Safety of intravitreal ziv-aflibercept in patients with diabetic macular edema, macular edema following retinal vein occlusion and neovascular age related macular degeneration in a Ghanaian population: A phase I randomized interventional study v1

Brief Background: Retinal vascular diseases are a significant cause of visual loss world-wide, including Ghana. Anti-vascular endothelial growth factor (anti-VEGF) such as aflibercept, ranibizumab and bevacizumab have become the standard of care for diabetic macular edema (DME), macular edema (ME) following retinal vein occlusions (RVO), and neovascular age related macular degeneration(nvAMD). Aflibercept has been approved by the United States of America (USA) Food and Drug Administration (FDA) for the treatment of DME, nvAMD, and ME following RVO. The recommended dose of intravitreal aflibercept is 2mg in 0.05ml administered monthly or initial monthly injections for the first 3 months followed by 2 monthly injections. Aflibercept is highly expensive (USD1850 per dose) and not available in many developing countries including Ghana. Ziv-aflibercept, a molecule structurally identical to aflibercept but differs due to its formulation with hyper-osmolality has been approved by the USA FDA for the treatment of metastatic colorectal cancers. Ziv-aflibercept, used off-label, has been found to be safe in patients with DME and nvAMD in phase 1 trials at a dose of 1.25mg in 0.05ml. The cost of compounded ziv-aflibercept is much reduced to USD 67 per dose. The 1.25mg dose of ziv-aflibercept is below that recommended for intravitreal injections of aflibercept. However, to the best of our knowledge, there are no data available on the safety of 2mg of ziv-aflibercept, although in vitro studies indicate that it is safe. Furthermore, there is no data on the intravitreal administration of ziv-aflibercept in the Ghanaian population to date. Aim: To evaluate the safety of 1.25mg and 2mg ziv-aflibercept in Ghanaian population with retinal vascular diseases. Methodology: This is a prospective, randomised, double masked, phase 1, interventional study. Twenty (20) patients with centre involving DME, ME following RVO, and nvAMD will be assigned to 2 groups: 1.25mg/0.05ml (control) and 2mg/0.08ml ziv- aflibercept and will receive 3 doses of ziv-aflibercept at 4 weekly intervals. Intraocular pressure will be determined 30 minutes following injection and in subsequent visits. Safety data will be collected at days 1and 7 after initiation of treatment, and at 4, 8 and 12 weeks. Primary outcome measures are ocular safety parameters- including the incidence of pain, blurred vision, raised intraocular pressure, intraocular inflammation and endophthalmitis(eye infection), as well as systemic safety at 4 weeks. Secondary outcome measures are ocular and systemic safety parameters at 12 weeks, change in BCVA (ETDRS letters), central subfield foveal thickness (CSFT) and central retinal thickness (CRT) as measured on optical coherent tomography (OCT) at 4 and 12 weeks. Expected Outcome: We seek to evaluate the safety of 2 different doses of ziv-aflibercept in patients with DME, ME following RVO and nvAMD in a Ghanaian population. We expect that there will be no differences in safety between the 2 doses of ziv-aflibercept.