Enhancement of Stroke Rehabilitation With Levodopa

NCT03735901 | Active Not Recruiting Phase 3

• 1 other identifier: 2018-02021; me16Engelter
• Study Type: interventional
• Target: 610
• Locations: 1 country
• Sites: 24

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 stroke patients. Study participants will be randomized 1:1.

Conditions

Acute Stroke; Stroke Rehabilitation

Keywords

Levodopa / Carbidopa; Fugl-Meyer-Motor-Assessment (FMMA); Acute ischemic stroke; Acute hemorrhagic stroke; Rehabilitation; Recovery; Randomized controlled trial

Outcome Measures

Primary Outcomes (1)

• Fugl-Meyer-Motor Assessment Score (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 Outcomes (20)

• NIH-Stroke Scale Score (NIHSS)

  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

• Modified Rankin Scale Score (mRS)

  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

• Stroke rehabilitation outcomes for disease specific morbidity and quality of life - PROMIS 29

  Assessed 5 weeks after randomization, 3 months +/- 14 days after randomization, 6 months +/- 20 days after randomization and 12 months +/- 30 days after randomization

• Stroke rehabilitation outcomes for disease specific morbidity and quality of life - PROMIS 10

  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

• Patient-reported assessment of relevance of motor improvement

  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

Study Arms (2)

Experimental Intervention

ACTIVE COMPARATOR

White Investigational Medicinal Product (IMP)- capsules of a combination of IMP Levodopa 100mg/Carbidopa 25mg.

Drug: IMP Levodopa 100mg/Carbidopa 25mg

Control Intervention

PLACEBO COMPARATOR

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

Interventions

IMP Levodopa 100mg/Carbidopa 25mg DRUG

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.

Experimental Intervention

Matching placebo DRUG

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.

Control Intervention

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Acute ischemic or hemorrhagic (i.e. intracerebral hemorrhage excluding subarachnoid hemorrhage and cerebral 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Hospital, Basel, Switzerland: lead
• Swiss National Science Foundation: collaborator

Study Sites (24)

Kantonsspital Aarau, Neurozentrum

Aarau, 5001, Switzerland

Location

RehaClinic AG

Bad Zurzach, 5330, Switzerland

Location

Kantonsspital Baden

Baden, 5404, Switzerland

Location

Felix Platter Spital

Basel, 4002, Switzerland

Location

Stroke-Center Universitätsspital Basel

Basel, Switzerland

Location

Inselspital, Universitätsklinik für Neurologie

Bern, 3010, Switzerland

Location

Kantonsspital Graubünden, Departement Innere Medizin / Neurologie

Chur, 7000, Switzerland

Location

HFR Fribourg Hopital Cantonal, U. de Neurologie

Fribourg, 1708, Switzerland

Location

Centre hospitalier universitaire vaudois, Service de Neurologie

Lausanne, 1011, Switzerland

Location

HFR Meyriez-Murten, Clinique de Réhabilitation

Meyriez, 3280, Switzerland

Location

Kantonsspital Münsterlingen

Münsterlingen, 8596, Switzerland

Location

Reha Rheinfelden

Rheinfelden, 4310, Switzerland

Location

Kantonsspital St.Gallen, Klinik für Neurologie

Sankt Gallen, 9007, Switzerland

Location

Hôpital du Valais - Sion, Service de neurologie

Sion, 1950, Switzerland

Location

Hôpital du Valais - Sion

Sion, 1950, Switzerland

Location

Rehazentrum Valens, Klinik für Neurologie und Neurorehabilitation

Valens, 7317, Switzerland

Location

Cereneo Schweiz AG

Vitznau, 6354, Switzerland

Location

Zürcher RehaZentrum Wald

Wald, 8636, Switzerland

Location

Rheinburg Klinik AG

Walzenhausen, 9428, Switzerland

Location

Kantonsspital Winterthur

Winterthur, 8401, Switzerland

Location

Rehaklinik Zihlschlacht

Zihlschlacht, 8588, Switzerland

Location

Klinik Lengg AG

Zurich, 8008, Switzerland

Location

Head Stroke Center Klinik Hirslanden

Zurich, 8032, Switzerland

Location

Universitätsspital Zürich, Klinik für Neurologie

Zurich, 8091, Switzerland

Location

Related Publications (1)

• Engelter ST, Kaufmann JE, Zietz A, Luft AR, Polymeris A, Altersberger VL, Wiesner K, Wiegert M, Held JPO, Rottenberger Y, Schwarz A, Medlin F, Accolla EA, Foucras S, Kagi G, De Marchis GM, Politz S, Greulich M, Tarnutzer AA, Sturzenegger R, Katan M, Fischer U, Nedeltchev K, Schar J, Van Den Keybus Deglon K, Rapin PA, Salerno A, Seiffge DJ, Auer E, Lippert J, Bonati LH, Schuster-Amft C, Gaumann S, Chabwine JN, Humm A, Moller JC, Schweinfurther R, Bujan B, Jedrysiak P, Sandor PS, Gonzenbach R, Mylius V, Lutz D, Lienert C, Peters N, Michel P, Muri RM, Schadelin S, Hemkens LG, Ford GA, Lyrer PA, Gensicke H, Traenka C; ESTREL Investigators. Levodopa Added to Stroke Rehabilitation: The ESTREL Randomized Clinical Trial. JAMA. 2025 Nov 4;334(17):1523-1532. doi: 10.1001/jama.2025.15185.

  PMID: 40982270 DERIVED

MeSH Terms

Conditions

Stroke; Ischemic Stroke

Interventions

Carbidopa

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Methyldopa; Dihydroxyphenylalanine; Catecholamines; Amines; Organic Chemicals; Hydrazines; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Study Officials

• Stefan Engelter, Prof. MD

  Felix-Platter Spital Basel

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: double-blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Study participants will be randomized 1:1

Study Record Dates

• First Submitted: November 7, 2018
• First Posted: November 8, 2018
• Study Start: June 14, 2019
• Primary Completion: August 27, 2024
• Study Completion (Estimated): June 30, 2029
• Last Updated: October 15, 2024

Record last verified: 2024-10

Locations

CH (24)