Perfusion Augmentation Through Exercise (PERFEX)

Changes in PERFusion and Cerebrovascular Reactivity Through Aerobic EXercise Training After Ischemic Stroke - a Proof of Concept Randomized Controlled Trial

Large cerebral vessel occlusion is a common phenomenon in the general population and accounts for 13-35% of ischemic strokes. Chronic stenosis in the large cerebral arteries is associated with cerebral hypoperfusion, cognitive decline and an increased risk of stroke or recurrent stroke, respectively.

Even with upgrowth of surgical or endovascular interventions, mechanical reopening of the occluded vessels is often not possible. Alternative treatment opportunities include minimal-to-moderate blood pressure elevation (typically by ceasing antihypertensives) waiting for collateral circulation to develop spontaneously. Another conservative approach to increase cerebral perfusion is aerobic exercising. Physical activity has shown to lead to cerebral blood flow increase, especially in activated brain areas of healthy human and rat models. However, it is remains unknown, how physiological adaptation to physical activity expresses in persons after stroke due to large vessel occlusion. Herein, it is hypothesized that aerobic exercise facilitates the development of an extensive and functional vascular collateral network in persons with ischemic stroke and perfusion compromise.

Study Overview

• Status: Not yet recruiting
• Conditions: Stroke, Ischemic
• Intervention / Treatment: Behavioral: Aerobic treadmill training; Behavioral: Stretching exercise

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anne Schwarz, PhD; Phone Number: +41442555645; Email: anne.schwarz@usz.ch

Study Locations

• Switzerland
  • Zürich, Switzerland
    • University Hospital Zurich
    • Contact: Christoph Globas, MD; Phone Number: +41442555511; Email: christoph.globas@usz.ch
  • Zürich, Switzerland
    • Ambulante Reha Triemli Zürich
  • Zürich, Switzerland
    • Klinik Lengg AG
    • Contact: Bartosz Bujan, MD; Phone Number: +41443876767; Email: bartosz.bujan@kliniklengg.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and Female patients of 18 years of age or above
• Subjects after ischemic cerebral stroke (≥ 3 months) due to large vessel occlusion
• Subjects do not qualify for flow augmentation through ECIC bypass or endovascular treatment
• Persistent deficit in BOLD-CVR
• Functional Ambulatory Categories >2
• Discharged from hospitalization / inpatient rehabilitation
• Living independent before stroke (mRS ≤3)
• Written Informed Consent

Exclusion Criteria:

