Apomorphine in Severe Brain-injured Patients

NCT05213169 | Recruiting Phase 2

• 1 other identifier: 2017/81b
• Study Type: interventional
• Target: 48
• Locations: 2 countries
• Sites: 4

Brief 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.

Conditions

Disorder of Consciousness

Keywords

unresponsive wakefulness syndrome; minimally conscious state; apomorphine; treatment

Outcome Measures

Primary Outcomes (1)

• Change from Baseline Coma Recovery Scale - Revised (CRS-R)

  The CRS-R is a standardized validated neurobehavioral scale designed to assess patients with disorders of consciousness. It is divided in 6 subscales: Auditory Function (0-4 points), Visual Function (0-5 points), Motor Function (0-6 points), Oromotor/Verbal Function (0-3 points), Communication (0-2 points), Arousal (0-3 points). The subscores are summed to calculate a total score ranging from 0 to 23 points. Higher scores indicate better functions. More importantly, it provides the patient's diagnosis (coma, UWS, MCS-, MCS+, EMCS) based on the presence of specific items in different subscales (regardless of total score). Analyses will look for changes of diagnosis, changes of total score and changes of each subscore before, during and after apomorphine treatment.

  up to 90 days (5 CRS-R baseline, 5 CRS-R treatment, 5 CRS-R follow-up)

Secondary Outcomes (11)

• Change from Baseline Nociception Coma Scale - Revised (NCS-R)

  up to 90 days (5 NCS-R baseline, 5 NCS-R treatment, 5 NCS-R follow-up)

• Change from Baseline Disability Rating Scale (DRS)

  up to 90 days (5 DRS baseline, 5 DRS treatment, 5 DRS follow-up)

• Change from Baseline Wessex Head Injury Matrix (WHIM)

  up to 90 days (5 WHIM baseline, 5 WHIM treatment, 5 WHIM follow-up)

• Change from Baseline Circadian rhythm

  up to 90 days (constant recording from enrollment)

• functional Magnetic Resonance Imaging (fMRI)

  up to 90 days (fMRI before treatment initiation and after treatment completion)

Study Arms (2)

Apomorphine

EXPERIMENTAL

Apomorphine hydrochloride subcutaneous infusion 12 hours per day during 30 days: titration phase from 0 to 4 mg/h (5 days), maintenance phase at 4 mg/h, titration-maintenance phase with possible increase up to 6 mg/h depending on tolerance (18 days). Domperidone 20mg t.i.d per os (or via gastric tube) will be initiated to reduce common side effects 2 days before the initiation of apomorphine and maintained at least 7 days before an optional tapering off in the absence side effects.

Drug: Apomorphine Hydrochloride 5mg/ml

Isotonic saline

PLACEBO COMPARATOR

Sodium chloride infusion following the administration procedure described for apomorphine

Other: Sodium chloride 9mg/ml

Interventions

Apomorphine Hydrochloride 5mg/ml DRUG

Product administered using an external continuous subcutaneous infusion pump.

Apomorphine

Sodium chloride 9mg/ml OTHER

Product administered using an external continuous subcutaneous infusion pump.

Isotonic saline

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years old.
• Clinically stable, not dependent on medical ventilators for respiration.
• Diagnosed as in an unresponsive wakefulness syndrome or minimally conscious state according to the international criteria and based on at least 2 consistent CRS-R in the 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 brain injury.
• No neurological medications other than anti-epileptic or anti-spasticity drugs within 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).

You may not qualify if:

• 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 the last 4 weeks or 4 half-lives of the drug.
• Use of drugs with known significant prolongation of the QT interval (e.g. class 1 antiarrythmics, sotalol, macrolides, quinolones, antipsychotic drugs, tricyclic antidepressants. 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 electrolyte disturbance).
• A history of previous neurological functional impairment.
• Contraindication to MRI, EEG, or PET (e.g., electronic implanted devices, active epilepsy, external ventricular drain).

Sponsors & Collaborators

• University of Liege: lead
• Centre Hospitalier Neurologique William Lennox (Belgium): collaborator
• Hôpital Valdor - ISoSL (Belgium): collaborator
• VITHAS hospitales (Spain): collaborator

Study Sites (4)

University of Liege

Liège, Liege, 4000, Belgium

ACTIVE NOT RECRUITING

Hôpital Valdor - ISoSL

Liège, Liège, 4000, Belgium

RECRUITING

Centre Hospitalier Neurologique William Lennox

Ottignies-Louvain-la-Neuve, 1340, Belgium

RECRUITING

VITHAS

Valencia, 46035, Spain

NOT YET RECRUITING

Related Publications (4)

• Fridman EA, Calvar J, Bonetto M, Gamzu E, Krimchansky BZ, Meli F, Leiguarda RC, Zafonte R. Fast awakening from minimally conscious state with apomorphine. Brain Inj. 2009 Feb;23(2):172-7. doi: 10.1080/02699050802649662.

  PMID: 19191097 BACKGROUND

• Fridman EA, Krimchansky BZ, Bonetto M, Galperin T, Gamzu ER, Leiguarda RC, Zafonte R. Continuous subcutaneous apomorphine for severe disorders of consciousness after traumatic brain injury. Brain Inj. 2010;24(4):636-41. doi: 10.3109/02699051003610433.

  PMID: 20235766 BACKGROUND

• Gosseries O, Charland-Verville V, Thonnard M, Bodart O, Laureys S, Demertzi A. Amantadine, apomorphine and zolpidem in the treatment of disorders of consciousness. Curr Pharm Des. 2014;20(26):4167-84.

  PMID: 24025057 BACKGROUND

• Sanz LRD, Lejeune N, Blandiaux S, Bonin E, Thibaut A, Stender J, Farber NM, Zafonte RD, Schiff ND, Laureys S, Gosseries O. Treating Disorders of Consciousness With Apomorphine: Protocol for a Double-Blind Randomized Controlled Trial Using Multimodal Assessments. Front Neurol. 2019 Mar 19;10:248. doi: 10.3389/fneur.2019.00248. eCollection 2019.

  PMID: 30941094 BACKGROUND

MeSH Terms

Conditions

Consciousness Disorders; Persistent Vegetative State

Interventions

Apomorphine; Sodium Chloride

Condition Hierarchy (Ancestors)

Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurocognitive Disorders; Mental Disorders; Brain Damage, Chronic; Brain Diseases; Central Nervous System Diseases; Unconsciousness

Intervention Hierarchy (Ancestors)

Aporphines; Benzylisoquinolines; Alkaloids; Heterocyclic Compounds; Isoquinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 4 or More Rings; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Olivia Gosseries, Ph.D.

  University of Liege

  PRINCIPAL INVESTIGATOR

• Steven Laureys, M.D., Ph.D.

  University hospital of Liège

  STUDY DIRECTOR

Central Study Contacts

Emilie Szymkowicz, MSc.

CONTACT

+32492319947; emilie.szymkowicz@uliege.be

Leandro RD Sanz, M.D.

CONTACT

+3243663915; leandro.sanz@uliege.be

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind trial
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Research Associate

Model Details: Apomorphine treatment or placebo

Study Record Dates

• First Submitted: December 20, 2021
• First Posted: January 28, 2022
• Study Start: June 18, 2021
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: April 15, 2025

Record last verified: 2025-04

Locations

ES (1); BE (3)