Performance of EArly Retinal Laser (PEARL)

Diabetes, an illness in which the body cannot manage blood sugar safely, is often thought of as a disease of wealth. In fact, over 80% of diabetes occurs in poor or middle-income countries, where rates are growing very quickly. In China, there is ten times more diabetes now than there was 30 years ago, and rates (12%) exceed the US. Over years, diabetes damages blood vessels and vision cells in the eye, and can cause blindness. Most diabetic blindness can be prevented with laser if caught early, but only 10% of rural diabetic persons in China receive care. A major reason is that standard treatment of diabetic eye disease ("DR") calls for patients to return for examinations until their eyes reach a late stage called "PDR", which may take many years, before any treatment is given. This can be very difficult for rural patients, who are often less educated and poorer, meaning they drop out before receiving care.

We have completed a review of papers written about earlier treatment of DR, at a stage called "No PDR" or "NPDR." This review showed studies are needed to prove that this approach is safe and beneficial, but evidence suggests that early treatment could be better to preserve vision, and easier for patients who might otherwise drop out of standard care. To fill the gap in evidence, we designed a study where patients with disease at an earlier stage ("NPDR," the Early Group) get laser treatment right away in one eye chosen by chance and the other eye only get laser if "PDR" develops later, which is the current standard. We will compare eyes treated at NPDR and PDR stages for several outcomes important to patients: vision, developing more serious "PDR" disease, and damage to the eye from treatment. An important goal of this study is to find out if patients who get early treatment are less likely to drop out of follow-up. Since one eye of a patient can't "drop out," we will also have a second group of people who will get later treatment in both eyes only if PDR develops ("Standard Group"). We will compare the rate of dropout between the Early and Standard group. The cost of Early versus Standard treatment will also be examined.

An equal number of urban and rural patients will be recruited, because our early work shows that rural patient are at special risk for dropping out, because of their lack of understanding of their disease, but we want to understand patients from both settings. Our study will have two main aims:

1. This kind of study, a "trial," is expensive and hard. We want to first do a small "Pilot" (100 patients each in Early and Standard groups, versus 300 in each for the main trial) to show that we can find enough patients, convince them to join the study, give them the treatment as selected by chance, follow them for 1 year and collect necessary data.

2. Care of DR in rich settings often depends on expensive tests or advanced training to define the stages ("NPDR," "PDR") and complications of treatment that require further care. Such tests and training may not be practical in poorer settings. In our study, trained local doctors will define stages and find complications using simple, cheap examinations. We will compare their results against more expensive tests and photo grading by experts to find out how well this simpler and cheaper approach works. Finding out if these locally appropriate ways work is very important for diabetic eye are in poorer areas, and will be an important part of our Pilot study.

Our team includes Chinese and UK experts in diabetic eye care, statistics and trials such as this one. Patients will be recruited at the First Affiliated Hospital in Guangzhou, which has one of the largest diabetic clinics in China, and treated at Zhongshan Ophthalmic Hospital (ZOC), China's largest eye hospital. The main investigator, Prof Congdon, is an eye doctor based now in the UK, who has worked in China at ZOC for many years, is fluent in Chinese, and will help to link teams

The prevalence of diabetes in China has risen tenfold since 1981. Virtually all of China's 114 million diabetic persons will develop diabetic retinopathy (DR) eventually, and timely laser treatment reduces blindness by 50%. Still, only 10% of rural persons with DR in China receive treatment, partly because current care requires them to be followed for several years before reaching treatment criteria, during which many are lost.

Our recent review suggests that earlier treatment, which could reduce the compliance burden, may be clinically efficacious and cost effective, but current evidence is insufficient. Our pilot work confirms rural patients find long-term adherence difficult, and earlier treatment is acceptable to patients and providers. We now propose a pilot randomised trial to determine whether earlier laser treatment improves outcomes and compliance among those with diabetic retinopathy in China. Patients will be recruited from one of China's largest hospitals, and treated after training provided by the top-ranked eye hospital in the country. Participants with severe non-proliferative diabetic retinopathy (NPDR) in both eyes will be randomized to receive: pan-retinal photocoagulation (PRP) applied immediately in one eye at random and PRP in the fellow eye only when proliferative diabetic retinopathy (PDR) develops (Early Intervention-n=100) or PRP at the PDR stage in both eyes (Standard Care group-n=100). The latter group is needed in particular, to test whether early laser treatment has an effect on adherence.

