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Enhancement of Stroke Rehabilitation With Levodopa (ESTREL)

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ClinicalTrials.gov Identifier: NCT03735901
Recruitment Status : Recruiting
First Posted : November 8, 2018
Last Update Posted : September 23, 2019
Sponsor:
Collaborator:
Swiss National Science Foundation
Information provided by (Responsible Party):
University Hospital, Basel, Switzerland

Brief Summary:
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 ischemic stroke patients. Study participants will be randomized 1:1.

Condition or disease Intervention/treatment Phase
Acute Ischemic Stroke Stroke Rehabilitation Drug: IMP Levodopa 100mg/Carbidopa 25mg Drug: Matching placebo Phase 3

Detailed Description:

Trial investigates whether Levodopa/Carbidopa compared to placebo given in addition to standardized rehabilitative therapy in patients with acute ischemic stroke is associated with

  1. improvements of physical function based on the patient's self-assessment
  2. improvement in patient-self assessed general health aspects, pain, mood, anxiety, fatigue and social participation
  3. long-term sustainability of a patient-relevant improvement of motor function
  4. improvement of selective hand and wrist movement
  5. a higher rate of patients walking independently of the help of another person.
  6. less severe impairment
  7. a higher level of activity of daily living
  8. 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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 610 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Study participants will be randomized 1:1
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: double-blind
Primary Purpose: Treatment
Official Title: Enhancement of Stroke Rehabilitation With Levodopa (ESTREL): a Randomized Placebo-controlled Trial
Actual Study Start Date : June 14, 2019
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Experimental Intervention
White Investigational Medicinal Product (IMP)- capsules of a combination of IMP Levodopa 100mg/Carbidopa 25mg.
Drug: IMP Levodopa 100mg/Carbidopa 25mg

Study treatment will comprise 3 phases:

  1. 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;
  2. full study treatment phase: from day 7 to day 34, 3 times per day (tid).
  3. 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.

Placebo Comparator: Control Intervention
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

Study treatment will comprise 3 phases:

  1. 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;
  2. full study treatment phase: from day 7 to day 34, Placebo capsules 3 times per day (tid).
  3. 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.




Primary Outcome Measures :
  1. Between-group difference of scores in the Fugl-Meyer-Motor Assessment (FMMA) [ Time Frame: 3 months +/- 14 days after randomization (= Visit 3) ]
    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)


Secondary Outcome Measures :
  1. Change in NIH-Stroke Scale score (NIHSS) [ Time Frame: 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 ]
    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.

  2. Change in modified Rankin Scale Score (mRS) [ Time Frame: 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 ]

    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.

    1. - No significant disability. Able to carry out all usual activities, despite some symptoms.
    2. - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.
    3. - Moderate disability. Requires some help, but able to walk unassisted.
    4. - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.
    5. - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.
    6. - Dead.

  3. Change in Stroke rehabilitation outcomes for disease specific morbidity and quality of life - PROMIS 29 [ Time Frame: Assessed 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12 months +/- 30 days after randomization ]
    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.

  4. Change in Stroke rehabilitation outcomes for disease specific morbidity and quality of life - PROMIS 10 [ Time Frame: Assessed 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12 months +/- 30 days after randomization ]
    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

  5. Change in Patient-reported assessment of relevance of motor improvement [ Time Frame: Assessed 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12 months +/- 30 days after randomization ]
    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)

  6. Change in Rivermead Mobility Index (RMI) [ Time Frame: 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 ]
    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.

  7. mortality (of any cause) [ Time Frame: Throughout the whole study period (Visit 1 = Baseline (day 0) to Visit 12 months +/- 30 days after randomization ]
    death rate

  8. recurrent stroke (any type) [ Time Frame: Throughout the whole study period (Visit 1 = Baseline (day 0) to Visit 12 months +/- 30 days after randomization ]
    recurrent stroke (any type)

  9. Rate of pre- specified Adverse Events of Interest [ Time Frame: Throughout the whole study period (Visit 1 = Baseline (day 0) to Visit 12 months +/- 30 days after randomization ]
    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)

  10. number of re-hospitalizations [ Time Frame: Throughout the whole study period (Visit 1 = Baseline (day 0) to Visit 12 months +/- 30 days after randomization ]
    re-hospitalization

  11. Change in Motricity Index (MI) [ Time Frame: 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 ]
    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)

  12. Change in Trunk Control Test (TCT) [ Time Frame: 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 ]
    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

  13. Change in Action Research Arm Test (ARAT) [ Time Frame: 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 ]
    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

  14. Change in Box- and Block Test (BBT) [ Time Frame: 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 ]
    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.

  15. Change in Functional Ambulation Categories (FAC) [ Time Frame: 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 ]

    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

    1. = Patient needs firm continuous support from 1 person who helps carrying weight and with balance
    2. = Patient needs continuous or intermittent support of one person to help with balance and coordination
    3. = Patient requires verbal supervision or stand-by help from one person without physical contact
    4. = Patient can walk independently on level ground, but requires help on stairs, slopes or uneven surfaces
    5. = Patient can walk independently anywhere

  16. Change in Ten-Meter Walk Test (10MWT) [ Time Frame: 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 ]
    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

  17. Change in Jamar dynamometer testing (JDT) [ Time Frame: 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 ]
    grip strength and strength of the forearm (in kilogram)

  18. Change in Montreal Cognitive Assessment (MoCA) [ Time Frame: 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 ]
    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)

  19. Change in Daily life physical activity [ Time Frame: 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 ]
    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

  20. Rate of Serious Adverse Event (SAE) [ Time Frame: Throughout the whole study period (Visit 1 = Baseline (day 0) to Visit 12 months +/- 30 days after randomization ]

