Relying on Pharmacotherapy to Improve Motor Gains in Chronic Stroke Survivors

NCT07588932 | Not Yet Recruiting Early Phase 1 FDA Drug

• 1 other identifier: 2024P003711
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Stroke

Keywords

Stroke; Rehabilitation; Pharmacotherapy; Robotic therapy

Outcome Measures

Primary Outcomes (1)

• Fugl-Meyer Assessment - Upper Extremity (FMA-UE)

  The FMA-UE is a widely used, standardized test that measures movement, coordination, and reflexes of the arm, wrist, and hand after a stroke. Scores reflect the degree of motor impairment, with higher scores indicating better motor function (range 0-66).

  Will be assessed at baseline, at 8 weeks, and at the end of the 12-week study

Secondary Outcomes (3)

• Action Research Arm Test (ARAT)

  Will be assessed at baseline, at 8 weeks, and at the end of the 12-week study.

• Stroke Impact Scale (SIS)

  Will be completed at baseline, at 8 weeks, and at the end of the 12-week study.

• Mini Mental State Exam (MMSE scale)

  Will be completed at baseline, at 8 weeks, and at the end of the 12-week study.

Study Arms (1)

Intervention

EXPERIMENTAL

Participants will be instructed to take Telmisartan, Cilostazol IR (immediate release), and Metformin ER (extended release) (herein referred to as "proposed pharmacotherapy") while undergoing robot-assisted upper-extremity training. Participants will take these medications either once a day (QD) or twice a day (BID) as described in the protocol.

Drug: Telmisartan, Metformin, Cilostazol

Interventions

Telmisartan, Metformin, Cilostazol DRUG

Participants will be instructed to take the low dose of the proposed pharmacotherapy (i.e., Telmisartan 20mg QD, Metformin ER 500mg QD, Cilostazol IR 50mg QD) during week 1 and the full dose (i.e., Telmisartan 40mg QD, Metformin ER 500mg BID, Cilostazol IR 50mg BID) starting on week 2. They will continue to take the full dose until completion of the six-week robot assessed upper extremity training period (week 3-8). At the end of this period, they will be instructed to take the low dose of the proposed pharmacotherapy for two more weeks. During the entire study, participants will be monitored for potential side-effects.

Also known as: Proposed pharmacotherapy

Intervention

Eligibility Criteria

• Age: 21 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults between 21 and 80 years of age.
• History of ischemic stroke.
• Stroke occurred at least six months prior to recruitment.
• Moderate to severe UE impairment (FMA-UE score between 15 and 40)
• MMSE score \>=20 and being able to safely follow three-step commands.

You may not qualify if:

• Contraindications to the pharmacotherapy (e.g., heart failure, known medication reaction or interactions with ongoing medication regimen).
• Taking dual antiplatelet therapy (e.g., Aspirin+Plavix) and/or other anticoagulation medications (e.g., Eliquis, coumadin) that cannot safely be modified or discontinued (as determined by the participant's primary care physician or by the medical monitor).
• Clinically significant somnolence and/or depression that would hinder active participation in motor training sessions.
• Taking any medication that the study physician determines to have a significant drug-drug interaction with Telmisartan, Cilostazol, and/or Metformin.
• Taking Telmisartan, Cilostazol, and/or Metformin in a dose that is different from the one used in the study and that cannot be adjusted to match the study dose (as determined by the participant's primary care physician or by the medical monitor).
• Taking medications with equivalent clinical effect (e.g., BP control) to Telmisartan, Cilostazol, and/or Metformin and that cannot be replaced by Telmisartan, Cilostazol, and/or Metformin (as determined by the participant's primary care physician or by the medical monitor).
• A body mass index (BMI) below 25 (as the proposed pharmacotherapy could cause hypoglycemia in participants with normal-low BMI).
• Severe musculoskeletal pathology or recent fractures affecting the impaired UE that would prevent safe use of the rehabilitation robotic system.
• Previous diagnosis of neurological diseases other than stroke that would have a negative impact on the response to the rehabilitation intervention (e.g., severe dystonia affecting the UE) or would prevent safe participation in RA UE training (e.g., uncontrolled seizures).
• Moderate to severe disability due to migraines as determined using the Migraine Disability Assessment test (score \> 10).
• Severe spasticity (Modified Ashworth Scale for spasticity ≥ 3 for UE muscles) that would prevent safe use of the robotic system utilized during training.
• Undergoing Botox treatment for pain/spasticity related to the affected upper extremity, in the 4 months prior to enrollment or during the study period.
• Cerebellar and/or hemorrhagic stroke.
• Severe aphasia limiting the ability to express needs or discomfort verbally or non-verbally.
• Visual impairments that would prevent proper use of interactive on-screen games during RA UE training.

Sponsors & Collaborators

• Spaulding Rehabilitation Hospital: lead
• Neuro-Innovators, Inc.: collaborator

Study Sites (1)

Spaulding Rehabilitation Hospital

Charlestown, Massachusetts, 02129, United States

Location

Related Publications (40)

• 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.

  PMID: 21153029 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.

  PMID: 35557626 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.

  PMID: 28634570 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.

  PMID: 35705953 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.

  PMID: 34192807 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.

  PMID: 26670084 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.

  PMID: 22763480 BACKGROUND

• Dobkin BH. Clinical practice. Rehabilitation after stroke. N Engl J Med. 2005 Apr 21;352(16):1677-84. doi: 10.1056/NEJMcp043511.

  PMID: 15843670 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.

  PMID: 9428832 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.

  PMID: 33811249 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.

  PMID: 20498620 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.

  PMID: 24632338 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.

  PMID: 17538008 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.

  PMID: 26686236 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.

  PMID: 28208711 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.

  PMID: 30223922 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.

  PMID: 11021956 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.

  PMID: 25315906 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.

  PMID: 37862207 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.

  PMID: 38264914 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.

  PMID: 38633955 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.

  PMID: 34890997 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.

  PMID: 32190918 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.

  PMID: 20601185 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.

  PMID: 22923444 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.

  PMID: 20126541 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.

  PMID: 34472456 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.

  PMID: 31535024 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.

  PMID: 25772174 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.

  PMID: 30005227 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.

  PMID: 31579328 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.

  PMID: 20175201 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.

  PMID: 32477057 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.

  PMID: 21901125 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.

  PMID: 27597165 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.

  PMID: 24649970 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.

  PMID: 22770240 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.

  PMID: 16645134 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.

  PMID: 32601121 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.

  PMID: 36868494 BACKGROUND

MeSH Terms

Conditions

Stroke

Interventions

Telmisartan; Metformin; Cilostazol

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Biguanides; Guanidines; Amidines; Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Quinolines

Study Officials

• Qing M Wang, MD, PhD

  Spaulding Rehabilitation Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Madison Costa, OT

CONTACT

617-952-6388; mcosta11@mgb.org

Erin Foley, OT

CONTACT

617-952-6388; efoley14@mgb.org

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of the Stroke Biological Recovery Laboratory

Study Record Dates

• First Submitted: May 9, 2026
• First Posted: May 15, 2026
• Study Start: May 18, 2026
• Primary Completion (Estimated): October 31, 2027
• Study Completion (Estimated): December 31, 2028
• Last Updated: May 15, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: At the time of publication of the manuscript summarizing the results of the study. De-identified individual participant data will be included in the Supplementary Materials section of the manuscript
• Access Criteria: We plan to publish an open access manuscript summarizing the results of the study and providing (in the Supplementary Materials section of the manuscript) de-identified individual participant data. Hence, de-identified individual participant data will be accessible by the public at large.

Locations

US (1)