PROMINENT-Eye Ancillary Study (Protocol AD)

Despite improved glycemic and systemic control for many patients with diabetes, over the past
several decades, diabetic retinopathy (DR) develops and progresses in a large proportion of
patients, and visual loss from diabetic eye complications continues to be a leading cause of
blindness in the US and other developed countries worldwide. Thus, even a modest ability to
prevent DR onset or to slow DR worsening might substantially reduce the number of patients at
risk for diabetes-related vision loss worldwide. Widespread use of an oral agent effective at
reducing worsening of DR might also decrease the numbers of patients who undergo treatment
for DR and diabetic macular edema (DME) and who are consequently at risk for side effects
that adversely affect visual function. Two major studies of fenofibrate, the Fenofibrate
Intervention and Event Lowering in Diabetes (FIELD) and The Action to Control Cardiovascular
Risk in Diabetes (ACCORD)-eye study, have demonstrated clinically important reduction in
progression of retinopathy in patients with diabetes assigned to fibrate compared with
placebo. However, despite the positive clinical trial results, fenofibrate has not gained
wide acceptance as a preventive agent by either ophthalmologists or primary diabetes care
providers. Thus, it is important to provide further evidence demonstrating whether or not
selectively increasing peroxisome proliferator-activated receptor alpha (PPARα) activity
reduces progression of retinopathy in patients with diabetes and non-proliferative diabetic
retinopathy at baseline. Pemafibrate is a more potent and selective PPARα modulator than
fenofibrate. Its efficacy is currently being evaluated in the Pemafibrate to Reduce
Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes (PROMINENT) study
for prevention of cardiovascular events in patients with type 2 diabetes. Given the large
study cohort with a substantial proportion likely to have DR and the multi-year duration of
the PROMINENT trial, this study represents a unique opportunity to assess effects of chronic
PPARα activation through pemafibrate therapy on DR outcomes.

Primary Study Objective: To assess whether treatment with pemafibrate (0.2 mg orally BID)
compared with placebo reduces the hazard rate of diabetic retinopathy worsening in adults
with type 2 diabetes and diabetic retinopathy without neovascularization in at least one eye
who are participating in the parent PROMINENT trial.