Amantadine for Neuroenhancement in Acute Patients Study

Study Overview
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Brief Summary
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Introduction: Many patients on intermediate care (IMC) and intensive care units (ICU) suffer from reduced consciousness. In this situation, a treatment attempt with Amantadine is often undertaken. While clinicians report good results with this approach, the treatment is off-label and the scientific evidence limited. Study design: Monocenter, phase IIb, proof of concept, open-label pilot study. Methods: 50 intensive care patients with reduced consciousness not otherwise explained will be treated with Amantadine for 5 days. Vigilance is checked before, during and after treatment (on discharge and after 3 months) using electroencephalography (EEG) and established clinical tests, for instance Glasgow Coma Scale (GCS), Glasgow Outcome Scale - Extended (GOS-E), Coma Recovery Scale Revised (CRS-R) and others. Results: The primary endpoint improvement of the GCS scale from screening to day 5 of at least 3 points is analysed according to the Simon design. The secondary endpoints (GCS continuous scale, modified Rankins Scale (mRS), National Institute of Health Stroke Scale (NIHSS), GOS-E, CRS-R and Montreal Cognitive Assessment (MoCA) after 90 days, Richmond Agitation-Sedation Scale (RASS) and Intensive Care Delirium Screening Checklist (ICDSC) will be analysed by mixed models with time (categorically coded) as only factor including all measurements up to 3 months follow up. Discussion: The investigators aim to shed light on an established clinical practice without sufficient scientific evidence. The investigators are aware that the power of our study is limited by design (no control group, no blinding). However, if successful, this study may be the basis for a randomized controlled trial in the future.

Official Title
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Amantadine for Neuroenhancement in Acute Patients Study - A Prospective Pilot Proof of Concept Phase IIb Study in Intensive and Intermediate Care Unit Patients

Conditions
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Disorder of Consciousness

