Relying on Pharmacotherapy to Improve Motor Gains in Chronic Stroke Survivors

Summary

The goal of this trial is to study if the concomitant administration of Telmisartan, Cilostazol IR (immediate release), and Metformin ER (extended release) can help stroke survivors make greater gains in movement and recovery during robot-assisted arm and hand rehabilitation.

Timeline

Start

2026-05-18

Primary completion

2027-12-31

Completion

2028-12-31

Publications

• Background Ahn CM, Hong SJ, Park JH, Kim JS, Lim DS. Cilostazol reduces the progression of carotid intima-media thickness without increasing the risk of bleeding in patients with acute coronary syndrome during a 2-year follow-up. Heart Vessels. 2011 Sep;26(5):502-10. doi: 10.1007/s00380-010-0093-1. Epub 2010 Dec 9.
• Background Akhtar N, Singh R, Kamran S, Babu B, Sivasankaran S, Joseph S, Morgan D, Shuaib A. Diabetes: Chronic Metformin Treatment and Outcome Following Acute Stroke. Front Neurol. 2022 Apr 26;13:849607. doi: 10.3389/fneur.2022.849607. eCollection 2022.
• Background Arbelaez-Quintero I, Palacios M. To Use or Not to Use Metformin in Cerebral Ischemia: A Review of the Application of Metformin in Stroke Rodents. Stroke Res Treat. 2017;2017:9756429. doi: 10.1155/2017/9756429. Epub 2017 May 28.
• Background Bourget C, Adams KV, Morshead CM. Reduced microglia activation following metformin administration or microglia ablation is sufficient to prevent functional deficits in a mouse model of neonatal stroke. J Neuroinflammation. 2022 Jun 15;19(1):146. doi: 10.1186/s12974-022-02487-x.
• Background Brown T, Forster RB, Cleanthis M, Mikhailidis DP, Stansby G, Stewart M. Cilostazol for intermittent claudication. Cochrane Database Syst Rev. 2021 Jun 30;6(6):CD003748. doi: 10.1002/14651858.CD003748.pub5.
• Background Choi BR, Kim DH, Back DB, Kang CH, Moon WJ, Han JS, Choi DH, Kwon KJ, Shin CY, Kim BR, Lee J, Han SH, Kim HY. Characterization of White Matter Injury in a Rat Model of Chronic Cerebral Hypoperfusion. Stroke. 2016 Feb;47(2):542-7. doi: 10.1161/STROKEAHA.115.011679. Epub 2015 Dec 15.
• Background Deguchi I, Furuya D, Fukuoka T, Tanahashi N. Effects of telmisartan on the cerebral circulation of hypertensive patients with chronic-stage stroke. Hypertens Res. 2012 Dec;35(12):1171-5. doi: 10.1038/hr.2012.105. Epub 2012 Jul 5.
• Background Dobkin BH. Clinical practice. Rehabilitation after stroke. N Engl J Med. 2005 Apr 21;352(16):1677-84. doi: 10.1056/NEJMcp043511.
• Background Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med. 1997 Dec;103(6):491-7. doi: 10.1016/s0002-9343(97)00254-4.
• Background Grissi M, Boudot C, Assem M, Candellier A, Lando M, Poirot-Leclercq S, Boullier A, Bennis Y, Lenglet G, Avondo C, Lalau JD, Choukroun G, Massy ZA, Kamel S, Chillon JM, Henaut L. Metformin prevents stroke damage in non-diabetic female mice with chronic kidney disease. Sci Rep. 2021 Apr 2;11(1):7464. doi: 10.1038/s41598-021-86905-9.
• Background Iwanami J, Mogi M, Tsukuda K, Min LJ, Sakata A, Jing F, Iwai M, Horiuchi M. Low dose of telmisartan prevents ischemic brain damage with peroxisome proliferator-activated receptor-gamma activation in diabetic mice. J Hypertens. 2010 Aug;28(8):1730-7. doi: 10.1097/HJH.0b013e32833a551a.
• Background Jin Q, Cheng J, Liu Y, Wu J, Wang X, Wei S, Zhou X, Qin Z, Jia J, Zhen X. Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke. Brain Behav Immun. 2014 Aug;40:131-42. doi: 10.1016/j.bbi.2014.03.003. Epub 2014 Mar 12.
• Background Jung KH, Chu K, Lee ST, Kim SJ, Song EC, Kim EH, Park DK, Sinn DI, Kim JM, Kim M, Roh JK. Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. J Pharmacol Exp Ther. 2007 Sep;322(3):1051-8. doi: 10.1124/jpet.107.120097. Epub 2007 May 30.
• Background Kim YR, Kim HN, Hong KW, Shin HK, Choi BT. Anti-depressant effects of phosphodiesterase 3 inhibitor cilostazol in chronic mild stress-treated mice after ischemic stroke. Psychopharmacology (Berl). 2016 Mar;233(6):1055-66. doi: 10.1007/s00213-015-4185-6. Epub 2015 Dec 21.
