Clinical trial NCT03623828: Treating Severe Brain-injured Patients With Apomorphine
Official title: Treating Severe Brain-injured Patients With Apomorphine: a Behavioral and Neuroimaging Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Disorder of Consciousness
Keywords: unresponsive wakefulness syndrome
minimally conscious state
apomorphine
crs-r
Lead sponsor: University of Liege
Sponsor class: OTHER
Collaborators: name: Université Catholique de Louvain
First posted: 2018-08-09
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is an open-label single-arm prospective pilot study. Included patients all undergo the same study protocol.
Primary purpose: TREATMENT

Brief summary: Background:

Patients who survive severe brain injury may develop chronic disorders of consciousness. 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 pilot study aims to verify the effects of apomorphine subcutaneous infusion in patients with disorders of consciousness, investigate the neural networks targeted by this treatment and evaluate the feasibility of a larger double-blind randomized placebo-controlled trial.

Methods/design:

This study is a prospective open-label pilot clinical trial. Six patients diagnosed with disorders of consciousness will be included to receive a 4-weeks regimen of daily subcutaneous infusions of apomorphine hydrochloride. Patients will be monitored for four weeks before the initiation of the therapy, closely during treatment and they will undergo a 4-weeks inpatient follow-up after washout, as well as a two-year long-term remote follow-up. Shortly before and after the treatment regimen, the subjects will receive a multimodal assessment battery including neuroimaging exams.

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, circadian rhythm modifications using actimetry, core body temperature recording and night electroencephalography (EEG), positron emission tomography (PET), resting-state high-density EEG 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-E, GOS-E), 2. brain metabolism (PET), 3. network connectivity (resting-state fMRI and high-density EEG) and 4. Circadian rhythm changes (actimetry, body temperature, night EEG).

Discussion:

Apomorphine is a promising and safe candidate for the treatment of disorders of consciousness but its efficacy, the profile of the responding population and its underlying mechanism remain to be determined. This pilot study 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 metabolism, functional connectivity and behavioral response. The investigators aim to better define the phenotype of potential responders to identify them more easily and develop personalized patient management. This preliminary study will lay ground for a subsequent larger-scale placebo-controlled double-blind trial which will provide quantitative data on effect size controlled for spontaneous recovery.


Eligibility criteria: Inclusion Criteria:

* 18-55 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 6 weeks post-insult (starting the apomorphine treatment at 10 weeks minimum)
* 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 in Coma Recovery Scale - Revised (CRS-R)
timeFrame: up to 90 days (10x before treatment, 6x during treatment and 5x after treatment)
Secondary outcomes:
measure: Nociception Coma Scale - Revised (NCS-R)
timeFrame: up to 90 days (5x before treatment, 4x during treatment and 5x after treatment)
measure: resting-state EEG
timeFrame: up to 90 days (4x before treatment, 4x during treatment and 4x after treatment)
measure: EEG with auditory paradigms
timeFrame: up to 90 days
measure: PET
timeFrame: up to 90 days (1x before treatment and 1x after treatment)
measure: fMRI
timeFrame: up to 90 days (1x before treatment and 1x after treatment)
measure: Circadian rythmycity using body movements
timeFrame: constant recording from enrollment up to 90 days
measure: Circadian rythmycity using body temperature variations
timeFrame: constant recording from enrollment up to 90 days
measure: Number of sleep cycles using night EEG
timeFrame: actimetry and core body temperature recorded during the whole study; night EEG 1x before treatment initiation and 1x after treatment withdrawal
measure: Glasgow Outcome Scale - Extended (GOS-E)
timeFrame: from 6 months post-treatment up to 24 months post-treatment (1x at 6 months, 1x at 12 months, 1x at 24 months)
measure: Phone-adapted CRS-R
timeFrame: from 6 months post-treatment up to 24 months post-treatment (1x at 6 months, 1x at 12 months, 1x at 24 months)
Other outcomes:
Locations:
city: Ottignies
country: Belgium
facility: Neurological Hospital Center William Lennox
state: Brabant Wallon
city: Liège
country: Belgium
facility: University Hospital of Liège
Study officials:
affiliation: University hospital of Liège
name: Steven Laureys, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
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.