Apomorphine in Severe Brain-injured Patients
ConditionDisorder of Consciousness
Trial statusRecruiting
Trial phasePhase 2, Phase 3
Trial typeInterventional
Biological sexAll
Age18-80
SponsorUniversity of Liege
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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.
Disqualifiers
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.
Trial design
Design model
Parallel
Treatments tested in this trial
Apomorphine Hydrochloride 5mg/ml
DrugProduct administered using an external continuous subcutaneous infusion pump.
Sodium chloride 9mg/ml
Other interventionProduct administered using an external continuous subcutaneous infusion pump.
Treatment groups
48 Participants
are divided into 2 treatment groupsGroup A: ApomorphineExperimental treatment 1 intervention
Group B: Isotonic salinePlacebo comparator 1 intervention
Trial outcomes
Primary outcomes
1
Change from Baseline 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.
Time frame
up to 90 days (5 CRS-R baseline, 5 CRS-R treatment, 5 CRS-R follow-up)Secondary outcomes
1
Change from Baseline 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 treatment.
Time frame
up to 90 days (5 NCS-R baseline, 5 NCS-R treatment, 5 NCS-R follow-up)2
Change from Baseline Disability Rating Scale (DRS)
The DRS is validated scale designed to assess disability including the impairment and handicap of patients. It is divided in 8 subscales: eye-opening (0-3 points), communication ability (0-4 points), motor response (0-5 points), feeding (0-3 points), toileting (0-3 points), grooming (0-3 points), level of functioning (0-5 points) and employability (0-3 points). The subscores are summed to calculate a total score ranging from 0 to 29 points. Higher scores indicate a higher disability. Analyses will look for changes of total score before, during and after treatment.
Time frame
up to 90 days (5 DRS baseline, 5 DRS treatment, 5 DRS follow-up)3
Change from Baseline Wessex Head Injury Matrix (WHIM)
The WHIM is validated matrix designed to assess recovery in patients with disorders of consciousness. It is composed of 62 sequential items covering communication ability, cognitive skills and social interaction. The total number of achieved items and the highest achieved item are recorded. Analyses will look for changes of the total number and the highest achieved items before, during and after treatment.
Time frame
up to 90 days (5 WHIM baseline, 5 WHIM treatment, 5 WHIM follow-up)4
Change from Baseline Circadian rhythm
Wrist actigraph recorded data on limb movements to calculate circadian rythmycity (measured in minutes) corresponding to the period of the biological temporal rhythms with oscillations around 24 hours.
Time frame
up to 90 days (constant recording from enrollment)Sponsors and contacts
Click on the lead sponsor to view all of their trials.
University of Liege
Lead sponsor
Centre Hospitalier Neurologique William Lennox (Belgium)
Collaborator
Hôpital Valdor - ISoSL (Belgium)
Collaborator
VITHAS hospitales (Spain)
Collaborator
Source ClinicalTrials.gov