Glaucoma Rehabilitation Using ElectricAI Transcranial Stimulation (GREAT) - Randomized Controlled Trial Using Combined Perceptual Learning and Transcranial Electrical Stimulation for Vision Enhancement

Improving Vision and Quality of Life in Patients With Glaucoma Using Non-invasive Brain Stimulation and Perceptual Learning: A Randomized Clinical Trial

Glaucoma is a complex disease that can result in progressive vision loss. It is the second leading cause of blindness, accounting for 23% of permanent blindness in Hong Kong. There are no treatments that restore vision lost to glaucoma. However, recent studies have shown that vision can be improved by perceptual learning (PL) and transcranial electrical stimulation (tES). This study will examine the effect of perceptual learning and tES on improving quality of life, visual function and functional performance in patients with peripheral field loss due to glaucoma. It is phase 2 of Glaucoma Rehabilitation Using ElectricAI Transcranial Stimulation (GREAT) project.

Study Overview

• Status: Recruiting
• Conditions: Glaucoma
• Intervention / Treatment: Other: Real-PL training + Real-tES(tDCS); Other: Real-PL training + Sham-tES (tDCS); Other: Placebo-PL training + Sham-tES (tDCS)

Detailed Description

Study design:

This study uses a prospective, double-masked, randomized, placebo-controlled training RCT design.

The eligible participants will be randomly allocated into 3 groups:

(A) Placebo-Perceptual learning + Sham-tES; (B) Real-Perceptual learning + Sham-tES; (C) Real-Perceptual learning + Real-tES.

All participants will complete forty-three study visits:

Visit 1: Eligibility assessment (refer to the recruitment criteria); Visit 2-3: Outcome measures (Pre-intervention/ baseline); Visit 4-13: 10 sessions intervention (1st batch); Visit 14-15: Interim 1 Outcome measures; Visit 16-25: 10 sessions intervention (2nd batch); Visit 26-27: Interim 2 Outcome measures; Visit 28-37: 10 sessions intervention (3rd batch); Visit 38-39: Post-training 1 Outcome measures; Visit 40-41: Post-training 2 Outcome measures (to evaluate the retention effect after 1 month); Visit 42-43: Post-training 3 Outcome measures (to evaluate the retention effect after 2 months).

Six sessions of assessment will be conducted: (1) Baseline; (2) Interim-1 (after 10-sessions training); (3) Interim-2 (after 20-sessions training); (4) Post-1 (after 30-sessions training); (5) Post-2 (1-month post training); and (6) Post-3 (2-month post training).

• Study Type: Interventional
• Enrollment (Estimated): 144
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Allen Cheong, PhD; Phone Number: 852-27666108; Email: allen.my.cheong@polyu.edu.hk
• Study Contact Backup: Name: Melinna Mei, PhD; Phone Number: 852-34002309; Email: melinna.mei@polyu.edu.hk

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • The Hong Kong Polytechnic University
    • Contact: Allen Cheong, PhD; Phone Number: 852-27666108; Email: allen.my.cheong@polyu.edu.hk
    • Contact: Melinna Mei, PhD; Phone Number: 852-34002309; Email: melinna.mei@polyu.edu.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age range from 18 to 80 years;
• Diagnosis of primary open angle or normal tension glaucoma with relative scotoma in both eyes;
• A relative scotoma defined as a Humphrey Field Analyser (HFA) threshold perimetry loss (mean deviation of -6dB) within the central 24 degree of the visual field for at least one eye;
• Best-corrected distance visual acuity of 6/12 or better (equivalent to 0.3 logMAR acuity or better to confirm that participant's central vision is preserved).
• Stable vision and visual field loss for at least 3 months;
• With a cognitive functional score of 22 or above in the Montreal Cognitive Assessment - Hong Kong version (HK-MoCA) (to confirm participant's intact cognitive function).

Exclusion Criteria:

