 for those of the lower limbs (FMMA-LE). A difference of 5.25 points for the upper extremity and 6 points for the lower extremity part of the score are described as minimal clinically important difference. For this study, based on these data, 6 points difference are considered a patient-relevant difference between both treatment groups for the primary endpoint. | Assessed 3 months +/- 14 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in NIH-Stroke Scale score (NIHSS) | To objectively quantify the impairment caused by a stroke. NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the minimum score being a 0. | Assessed at Day 0 (Randomization), 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12 months +/- 30 days after randomization | 
| Change in modified Rankin Scale Score (mRS) | Scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6, running from perfect health without symptoms to death. 0 - No symptoms. - No significant disability. Able to carry out all usual activities, despite some symptoms. - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. - Moderate disability. Requires some help, but able to walk unassisted. - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. - Dead. | Assessed at Day 0 (Randomization), 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12/24/36/48/60 months +/- 30 days after randomization | 
| Change in Stroke rehabilitation outcomes for disease specific morbidity and quality of life - PROMIS 29 | Patient-self-assessment in the following categories: 1) physical function, 2) anxiety, 3) depression, 4) fatigue, 5) sleep disturbance, 6) ability to participate in social roles and activities, 7) pain interference and 8) pain intensity. Each of the domains 1 to 7 are assessed with 4 questions. Items are scored on 1 of 5 levels based on the ability of the participant to perform activities or the self-assessment of the participant in the various domains. Pain intensity is scored on a visual analogue scale of 0 to 10. | Assessed 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12 months +/- 30 days after randomization | 
| Change in Stroke rehabilitation outcomes for disease specific morbidity and quality of life - PROMIS 10 | Patient-self-assessment Patient-Reported Outcomes Measurement Information System (PROMIS) 10 addresses general health aspects, quality of life, pain, mood, anxiety, fatigue and social participation; PROMIS-10 covers the outcome domains considered most important | Assessed 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12/24/36/48/60 months +/- 30 days after randomization | 
| Change in Patient-reported assessment of relevance of motor improvement | Patients Questionnaire asking whether there is improvement in motor function since the last study visit and if so, whether this improvement is relevant in patients personal perception (yes/ no) | Assessed 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12 months +/- 30 days after randomization | 
| Change in Rivermead Mobility Index (RMI) | 15 items that measure the ability of patients to make postural adjustments (e.g, move in bed), transfer (e.g. between bed to chair), walk, and use stairs and is scored from 0-15 Points. A RMI score of ≥ 7 translates into the ability of the patient walking independently of the assistance of another Person. | Assessed at Day 0 (Randomization), 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12/24/36/48/60 months +/- 30 days after randomization | 
| mortality (of any cause) | death rate | Throughout the whole study period from Day 1 to Visit 12/24/36/48/60 months +/- 30 days after randomization | 
| recurrent stroke (any type) | recurrent stroke (any type) | Throughout the whole study period from Day 1 to Visit 12/24/36/48/60 months +/- 30 days after randomization | 
| Rate of pre- specified Adverse Events of Interest | Nausea, Vomiting, Taste disturbances, Dry mouth, Anorexia, Arrhythmias, Postural hypotension Syncope (unconsciousness for a short time as a result of reduced blood flow to the brain), drowsiness (including sudden onset of sleep) Fatigue, Dementia, Psychoses (a distorted perception of reality), Hallucinations, Confusion, Euphoria, Abnormal dreams, Insomnia, Depression, Anxiety, Dizziness, Dystonia (involuntary contractions), Dyskinesia (inability to control voluntary movements), Chorea (sudden twitching of the face and shoulders) | Throughout the study period from Day 1 to Visit 3 ( 3 months +/- 14 days after randomization) | 
| number of re-hospitalizations | re-hospitalization | Throughout the whole study period (Visit 1 = Baseline (day 0) to Visit 12 months +/- 30 days after randomization | 
| Change in Motricity Index (MI) | Two subscales, one for the upper extremity (UE) (total score range 0 to 100) and one for the lower extremity (LE) (total score range 0 to 100). It measures isometric muscle strength (0 = no movement; 100 = normal) | Assessed at Day 0 (Randomization), 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12 months +/- 30 days after randomization | 
| Change in Trunk Control Test (TCT) | Assesses the trunk abilities of the patient , contains 4 items, with item scores ranging from 0 to 25. The sitting balance item assesses the patients' ability to sit during 30 seconds without trunk and feet support and has a predictive value for recovery of walking poststroke | Assessed at Day 0 (Randomization), 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12 months +/- 30 days after randomization | 