• Severe cardiac disease, such as instable angina pectoris, pericarditis, heart failure (New York Health Association > II°), or hemodynamically significant valvular dysfunction
• Complete arterial stenosis
• Peripheral artery disease with mild to moderate claudication at < 200m or 200-1000m of walking
• Contra-indication, such as a history of a seizure, prior electroconvulsive therapy, deep brain stimulators or other metal in the head, skull defect, pacemaker, neuroleptic medication
• Inability to follow the procedures of the study, e.g., due to language problems (unable to follow to stage commands), psychological disorders (major depression), and / or a neurodegenerative disease (dementia)
• Known or suspected non-compliance, documented drug, or alcohol abuse
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: aerobic treadmill training; Progressive graded, high-intensity aerobic treadmill training is delivered over 36 sessions at a frequency of 3x per week for 30-50 minutes of training per session over a period of 3 months. If possible, the training intensity is progressed from 40% to 80% of heart rate reserve, according to the supervising therapist.	Behavioral: Aerobic treadmill training; The intervention will be delivered based on the initial exercise testing and graded based by increasing the duration, speed and/or altitude of the treadmill training.
Active Comparator: stretching exercise; The control intervention includes stretching exercise therapy similarly heart rate controlled within limits up to 20% of heart rate reserve over 36 sessions at a frequency of 3x per week for 30 minutes.	Behavioral: Stretching exercise; Interventions, such as stretching, relaxation, passive soft-tissue technics (excl. manipulation) that do not elevate the heart rate above 20HRR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain imaging - cerebrovascular reactivity (CVR) by BOLD-fMRI	Functional brain tissue perfusion and tissue at risk based on cerebrovascular reactivity by blood oxygenation-level dependent functional magnetic resonance imaging (BOLD-fMRI), measured as the percentage BOLD signal change /mmHg CO2.	post-intervention (12 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain imaging - intravoxel incoherent motion (IVIM)	Functionality of brain microvasculature by measuring diffusion and perfusion components of tissue based on intravoxel incoherent motion	post-intervention (12 weeks)
Brain imaging - NOVA-qMRI	Blood flow velocity based on non-invasive optimal vessel analysis quantitative magnetic resonance imaging	post-intervention (12 weeks)
Brain imaging - Lesion volume	based on 3D T1 weighted imaging, 3D Fluid-Attenuated Inversion Recovery (FLAIR), Diffusion-Eighted Imaging (DWI)	post-intervention (12 weeks)
Brain imaging - Collateral status	Collateral status based on 3D time of flight angiography (TOF)	post-intervention (12 weeks)
Exercise stress testing	Cycle ergometer testing with spirometry	post-intervention (12 weeks)
Six-Minute Walk Test (6MWT)	Functional walking capacity in meters	post-intervention (12 weeks) + follow-up (+3 months)
Ten-Meter Walk Test (10MWT)	Walking speed in m/s	post-intervention (12 weeks) + follow-up (+3 months)
Fugl-Meyer Assessment of the Lower Extremity (FMMA-LE)	Stroke-specific motor impairment index to assess lower limb motor function with a total score ranging from 0 to 34 and higher scores indicating better performance.	post-intervention (12 weeks) + follow-up (+3 months)
Motricity Index of the Lower Extremity (MI-LE)	Muscle strength assessment of three major muscle groups of the lower extremity with a total score ranging from 0 to 100 and higher scores indicating better performance.	post-intervention (12 weeks) + follow-up (+3 months)
5-Chair-Rise-Test	Functional muscle strength, measured in seconds to complete the task.	post-intervention (12 weeks) + follow-up (+3 months)
International Physical Activity Questionnaire (IPAQ)	self-reported physical activity	post-intervention (12 weeks) + follow-up (+3 months)
Montreal Cognitive Assessment (MoCA)	Screening assessment of cognitive functions with a maximum score of 30 points.	post-intervention (12 weeks) + follow-up (+3 months)
Word list learning	Assessment of memory function	post-intervention (12 weeks) + follow-up (+3 months)
Digit Span Test / Corsi block	Assessment verbal and nonverbal working memory	post-intervention (12 weeks) + follow-up (+3 months)
Stroop test	Assessment of executive function and inhibition	post-intervention (12 weeks) + follow-up (+3 months)
European Quality of Life 5 Dimensions 5 Level (5Q-5D-5L)	Quality of life questionnaire that assesses 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) on a 5-level scale ranging from 1 - no, 2 - slight, 3 - moderate, 4 - severe to 5 - extreme problems or unstable to.	post-intervention (12 weeks) + follow-up (+3 months)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concomitant medications	covariate	post-intervention (12 weeks) + follow-up (+3 months)

Collaborators and Investigators

• Sponsor: University of Zurich
• Investigators: Principal Investigator: Christoph Globas, MD, University Hospital and University of Zurich

Study record dates

Study Major Dates

• Study Start (Anticipated): November 1, 2022
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: September 15, 2022
• First Submitted That Met QC Criteria: October 13, 2022
• First Posted (Actual): October 18, 2022

Study Record Updates

• Last Update Posted (Actual): October 18, 2022
• Last Update Submitted That Met QC Criteria: October 13, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: aerobic exercise; cerebral perfusion
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke
• Other Study ID Numbers: 2022-00438

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No