• Ocular diseases other than glaucoma (e.g. age-related macular degeneration, diabetic retinopathy, moderate to severe cataract) or severe hearing impairment (to ensure that participant can hear the instructions clearly during assessments and training);
• Severe medical problems (e.g. stroke, Parkinson's disease) or self-reported neurological (e.g. brain surgery, brain tumor, peripheral neuropathy), or cognitive disorders (e.g. diagnosed dementia or cognitive impairment);
• Self-reported vestibular or cerebellar dysfunction, history of vertigo;
• Using any medications for any neurological conditions or psychiatric drugs (e.g. sedative, hypnotic) that might interfere motor control;
• Contraindications for non-invasive brain stimulation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Real-PL + Real-tES (tDCS); Participant will receive 30 training sessions with real PL and real tES (tDCS): 3-4 sessions per week, about 1 hour per session	Other: Real-PL training + Real-tES(tDCS); PLtraining : around 40mins, tDCS: 20mins
Experimental: Real-PL + Sham-tES (tDCS); Participant will receive 30 training sessions with real PL and sham tES (tDCS): 3-4 sessions per week, about 1 hour per session	Other: Real-PL training + Sham-tES (tDCS); PL training : around 40mins, tDCS: 20mins
Placebo Comparator: Placebo-PL + Sham-tES (tDCS); Participant will receive 30 training sessions with placebo PL and sham tES (tDCS): 3-4 sessions per week , about 1 hour per session	Other: Placebo-PL training + Sham-tES (tDCS); PL training : around 40mins, tDCS: 20mins

