Amantadine for Neuroenhancement in Acute Patients Study

NCT05479032 | Recruiting Phase 2 DMC

• 1 other identifier: 2021-10
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

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.

Conditions

Disorder of Consciousness

Keywords

Amantadine; Neuroenhancement

Outcome Measures

Primary Outcomes (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.

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

Secondary Outcomes (11)

• Change in vigilance reflected by change in the Richmond Agitation-Sedation Scale (RASS)

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

• Change of vigilance measured by the Full Outline of UnResponsive (FOUR) score

  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)

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

• Change in symptoms measured by the National Institute of health Stroke Scale (NIHSS)

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

• Change in symptoms measured by the modified Rankin Scale (mRS)

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

Study Arms (1)

Treatment group

EXPERIMENTAL

Intensive care patients suffering from reduced consciousness not otherwise explained treated with Amantadine

Drug: Amantadine

Interventions

Amantadine DRUG

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

Treatment group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• University Hospital Tuebingen: lead

Study Sites (1)

Universitätsklinikum Tübingen

Tübingen, 72076, Germany

RECRUITING

Related Publications (35)

• 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.

  PMID: 15666573 BACKGROUND

• 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.

  PMID: 11430542 BACKGROUND

• 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.

  PMID: 19672078 BACKGROUND

• 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.

  PMID: 29095850 BACKGROUND

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

  BACKGROUND

• DGPPN, et al. (2016). S3-Leitlinie

  BACKGROUND

• 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.

  PMID: 32394130 BACKGROUND

• 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.

  PMID: 29790790 BACKGROUND

• 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.

  PMID: 15605342 BACKGROUND

• 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.

  PMID: 30034335 BACKGROUND

• 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.

  PMID: 2680078 BACKGROUND

• 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.

  PMID: 22474298 BACKGROUND

• 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.

  PMID: 31181997 BACKGROUND

• 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.

  PMID: 25572950 BACKGROUND

• 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.

  PMID: 46957 BACKGROUND

• Jennett B, Snoek J, Bond MR, Brooks N. Disability after severe head injury: observations on the use of the Glasgow Outcome Scale. J Neurol Neurosurg Psychiatry. 1981 Apr;44(4):285-93. doi: 10.1136/jnnp.44.4.285.

  PMID: 6453957 BACKGROUND

• Jibiki, I., K. Morikawa, and N. Yamaguchi.

  BACKGROUND

• Landucci E, Filippi L, Gerace E, Catarzi S, Guerrini R, Pellegrini-Giampietro DE. Neuroprotective effects of topiramate and memantine in combination with hypothermia in hypoxic-ischemic brain injury in vitro and in vivo. Neurosci Lett. 2018 Mar 6;668:103-107. doi: 10.1016/j.neulet.2018.01.023. Epub 2018 Jan 12.

  PMID: 29339173 BACKGROUND

• Leclerc AM, Riker RR, Brown CS, May T, Nocella K, Cote J, Eldridge A, Seder DB, Gagnon DJ. Amantadine and Modafinil as Neurostimulants Following Acute Stroke: A Retrospective Study of Intensive Care Unit Patients. Neurocrit Care. 2021 Feb;34(1):102-111. doi: 10.1007/s12028-020-00986-4.

  PMID: 32435964 BACKGROUND

• Li J, Zhang P, Wu S, Yuan R, Liu J, Tao W, Wang D, Liu M. Impaired consciousness at stroke onset in large hemisphere infarction: incidence, risk factors and outcome. Sci Rep. 2020 Aug 5;10(1):13170. doi: 10.1038/s41598-020-70172-1.

  PMID: 32759986 BACKGROUND

• Lutkenhoff ES, Chiang J, Tshibanda L, Kamau E, Kirsch M, Pickard JD, Laureys S, Owen AM, Monti MM. Thalamic and extrathalamic mechanisms of consciousness after severe brain injury. Ann Neurol. 2015 Jul;78(1):68-76. doi: 10.1002/ana.24423. Epub 2015 May 4.

  PMID: 25893530 BACKGROUND

• Meythaler JM, Brunner RC, Johnson A, Novack TA. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial. J Head Trauma Rehabil. 2002 Aug;17(4):300-13. doi: 10.1097/00001199-200208000-00004.

  PMID: 12105999 BACKGROUND

• Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr;53(4):695-9. doi: 10.1111/j.1532-5415.2005.53221.x.

  PMID: 15817019 BACKGROUND

• ratiopharm (2018). Fachinformation Amantadin-ratiopharm®200 mg Infusionslösung.

  BACKGROUND

• Reznik ME, Yaghi S, Jayaraman MV, McTaggart RA, Hemendinger M, Mac Grory BC, Burton TM, Cutting SM, Thompson BB, Wendell LC, Mahta A, Potter NS, Daiello LA, Kosar CM, Jones RN, Furie KL. Level of consciousness at discharge and associations with outcome after ischemic stroke. J Neurol Sci. 2018 Jul 15;390:102-107. doi: 10.1016/j.jns.2018.04.022. Epub 2018 Apr 14.