    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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Acute ischemic stroke ≤ 7 days prior to randomization
  • Clinically meaningful hemiparesis (i.e. ≥ 3 points on arm plus leg motor items of the NIH-stroke scale score)
  • 24-hour latency period in case of 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 or dopamine-agonists 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 according to the Swiss "Arzneimittelkompendium" (https://compendium.ch/prod/sinemet-tabl-25mg-100mg/d)
  • Pregnancy or lactation of women of child-bearing potential unwilling to use medically approved contraception whilst receiving Levodopa/Carbidopa or Placebo and 1 month thereafter

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03735901


Contacts
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Contact: Stefan Engelter, Prof. MD +41 61 326 4063 stefan.engelter@fps.ch
Contact: Christopher Tränka, Dr. med +41 61 328 64 02 christopher.traenka@usb.ch

Locations
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Switzerland
Kantonsspital Aarau, Neurozentrum Recruiting
Aarau, Switzerland, 5001
Contact: Krassen Nedeltchev, Prof. Dr. med    +41 62 838 66 75    krassen.nedeltchev@ksa.ch   
RehaClinic AG Active, not recruiting
Bad Zurzach, Switzerland, 5330
Kantonsspital Baden Recruiting
Baden, Switzerland, 5404
Contact: Alexander Tarnutzer, PD Dr. med    +41 56 486 16 10    alexander.tarnutzer@ksb.ch   
Felix Platter Spital Active, not recruiting
Basel, Switzerland, 4002
Stroke-Center Universitätsspital Basel Recruiting
Basel, Switzerland
Contact: Philippe Lyrer, Prof.Dr. med    +41 61 328 61 60    philippe.lyrer@usb.ch   
Inselspital, Universitätsklinik für Neurologie Recruiting
Bern, Switzerland, 3010
Contact: René M. Müri, Prof. Dr. med    +41 31 632 30 83    rene.mueri@insel.ch   
Kantonsspital Graubünden, Departement Innere Medizin / Neurologie Recruiting
Chur, Switzerland, 7000
Contact: Rolf Sturzenegger, Dr. med    +41 81 256 78 41    rolf.sturzenegger@ksgr.ch   
HFR Fribourg Hopital Cantonal, U. de Neurologie Recruiting
Fribourg, Switzerland, 1708
Contact: Friedrich Medlin, Dr. med    +41 26 306 22 37    Friedrich.Medlin@h-fr.ch   
Centre hospitalier universitaire vaudois, Service de Neurologie Recruiting
Lausanne, Switzerland, 1011
Contact: Patrik Michel, Prof. Dr. med    +41 79 556 84 16    patrik.michel@chuv.ch   
Luzerner Kantonsspital, Klinik für Neurologie und Neurorehabilitation Recruiting
Luzern 16, Switzerland, 6000
Contact: Thomas Nyffeler, Prof. Dr. med    +41 41 205 51 49    thomas.nyffeler@luks.ch   
HFR Meyriez-Murten, Clinique de Réhabilitation Active, not recruiting
Meyriez, Switzerland, 3280
Kantonsspital Münsterlingen Recruiting
Münsterlingen, Switzerland, 8596
Contact: Ludwig Schelosky, Dr. med.    +41 71 686 2541    ludwig.schelosky@stgag.ch   
Reha Rheinfelden Active, not recruiting
Rheinfelden, Switzerland, 4310
Hôpital du Valais - Sion, Service de neurologie Recruiting
Sion, Switzerland, 1950
Contact: Christophe Bonvin, Dr. med.    +41 27 603 85 63    christophe.bonvin@hopitalvs.ch   
Hôpital du Valais - Sion Active, not recruiting
Sion, Switzerland, 1950
Kantonsspital St.Gallen, Klinik für Neurologie Recruiting
St.Gallen, Switzerland, 9007
Contact: Georg Kägi, Dr. med    +41 71 494 16 52    georg.kaegi@kssg.ch   
Rehazentrum Valens, Klinik für Neurologie und Neurorehabilitation Active, not recruiting
Valens, Switzerland, 7317
Cereneo Schweiz AG Active, not recruiting
Vitznau, Switzerland, 6354
Zürcher RehaZentrum Wald Active, not recruiting
Wald, Switzerland, 8636
Rheinburg Klinik AG Active, not recruiting
Walzenhausen, Switzerland, 9428
Kantonsspital Winterthur Recruiting
Winterthur, Switzerland, 8401
Contact: Matthias Greulich, Dr. med    +41 (0)52 266 45 60    Matthias.Greulich@ksw.ch   
Rehaklinik Zihlschlacht Active, not recruiting
Zihlschlacht, Switzerland, 8588
Klinik Lengg AG Active, not recruiting
Zürich, Switzerland, 8008
Universitätsspital Zürich, Klinik für Neurologie Recruiting
Zürich, Switzerland, 8091
Contact: Andreas Luft, Prof. Dr. med    +41 44 255 54 00    andreas.luft@usz.ch   
Sponsors and Collaborators
University Hospital, Basel, Switzerland
Swiss National Science Foundation
Investigators
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Principal Investigator: Stefan Engelter, Prof. MD Felix-Platter Spital Basel

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Responsible Party: University Hospital, Basel, Switzerland
ClinicalTrials.gov Identifier: NCT03735901     History of Changes
Other Study ID Numbers: 2018-02021; me16Engelter
First Posted: November 8, 2018    Key Record Dates
Last Update Posted: September 23, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University Hospital, Basel, Switzerland:
Levodopa/ Carbidopa
Fugl-Meyer-Motor-Assessment (FMMA)
Additional relevant MeSH terms:
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Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Stroke
Levodopa
Carbidopa
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Aromatic Amino Acid Decarboxylase Inhibitors
Enzyme Inhibitors