Metformin as a Neuroprotective Therapy for Glaucoma - A Randomized Controlled Trial

125 POAG patients who show progressive RNFL/GCIPL thinning by TPA or GPA in at least one eye will be consecutively recruited from the HKU Eye Centre, Grantham Hospital after obtaining written informed consent at the screening visit. All investigations will be performed at HKU Eye Centre. The study will be conducted in accordance with the ethical standards stated in the 2013 Declaration of Helsinki and in compliance with Good Clinical Practice. They will have clinical examination, Goldmann applanation tonometry (GAT), OCT RNFL imaging, and perimetry at the screening, baseline, and follow-up visits. POAG is defined by eyes with open angles by dark room gonioscopy and glaucomatous optic disc damage (narrowed neuroretinal rim, RNFL defects, and optic disc excavation), with or without visual field defects, and without iris trabecular contact for >180 degrees by dark room anterior segment OCT.

Patients will be randomly assigned in a 1:1 ratio to receive, twice daily, oral metformin 750mg (i.e. 1500mg/day) or identical-appearing oral placebo. The investigators and patients will be blinded to the treatment assignment. Randomization with stratification by age, gender, VF MD, spherical equivalent, mean IOP measurement over the past 3 years, and number of glaucoma medications will be performed using an open-source computer program MinimPy. Patients and investigators will be unaware of treatment allocations and have no access to the randomization sequence or codes. The metformin and placebo tablets will be in identical appearance and uniformly packaged. OCT imaging of the RNFL, and VF testing will be performed at baseline, 1 month, 4 months, and every 2 months thereafter up to 24 months, with two repeated OCT and VF measurements at baseline, 1 month, and 24 months. Compliance with oral metformin/placebo use will be assessed by evaluating opened and unopened metformin/placebo packs at each follow-up visit.

Clinical examination including VA measurement, slit-lamp biomicroscopy for the anterior and posterior segments, and IOP measurement will be performed at the screening, baseline and all follow-up visits. Dark room indentation gonioscopy, anterior segment OCT imaging, axial length and central corneal thickness (CCT) measurements, and refraction will be performed at the screening and the last follow-up visits. Corneal hysteresis will be measured at the baseline visit using the Ocular Response Analyzer (Reichert Ophthalmic Instruments, Depew, NY, USA). Dilated fundus examination will be performed at the baseline visit and then yearly. Montreal Cognitive Assessment will be administered at the screening visit. Patients with a score of ≤25 will be excluded.

RNFL/GCIPL imaging will be performed with a swept-source OCT (Triton OCT, Topcon, Japan) using a wide-field scan covering the parapapillary region and the macula (512x256 pixels in 12x9mm2). Scans with a signal strength <40 (manufacturer recommendation), motion artifact, poor centration, RNFL segmentation errors or missing data (e.g. blinking) are discarded with re-scanning performed in the same visit. The average RNFL thickness will be measured for analysis of the primary outcome measure (i.e. the rate of change of average RNFL thickness). To identify patients with progressive RNFL/GCIPL thinning for study inclusion, RNFL/GCIPL thickness data of the individual pixels in serial RNFL/GCIPL thickness maps before the time of recruitment will be exported for TPA. The algorithm of TPA has been described. In brief, TPA performs pixel-by-pixel linear regression analysis between RNFL thickness and time for evaluation of progressive RNFL thinning after registering and aligning serial OCT scans in corresponding retinal locations of an eye. To minimize type I errors consequential to multiple testing in an eye, the RNFL thickness maps will be condensed from 512x256 pixels to 128x64 superpixels with a false discovery rate (FDR) controlled at 5% (an FDR of 5% suggests that 5% of the superpixels detected with a significant negative slope between RNFL thickness and time would be false positives). Progressive RNFL/GCIPL thinning is defined when there are ≥20 contiguous superpixels with a significant negative trend for at least two consecutive visits. Patients with progressive RNFL/GCIPL thinning detected by TPA or GPA (Carl Zeiss Meditec) in at least one eye will be invited for study inclusion.

Perimetry will be performed with the Humphrey Field Analyzer 3 (Carl Zeiss Meditec, Dublin, CA) using the 24-2 SITA standard program. A reliable VF test has fixation losses <20% and false positive rate <15%. Eyes with unreliable test results will receive repeated testing in the same visit. Definition of VF progression VF progression is identified when there are ≥3 points that showed significant change compared with 2 baseline examinations for at least 3 consecutive tests (i.e. "likely progression" in the Guided Progression Analysis) according to the EMGT criteria.