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Disorder of ConsciousnessPhase 2/3APODoCNCT05213169

Apomorphine in Severe Brain-injured Patients

A Phase 2/3 study testing Apomorphine Hydrochloride 5mg/ml and Sodium chloride 9mg/ml in people with Disorder of Consciousness, run by University of Liege at 4 sites in 2 countries.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 80 years
Conditions the study is for
Disorder of Consciousness
What is being tested?
Apomorphine Hydrochloride 5mg/ml and Sodium chloride 9mg/ml
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
48 participants
Where
4 sitesin 2 countries
Study dates
18 Jun 2021to 31 Dec 2026
Phase
Phase 2/3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 18-80 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).

Who cannot join

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

Trial locations and contacts

4 sites in 2 countries. Contact the study team or a site near you to ask about taking part.

Emilie Szymkowicz, MSc. contact

+32492319947

emilie.szymkowicz@uliege.be

Leandro RD Sanz, M.D. contact

+3243663915

leandro.sanz@uliege.be

4 sites in 2 countries

Belgium3 sites, 2 recruiting

  • University of Liege

    Liège, Liege, 4000

    Active, not recruiting

  • Hôpital Valdor - ISoSL

    Liège, Liège, 4000

    Gwennaig Joris, MSc, g.joris@isosl.be

    Céline Aussems, MD

    Recruiting

  • Centre Hospitalier Neurologique William Lennox

    Ottignies-Louvain-la-Neuve, 1340

    Nicolas Lejeune, M.D., Ph.D., +3210430298, nicolas.lejeune@chnwl.be

    Nicolas Lejeune, M.D., Ph.D.

    Recruiting

Other trials in Belgium

Spain1 site, 1 recruiting

  • VITHAS

    Valencia, 46035

    Loles Navarro Pérez, Ph.D., loles@neurorhb.com

    Roberto Llorens, Ph.D., enoe@comv.es

    Not yet recruiting

Other trials in Spain

About this study

Official title: Randomized Controlled Trial of Apomorphine in Severe Brain-injured Patients: a Double-blind Behavioral and Neuroimaging Study

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.

Read more

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.

Being tested
Apomorphine Hydrochloride 5mg/ml, Sodium chloride 9mg/ml
Keywords
unresponsive wakefulness syndrome, minimally conscious state, apomorphine, treatment
Medical subject headings
Consciousness Disorders, Persistent Vegetative State

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Apomorphine Hydrochloride 5mg/mlDrug

    Product administered using an external continuous subcutaneous infusion pump.

  • Sodium chloride 9mg/mlOther

    Product administered using an external continuous subcutaneous infusion pump.

Study groups in NCT05213169
Study groupRoleWhat they receive
ApomorphineExperimentalApomorphine 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.
Receives: Drug: Apomorphine Hydrochloride 5mg/ml
Isotonic salinePlacebo comparatorSodium chloride infusion following the administration procedure described for apomorphine
Receives: Other: Sodium chloride 9mg/ml

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

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

Secondary outcomes (11)

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

    The NCS-R is a standardized validated scale designed to assess the perception of pain in patients with disorders of consciousness unable to functionally communicate. It is divided in 3 subscales: Motor Response (0-3 points), Verbal Response (0-3 points) and Facial Expression (0-3 points). The subscores are summed to calculate a total score ranging from 0 to 9 points. Higher scores indicate a higher perception of pain. Analyses will look for changes of total score and changes of each subscore before, during and after treatment.

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

  2. Change from Baseline Disability Rating Scale (DRS)

    The DRS is validated scale designed to assess disability including the impairment and handicap of patients. It is divided in 8 subscales: eye-opening (0-3 points), communication ability (0-4 points), motor response (0-5 points), feeding (0-3 points), toileting (0-3 points), grooming (0-3 points), level of functioning (0-5 points) and employability (0-3 points). The subscores are summed to calculate a total score ranging from 0 to 29 points. Higher scores indicate a higher disability. Analyses will look for changes of total score before, during and after treatment.

