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Disorder of ConsciousnessPhase 2ANNESNCT05479032

Amantadine for Neuroenhancement in Acute Patients Study

A Phase 2 study testing Amantadine in people with Disorder of Consciousness, run by University Hospital Tuebingen at 1 site in Germany.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Disorder of Consciousness
What is being tested?
Amantadine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
50 participants
Where
1 siteGermany
Study dates
1 Mar 2023to 31 Dec 2024
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 11Show fewer
  • 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

Who cannot join

  • 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)

Trial locations and contacts

1 site in 1 country.

Katharina Feil, attending physician contact

07071/29-61753

katharina.feil@uni-tuebingen.de

Annerose Mengel, attending physician contact

07071/29-85354

annerose.mengel@med.uni-tuebingen.de

Germany1 site, 1 recruiting

  • Universitätsklinikum Tübingen

    Tübingen, 72076

    Katharina Feil, PD Dr., katharina.feil@uni-tuebingen.de

    Annerose Mengel, PD Dr.

    Recruiting

Other trials in Germany

About this study

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

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.

Read more

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.

Being tested
Amantadine
Keywords
Amantadine, Neuroenhancement
Medical subject headings
Consciousness Disorders

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AmantadineDrug

    2x100 mg Amantadine for 3-5 days (dosage can be doubled in case of missing response to treatment after 48 hours)

Study groups in NCT05479032
Study groupRoleWhat they receive
Treatment groupExperimentalIntensive care patients suffering from reduced consciousness not otherwise explained treated with Amantadine
Receives: Drug: Amantadine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Level of vigilance measured by change in the Glasgow Coma Scale (GCS); a patient is defined as responder if his/her score increases 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.

    Measured: Assessment will take place before treatment (baseline value) and after 120 hours after treatment begin.

Secondary outcomes (11)

  1. Change in vigilance reflected 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).

    Measured: Assessment will take place before treatment (baseline value) and after 3 months.

  2. Change of vigilance measured by 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).

    Measured: Assessment will take place before treatment (baseline value) and after 3 months.

  3. 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)

    Measured: Assessment will take place before treatment (baseline value) and after 3 months.

  4. Change in symptoms measured by 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).

    Measured: Assessment will take place before treatment (baseline value) and after 3 months.

  5. Change in symptoms measured by 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)

    Measured: Assessment will take place before treatment (baseline value) and after 3 months.

  6. Change of vigilance measured by 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).

    Measured: Assessment will take place before treatment (baseline value) and after 3 months.

  7. Change of vigilance measured by 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)

    Measured: Assessment will take place before treatment (baseline value) and after 3 months.

  8. Change of vigilance measured by 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.

    Measured: Assessment will take place before treatment (baseline value) and after 3 months.

  9. Survival

    Mortality

    Measured: Assessment will take place before treatment (baseline value) and after 3 months.

  10. Change 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).

    Measured: Assessment will take place before treatment (baseline value) and after 3 months.

  11. Clinical change measured by 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.

    Measured: Assessment will take place before treatment (baseline value) and after 3 months.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Jul 2022
  2. Study start1 Mar 2023
  3. Primary completion30 Oct 2024 (estimated)
  4. Study completion31 Dec 2024 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
50 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05479032
Sponsor's protocol ID
2021-10
Acronym
ANNES
Status last verified
Feb 2024
First submitted
24 Jun 2022
Last updated
1 Feb 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Publications

  • Arciniegas DB, Frey KL, Anderson CA, Brousseau KM, Harris SN. Amantadine for neurobehavioural deficits following delayed post-hypoxic encephalopathy. Brain Inj. 2004 Dec;18(12):1309-18. doi: 10.1080/02699050410001720130.

    PubMed 15666573

  • Bergeron N, Dubois MJ, Dumont M, Dial S, Skrobik Y. Intensive Care Delirium Screening Checklist: evaluation of a new screening tool. Intensive Care Med. 2001 May;27(5):859-64. doi: 10.1007/s001340100909.

    PubMed 11430542

  • Brioschi A, Gramigna S, Werth E, Staub F, Ruffieux C, Bassetti C, Schluep M, Annoni JM. Effect of modafinil on subjective fatigue in multiple sclerosis and stroke patients. Eur Neurol. 2009;62(4):243-9. doi: 10.1159/000232927. Epub 2009 Aug 7.