Intervention / Treatment
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* Drug: Amantadine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be ≥ 18 years at the time of signing the informed consent. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures or informed consent is signed As subject has per definition reduced consciousness and therefore is not in a position to provide written informed consent, inclusion of this patient is possible if the patient will give basic informed consent seven days after enrollment. Alternatively, the patient's relatives can give written informed consent. Able to adhere to the study visit schedule and other protocol requirements. Subject (male or female) is willing to use highly effective methods during treatment and for 4 days (male or female) after the end of treatment (adequate: combined hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner1, sexual abstinence2). Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment. All subjects must agree not to share medication. Reduced consciousness, defined as GCS <8, not otherwise explained Inconspicuous EEG and ECG Exclusion Criteria: Women during pregnancy and lactation. History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product. Participation in other clinical trials or observation period of competing trials. Age < 18 years Reduced consciousness, otherwise sufficiently explained Delirium (Intensive Care Delirium Screening Checklist (ICDSC) > 4 or >5 in aphasic patients) History of epileptic seizures or status epilepticus Pre-existing cardial conditions (e.g. heart failure (NYHA IV), cardiomyopathy, myocarditis, arrythmia (patients with a QTc time increase of >60ms or interval of >480ms have to be excluded from treatment), simultaneous treatment with other QT time elongating drugs, hypo-magnesaemia or -kalemia)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment group<br>Intensive care patients suffering from reduced consciousness not otherwise explained treated with Amantadine | Drug: Amantadine<br>* 2x100 mg Amantadine for 3-5 days (dosage can be doubled in case of missing response to treatment after 48 hours)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of vigilance measured by change in the Glasgow Coma Scale (GCS); a patient is defined as responder if he/she improves by at least 3 points. | The Glasgow Coma Scale (GCS) (Teasdale and Jennett, 1974) is a clinical scale used to measure a patient's level of consciousness. The GCS assesses patients based on their ability to perform limb and eye movements as well as to speak. These three categories represent the core elements of the scale: eye, verbal, and motor. A person's GCS score can range from 3 (completely unresponsive) to 15 (completely responsive). This score is fast, easily and reliably to perform and can be used in emergency situations and also to monitor hospitalized patients. | Assessment will take place before treatment (baseline value) and after 120 hours after treatment begin. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of vigilance measured by change in the Richmond Agitation-Sedation Scale (RASS) | The Richmond Agitation Sedation Scale is a ten-step scale for assessment and quantification of sedation as well as agitation with the value '0' describing the physiological state, a value of '-5' deep sedation and '+4' severe agitation (Sessler et al., 2001). | Assessment will take place before treatment (baseline value) and after 3 months. | 
| Improvement of vigilance measured by change in the Full Outline of UnResponsive (FOUR) score | The FOUR Score is a clinical grading scale for the assessment of patients with an impaired level of consciousness. FOUR is an acronym for Full Outline of UnResponsiveness. It is a 17-point scale with potential scores ranging from 0-16 (decreasing score associated with a worsening level of consciousness). The FOUR score overcomes some of the shortcomings of the GCS by assessing the four domains of neurological function: eye responses, motor responses, brainstem reflexes, and even breathing pattern (Wijdicks et al., 2005). | Assessment will take place before treatment (baseline value) and after 3 months. | 
| Appearance of delirium measured by change in the Intensive Care Delirium Screening Checklist (ICDSC) | The Intensive Care Delirium Screening Checklist can easily and quickly be applied by a clinician or a nurse in the critical care setting to screen all patients for a delirium (even when communication is compromised in case of aphasia). A value of 4 or more points corresponds with delirium. (Bergeron et al., 2001) | Assessment will take place before treatment (baseline value) and after 3 months. | 
| Improvement of symptoms measured by change in the National Institute of health Stroke Scale (NIHSS) | The National Institutes of Health Stroke Scale (NIHSS) is used to objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items, each of which scores a specific ability be-tween 0 and 4. For each item, a score of 0 indicates normal function, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42 (NIH, National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/sites/default/files/NIH_Stroke_Scale_Booklet.pdf). | Assessment will take place before treatment (baseline value) and after 3 months. | 
| Improvement of symptoms measured by change in the modified Rankin Scale (mRS) | The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It ranges from 0 (no symptoms) to 6 (death). (Wilson et al., 2002) | Assessment will take place before treatment (baseline value) and after 3 months. | 
| Improvement of vigilance measured by change in the Glasgow Outcome Scale - Extended (GOS-E) | The Glasgow Outcome Score (GOS) is a scale for patients with brain injuries, such as cerebral traumas or strokes that groups the victims by the objective degree of recovery (Jennett, 1975). Later, the same authors proposed to split the 3 better categories (severe disability to good recovery, i.e. 3 to 5) in lower and upper sub-categories, leading to the extended version of the scale (GOS-E) which includes 6 plus 2 (death and vegetative state), i.e. 8 categories in total (Jennett et al., 1981). | Assessment will take place before treatment (baseline value) and after 3 months. | 
| Improvement of vigilance measured by change in the Coma Recovery Scale revised (CRS-R) | The Coma Recovery Scale - Revised (CRS-R) is a standardized neurobehavioral assessment instrument for the usage in patients with disorders of consciousness. It is intended to establish diagnosis, monitor recovery, predict outcome as well as assess treatment effectiveness. A low score reflects reflexive activity, while a high score mirrors cognitively-mediated behaviors (Giacino et al., 2004) | Assessment will take place before treatment (baseline value) and after 3 months. | 
| Improvement of vigilance measured by change in the Montreal Cognitive Assessment (MoCA) | The Montreal Cognitive Assessment (MoCA) is a widely used screening assessment for detecting cognitive impairment (Nasreddine et al., 2005). It was validated in the setting of mild cognitive impairment, and has subsequently been adopted in numerous other clinical settings. A high score corresponds to high cognitive functioning. | Assessment will take place before treatment (baseline value) and after 3 months. | 
| Survival |  | Assessment will take place before treatment (baseline value) and after 3 months. | 
| Improvement of vigilance measured by EEG (ratio of fast and slow oscillations) | A regular EEG will be recorded regularly as part of our routine clinical procedures in patients with reduced vigilance. Reduced vigilance is typically reflected by slow oscillations like delta or theta, thus vigilance will be measured by ratio between fast oscillations (alpha, beta) and slow oscillations (theta, delta). | Assessment will take place before treatment (baseline value) and after 3 months. | 
| Clinical improvement measured by change in the therapists' questionnaire | Therapists' questionnaire: This is a self-developed questionnaire for nursing staff as well as physiotherapists to even capture and assess the subtle clinical changes that might escape the standard scales within this heterogenous patient cohort. The seven items investigated mainly cover the patients' ability to - even at a very low level - interact with his/her environment and take part in e.g. physiotherapeutic procedures. Its total score ranges from 0 (best) to 21 (worst) points. | Assessment will take place before treatment (baseline value) and after 3 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amantadine, Neuroenhancement