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

  3. Change from Baseline Wessex Head Injury Matrix (WHIM)

    The WHIM is validated matrix designed to assess recovery in patients with disorders of consciousness. It is composed of 62 sequential items covering communication ability, cognitive skills and social interaction. The total number of achieved items and the highest achieved item are recorded. Analyses will look for changes of the total number and the highest achieved items before, during and after treatment.

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

  4. Change from Baseline Circadian rhythm

    Wrist actigraph recorded data on limb movements to calculate circadian rythmycity (measured in minutes) corresponding to the period of the biological temporal rhythms with oscillations around 24 hours.

    Measured: up to 90 days (constant recording from enrollment)

  5. functional Magnetic Resonance Imaging (fMRI)

    MRI functional connectivity using a seed-voxel approach, between regions of interest (here: striatum, globus pallidus interna, thalamus and prefrontal cortex) and the time course from all other brain voxels.

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

  6. Positron Emission Tomography (PET)

    Quantification of PET signal using standardized uptake values of fluorodeoxyglucose.

    Measured: up to 90 days (PET before treatment initiation and after treatment completion)

  7. Conventional Electroencephalography (cEEG)

    EEG spectral power within fixed bands or dynamic connectivity using median spectral connectivity and graph-theoretic topology metrics (clustering coefficient, path length, modularity and participation coefficient).

    Measured: up to 90 days (4 cEEG baseline, 5 cEEG treatment, 5 cEEG follow-up)

  8. 24-hour Electroencephalography (24-h EEG)

    24-h EEG recordings to calculate the number of sleep cycles during day and night as well as the duration spent in each phase of sleep.

    Measured: up to 90 days (24-h EEG before treatment initiation and after treatment completion)

  9. High-Density Electroencephalography (HD-EEG)

    Multivariate classifier giving the probabilty to have signs of consciousness based on a machine-learning approach using 120 EEG markers.

    Measured: up to 90 days (HD-EEG before treatment initiation and after treatment completion)

  10. Glasgow Outcome Scale - Extended (GOS-E)

    The GOS-E is a standardized validated scale designed to assess the the functional outcome of patients with disorders of consciousness. It is a single score ranging from 1 (dead) to 8 (upper good recovery). Higher scores indicate a higher functional recovery. It will be performed remotely by telephone contact with the patient or their relatives.

    Analyses will look at differences in GOS-E score between responders and non-responders to apomorphine treatment, as well as differences in time within individual patients.

    Measured: from 6 months post-treatment up to 24 months post-treatment (GOS-E at 6 months,12 months and 24 months)

  11. Phone-adapted CRS-R

    The phone-adapted CRS-R is a scale designed to assess remotely patients with disorders of consciousness. Unlike the CRS-R, it does not comprise subcores or a total score, but provides the clinical diagnosis of the patient (coma, UWS, MCS-, MCS+, EMCS) using the same diagnostic items as the CRS-R.

    Analyses will look at differences in Phone-adapted CRS-R diagnosis between responders and non-responders to apomorphine treatment, as well as differences in time within individual patients.

    Measured: from 6 months post-treatment up to 24 months post-treatment (phone-adapted CRS-R at 6 months,12 months and 24 months)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Jan 2022
  2. Study start18 Jun 2021
  3. Primary completion31 Dec 2026 (estimated)
  4. Study completion31 Dec 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Apomorphine treatment or placebo
Masking
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
48 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05213169
Sponsor's protocol ID
2017/81b
Acronym
APODoC
Status last verified
Apr 2025
First submitted
20 Dec 2021
Last updated
15 Apr 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Publications

  • 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.

    PubMed 19191097

  • 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.

    PubMed 20235766

  • 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.

    PubMed 24025057

  • 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.

    PubMed 30941094

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Apomorphine Hydrochloride 5mg/ml and Sodium chloride 9mg/ml in people with Disorder of Consciousness, run by University of Liege at 4 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 15 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in Belgium, Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Emilie Szymkowicz, MSc. (+32492319947, emilie.szymkowicz@uliege.be), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change from Baseline Coma Recovery Scale - Revised (CRS-R) (time frame: up to 90 days (5 CRS-R baseline, 5 CRS-R treatment, 5 CRS-R follow-up)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05213169, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Apr 2025.

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