Apomorphine in Severe Brain-injured Patients

Last updated: April 10, 2025
Sponsor: University of Liege
Overall Status: Active - Recruiting

Phase

2/3

Condition

N/A

Treatment

Sodium chloride 9mg/ml

Apomorphine Hydrochloride 5mg/ml

Clinical Study ID

NCT05213169
2017/81b
  • Ages 18-80
  • All Genders

Study Summary

Background:

Patients who survive severe brain injury may develop chronic disorders of consciousness (DoC). Treating these patients to improve recovery is extremely challenging because of scarce and inefficient therapeutical options. Among pharmacological treatments, apomorphine, a potent direct dopamine agonist, has exhibited promising behavioral effects, but its true efficacy and its mechanism remains unknown. This randomized controlled study aims to verify the effects of apomorphine subcutaneous infusion in patients with disorders of consciousness and investigate the neural networks targeted by this treatment.

Methods/design:

The double-blind randomized controlled trial will include 48 patients: 24 patients will be randomly assigned to the apomorphine and 24 to the placebo group. Investigators and the patients will be unaware of the nature of the treatment rendered.

Primary outcome will be determined as behavioral response to treatment as measured by changes of diagnosis using the Coma Recovery Scale - Revised (CRS-R), while secondary outcome measures will include the Nociception Coma Scale - Revised (NCS-R), Disability Rating Scale (DRS), Wessex Head Injury Matrix (WHIM), circadian rhythm using actimetry, electroencephalography (EEG), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). The Glasgow Outcome Scale - Extended (GOS-E) and a phone-adapted version of the CRS-R will be used for long-term follow-up.

Statistical analyses will focus on the detection of changes induced by apomorphine treatment at the individual level (comparing data before and after treatment) and at the group level (comparing responders with non-responders). Response to treatment will be measured at four different levels: 1. behavioral response (CRS-R, NCS-R, DRS, WHIM, GOS-E, phone CRS-R), 2. brain metabolism (PET), 3. network connectivity (resting-state fMRI, clinical EEG and high-density EEG) and 4. Circadian rhythm changes (actimetry, body temperature, 24h-EEG).

Discussion:

Apomorphine is a promising and safe strategy for the treatment of DoC but efficacy, profile of the responding population and underlying mechanism remain to be determined. This trial will provide unprecedented data that will allow to investigate the response to apomorphine using multimodal methods and shed new light on the brain networks targeted by this drug in terms of behavioral response, functional connectivity and metabolism.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  • 18-80 years old.

  • Clinically stable, not dependent on medical ventilators for respiration.

  • Diagnosed as in an unresponsive wakefulness syndrome or minimally conscious stateaccording to the international criteria and based on at least 2 consistent CRS-R inthe last 14 days (one CRS-R in the last 7 days).

  • More than 4 weeks post-insult.

  • No serious neurological impairments others than related to their acquired braininjury.

  • No neurological medications other than anti-epileptic or anti-spasticity drugswithin the last two weeks.

  • No use of dopaminergic medications other than apomorphine within the last two weeks.

  • Informed consent from legal representative of the patient (if patients recover,their consent will also be obtained).

Exclusion

Exclusion Criteria:

  • Use of dopamine agonists or antagonists (e.g. amantadine, bromocriptine, l-dopa,pramipexole, ropinirole, amphetamine, bupropion, methylphenidate / risperidone,haloperidol, chlorpromazine, flupentixol, clozapine, olanzapine, quetiapine) in thelast 4 weeks or 4 half-lives of the drug.

  • Use of drugs with known significant prolongation of the QT interval (e.g. class 1antiarrythmics, sotalol, macrolides, quinolones, antipsychotic drugs, tricyclicantidepressants. Methadone, chloroquine, quinine)

  • A corrected QT interval over 480ms (calculated using Bazett's formula on a standard 12-lead ECG recorded in the last 14 days) or other risk factors for arrhythmia (congestive cardiac failure, severe hepatic impairment or significant electrolytedisturbance).

  • A history of previous neurological functional impairment.

  • Contraindication to MRI, EEG, or PET (e.g., electronic implanted devices, activeepilepsy, external ventricular drain).

  • Use of nitrates or other vasodilators, central nervous system acting agents such asbarbiturates, morphine and related drugs (relative exclusion criterion)

Study Design

Total Participants: 48
Treatment Group(s): 2
Primary Treatment: Sodium chloride 9mg/ml
Phase: 2/3
Study Start date:
June 18, 2021
Estimated Completion Date:
December 31, 2026

Connect with a study center

  • University of Liege

    Liege, 4000
    Belgium

    Site Not Available

  • Hôpital Valdor - ISoSL

    Liège, 4000
    Belgium

    Active - Recruiting

  • Centre Hospitalier Neurologique William Lennox

    Ottignies-Louvain-la-Neuve, 1340
    Belgium

    Active - Recruiting

  • Radboud University Medical Centre

    Nijmegen, 6525
    Netherlands

    Site Not Available

  • VITHAS

    Valencia, 46035
    Spain

    Site Not Available

  • Centre Hospitalier Universitaire Vaudois

    Lausanne, 1011
    Switzerland

    Site Not Available

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