Relying on Pharmacotherapy to Improve Motor Gains in Chronic Stroke Survivors

Official title

Relying on Pharmacotherapy to Improve Motor Gains of Robot-Assisted Upper-Extremity Rehabilitation in Chronic Stroke Survivors

Overview

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.

Detailed description

The overall objective of the proposed study is to assess the viability of a pharmacotherapy combining Telmisartan, Cilostazol IR, and Metformin ER to affect the motor gains achieved via robot-assisted (RA) upper-extremity (UE) rehabilitation in stroke survivors. The hypothesis underlying the study design is that concomitant administration of Telmisartan, Cilostazol IR, and Metformin ER (herein referred to as "the proposed pharmacotherapy") leads to enhancing motor and non-motor gains observed in stroke survivors in response to RA UE rehabilitation. Participants will take these medications either once a day (QD) or twice a day (BID) as described in the protocol.

To test this hypothesis, we plan to accomplish the following primary and secondary aims.

Primary Aims:

* 1 To determine if administration of the proposed pharmacotherapy in combination with RA UE rehabilitation leads to greater improvements in UE motor impairment than previously observed in clinical trials relying on RA UE rehabilitation alone. * 2 To evaluate potential adverse events when using the proposed pharmacotherapy in combination with RA UE rehabilitation.

Secondary Aim:

#1 To determine if the proposed pharmacotherapy in combination with RA UE rehabilitation improves UE functional ability, health related quality of life, and cognition.

Exploratory Aims:

* 1 To determine the association between response to the proposed pharmacotherapy and serum-based biomarkers collected at baseline (i.e., evaluation session prior to training), during the first training session (beginning and end of the session), during the last training session (beginning and end of the session), and during the 3-month follow-up evaluation session. * 2 To evaluate the retention of motor and cognitive gains at 1-month post-intervention.

Interventions

• Drug Telmisartan, Metformin, Cilostazol
  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 p

Primary outcome measures

• Fugl-Meyer Assessment - Upper Extremity (FMA-UE) [Time frame: Will be assessed at baseline, at 8 weeks, and at the end of the 12-week study]

Secondary outcome measures (3)

• Action Research Arm Test (ARAT) [Time frame: Will be assessed at baseline, at 8 weeks, and at the end of the 12-week study.]
• Stroke Impact Scale (SIS) [Time frame: Will be completed at baseline, at 8 weeks, and at the end of the 12-week study.]
• Mini Mental State Exam (MMSE scale) [Time frame: Will be completed at baseline, at 8 weeks, and at the end of the 12-week study.]

Eligibility criteria

Inclusion criteria

• 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.

Exclusion criteria

• 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.
• Severe hemispatial neglect as assessed using the Line Bisection Test (missed lines >2).
• Severely impaired trunk control that would prevent sitting safely on a chair without arms.
• Individuals who present with the following on the impaired UE: open wounds, fragile skin, and under contact precautions due to an active infection.
• Participation in another therapy focused on the recovery of the impaired UE.
• Subjects with cardiac pacemakers, electronic pumps, or any other implanted medical devices that are not US-certified (and hence might be affected by the electromagnetic interference generated by the robot).
• Any condition that would prevent proper/safe use of the robotic system, such as proprioceptive deficits that impair the ability to process haptic or visual feedback, or unstable shoulder joint as assessed by physical examination.
• Current pregnancy.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Spaulding Rehabilitation Hospital — Charlestown

Publications

• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Dobkin BH. Clinical practice. Rehabilitation after stroke. N Engl J Med. 2005 Apr 21;352(16):1677-84. doi: 10.1056/NEJMcp043511. PMID 15843670

Identifiers

NCT: NCT07588932 · 2024P003711

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