Amantadine for Neuroenhancement in Acute Patients Study

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.

Timeline

Start

2023-03-01

Primary completion

2024-10-30

Completion

2024-12-31

Publications

• Background 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Background ratiopharm (2018). Fachinformation Amantadin-ratiopharm®200 mg Infusionslösung.
• Background Reznik ME, Yaghi S, Jayaraman MV, McTaggart RA, Hemendinger M, Mac Grory B, 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Background Young GB. Coma. Ann N Y Acad Sci. 2009 Mar;1157:32-47. doi: 10.1111/j.1749-6632.2009.04471.x.
• 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.

Drugs

Indications

No indication recorded.