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

Overview

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.

Interventions

• Drug Apomorphine Hydrochloride 5mg/ml
  Product administered using an external continuous subcutaneous infusion pump.
• Other Sodium chloride 9mg/ml
  Product administered using an external continuous subcutaneous infusion pump.

Primary outcome measures

• 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)]

Secondary outcome measures (11)

• Change from Baseline Nociception Coma Scale - Revised (NCS-R) [Time frame: up to 90 days (5 NCS-R baseline, 5 NCS-R treatment, 5 NCS-R follow-up)]
• Change from Baseline Disability Rating Scale (DRS) [Time frame: up to 90 days (5 DRS baseline, 5 DRS treatment, 5 DRS follow-up)]
• Change from Baseline Wessex Head Injury Matrix (WHIM) [Time frame: up to 90 days (5 WHIM baseline, 5 WHIM treatment, 5 WHIM follow-up)]
• Change from Baseline Circadian rhythm [Time frame: up to 90 days (constant recording from enrollment)]
• functional Magnetic Resonance Imaging (fMRI) [Time frame: up to 90 days (fMRI before treatment initiation and after treatment completion)]
• Positron Emission Tomography (PET) [Time frame: up to 90 days (PET before treatment initiation and after treatment completion)]
• Conventional Electroencephalography (cEEG) [Time frame: up to 90 days (4 cEEG baseline, 5 cEEG treatment, 5 cEEG follow-up)]
• 24-hour Electroencephalography (24-h EEG) [Time frame: up to 90 days (24-h EEG before treatment initiation and after treatment completion)]
• High-Density Electroencephalography (HD-EEG) [Time frame: up to 90 days (HD-EEG before treatment initiation and after treatment completion)]
• Glasgow Outcome Scale - Extended (GOS-E) [Time frame: from 6 months post-treatment up to 24 months post-treatment (GOS-E at 6 months,12 months and 24 months)]
• Phone-adapted CRS-R [Time frame: from 6 months post-treatment up to 24 months post-treatment (phone-adapted CRS-R at 6 months,12 months and 24 months)]

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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Belgium · 3 centers

• University of Liege — Liège
• Hôpital Valdor - ISoSL — Liège
• Centre Hospitalier Neurologique William Lennox — Ottignies-Louvain-la-Neuve

Spain · 1 center

• VITHAS — Valencia

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. PMID 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. PMID 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. PMID 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. PMID 30941094

Identifiers

NCT: NCT05213169 · 2017/81b

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