Treating Severe Brain-injured Patients With Apomorphine

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

Interventions

DRUG

Apomorphine Hydrochloride 50Mg/10mL Prefilled Syringe

Product administered using an external continuous subcutaneous infusion pump.

Sponsors & Collaborators

• Université Catholique de Louvain

  collaborator OTHER

• University of Liege

  lead OTHER

Principal Investigators

• Steven Laureys, M.D., Ph.D. · University hospital of Liège

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Max Age

55 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2018-10-03

Primary Completion

2021-04-28

Completion

2022-11-13

Countries

• Belgium

Study Locations