Back to resultsAmantadine for Neuroenhancement in Acute Patients Study (ANNES)
Primary Purpose
Disorder of Consciousness
Status
Not yet recruiting
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Amantadine
Sponsored by
About this trial
This is an interventional treatment trial for Disorder of Consciousness focused on measuring Amantadine, Neuroenhancement
Eligibility Criteria
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)
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment group
Arm Description
Intensive care patients suffering from reduced consciousness not otherwise explained treated with Amantadine
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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).
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).
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)
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).
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)
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).
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)
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.
Survival
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).
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.
Full Information
NCT ID
NCT05479032
First Posted
June 24, 2022
Last Updated
July 26, 2022
Sponsor
University Hospital Tuebingen
1. Study Identification
Unique Protocol Identification Number
NCT05479032
Brief Title
Amantadine for Neuroenhancement in Acute Patients Study
Acronym
ANNES
Official Title
Amantadine for Neuroenhancement in Acute Patients Study - A Prospective Pilot Proof of Concept Phase IIb Study in Intensive and Intermediate Care Unit Patients
Study Type
Interventional
2. Study Status
Record Verification Date
June 2022
Overall Recruitment Status
Not yet recruiting
Study Start Date
September 2022 (Anticipated)
Primary Completion Date
September 2023 (Anticipated)
Study Completion Date
September 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital Tuebingen
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Disorder of Consciousness
Keywords
Amantadine, Neuroenhancement
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Treatment group
Arm Type
Experimental
Arm Description
Intensive care patients suffering from reduced consciousness not otherwise explained treated with Amantadine
Intervention Type
Drug
Intervention Name(s)
Amantadine
Intervention Description
2x100 mg Amantadine for 3-5 days (dosage can be doubled in case of missing response to treatment after 48 hours)
Primary Outcome Measure Information:
Title
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.
Description
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.
Time Frame
Assessment will take place before treatment (baseline value) and after 120 hours after treatment begin.
Secondary Outcome Measure Information:
Title
Improvement of vigilance measured by change in the Richmond Agitation-Sedation Scale (RASS)
Description
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).
Time Frame
Assessment will take place before treatment (baseline value) and after 3 months.
Title
Improvement of vigilance measured by change in the Full Outline of UnResponsive (FOUR) score
Description
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).
Time Frame
Assessment will take place before treatment (baseline value) and after 3 months.
Title
Appearance of delirium measured by change in the Intensive Care Delirium Screening Checklist (ICDSC)
Description
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)
Time Frame
Assessment will take place before treatment (baseline value) and after 3 months.
Title
Improvement of symptoms measured by change in the National Institute of health Stroke Scale (NIHSS)
Description
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).
Time Frame
Assessment will take place before treatment (baseline value) and after 3 months.
Title
Improvement of symptoms measured by change in the modified Rankin Scale (mRS)
Description
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)
Time Frame
Assessment will take place before treatment (baseline value) and after 3 months.
Title
Improvement of vigilance measured by change in the Glasgow Outcome Scale - Extended (GOS-E)
Description
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).
Time Frame
Assessment will take place before treatment (baseline value) and after 3 months.
Title
Improvement of vigilance measured by change in the Coma Recovery Scale revised (CRS-R)
Description
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)
Time Frame
Assessment will take place before treatment (baseline value) and after 3 months.
Title
Improvement of vigilance measured by change in the Montreal Cognitive Assessment (MoCA)
Description
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.
Time Frame
Assessment will take place before treatment (baseline value) and after 3 months.
Title
Survival
Time Frame
Assessment will take place before treatment (baseline value) and after 3 months.
Title
Improvement of vigilance measured by EEG (ratio of fast and slow oscillations)
Description
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).
Time Frame
Assessment will take place before treatment (baseline value) and after 3 months.
Title
Clinical improvement measured by change in the therapists' questionnaire
Description
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.
Time Frame
Assessment will take place before treatment (baseline value) and after 3 months.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Katharina Feil, attending physician
Phone
07071/29-61753
Email
katharina.feil@uni-tuebingen.de
First Name & Middle Initial & Last Name or Official Title & Degree
Annerose Mengel, attending physician
Phone
07071/29-85354
Email
annerose.mengel@med.uni-tuebingen.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Katharina Feil, attending physician
Organizational Affiliation
University Hospital Tübingen, Deparment for Neurology and Stroke
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Annerose Mengel, attending physician
Organizational Affiliation
University Hospital Tübingen, Deparment for Neurology and Stroke
Official's Role
Principal Investigator
12. IPD Sharing Statement
Plan to Share IPD
Undecided
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Amantadine for Neuroenhancement in Acute Patients Study
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