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual field test	Visual field test is measured monocularly using the 24-2 Swedish interactive threshold algorithm (SITA) standard tests by Humphrey Visual Field Analyzer (HFA, Carl Zeiss Meditec Inc., California). The mean deviation (MD), pattern standard deviation (PSD), and visual field index (VFI) are recorded and the MD of 24-2 visual field test is used as primary outcome of intervention effectiveness.	Change from baseline at 5weeks, change from baseline at 10weeks, change from baseline at 15weeks, change from baseline at 19weeks, changes from baseline at 23weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Balance function	Balance function will be evaluated for the following two conditions: Static Balance: Participants will be asked to stand on a force place with a foam while performing visual searching. Parameters including maximum antero-posterior amplitude (mm), maximum medio-lateral amplitude (mm), total sway path (mm), and root mean square sway (mm/s) will be analyzed.; Perturbed Balance: Participants will be asked to stand on a force place which will translate forward or backward while performing visual searching. Parameters including latency (ms) reacting to the perturbation, maximum antero-posterior amplitude (mm), maximum medio-lateral amplitude (mm), total sway path (mm), and root mean square sway (mm/s) will be analyzed.	Change from baseline at 5weeks, change from baseline at 10weeks, change from baseline at 15weeks, change from baseline at 19weeks, changes from baseline at 23weeks
Electroencephalography (EEG)	64-channel electroencephalography(EEG) recordings from Neuroscan will be used to understand the electrophysiological changes in the intervention. A standard visual evoked potential task (VEP) and a specific designed SSVEP task will be used to assess the functional integrity of central vision and peripheral function. Besides, resting-state EEG will be recorded to measure the functional connectivity at different timepoints. ERP components (such as P100, N1 and N2) in VEP, tagging frequency response in SSVEP, and the power correlation in resting state will be analyzed as physiological indicators.	Change from baseline at 15weeks, change from baseline at 19weeks, changes from baseline at 23weeks
Questionnaires for QoL	National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ 25) and Low Vision Quality of Life (LVQoL) will be used to evaluate the patient-perceived outcome of the intervention on daily living. In NEI-VFQ 25, more positive person measures indicates greater visual ability, and more negative person measures have less visual ability. In the LVQoL, the completion results in a summed score between 0 (a low quality of life) and 125 (a high quality of life).	Change from baseline at 15weeks, change from baseline at 19weeks, changes from baseline at 23weeks
Gait Test	All participants will be asked to walk along a 7-m walkway at their normal pace. Two disturbing factors will be introduced while walking: visual searching task and obstacle crossing. For trials with visual search, visual stimuli will be presented on the monitor (located at the end of the walkway) when the participant crosses the obstacle. For trials with obstacle crossing, an obstacle with two different colors (grey for low contrast and yellow for high contrast obstacle) of two different heights (2.5x60x5 cm or 2.5x60x15 cm) are positioned at the middle of the walkway. Participants' gait parameters including hip flexion/extension (degree), knee Min/Max (degree), ankle flexion/extension (degree), head flexion/extension (degree), walking speed (mm/s), step width (mm), and toe clearance(mm) will be measured and analyzed for each condition.	Change from baseline at 15weeks, change from baseline at 19weeks, changes from baseline at 23weeks
High Resolution Perimetry (HRP)	The current HRP is a valid and reliable computer-based visual field assessment based upon a previously well-established program. The revised HRP uses circular geometry instead of a rectangle to present stimuli, while maintaining its high-resolution advantage. During the HRP test, suprathreshold stimuli are presented in a radial pattern within 20 degrees, with a step size of 3 degrees. These stimuli are presented monocularly at a total of 98 positions, with the order of presentation randomized. To ensure a stable result and accurate assessment of participants' responses, the HRP test is repeated five times. Throughout the HRP test, fixation is monitored by an infrared eye tracker (SR Research, Eyelink Portable Duo).	Change from baseline at 5weeks, change from baseline at 10weeks, change from baseline at 15weeks, change from baseline at 19weeks, changes from baseline at 23weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Magnetic resonance spectroscopy (Optional)	Magnetic resonance spectroscopy (MRS) is a non-invasive imaging technique that can be used to study the chemical composition of tissues, including the brain. Changes in GABAergic and Glutamatergic concentrations within the MRS voxels will be used to evaluate the mechanistic changes in the brain. To study the mechanism of glaucoma, we plan to use MEGA-PRESS in primary visual cortex(V1) of the brain to understand the neural and metabolic mechanisms.	Change from baseline at 15 weeks
BDNF concentration in serum and tears (Optional)	Serum BDNF concentration will be measured using an enzyme-linked immunoassay (ELISA) kit and liquid chromatography-mass spectrometry(LCMS). DNA will be extracted from the leucocytes for the determination of BDNF Val66Met polymorphism (rs6265G>A) using a method based on polymerase chain reaction (PCR). Collection of tear sample by capillary tube (10 ul) or Schirmer Strip in labelled eppendorf tube and keep them frozen immediately. Tear BDNF concentration will be measured using an enzyme-linked immunoassay (ELISA) kit and liquid chromatography-mass spectrometry.	Change from baseline at 15 weeks
Cortisol concentration in serum and tears (Optional)	Cortisol concentration will be measured using an enzyme-linked immunoassay (ELISA) kit and liquid chromatography-mass spectrometry(LCMS). Collection of tear sample by capillary tube (10 ul) or Schirmer Strip in labelled eppendorf tube and keep them frozen immediately. Tear Cortisol concentration will be measured using an enzyme-linked immunoassay (ELISA) kit and liquid chromatography-mass spectrometry.	Change from baseline at 15 weeks
Questionnaire of psychological state	Perceived Stress Scale (PSS-10) and Patient Health Questionnaire - 9 (PHQ9) will be used to evaluated the stress and depression severity of the outcome of the intervention of participant. Individual scores on the PSS-10 can range from 0 to 40 with higher scores indicating higher perceived stress. In PHQ9, the completion results in a summed score between 0 (none minimal) to 27 (severe).	Change from baseline at 15weeks, change from baseline at 19weeks, change from baseline at 23weeks.
Questionnaire of fear of falling	Falling is a significant concern for glaucoma patients, with the fear of falling being a major contributing factor to the incidence of falls. Moreover, fear of falling is associated with a decreased physical and social activity. The Chinese version of the Falls Efficacy Scale- International (FES-I) is a validated and reliable questionnaire used to assess fear of falling in everyday life. This questionnaire includes sixteen items that are related to common daily activities, each graded on a scale of from 1 (not at all concerned) to 4 (very concerned). Higher scores indicate a greater concern about falling, which may indicate a poorer balance ability.	Change from baseline at 15weeks, change from baseline at 19weeks, change from baseline at 23weeks.
Kinetic visual field	The kinetic test is highly sensitive in detecting changes in the far peripheral visual field, which significantly correlates with balance function and gait performance. The binocular kinetic visual field is measured using Octopus 900 perimetry (Haag-Streit AG, Switzerland). Tests are done in the kinetic mode using the standard protocol (sixteen vectors), with a stimulus size of III4e moving at a speed of 5 degrees/sec to map the hill of vision. Any changes in the area of the isopter over time would indicate the effect of training on the kinetic visual field.	Change from baseline at 15weeks, change from baseline at 19weeks, change from baseline at 23weeks.

Collaborators and Investigators

• Sponsor: The Hong Kong Polytechnic University
• Collaborators: The University of Hong Kong; University of Magdeburg; University of Waterloo

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2023
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: May 3, 2023
• First Submitted That Met QC Criteria: May 16, 2023
• First Posted (Actual): May 24, 2023

Study Record Updates

• Last Update Posted (Actual): October 29, 2024
• Last Update Submitted That Met QC Criteria: October 28, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: glaucoma; transcranial direct current stimulation (tDCS); perceptual learning (PL)
• Additional Relevant MeSH Terms: Eye Diseases; Ocular Hypertension; Glaucoma
• Other Study ID Numbers: HSEARS20190905001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: available: 3mths after data complication
• IPD Sharing Access Criteria: The requestor's affiliation and purpose are required to get the access.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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