Cognitive Level Enhancement Through Vision Exams and Refraction (CLEVER)

Cognitive Level Enhancement Through Vision Exams and Refraction: a Randomized Controlled Trial to Assess Impact of Near and Distance Spectacles on Reducing Rates of Cognitive Decline With Aging in Community Dwelling Older People in India

L.V. Prasad Eye Institute, National Institute of Mental Health and Neuro Sciences, India, The George Institute, Johns Hopkins University, University of Michigan, Clearly, Belfast Health and Social Care Trust

The investigators aim to conduct a mixed-method study in which a randomised controlled trial (RCT) and a descriptive qualitative study will be conducted. The RCT aims to determine whether free near and distance glasses provided to residents in Hyderabad, India, aged ≥ 60 years, with under- or un- corrected refractive error and normal baseline hearing and cognition (HMSE > 18), can improve quality of life, reduce falls, reduce depression, improve social interaction and physical activity cost-effectively over 36 months. The primary qualitative research aim is to a) contextualize the RCT with information on the milieu and culture in which the trial will be conducted; b) provide data on the lived experiences of older adults with reduced vision in the study area, and c) conduct a process evaluation of the trial. The primary outcome measure is the three-year change in cognition measured by LASI- DAD (Longitudinal Aging Study in India(LASI)- Diagnostic Assessment of Dementia(DAD) global cognitive score. Secondary Outcome Measures: Domain-specific cognitive function (orientation, executive function, language/fluency, memory), quality of life (WHOQOL BREF), self-reported visual functioning (INDVFQ), falls, mobility, depression (PHQ9), glasses compliance, cost-effectiveness (total intervention cost per additional quality-adjusted life years(QALY) gained in the intervention group), social interaction/isolation (Social Networking Index, SNI), self-reported physical activity (GPAQ). An additional secondary outcome will be LASI-DAD global cognitive score analysed by excluding any tests determined pre-hoc to depend on visual acuity.

The number of people living with dementia globally will rise from 50 million in 2017 to 131.5 million by 2050. The majority reside in low and middle-income countries (LMICs), where a 223% increase in the burden of dementia is expected from 2015 to 2050. The household cost of caring for demented relatives in India was £2.48 billion in 2013, where total expenses for dementia care will soon consume 0.5% of Gross Domestic Product (GDP). Despite the rapidly-growing burden of dementia in India, only 1 in 10 affected are diagnosed or treated. Proven preventive strategies are desperately needed to close the gap, and could reduce incidence by an estimated 41%, especially early, at the stage of mild cognitive impairment, which itself increases risk of dementia by 23-fold. Existing interventions have predominantly been evaluated in high-income countries (HIC), despite the acknowledged need for prevention in low resource settings. India's national dementia strategy, documented in the Alzheimer's and Related Society of India (ARDSI) Report (2018) and Dementia in India (2020), echo the WHO Dementia Global Action Plan (2017) in prioritising evidence-based approaches to reduce risk. The elderly, at greatest risk for cognitive disorders, also have the highest prevalence of vision impairment, which affects 2.2 billion persons globally. Growing longitudinal evidence links vision impairment and risk of cognitive decline, with population studies in the United States reporting a 55% increased 9-year risk of new cognitive impairment among visually impaired persons. Longitudinal studies elsewhere in the United States, France, Singapore and China report similar results. While vision impairment is a strong predictor of future cognitive performance, cognition is relatively weakly linked to future visual decline. Both distance impairment and impairment of near vision, a nearly universal part of aging without refractive correction, have been implicated. Observational studies also suggest vision care slows rates of cognitive decline by up to 50%. The association between vision loss and cognitive decline and dementia, while consistent and strong, is not well understood, and various causal pathways have been posited. These include common neurodegenerative or micro vascular aetiology, increased cognitive load, and limited social contact and physical activity due to poor vision, each independently shown to elevate risk of dementia. Studies investigating the role of vision correction in slowing cognitive decline will have a significant impact in developing strategies to reduce the burden of dementia. Design: single centre, open label, two-arm, parallel group, stratified, interventional randomised trial with a qualitative component Rationale: Despite considerable longitudinal observational evidence, there have been no randomised trials to investigate whether providing near and distance glasses can slow cognitive decline in the elderly. Proof of a causative association between vision correction and the slowing of cognitive decline is needed to potentiate investment in inexpensive vision care for prevention. This requires randomised trials, and none have yet been done. Study Plan: Eligibility assessments conducted for 1300 participants. After providing the consent and meeting the eligibility criteria, 760 participants randomised to intervention and control groups. Annual follow-ups for 3 years for both groups. Lost to follow ups documented with reason for both groups. Missed data for both groups analysed as intention to treat (ITT) and will be excluded from analysis with reasons documented. Primary outcomes: Three-year change in cognition measured by LASI-DAD global cognitive score. Secondary Outcome Measures: Domain-specific cognitive function (orientation, executive function, language/fluency, memory), quality of life (WHOQOL BREF), self-reported visual functioning (INDVFQ), falls, mobility, depression (PHQ9), glasses compliance, cost-effectiveness (total intervention cost per additional QALY gained in the intervention group), social interaction/isolation (Social Networking Index, SNI), self-reported physical activity (GPAQ). An additional secondary outcome will be LASI-DAD global cognitive score analysed by excluding any tests determined pre-hoc to depend on visual acuity. Hindi Mental State Examination, Medical history and comorbidity questionnaire, Hearing Questionnaire, Client Services Receipt Inventory. Statistical methods: The primary analysis will use a significance level of <0.05 and will compare the change in LASI-DAD global cognitive score (primary outcome, with sensitivity analysis including and excluding vision-dependent tests) between groups using a 2-sample t-test. Both the raw comparison, and the comparison adjusting for potential determinants of change in cognitive status, such as baseline cognitive score, age, sex and education (further covariates will be detailed in the SAP) using general linear models. Similar methods will be used for other time-points and secondary outcomes that are continuous data. Justification for sample size: Imputing three-year un-intervened decline in the outcome variable (LASI-DAD global score from cross-sectional, age-stratified data17, at 29% effect size (from the ACHIEVE study), 502 participants give 90% power at p = 0.05 (two-tailed) based on a two-sample test. With annual follow-up loss of 13% based on estimation from previous studies done in India, 760 total participants are needed across the two study groups. With 60% prevalence of uncorrected distance and/or near refractive error, the total number of people needing to be screened is estimated at approximately 1300.

