search
Back to results

Apomorphine in Severe Brain-injured Patients (APODoC)

Primary Purpose

Disorder of Consciousness

Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Apomorphine Hydrochloride 5mg/ml
Sodium chloride 9mg/ml
Sponsored by
University of Liege
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Disorder of Consciousness focused on measuring unresponsive wakefulness syndrome, minimally conscious state, apomorphine, treatment

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 18-55 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).

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)

Sites / Locations

  • University of Liege
  • Hôpital Valdor - ISoSLRecruiting
  • Centre Hospitalier Neurologique William LennoxRecruiting
  • VITHAS

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Apomorphine

Isotonic saline

Arm Description

Apomorphine hydrochloride subcutaneous infusion 12 hours per day during 30 days: titration phase from 0 to 4 mg/h (5 days), maintenance phase at 4 mg/h, titration-maintenance phase with possible increase up to 6 mg/h depending on tolerance (18 days). Domperidone 20mg t.i.d per os (or via gastric tube) will be initiated to reduce common side effects 2 days before the initiation of apomorphine and maintained at least 7 days before an optional tapering off in the absence side effects.

Sodium chloride infusion following the administration procedure described for apomorphine

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
functional Magnetic Resonance Imaging (fMRI)
MRI functional connectivity using a seed-voxel approach, between regions of interest (here: striatum, globus pallidus interna, thalamus and prefrontal cortex) and the time course from all other brain voxels.
Positron Emission Tomography (PET)
Quantification of PET signal using standardized uptake values of fluorodeoxyglucose.
Conventional Electroencephalography (cEEG)
EEG spectral power within fixed bands or dynamic connectivity using median spectral connectivity and graph-theoretic topology metrics (clustering coefficient, path length, modularity and participation coefficient).
24-hour Electroencephalography (24-h EEG)
24-h EEG recordings to calculate the number of sleep cycles during day and night as well as the duration spent in each phase of sleep.
High-Density Electroencephalography (HD-EEG)
Multivariate classifier giving the probabilty to have signs of consciousness based on a machine-learning approach using 120 EEG markers.
Glasgow Outcome Scale - Extended (GOS-E)
The GOS-E is a standardized validated scale designed to assess the the functional outcome of patients with disorders of consciousness. It is a single score ranging from 1 (dead) to 8 (upper good recovery). Higher scores indicate a higher functional recovery. It will be performed remotely by telephone contact with the patient or their relatives. Analyses will look at differences in GOS-E score between responders and non-responders to apomorphine treatment, as well as differences in time within individual patients.
Phone-adapted CRS-R
The phone-adapted CRS-R is a scale designed to assess remotely patients with disorders of consciousness. Unlike the CRS-R, it does not comprise subcores or a total score, but provides the clinical diagnosis of the patient (coma, UWS, MCS-, MCS+, EMCS) using the same diagnostic items as the CRS-R. Analyses will look at differences in Phone-adapted CRS-R diagnosis between responders and non-responders to apomorphine treatment, as well as differences in time within individual patients.

Full Information

First Posted
December 20, 2021
Last Updated
April 6, 2023
Sponsor
University of Liege
Collaborators
Centre Hospitalier Neurologique William Lennox (Belgium), Hôpital Valdor - ISoSL (Belgium), VITHAS hospitales (Spain)
search

1. Study Identification

Unique Protocol Identification Number
NCT05213169
Brief Title
Apomorphine in Severe Brain-injured Patients
Acronym
APODoC
Official Title
Randomized Controlled Trial of Apomorphine in Severe Brain-injured Patients: a Double-blind Behavioral and Neuroimaging Study
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 18, 2021 (Actual)
Primary Completion Date
June 30, 2025 (Anticipated)
Study Completion Date
June 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Liege
Collaborators
Centre Hospitalier Neurologique William Lennox (Belgium), Hôpital Valdor - ISoSL (Belgium), VITHAS hospitales (Spain)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Disorder of Consciousness
Keywords
unresponsive wakefulness syndrome, minimally conscious state, apomorphine, treatment

