Clinical trial NCT05213169: Apomorphine in Severe Brain-injured Patients
Official title: Randomized Controlled Trial of Apomorphine in Severe Brain-injured Patients: a Double-blind Behavioral and Neuroimaging Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Disorder of Consciousness
Keywords: unresponsive wakefulness syndrome
minimally conscious state
apomorphine
treatment
Lead sponsor: University of Liege
Sponsor class: OTHER
Collaborators: name: Centre Hospitalier Neurologique William Lennox (Belgium)
name: Hôpital Valdor - ISoSL (Belgium)
name: VITHAS hospitales (Spain)
First posted: 2022-01-28
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Apomorphine treatment or placebo
Primary purpose: TREATMENT

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.


Eligibility criteria: 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 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).

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 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)

Primary outcomes:
measure: Change from Baseline Coma Recovery Scale - Revised (CRS-R)
timeFrame: up to 90 days (5 CRS-R baseline, 5 CRS-R treatment, 5 CRS-R follow-up)
Secondary outcomes:
measure: Change from Baseline Nociception Coma Scale - Revised (NCS-R)
timeFrame: up to 90 days (5 NCS-R baseline, 5 NCS-R treatment, 5 NCS-R follow-up)
measure: Change from Baseline Disability Rating Scale (DRS)
timeFrame: up to 90 days (5 DRS baseline, 5 DRS treatment, 5 DRS follow-up)
measure: Change from Baseline Wessex Head Injury Matrix (WHIM)
timeFrame: up to 90 days (5 WHIM baseline, 5 WHIM treatment, 5 WHIM follow-up)
measure: Change from Baseline Circadian rhythm
timeFrame: up to 90 days (constant recording from enrollment)
measure: functional Magnetic Resonance Imaging (fMRI)
timeFrame: up to 90 days (fMRI before treatment initiation and after treatment completion)
measure: Positron Emission Tomography (PET)
timeFrame: up to 90 days (PET before treatment initiation and after treatment completion)
measure: Conventional Electroencephalography (cEEG)
timeFrame: up to 90 days (4 cEEG baseline, 5 cEEG treatment, 5 cEEG follow-up)
measure: 24-hour Electroencephalography (24-h EEG)
timeFrame: up to 90 days (24-h EEG before treatment initiation and after treatment completion)
measure: High-Density Electroencephalography (HD-EEG)
timeFrame: up to 90 days (HD-EEG before treatment initiation and after treatment completion)
measure: Glasgow Outcome Scale - Extended (GOS-E)
timeFrame: from 6 months post-treatment up to 24 months post-treatment (GOS-E at 6 months,12 months and 24 months)
measure: Phone-adapted CRS-R
timeFrame: from 6 months post-treatment up to 24 months post-treatment (phone-adapted CRS-R at 6 months,12 months and 24 months)
Other outcomes:
Locations:
city: Liege
country: Belgium
facility: University of Liege
city: Liège
country: Belgium
facility: Hôpital Valdor - ISoSL
city: Ottignies-Louvain-la-Neuve
country: Belgium
facility: Centre Hospitalier Neurologique William Lennox
city: Valencia
country: Spain
facility: VITHAS
Study officials:
affiliation: University of Liege
name: Olivia Gosseries, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University hospital of Liège
name: Steven Laureys, M.D., Ph.D.
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.