CLEVER is a single centre, open label, 2-arm, parallel group, stratified, interventional randomised trial, with allocation ratio of 1:1 powered to test superiority of the impact of providing spectacles on rates of cognitive decline among older adults.

All participants randomised to the intervention group will be provided with free near and/or distance spectacles based on the results of refraction. The participants will be asked to choose from an assortment of 20 frames. Participants will be asked to report to the project coordinator in case of any issue with spectacles or if spectacles are lost or broken. Replacement glasses will be provided in case of broken or lost spectacles whenever required. Participants will undergo annual eye exams and refraction, and change of glasses will be prescribed as needed.

All participants randomised to the control group will receive a prescription for spectacles and given free near and/or distance glasses as needed at study close out.

Intervention Description: All participants randomised to the intervention group will be provided with free near and/or distance spectacles based on the results of refraction.

The metric or method of measurement to be used: LASI-DAD global cognitive score. The best possible score is 360 and the worst possible score is 0.

The metric or method of measurement to be used: Quality of Life using WHO BREF questionnaire. Higher scores (for 4 domains) indicate higher quality of life and vice versa (it is a continuum)

The metric or method of measurement to be used: Cost-effectiveness using Client Service Receipt Inventory

The metric or method of measurement to be used: Social Networking Index. The best possible score is 12 and the worst possible score is 0

The metric or method of measurement to be used: Global Physical Activity Questionnaire Self-reported physical activity: Global Physical Activity Questionnaire (GPAQ).

The metric or method of measurement to be used: Quick Screen for falls Risk. The worst possible score is 7% and the best possible score is 49%

The metric or method of measurement to be used: Patient Health Questionnaire, PHQ9. Worst score is 0 and best possible score is 27

The metric or method of measurement to be used: Use of glasses during follow-up visits. The best possible score is 1 and the worst possible score is 0

The metric or method of measurement to be used: Indian VFQ. The measure will be in logits (using Rasch-scaled interval scores) and it is a continuum with positive person scores indicating lower visual functioning and negative scores indicating better visual functioning.

The metric or method of measurement to be used: Hindi Mental State Examination. The best possible score is 31 and the worst possible score is 0.

Inclusion Criteria Community dwelling Residency a. Participants must plan to reside in the local area for the study duration Presenting vision in the better eye due to uncorrected refractive error Impaired distance vision less than 6/12 Near vision less than N8 at 40 cm Presenting vision in the better eye due to under-corrected refractive error Impaired distance vision less than 6/12 Near vision less than N8 at 40 cm Willingness to participate to be randomized to adhere to the protocol Exclusion criteria Impaired baseline cognition a. HMSE score less than or equal to 18 Non-refractive causes of vision impairment Severely impaired mobility immobile bedridden wheelchair using walker Severe medical illness likely to limit the life span Cancer Heart disease Stroke HIV or AIDS Chronic lung disease Kidney disease Hearing loss assessment self-reported hearing impairment inability to hear inability to repeat short phrases in local languages

All Individual Participant Data(IPD) will be stored in anonymised format. The IPD that includes personal identifiable information will be deleted when the data collection process is complete and before the initiation of data analysis. Only de-identified data will be shared with all the researchers for analysis. The primary analysis will be conducted on all outcome data obtained from all enrolled participants as randomised.

All deidentified IPD will be available from September 2022 (anticipated Trial start date) to September 2035 (inclusive of analysis, publication and archival).

Following publication of the primary and secondary outcomes there may be scope to conduct additional analyses on the data collected. In such instances formal requests for data will need to be made in writing to the Chief Investigator, who will discuss this with the Sponsor. The study will comply with the good practice principles for sharing individual participant data from publicly funded clinical trials and data sharing will be undertaken in accordance with the required regulatory requirements

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