| Change in Action Research Arm Test (ARAT) | Assesses the patients' ability to grasp (subscale with 6 items), grip (subscale with 4 items), pinch (subscale with 6 items) and perform gross movements (subscale with 3 items) with the upper extremity. Score: 0 = no movement / 1= movement task is partially performed / 2 = movement task is completed but takes abnormally long / 3 = movement is performed normally | Assessed at Day 0 (Randomization), 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12 months +/- 30 days after randomization | 
| Change in Box- and Block Test (BBT) | Patients (seated in front of a square box with two compartments) are asked to move as many wooden cubes as possible from one compartment to the other within 60 seconds of testing time. | Assessed at Day 0 (Randomization), 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12 months +/- 30 days after randomization | 
| Change in Functional Ambulation Categories (FAC) | Classification (score range 0 to 5) regarding the ability to walk independently, with or without a walking aid and takes the type of walking surface into account. Rating: 0 = Patient cannot walk, or needs help from 2 or more persons = Patient needs firm continuous support from 1 person who helps carrying weight and with balance = Patient needs continuous or intermittent support of one person to help with balance and coordination = Patient requires verbal supervision or stand-by help from one person without physical contact = Patient can walk independently on level ground, but requires help on stairs, slopes or uneven surfaces = Patient can walk independently anywhere | Assessed at Day 0 (Randomization), 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12/24/36/48/60 months +/- 30 days after randomization | 
| Change in Ten-Meter Walk Test (10MWT) | Walking speed and cadence over a 10 meter track at both a comfortable and a maximum Speed; time in seconds over 10-meter walking distance | Assessed at Day 0 (Randomization), 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12 months +/- 30 days after randomization | 
| Change in Jamar dynamometer testing (JDT) | grip strength and strength of the forearm (in kilogram) | Assessed at Day 0 (Randomization), 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12 months +/- 30 days after randomization | 
| Change in Montreal Cognitive Assessment (MoCA) | Assesses cognitive domains: Short-term memory recall task (5 points).Visuospatial abilities assessed using clock-drawing task (3 points) and 3-dimensional cube copy (1 point). Executive functions assessed using alternation task. Attention, concentration, working memory evaluated using a sustained attention task (target detection using tapping; 1 point), serial subtraction task (3 points), digits forward and backward (1 point each). Languages assessed using 3-item confrontation naming task with low-familiarity animals (lion, camel, rhinoceros; 3 points), repetition of 2 complex sentences (2 points), and fluency task. Orientation to time and place evaluated by asking for date and city in which the test is occurring (6 points). A score of 26 or over is considered to be normal (range 0 to 30) | Assessed at Day 0 (Randomization), 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12 months +/- 30 days after randomization | 
| Change in Daily activity measurement with movement sensor | Movement sensors allow assessment of physical activity engagement and upper limb use in daily life situations without physically hampering the patient in the performance of their daily activities | Assessed at Day 0 (Randomization), 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12 months +/- 30 days after randomization | 
| Rate of Serious Adverse Event (SAE) | Any untoward medical occurrence that: results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect | Throughout the study period from Day 1 to Visit 3 ( 3 months +/- 14 days after randomization) | 
| Between-group difference of scores in the Fugl-Meyer-Motor Assessment (FMMA) | FMMA is a stroke-specific impairment index designed to assess motor recovery. Scale items are scored on the basis of ability to complete the item using a 3-point ordinal scale (0=cannot perform; 1=performs partially and 2= performs fully). FMMA total scores range from 0 (no movements) to 100 (normal movements) with 66 points for movements of the upper limbs (FMMA-UE) and 34 for those of the lower limbs (FMMA-LE). A difference of 5.25 points for the upper extremity and 6 points for the lower extremity part of the score are described as minimal clinically important difference. For this study, based on these data, 6 points difference are considered a patient-relevant difference between both treatment groups for the primary endpoint. | Assessed at Day 0 (Randomization), 5 weeks after randomization, 6 months +/- 20 days after randomization and 12 months +/- 30 days after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Levodopa/ Carbidopa, Fugl-Meyer-Motor-Assessment (FMMA), acute ischemic stroke, acute hemorrhagic stroke, Rehabilitation, Recovery