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Apomorphine treatment or placebo
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
Double-blind trial
Allocation
Randomized
Enrollment
48 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Apomorphine
Arm Type
Experimental
Arm Description
Apomorphine hydrochloride subcutaneous infusion 12 hours per day during 30 days: titration phase from 0 to 4 mg/h (5 days), maintenance phase at 4 mg/h, titration-maintenance phase with possible increase up to 6 mg/h depending on tolerance (18 days). Domperidone 20mg t.i.d per os (or via gastric tube) will be initiated to reduce common side effects 2 days before the initiation of apomorphine and maintained at least 7 days before an optional tapering off in the absence side effects.
Arm Title
Isotonic saline
Arm Type
Placebo Comparator
Arm Description
Sodium chloride infusion following the administration procedure described for apomorphine
Intervention Type
Drug
Intervention Name(s)
Apomorphine Hydrochloride 5mg/ml
Intervention Description
Product administered using an external continuous subcutaneous infusion pump.
Intervention Type
Other
Intervention Name(s)
Sodium chloride 9mg/ml
Intervention Description
Product administered using an external continuous subcutaneous infusion pump.
Primary Outcome Measure Information:
Title
Change from Baseline Coma Recovery Scale - Revised (CRS-R)
Description
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 Outcome Measure Information:
Title
Change from Baseline Nociception Coma Scale - Revised (NCS-R)
Description
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)
Title
Change from Baseline Disability Rating Scale (DRS)
Description
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)
Title
Change from Baseline Wessex Head Injury Matrix (WHIM)
Description
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)
Title
Change from Baseline Circadian rhythm
Description
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)
Title
functional Magnetic Resonance Imaging (fMRI)
Description
MRI functional connectivity using a seed-voxel approach, between regions of interest (here: striatum, globus pallidus interna, thalamus and prefrontal cortex) and the time course from all other brain voxels.
Time Frame
up to 90 days (fMRI before treatment initiation and after treatment completion)
Title
Positron Emission Tomography (PET)
Description
Quantification of PET signal using standardized uptake values of fluorodeoxyglucose.
Time Frame
up to 90 days (PET before treatment initiation and after treatment completion)
Title
Conventional Electroencephalography (cEEG)
Description
EEG spectral power within fixed bands or dynamic connectivity using median spectral connectivity and graph-theoretic topology metrics (clustering coefficient, path length, modularity and participation coefficient).
Time Frame
up to 90 days (4 cEEG baseline, 5 cEEG treatment, 5 cEEG follow-up)
Title
24-hour Electroencephalography (24-h EEG)
Description
24-h EEG recordings to calculate the number of sleep cycles during day and night as well as the duration spent in each phase of sleep.
Time Frame
up to 90 days (24-h EEG before treatment initiation and after treatment completion)
Title
High-Density Electroencephalography (HD-EEG)
Description
Multivariate classifier giving the probabilty to have signs of consciousness based on a machine-learning approach using 120 EEG markers.
Time Frame
up to 90 days (HD-EEG before treatment initiation and after treatment completion)
Title
Glasgow Outcome Scale - Extended (GOS-E)
Description
The GOS-E is a standardized validated scale designed to assess the the functional outcome of patients with disorders of consciousness. It is a single score ranging from 1 (dead) to 8 (upper good recovery). Higher scores indicate a higher functional recovery. It will be performed remotely by telephone contact with the patient or their relatives. Analyses will look at differences in GOS-E score between responders and non-responders to apomorphine treatment, as well as differences in time within individual patients.
Time Frame
from 6 months post-treatment up to 24 months post-treatment (GOS-E at 6 months,12 months and 24 months)
Title
Phone-adapted CRS-R
Description
The phone-adapted CRS-R is a scale designed to assess remotely patients with disorders of consciousness. Unlike the CRS-R, it does not comprise subcores or a total score, but provides the clinical diagnosis of the patient (coma, UWS, MCS-, MCS+, EMCS) using the same diagnostic items as the CRS-R. Analyses will look at differences in Phone-adapted CRS-R diagnosis between responders and non-responders to apomorphine treatment, as well as differences in time within individual patients.
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)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Emilie Szymkowicz, MSc.
Phone
+32492319947
Email
emilie.szymkowicz@uliege.be
First Name & Middle Initial & Last Name or Official Title & Degree
Leandro RD Sanz, M.D.
Phone
+3243663915
Email
leandro.sanz@uliege.be
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Olivia Gosseries, Ph.D.
Organizational Affiliation
University of Liege
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Steven Laureys, M.D., Ph.D.
Organizational Affiliation
University Hospital of Liège
Official's Role
Study Director
Facility Information:
Facility Name
University of Liege
City
Liege
ZIP/Postal Code
4000
Country
Belgium
Individual Site Status
Active, not recruiting
Facility Name
Hôpital Valdor - ISoSL
City
Liège
ZIP/Postal Code
4000
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gwennaig Joris, MSc
Email
g.joris@isosl.be
First Name & Middle Initial & Last Name & Degree
Céline Aussems, MD
Facility Name
Centre Hospitalier Neurologique William Lennox
City
Ottignies-Louvain-la-Neuve
ZIP/Postal Code
1340
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nicolas Lejeune, M.D., Ph.D.
Phone
+3210430298
Email
nicolas.lejeune@chnwl.be
First Name & Middle Initial & Last Name & Degree
Nicolas Lejeune, M.D., Ph.D.
Facility Name
VITHAS
City
Valencia
ZIP/Postal Code
46035
Country
Spain
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Loles Navarro Pérez, Ph.D.
Email
loles@neurorhb.com
First Name & Middle Initial & Last Name & Degree
Roberto Llorens, Ph.D.
Email
enoe@comv.es
First Name & Middle Initial & Last Name & Degree
Enrique Noé, M.D., Ph.D.

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
19191097
Citation
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.
Results Reference
background
PubMed Identifier
20235766
Citation
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.
Results Reference
background
PubMed Identifier
24025057
Citation
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.
Results Reference
background
PubMed Identifier
30941094
Citation
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.
Results Reference
background

Learn more about this trial

Apomorphine in Severe Brain-injured Patients

We'll reach out to this number within 24 hrs