Treating Severe Brain-injured Patients With Apomorphine

NCT03623828 | Unknown Phase 2

• 1 other identifier: 2017/81a
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 2

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.

Conditions

Disorder of Consciousness

Keywords

unresponsive wakefulness syndrome; minimally conscious state; apomorphine; crs-r

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (10)

• Nociception Coma Scale - Revised (NCS-R)

  up to 90 days (5x before treatment, 4x during treatment and 5x after treatment)

• resting-state EEG

  up to 90 days (4x before treatment, 4x during treatment and 4x after treatment)

• EEG with auditory paradigms

  up to 90 days

• PET

  up to 90 days (1x before treatment and 1x after treatment)

• fMRI

  up to 90 days (1x before treatment and 1x after treatment)

Study Arms (1)

Apomorphine treatment

EXPERIMENTAL

Treatment by apomorphine hydrochloride subcutaneous infusion 12 hours per day during 30 days: 5-days titration phase (increasing doses from 0 to 4 mg/h), 7 days of maintenance at 4 mg/h and 18 days of maintenance phase with possible increase up to 6 mg/h if well tolerated. Two days before the initiation of apomorphine, domperidone 20mg t.i.d per os (or via gastric tube) will be initiated to reduce common side effects. It will be maintained at least 7 days before an optional tapering off in the absence of nausea of vomiting.

Drug: Apomorphine Hydrochloride 50Mg/10mL Prefilled Syringe

Interventions

Apomorphine Hydrochloride 50Mg/10mL Prefilled Syringe DRUG

Product administered using an external continuous subcutaneous infusion pump.

Also known as: APO-go PFS 5mg/ml

Apomorphine treatment

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

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 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).

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
• Université Catholique de Louvain: collaborator

Study Sites (2)

Neurological Hospital Center William Lennox

Ottignies, Brabant Wallon, 1340, Belgium

Location

University Hospital of Liège

Liège, 4000, Belgium

Location

Related Publications (5)

• 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, Szymkowicz E, Bonin EAC, Panda R, Sala A, Thibaut A, Huerta-Gutierrez R, Dardenne N, Dikenstein D, Van Goethem S, Ledoux D, Hustinx R, Stender J, Farber NM, Zafonte RD, Schiff ND, Laureys S, Gosseries O. Apomorphine for prolonged disorders of consciousness: a multimodal open-label study. EClinicalMedicine. 2024 Nov 15;78:102925. doi: 10.1016/j.eclinm.2024.102925. eCollection 2024 Dec.

  PMID: 39624459 DERIVED

• 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 DERIVED

MeSH Terms

Conditions

Consciousness Disorders; Persistent Vegetative State

Interventions

Apomorphine

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

Study Officials

• Steven Laureys, M.D., Ph.D.

  University hospital of Liège

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: This is an open-label single-arm prospective pilot study. Included patients all undergo the same study protocol.

Study Record Dates

• First Submitted: July 25, 2018
• First Posted: August 9, 2018
• Study Start: October 3, 2018
• Primary Completion: April 28, 2021
• Study Completion: November 13, 2022
• Last Updated: February 9, 2022

Record last verified: 2022-02

Locations

BE (2)