• Background Kim YR, Kim HN, Hong KW, Shin HK, Choi BT. Antidepressant Effects of Aripiprazole Augmentation for Cilostazol-Treated Mice Exposed to Chronic Mild Stress after Ischemic Stroke. Int J Mol Sci. 2017 Feb 8;18(2):355. doi: 10.3390/ijms18020355.
• Background Li T, Zhang Y, Zhu B, Wu C, Chen Y. Telmisartan regulates the development of cerebral ischemia by alleviating endoplasmic reticulum stress. Pharmazie. 2018 Oct 1;73(10):585-588. doi: 10.1691/ph.2018.8592.
• Background Littlejohn T, Mroczek W, Marbury T, VanderMaelen CP, Dubiel RF. A prospective, randomized, open-label trial comparing telmisartan 80 mg with valsartan 80 mg in patients with mild to moderate hypertension using ambulatory blood pressure monitoring. Can J Cardiol. 2000 Sep;16(9):1123-32. English, French.
• Background Liu Y, Tang G, Li Y, Wang Y, Chen X, Gu X, Zhang Z, Wang Y, Yang GY. Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion. J Neuroinflammation. 2014 Oct 15;11:177. doi: 10.1186/s12974-014-0177-4.
• Background Loan A, Syal C, Lui M, He L, Wang J. Promising use of metformin in treating neurological disorders: biomarker-guided therapies. Neural Regen Res. 2024 May;19(5):1045-1055. doi: 10.4103/1673-5374.385286.
• Background Martin SS, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, Baker-Smith CM, Barone Gibbs B, Beaton AZ, Boehme AK, Commodore-Mensah Y, Currie ME, Elkind MSV, Evenson KR, Generoso G, Heard DG, Hiremath S, Johansen MC, Kalani R, Kazi DS, Ko D, Liu J, Magnani JW, Michos ED, Mussolino ME, Navaneethan SD, Parikh NI, Perman SM, Poudel R, Rezk-Hanna M, Roth GA, Shah NS, St-Onge MP, Thacker EL, Tsao CW, Urbut SM, Van Spall HGC, Voeks JH, Wang NY, Wong ND, Wong SS, Yaffe K, Palaniappan LP; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. 2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association. Circulation. 2024 Feb 20;149(8):e347-e913. doi: 10.1161/CIR.0000000000001209. Epub 2024 Jan 24.
• Background Matsumoto S, Ohama R, Hoei T, Tojo R, Nakamura T. Two Cases Showing That Cilostazol Administration Leads to an Increase in Cerebral Blood Flow and Has a Positive Effect on Rehabilitation. Cureus. 2024 Mar 18;16(3):e56376. doi: 10.7759/cureus.56376. eCollection 2024 Mar.
• Background Mendonca IP, Paiva IHR, Duarte-Silva EP, Melo MG, Silva RSD, Oliveira WH, Costa BLDSAD, Peixoto CA. Metformin and fluoxetine improve depressive-like behavior in a murine model of Parkinsons disease through the modulation of neuroinflammation, neurogenesis and neuroplasticity. Int Immunopharmacol. 2022 Jan;102:108415. doi: 10.1016/j.intimp.2021.108415. Epub 2021 Dec 8.
• Background Munoz-Arenas G, Pulido G, Trevino S, Vazquez-Roque R, Flores G, Moran C, Handal-Silva A, Guevara J, Venegas B, Diaz A. Effects of metformin on recognition memory and hippocampal neuroplasticity in rats with metabolic syndrome. Synapse. 2020 Sep;74(9):e22153. doi: 10.1002/syn.22153. Epub 2020 Apr 6.
• Background Park WS, Jung WK, Lee DY, Moon C, Yea SS, Park SG, Seo SK, Park C, Choi YH, Kim GY, Choi JS, Choi IW. Cilostazol protects mice against endotoxin shock and attenuates LPS-induced cytokine expression in RAW 264.7 macrophages via MAPK inhibition and NF-kappaB inactivation: not involved in cAMP mechanisms. Int Immunopharmacol. 2010 Sep;10(9):1077-85. doi: 10.1016/j.intimp.2010.06.008. Epub 2010 Jun 19.
• Background Pekna M, Pekny M, Nilsson M. Modulation of neural plasticity as a basis for stroke rehabilitation. Stroke. 2012 Oct;43(10):2819-28. doi: 10.1161/STROKEAHA.112.654228. Epub 2012 Aug 23. No abstract available.
• Background Potter WB, O'Riordan KJ, Barnett D, Osting SM, Wagoner M, Burger C, Roopra A. Metabolic regulation of neuronal plasticity by the energy sensor AMPK. PLoS One. 2010 Feb 1;5(2):e8996. doi: 10.1371/journal.pone.0008996.
• Background Rogalewski A, Schabitz WR. Stroke recovery enhancing therapies: lessons from recent clinical trials. Neural Regen Res. 2022 Apr;17(4):717-720. doi: 10.4103/1673-5374.314287.
