Novel ERG for Detection of Hydroxychloroquine Retinopathy

A Feasibility Study Using Novel, Portable Electroretinography Devices to Detect Hydroxychloroquine Retinopathy

The purpose of the study is to investigate novel electroretinography (ERG) devices in the detection of hydroxychloroquine retinopathy. Two devices (the RETEval full-field and flicker ERG and UTAS multifocal ERG) will be evaluated in this study, comparing device outputs to standard of care screening tests, in groups of participants characterised by presence or absence of hydroxychloroquine-related retinopathy.

Study Overview

• Status: Recruiting
• Conditions: Hydroxychloroquine Retinopathy
• Intervention / Treatment: Diagnostic test: Hand-Held Full-Field Skin-Electrode Electroretinography (Device to be evaluated); Diagnostic test: Trolley-Mounted Multifocal Skin-Electrode Electroretinography (Device to be evaluated); Diagnostic test: Spectral-Domain Optical Coherence Tomography (Standard of Care test); Diagnostic test: Macular Autofluorescence (Standard of Care test)

Detailed Description

Hydroxychloroquine (HCQ) is a widely used drug used to treat disorders of inflammation in the body with up to 320,000 people estimated to be on this drug in the UK alone. Retinopathy due to HCQ is a significant problem, necessitating yearly screening which can only realistically take place in hospital eye units where funding and capacity constraints limit the provision of services.

Electroretinography is a non-invasive method of testing for eye retinal problems, which works by flashing light (in certain patterns and brightness) into eyes and measuring the electrical response through fine wires placed on the eye surface or behind the eyelid, and is considered by many authors to be a gold-standard test to detect HCQ retinopathy. Their use has been limited due to the high expertise required to undertake and interpret tests, limited availability of testing, and high test burden, however newer electroretinography devices have been developed by a company called LKC Technologies, which are faster to perform, use leads placed on the skin (rather than the eye surface) which are more comfortable, easier to use by healthcare technicians, and can be done without the need for dilating eyedrops. The two devices being tested in this study are:

• The RETEval = a handheld electroretinography testing device
• The UTAS multifocal ERG = a trolley-mounted electroretinography testing device

These innovations may make testing far easier to develop in both hospital eye service, and potentially even general settings such as outpatient clinics, general practices, and optometrists. This study aims to evaluate the performance of devices to detect and classify participants in 4 main groups:

• Normative control participants (n=35)
• Patients taking HCQ but without retinopathy (n=35)
• Patients taking HCQ with indeterminate features of retinopathy (also known as POSSIBLE retinopathy) (n=35)
• Patients taking HCQ with definite retinopathy

Device outputs will be analysed and compared with masked graded screening results (incorporating spectral-domain macular optical coherence tomography and autofluorescence as standard, taken on the same visit) to generate device- and device-output-specific sensitivities and specificities. If a signal is found, the feasibility outcomes from this study will inform the study methodology and timelines for a larger trial if necessary.

• Study Type: Observational
• Enrollment (Estimated): 140

Contacts and Locations

• Study Contact: Name: Dr Chan Ning Lee; Phone Number: 020 3299 1297; Email: channing.lee2@nhs.net
• Study Contact Backup: Name: Ophthalmology research inbox; Phone Number: 020 3299 1297; Email: kch-tr.ophthalmologyresearch@nhs.net

Study Locations

• United Kingdom
  • London, United Kingdom, SE5 9RS
    • Recruiting
    • King's College Hospital
    • Contact: Dr Chan Ning Lee; Email: channing.lee2@nhs.net
    • Contact: Ophthalmology research inbox; Email: kch-tr.ophthalmologyresearch@nhs.net

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Age- and sex-matched control group (n=35) On hydroxychloroquine without retinopathy (n=35) On hydroxychloroquine with possible retinopathy (n=35) On hydroxychloroquine with definite retinopathy (n=35)

Description

Inclusion Criteria:

1. Age ≥18 years

2. HCQ groups:

   a. HCQ use >5 years for patients without any high-risk factors, or >1 year in patients with one or more high-risk factors for HCQ retinopathy, namely: i. Dose >5mg/kg per day actual body weight (ABW) ii. Estimated glomerular filtration rate (eGFR) of <60mls/min/1.73m2 iii. Concomitant tamoxifen use

3. Control group:

   1. No prior HCQ exposure

Exclusion Criteria:

1. Cataract grade ≥3 of any subtype
2. Recent cataract surgery within 4 weeks of recruitment
3. Significant media opacity or corneal disease including, but not limited to, corneal oedema, corneal scarring, keratoconus, previous corneal transplants, severe keratoconjunctivitis sicca (requiring the use of topical serum, immunosuppressive or analogous therapy, or procedural treatment).
4. Significant macular co-pathology including, but not limited to, macular degeneration, macular scarring, cystic macular oedema (for any reason), staphyloma.
5. Inherited retinal and/or macular dystrophies including colour vision deficiencies
6. Active or previous posterior uveitis or pan-uveitis
7. Aphakia
8. High refractive error >6.00 dioptres
9. Amblyopia
10. Diabetes
11. Retinal angiopathies including, but no limited to, retinal vein occlusion, retinal artery occlusion, ocular ischaemic syndrome, HIV retinopathy, Sickle cell disease, radiation retinopathy
12. Visually significant surgical retinal disease including epiretinal membrane, macular hole, retinal detachment, retinal tear
13. Previous retinal laser or intravitreal treatment
14. Moderate or worse glaucoma
15. Optic atrophy
16. Photosensitive epilepsy
17. Ungradable HCQ retinopathy screening images
18. Periocular infection or rash (recruitment can be deferred until acute pathology has resolved)
19. Unable or unwilling to undertake study activities
20. Any active use or history of the following medications:

Amiodarone Canthaxanthin Deferoxamine Digoxin Ethambutol Interferon-alpha Melatonin Nefazodone Sildenafil Vigabatrin Chloroquine Quinine

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Normative Controls; Age- and sex- matched normal controls	Diagnostic test: Hand-Held Full-Field Skin-Electrode Electroretinography (Device to be evaluated); RETEval Complete hand-held electroretinogram; Diagnostic test: Trolley-Mounted Multifocal Skin-Electrode Electroretinography (Device to be evaluated); UTAS multifocal electroretinogram; Diagnostic test: Spectral-Domain Optical Coherence Tomography (Standard of Care test); Heidelberg Engineering Spectralis Spectral-Domain Optical Coherence Tomography (macular structural scan); Diagnostic test: Macular Autofluorescence (Standard of Care test); Heidelberg Engineering Spectralis Autofluorescence imaging (macular structural image)
On Hydroxychloroquine, NO retinopathy; Participants over 18 years on hydroxychloroquine without hydroxychloroquine-related retinopathy	Diagnostic test: Hand-Held Full-Field Skin-Electrode Electroretinography (Device to be evaluated); RETEval Complete hand-held electroretinogram; Diagnostic test: Trolley-Mounted Multifocal Skin-Electrode Electroretinography (Device to be evaluated); UTAS multifocal electroretinogram; Diagnostic test: Spectral-Domain Optical Coherence Tomography (Standard of Care test); Heidelberg Engineering Spectralis Spectral-Domain Optical Coherence Tomography (macular structural scan); Diagnostic test: Macular Autofluorescence (Standard of Care test); Heidelberg Engineering Spectralis Autofluorescence imaging (macular structural image)
On Hydroxychloroquine, POSSIBLE retinopathy; Participants over 18 years on hydroxychloroquine with possible (indeterminate) hydroxychloroquine-related retinopathy	Diagnostic test: Hand-Held Full-Field Skin-Electrode Electroretinography (Device to be evaluated); RETEval Complete hand-held electroretinogram; Diagnostic test: Trolley-Mounted Multifocal Skin-Electrode Electroretinography (Device to be evaluated); UTAS multifocal electroretinogram; Diagnostic test: Spectral-Domain Optical Coherence Tomography (Standard of Care test); Heidelberg Engineering Spectralis Spectral-Domain Optical Coherence Tomography (macular structural scan); Diagnostic test: Macular Autofluorescence (Standard of Care test); Heidelberg Engineering Spectralis Autofluorescence imaging (macular structural image)
On Hydroxychloroquine, DEFINITE retinopathy; Participants over 18 years on hydroxychloroquine with definite hydroxychloroquine-related retinopathy	Diagnostic test: Hand-Held Full-Field Skin-Electrode Electroretinography (Device to be evaluated); RETEval Complete hand-held electroretinogram; Diagnostic test: Trolley-Mounted Multifocal Skin-Electrode Electroretinography (Device to be evaluated); UTAS multifocal electroretinogram; Diagnostic test: Spectral-Domain Optical Coherence Tomography (Standard of Care test); Heidelberg Engineering Spectralis Spectral-Domain Optical Coherence Tomography (macular structural scan); Diagnostic test: Macular Autofluorescence (Standard of Care test); Heidelberg Engineering Spectralis Autofluorescence imaging (macular structural image)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The sensitivity and specificity of both devices to discriminate between NO, POSSIBLE and DEFINITE hydroxychloroquine retinopathy compared to standard screening tests	Primary Outcome	All tests required to determine sensitivity and specificity of both devices compared to standard retinal imaging will be completed in a single visit. Safety will be evaluated up to 1 week post-visit.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To compare the sensitivity and specificity of undilated versus dilated testing with the multifocal ERG device, for all categories of hydroxychloroquine retinopathy	Secondary Outcome	All tests required to determine this outcome will be completed at a single visit. Safety will be evaluated up to 1 week post-visit.
To determine the patient acceptability of both devices evaluated using standardised, study-specific questionnaires	Feasibility Outcome	All tests required to determine this outcome will be completed at a single visit. Safety will be evaluated up to 1 week post-visit.
To determine the proportion and recruitment rate of patients in each category of hydroxychloroquine retinopathy who consent to join this study.	Feasibility Outcome	All tests required to determine this outcome will be completed at a single visit. Safety will be evaluated up to 1 week post-visit.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine which ERG waveform features (such as implicit time or amplitude) from both devices best discriminate participants with NO hydroxychloroquine retinopathy from those with POSSIBLE and DEFINITE hydroxychloroquine retinopathy	Exploratory Outcome	All tests required to determine this outcome will be completed at a single visit. Safety will be evaluated up to 1 week post-visit.
To determine if both device waveforms correlate with standard mfERG waveforms in patients receiving hydroxychloroquine	Exploratory Outcome	All tests required to determine this outcome will be completed at a single visit. Novel device ERG waveforms will be compared with standard mfERG where undertaken in the preceding 12 months. Safety will be evaluated up to 1 week post-visit.

Collaborators and Investigators

• Sponsor: King's College Hospital NHS Trust
• Collaborators: LUPUS UK; King's College Hospital Charity
• Investigators: Study Chair: Professor Timothy L Jackson, King's College Hospital NHS Trust

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2024
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): May 1, 2026

Study Registration Dates

• First Submitted: August 29, 2023
• First Submitted That Met QC Criteria: September 6, 2023
• First Posted (Actual): September 13, 2023

Study Record Updates

• Last Update Posted (Actual): August 6, 2025
• Last Update Submitted That Met QC Criteria: August 1, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Electroretinography; Diagnostic Evaluation
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Diseases
• Other Study ID Numbers: IRAS 317611

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No