At 1 year follow-up, the primary outcome will be progression to PDR, with secondary outcomes including loss of vision, complications, quality of life and cost effectiveness.

In addition to informing a full trial, this study will address questions of importance to diabetic eye care in low resource settings by validating physician clinical diagnosis of DR compared to more expensive technologies and testing a simplified definition of severe NPDR.

China has 114 million persons with diabetes, more than any other country. Among rural-dwellers, who make up half China's population, only 10% of diabetic persons with eye disease (DR) receive treatment. Diabetes prevalence has grown ten-fold in China over the last 30 years. Given that glycaemic control in China is poor, and with the lag time necessary to develop diabetic eye disease, we can anticipate similar explosive growth of DR, placing enormous strains on health care resources. Though laser has been proven effective against DR, proven delivery models do not exist for the extensive rural populations in China and elsewhere in Asia. There is great need for treatment protocols that will promote patient adherence, and validation of simple, inexpensive cutoffs and diagnostic techniques appropriate for local practitioners. Our trial would be expected to benefit the following groups:
CHINESE PATIENTS: Most rural Chinese diabetic patients currently do not receive eye care, even though laser has been proven to eliminate the majority of blindness if delivered in timely fashion. If early laser treatment improves acceptance of sight-saving care, millions of rural patients could avoid blindness. If early treatment also proves more effective, reductions in blindness could be even greater. Loss of vision has not only been associated with reduction in quality of life by over 50%, but is also an important risk factor for mortality in LMICs. DR strikes primarily during the working years, and better treatments could allow patients to remain employed
CHINESE MINISTRY OF HEALTH: The MOH Blindness Prevention Plan has placed a high priority on making diabetic eye care more accessible for rural patients, and they have expressed a strong interest in scaling up proven models appropriate for rural practitioners. Prof Congdon has a proven track record of successful advocacy based on vision trial results in China, including a recently-approved national children's glasses distribution program based on part on evidence of significantly improved educational outcomes with provision of glasses in a trial he and collaborators carried out.
PRACTITIONERS AND RURAL HEALTHCARE INSTITUTIONS: Rural practitioners need treatment cutoffs for diabetic eye disease which are simple to apply, while the healthcare institutions in which they work require validated diagnostic techniques which avoid costly equipment. In addition to preparing for our proposed main trial, our pilot will also validate a simplified definition for Severe Non-Proliferative diabetic retinopathy which relies only on easy-to-appreciate changes in the retina. Additionally, we will assess the accuracy and cost-effectiveness of examinations by trained clinicians using only commonly-available equipment when compared to more expensive "gold standard" technology such as Fluorescein Angiography and Optical Coherence Tomography. If these simpler and less expensive approaches are validated, they will greatly reduce the cost of capacity-building for diabetic eye care in this and similar rural settings in LMICs.
FAMILIES: Patients with vision disability often cannot contribute fully to their families, through outside earnings, childcare and other home activities. They often require care which may reduce educational and work opportunities for other family members. Lessening the burden of blindness has been proven to bring significant and measurable financial benefits to families.
THE RESEARCH COMMUNITY AND RESEARCH FUNDERS: A successful main trial will build capacity both in diabetic care and trial methodology in China and the UK , and we envisage making several independent Fellowship applications for young talented researchers involved in our work, from both countries.
PATIENTS, HEALTHCARE PROFESSIONALS AND POLICY-MAKERS IN OTHER COUNTRIES: The prevalence of type 2 diabetes has also been increasing in other LMICs such as sub-Saharan Africa, where the lessons learned in China would likely be applicable.