Randomized Controlled Trial of Apomorphine in Severe Brain-injured Patients: a Double-blind Behavioral and Neuroimaging Study
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 48
- 试验地点
- 4
- 主要终点
- Change from Baseline Coma Recovery Scale - Revised (CRS-R)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Double-blind trial
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
排除标准
- •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)
研究组 & 干预措施
Apomorphine
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.
干预措施: Apomorphine Hydrochloride 5mg/ml (Drug)
Isotonic saline
Sodium chloride infusion following the administration procedure described for apomorphine
干预措施: Sodium chloride 9mg/ml (Other)
结局指标
主要结局
Change from Baseline Coma Recovery Scale - Revised (CRS-R)
时间窗: up to 90 days (5 CRS-R baseline, 5 CRS-R treatment, 5 CRS-R follow-up)
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.
次要结局
- Change from Baseline Wessex Head Injury Matrix (WHIM)(up to 90 days (5 WHIM baseline, 5 WHIM treatment, 5 WHIM follow-up))
- Positron Emission Tomography (PET)(up to 90 days (PET before treatment initiation and after treatment completion))
- Change from Baseline Nociception Coma Scale - Revised (NCS-R)(up to 90 days (5 NCS-R baseline, 5 NCS-R treatment, 5 NCS-R follow-up))
- Change from Baseline Circadian rhythm(up to 90 days (constant recording from enrollment))
- functional Magnetic Resonance Imaging (fMRI)(up to 90 days (fMRI before treatment initiation and after treatment completion))
- Change from Baseline Disability Rating Scale (DRS)(up to 90 days (5 DRS baseline, 5 DRS treatment, 5 DRS follow-up))
- Conventional Electroencephalography (cEEG)(up to 90 days (4 cEEG baseline, 5 cEEG treatment, 5 cEEG follow-up))
- 24-hour Electroencephalography (24-h EEG)(up to 90 days (24-h EEG before treatment initiation and after treatment completion))
- Glasgow Outcome Scale - Extended (GOS-E)(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(from 6 months post-treatment up to 24 months post-treatment (phone-adapted CRS-R at 6 months,12 months and 24 months))
- High-Density Electroencephalography (HD-EEG)(up to 90 days (HD-EEG before treatment initiation and after treatment completion))
研究者
Olivia Gosseries
Research Associate
University of Liege