Intravitreal injection of a Rho-kinase inhibitor (fasudil) combined with bevacizumab versus bevacizumab monotherapy for diabetic macular oedema: a pilot randomised clinical trial

Correspondence to Professor Hamid Ahmadieh, Ophthalmic Research Center, Labbafinejad Medical Center, Tehran 16666, Iran; [email protected]

Introduction

Diabetic macular oedema (DME) is the leading cause of decreased vision in patients with diabetes.¹Currently, anti-vascular endothelial growth factor (VEGF) agents are the main treatment modality for DME.²This type of treatment, however, has some limitations. One of the principal mechanisms leading to an increase in retinal vessel permeability in patients with diabetes is endothelial cell damage. VEGF inhibition alone cannot control local inflammation and stop the endothelial damage induced by leucocytes.^{3 4}

An in vitro study showed that upregulation of the Rho/Rho kinase (ROCK) pathway in diabetes promotes leucocyte adhesion to the microvasculature by affecting the expression of the adhesion molecules.⁵ A recent clinical study demonstrated that the serum levels of tumour necrosis factor (TNF)-α and its receptors were significantly elevated in patients with diabetes. TNF-α-induced increased intercellular adhesion molecule-1 (ICAM-1) expression was significantly suppressed by ROCK inhibitors.⁶

Fasudil, as a ROCK inhibitor, has been shown to inhibit leucocyte-induced endothelial damage in both in vitro and in vivo studies.^{7 8} Two previous human studies have demonstrated the safety and efficacy of intravitreal injection of fasudil in patients with severe DME.^{9 10}

The present pilot clinical trial was conducted to compare the efficacy of combined intravitreal injection of fasudil and bevacizumab with the efficacy of intravitreal injection of bevacizumab alone in the management of severe DME.

Methods

Participants

In this prospective randomised controlled trial (RCT), 44 eyes of 44 patients with diabetes mellitus type 2 were recruited at Labbafinejad Medical Center, Tehran, Iran, from October 2014 to December 2015. Eyes with severe DME and best-corrected visual acuity (BCVA) <70 ETDRS letters equal to 20/40 Snellen visual acuity were included in this pilot RCT. Severe DME was defined as centre-involving macular oedema and central subfield macular thickness≥350µm associated with large cystoid changes with or without neurosensory detachment.^{10 11} Patients with active proliferative diabetic retinopathy and those with a history of vitrectomy were excluded from the study. In addition, eyes with a history of intravitreal bevacizumab (IVB) injection and/or macular laser photocoagulation (MPC) during the past three months and eyes with a history of cataract surgery within the past six months...