    PubMed 19672078

  • Clarencon F, Bardinet E, Martinerie J, Pelbarg V, Menjot de Champfleur N, Gupta R, Tollard E, Soto-Ares G, Ibarrola D, Schmitt E, Tourdias T, Degos V, Yelnik J, Dormont D, Puybasset L, Galanaud D; Neuro Imaging for Coma Emergence and Recovery (NICER) consortium. Lesions in deep gray nuclei after severe traumatic brain injury predict neurologic outcome. PLoS One. 2017 Nov 2;12(11):e0186641. doi: 10.1371/journal.pone.0186641. eCollection 2017.

    PubMed 29095850

  • DGN and AWMF (2016). S3-Leitlinie "Idiopathisches Parkinson-Syndrom". AWMF-Register-Nummer: 030-010. 2016.

  • DGPPN, et al. (2016). S3-Leitlinie

  • Gagnon DJ, Leclerc AM, Riker RR, Brown CS, May T, Nocella K, Cote J, Eldridge A, Seder DB. Amantadine and Modafinil as Neurostimulants During Post-stroke Care: A Systematic Review. Neurocrit Care. 2020 Aug;33(1):283-297. doi: 10.1007/s12028-020-00977-5.

    PubMed 32394130

  • Ghalaenovi H, Fattahi A, Koohpayehzadeh J, Khodadost M, Fatahi N, Taheri M, Azimi A, Rohani S, Rahatlou H. The effects of amantadine on traumatic brain injury outcome: a double-blind, randomized, controlled, clinical trial. Brain Inj. 2018;32(8):1050-1055. doi: 10.1080/02699052.2018.1476733. Epub 2018 May 23.

    PubMed 29790790

  • Giacino JT, Kalmar K, Whyte J. The JFK Coma Recovery Scale-Revised: measurement characteristics and diagnostic utility. Arch Phys Med Rehabil. 2004 Dec;85(12):2020-9. doi: 10.1016/j.apmr.2004.02.033.

    PubMed 15605342

  • Gower A, Tiberi M. The Intersection of Central Dopamine System and Stroke: Potential Avenues Aiming at Enhancement of Motor Recovery. Front Synaptic Neurosci. 2018 Jul 6;10:18. doi: 10.3389/fnsyn.2018.00018. eCollection 2018.

    PubMed 30034335

  • Gualtieri T, Chandler M, Coons TB, Brown LT. Amantadine: a new clinical profile for traumatic brain injury. Clin Neuropharmacol. 1989 Aug;12(4):258-70. No abstract available.

    PubMed 2680078

  • Hubsher G, Haider M, Okun MS. Amantadine: the journey from fighting flu to treating Parkinson disease. Neurology. 2012 Apr 3;78(14):1096-9. doi: 10.1212/WNL.0b013e31824e8f0d.

    PubMed 22474298

  • Jang SH, Chang CH, Jung YJ, Kim JH, Kwon YH. Relationship Between Impaired Consciousness and Injury of Ascending Reticular Activating System in Patients With Intracerebral Hemorrhage. Stroke. 2019 Aug;50(8):2234-2237. doi: 10.1161/STROKEAHA.118.023710. Epub 2019 Jun 11.

    PubMed 31181997

  • Jang SH, Kim HS. Aneurysmal subarachnoid hemorrhage causes injury of the ascending reticular activating system: relation to consciousness. AJNR Am J Neuroradiol. 2015 Apr;36(4):667-71. doi: 10.3174/ajnr.A4203. Epub 2015 Jan 8.

    PubMed 25572950

  • Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet. 1975 Mar 1;1(7905):480-4. doi: 10.1016/s0140-6736(75)92830-5.

    PubMed 46957

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Amantadine in people with Disorder of Consciousness, run by University Hospital Tuebingen at 1 site in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 1 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Katharina Feil, attending physician (07071/29-61753, katharina.feil@uni-tuebingen.de), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Level of vigilance measured by change in the Glasgow Coma Scale (GCS); a patient is defined as responder if his/her score increases by at least 3 points. (time frame: Assessment will take place before treatment (baseline value) and after 120 hours after treatment begin.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05479032, which also lists 35 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2024.

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