Treating Severe Brain-injured Patients With Apomorphine

Disorder of Consciousness Clinical Trial

Official title:

Treating Severe Brain-injured Patients With Apomorphine: a Behavioral and Neuroimaging Study

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03623828
• Other study ID #: 2017/81a
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: October 3, 2018
• Est. completion date: November 13, 2022

Study information

• Verified date: February 2022
• Source: University of Liege
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 8
• Est. completion date: November 13, 2022
• Est. primary completion date: April 28, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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)

Related Conditions & MeSH terms

• Consciousness Disorders
• Disorder of Consciousness

Intervention

Drug:
• Apomorphine Hydrochloride 50Mg/10mL Prefilled Syringe
Product administered using an external continuous subcutaneous infusion pump.

Locations

Country	Name	City	State
Belgium	University Hospital of Liège	Liège
Belgium	Neurological Hospital Center William Lennox	Ottignies	Brabant Wallon

Sponsors (2)

Lead Sponsor	Collaborator
University of Liege	Université Catholique de Louvain

Country where clinical trial is conducted

Belgium, 

References & Publications (3)

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. — View 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. — View 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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline in 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 (10x before treatment, 6x during treatment and 5x after treatment)
Secondary	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 apomorphine treatment.	up to 90 days (5x before treatment, 4x during treatment and 5x after treatment)
Secondary	resting-state EEG	Changes in 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) after apomorphine treatment.	up to 90 days (4x before treatment, 4x during treatment and 4x after treatment)
Secondary	EEG with auditory paradigms	Multivariate classifier giving the probabilty to have signs of consciousness based on a machine-learning approach using 120 EEG markers.	up to 90 days
Secondary	PET	Changes in quantification of PET signal using standardized uptake values of fluorodeoxyglucose after apomorphine treatment.	up to 90 days (1x before treatment and 1x after treatment)
Secondary	fMRI	Changes in 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, after apormorphine treatment	up to 90 days (1x before treatment and 1x after treatment)
Secondary	Circadian rythmycity using body movements	We use wrist actigraph recorded data on limb movements to calculate circadian rythmycity, measured in minutes. It corresponds to the period of the biological temporal rhythms with oscillations around 24 hours.	constant recording from enrollment up to 90 days
Secondary	Circadian rythmycity using body temperature variations	We use data recorded from non-invasive body temperature measurement devices to calculate circadian rythmycity, measured in minutes. It corresponds to the period of the biological temporal rhythms with oscillations around 24 hours.	constant recording from enrollment up to 90 days
Secondary	Number of sleep cycles using night EEG	We use data measured with whole-night EEG recordings to calculate the number of sleep cycles during one night and the duration spent in each phase of sleep.	actimetry and core body temperature recorded during the whole study; night EEG 1x before treatment initiation and 1x after treatment withdrawal
Secondary	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.	from 6 months post-treatment up to 24 months post-treatment (1x at 6 months, 1x at 12 months, 1x at 24 months)
Secondary	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.	from 6 months post-treatment up to 24 months post-treatment (1x at 6 months, 1x at 12 months, 1x at 24 months)