Treating Severe Brain-injured Patients With Apomorphine
Status:
Recruiting
Trial end date:
2023-08-01
Target enrollment:
Participant gender:
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.