PROJECT SUMMARY/ABSTRACT Glaucoma drainage device (GDD) surgery has gained popularity in managing patients with medically uncontrolled glaucoma. However, one of the major long-term complications of GDD is progressive corneal endothelial cell loss (ECL) leading to corneal decompensation, which requires complex care. Although surgical techniques have been modified to insert the tube into the ciliary sulcus to address this issue, anterior chamber (AC) tube placement remains the preferred location, as there is a lack of convincing data to validate the advantages of sulcus placement. For example, (1) Direct comparison of endothelial cell loss (ECL) after sulcus versus AC tube placement is limited to three retrospective studies; (2) Studies are inconsistent regarding whether intraocular pressure (IOP) and other surgical outcomes are similar after sulcus tube or AC tube placement; (3) Question remains whether a sulcus tube cause more AC microenvironment change due to higher chance of having chronic tube-iris touch than an AC tube, jeopardizing endothelial cell health, IOP control, or other surgical outcomes of the sulcus tube. To answer these questions, we propose a multi-center, outcome-masked clinical trial randomizing 240 subjects to sulcus tube versus AC tube placement. In this trial, we will compare ECL (specific aim 1), IOP control (specific aim 2) and AC microenvironment (specific aim 3) after GDD implantation with tube placement in the ciliary sulcus versus the anterior chamber. In the setting of increased use of GDDs, our proposed trial to identify better approaches to decrease its corneal complications is of substantial interest to both corneal and glaucoma specialists. Department of Ophthalmology at University of California San Francisco (UCSF), Francis I. Proctor Foundation at UCSF, University of Pennsylvania (UPenn), and 4 high-volume centers for GDD implantation will jointly execute this trial. The Department of Ophthalmology at UCSF will serve as Clinical Coordinating Center. UPenn will be the Data Coordinating Center. Francis I. Proctor Foundation will be the imaging reading center and metagenomic RNA deep sequencing analysis (MDS) center. This trial is innovative for a number of reasons including the randomization of surgery (sulcus tube versus AC tube) and application of novel MDS analysis (examining postoperative AC microenvironment), none of which has been prospectively studied before. It is aligned with the priorities of the NEI, studying high- resolution imaging techniques such as endothelial cell imaging and anterior-segment optical coherence to guide post-operative treatment and as potential surrogate trial endpoints in future trials. This world class team of collaborators have a proven track record for executing large NEI-funded trials in ophthalmology, and are well positioned to answer the important questions presented in this proposal.