• Background Ruddy RM, Adams KV, Morshead CM. Age- and sex-dependent effects of metformin on neural precursor cells and cognitive recovery in a model of neonatal stroke. Sci Adv. 2019 Sep 11;5(9):eaax1912. doi: 10.1126/sciadv.aax1912. eCollection 2019 Sep.
• Background Saisho Y. Metformin and Inflammation: Its Potential Beyond Glucose-lowering Effect. Endocr Metab Immune Disord Drug Targets. 2015;15(3):196-205. doi: 10.2174/1871530315666150316124019.
• Background Sakamoto T, Ohashi W, Tomita K, Hattori K, Matsuda N, Hattori Y. Anti-inflammatory properties of cilostazol: Its interruption of DNA binding activity of NF-kappaB from the Toll-like receptor signaling pathways. Int Immunopharmacol. 2018 Sep;62:120-131. doi: 10.1016/j.intimp.2018.06.021. Epub 2018 Jul 10.
• Background Senda J, Ito K, Kotake T, Kanamori M, Kishimoto H, Kadono I, Nakagawa-Senda H, Wakai K, Katsuno M, Nishida Y, Ishiguro N, Sobue G. Cilostazol use is associated with FIM cognitive improvement during convalescent rehabilitation in patients with ischemic stroke: a retrospective study. Nagoya J Med Sci. 2019 Aug;81(3):359-373. doi: 10.18999/nagjms.81.3.359.
• Background Shin HK, Lee HR, Lee DH, Hong KW, Lee JH, Park SY, Lee SJ, Lee JS, Lee WS, Rhim BY, Kim CD. Cilostazol enhances neovascularization in the mouse hippocampus after transient forebrain ischemia. J Neurosci Res. 2010 Aug 1;88(10):2228-38. doi: 10.1002/jnr.22376.
• Background Tanaka K, Matsumoto S, Yamada T, Yamasaki R, Suzuki M, Kido MA, Kira JI. Reduced Post-ischemic Brain Injury in Transient Receptor Potential Vanilloid 4 Knockout Mice. Front Neurosci. 2020 May 12;14:453. doi: 10.3389/fnins.2020.00453. eCollection 2020.
• Background Thoene-Reineke C, Rumschussel K, Schmerbach K, Krikov M, Wengenmayer C, Godes M, Mueller S, Villringer A, Steckelings U, Namsolleck P, Unger T. Prevention and intervention studies with telmisartan, ramipril and their combination in different rat stroke models. PLoS One. 2011;6(8):e23646. doi: 10.1371/journal.pone.0023646. Epub 2011 Aug 25.
• Background Veerbeek JM, Langbroek-Amersfoort AC, van Wegen EE, Meskers CG, Kwakkel G. Effects of Robot-Assisted Therapy for the Upper Limb After Stroke. Neurorehabil Neural Repair. 2017 Feb;31(2):107-121. doi: 10.1177/1545968316666957. Epub 2016 Sep 24.
• Background Venna VR, Li J, Hammond MD, Mancini NS, McCullough LD. Chronic metformin treatment improves post-stroke angiogenesis and recovery after experimental stroke. Eur J Neurosci. 2014 Jun;39(12):2129-38. doi: 10.1111/ejn.12556. Epub 2014 Mar 21.
• Background Wang J, Gallagher D, DeVito LM, Cancino GI, Tsui D, He L, Keller GM, Frankland PW, Kaplan DR, Miller FD. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell. 2012 Jul 6;11(1):23-35. doi: 10.1016/j.stem.2012.03.016.
• Background Watanabe T, Zhang N, Liu M, Tanaka R, Mizuno Y, Urabe T. Cilostazol protects against brain white matter damage and cognitive impairment in a rat model of chronic cerebral hypoperfusion. Stroke. 2006 Jun;37(6):1539-45. doi: 10.1161/01.STR.0000221783.08037.a9. Epub 2006 Apr 27.
• Background Westphal LP, Widmer R, Held U, Steigmiller K, Hametner C, Ringleb P, Curtze S, Martinez-Majander N, Tiainen M, Nolte CH, Scheitz JF, Erdur H, Polymeris AA, Traenka C, Eskandari A, Michel P, Heldner MR, Arnold M, Zini A, Vandelli L, Coutinho JM, Groot AE, Padjen V, Jovanovic DR, Bejot Y, Breniere C, Turc G, Seners P, Pezzini A, Magoni M, Leys D, Gilliot S, Scherrer MJ, Kagi G, Luft AR, Gensicke H, Nederkoorn P, Tatlisumak T, Engelter ST, Wegener S; Thrombolysis in Ischemic Stroke Patients (TRISP) Study Group. Association of prestroke metformin use, stroke severity, and thrombolysis outcome. Neurology. 2020 Jul 28;95(4):e362-e373. doi: 10.1212/WNL.0000000000009951. Epub 2020 Jun 29.
• Background Yang X, Shi X, Xue X, Deng Z. Efficacy of Robot-Assisted Training on Rehabilitation of Upper Limb Function in Patients With Stroke: A Systematic Review and Meta-analysis. Arch Phys Med Rehabil. 2023 Sep;104(9):1498-1513. doi: 10.1016/j.apmr.2023.02.004. Epub 2023 Mar 1.

Drugs

Indications