Treating Severe Brain-injured Patients With Apomorphine: a Behavioral and Neuroimaging Study
试验速览
- 阶段
- 2 期
- 入组人数
- 8
- 试验地点
- 2
- 主要终点
- Change from baseline in 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. 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
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 treatment
Treatment by apomorphine hydrochloride subcutaneous infusion 12 hours per day during 30 days: 5-days titration phase (increasing doses from 0 to 4 mg/h), 7 days of maintenance at 4 mg/h and 18 days of maintenance phase with possible increase up to 6 mg/h if well tolerated.
Two days before the initiation of apomorphine, domperidone 20mg t.i.d per os (or via gastric tube) will be initiated to reduce common side effects. It will be maintained at least 7 days before an optional tapering off in the absence of nausea of vomiting.
干预措施: Apomorphine Hydrochloride 50Mg/10mL Prefilled Syringe (Drug)
结局指标
主要结局
Change from baseline in Coma Recovery Scale - Revised (CRS-R)
时间窗: up to 90 days (10x before treatment, 6x during treatment and 5x after treatment)
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
- PET(up to 90 days (1x before treatment and 1x after treatment))
- Number of sleep cycles using night EEG(actimetry and core body temperature recorded during the whole study; night EEG 1x before treatment initiation and 1x after treatment withdrawal)
- fMRI(up to 90 days (1x before treatment and 1x after treatment))
- Nociception Coma Scale - Revised (NCS-R)(up to 90 days (5x before treatment, 4x during treatment and 5x after treatment))
- Circadian rythmycity using body movements(constant recording from enrollment up to 90 days)
- Phone-adapted CRS-R(from 6 months post-treatment up to 24 months post-treatment (1x at 6 months, 1x at 12 months, 1x at 24 months))
- resting-state EEG(up to 90 days (4x before treatment, 4x during treatment and 4x after treatment))
- Glasgow Outcome Scale - Extended (GOS-E)(from 6 months post-treatment up to 24 months post-treatment (1x at 6 months, 1x at 12 months, 1x at 24 months))
- EEG with auditory paradigms(up to 90 days)
- Circadian rythmycity using body temperature variations(constant recording from enrollment up to 90 days)
研究者
Steven Laureys
Principal Investigator
University of Liege