  PMID: 29801867 BACKGROUND

• Rohaut B, Doyle KW, Reynolds AS, Igwe K, Couch C, Matory A, Rizvi B, Roh D, Velazquez A, Megjhani M, Park S, Agarwal S, Mauro CM, Li G, Eliseyev A, Perlbarg V, Connolly S, Brickman AM, Claassen J. Deep structural brain lesions associated with consciousness impairment early after hemorrhagic stroke. Sci Rep. 2019 Mar 12;9(1):4174. doi: 10.1038/s41598-019-41042-2.

  PMID: 30862910 BACKGROUND

• Sessler CN, Grap MJ, Brophy GM. Multidisciplinary management of sedation and analgesia in critical care. Semin Respir Crit Care Med. 2001;22(2):211-26. doi: 10.1055/s-2001-13834.

  PMID: 16088675 BACKGROUND

• Stinton C, McKeith I, Taylor JP, Lafortune L, Mioshi E, Mak E, Cambridge V, Mason J, Thomas A, O'Brien JT. Pharmacological Management of Lewy Body Dementia: A Systematic Review and Meta-Analysis. Am J Psychiatry. 2015 Aug 1;172(8):731-42. doi: 10.1176/appi.ajp.2015.14121582. Epub 2015 Jun 18.

  PMID: 26085043 BACKGROUND

• Suarez JI, Tarr RW, Selman WR. Aneurysmal subarachnoid hemorrhage. N Engl J Med. 2006 Jan 26;354(4):387-96. doi: 10.1056/NEJMra052732. No abstract available.

  PMID: 16436770 BACKGROUND

• Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974 Jul 13;2(7872):81-4. doi: 10.1016/s0140-6736(74)91639-0. No abstract available.

  PMID: 4136544 BACKGROUND

• Wijdicks EF, Bamlet WR, Maramattom BV, Manno EM, McClelland RL. Validation of a new coma scale: The FOUR score. Ann Neurol. 2005 Oct;58(4):585-93. doi: 10.1002/ana.20611.

  PMID: 16178024 BACKGROUND

• Wilson JT, Hareendran A, Grant M, Baird T, Schulz UG, Muir KW, Bone I. Improving the assessment of outcomes in stroke: use of a structured interview to assign grades on the modified Rankin Scale. Stroke. 2002 Sep;33(9):2243-6. doi: 10.1161/01.str.0000027437.22450.bd.

  PMID: 12215594 BACKGROUND

• Winstein CJ, Stein J, Arena R, Bates B, Cherney LR, Cramer SC, Deruyter F, Eng JJ, Fisher B, Harvey RL, Lang CE, MacKay-Lyons M, Ottenbacher KJ, Pugh S, Reeves MJ, Richards LG, Stiers W, Zorowitz RD; American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Quality of Care and Outcomes Research. Guidelines for Adult Stroke Rehabilitation and Recovery: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2016 Jun;47(6):e98-e169. doi: 10.1161/STR.0000000000000098. Epub 2016 May 4.

  PMID: 27145936 BACKGROUND

• Young GB. Coma. Ann N Y Acad Sci. 2009 Mar;1157:32-47. doi: 10.1111/j.1749-6632.2009.04471.x.

  PMID: 19351354 BACKGROUND

• Hofmann A, Blum C, Single C, Adeyemi K, Schwarz P, Siokas V, Rattay TW, Haberle HA, Riessen R, Brendel B, Haug I, Bosel R, Zago M, Martus P, Ziemann U, Mengel A, Feil K. Amantadine for NeuroenhaNcement in acutE patients Study - a protocol for a prospective pilot proof of concept phase IIb study in intensive and intermediate care unit patients (ANNES). BMC Neurol. 2023 Aug 22;23(1):308. doi: 10.1186/s12883-023-03345-w.

  PMID: 37608315 DERIVED

Related Links

• Simon design calculator

MeSH Terms

Conditions

Consciousness Disorders

Interventions

Amantadine

Condition Hierarchy (Ancestors)

Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Adamantane; Bridged-Ring Compounds; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Katharina Feil, attending physician

  University Hospital Tübingen, Deparment for Neurology and Stroke

  PRINCIPAL INVESTIGATOR

• Annerose Mengel, attending physician

  University Hospital Tübingen, Deparment for Neurology and Stroke

  PRINCIPAL INVESTIGATOR

Central Study Contacts

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 24, 2022
• First Posted: July 28, 2022
• Study Start: March 1, 2023
• Primary Completion: October 30, 2024
• Study Completion: December 31, 2024
• Last Updated: February 1, 2024

Record last verified: 2024-02

Locations

DE (1)