Evaluation of Oral Minocycline in the Treatment of Geographic Atrophy Associated With Age-Related Macular Degeneration

Objective: Age-related macular degeneration (AMD), the leading cause of blindness in people over age 65 in the United States, is a heterogeneous clinical entity in which retinal degeneration occurs predominantly in the macula in the context of aging and leads to impairment of central visual acuity (VA). AMD occurs in two general forms, one of which involves choroidal neovascularization (CNV) with subsequent formation of a disciform scar. This is often referred to as the neovascular or wet form. A second form, the subject of this study, is termed dry /atrophic macular degeneration or otherwise geographic atrophy (GA) and involves a slow progressive atrophy of retinal pigment epithelial (RPE) cells and photoreceptors in the macula, also resulting in central vision loss. GA is estimated to affect up to one million persons in the U.S. and there is no current treatment that can prevent its onset or retard its progression.

While the etiology of GA is not completely understood, inflammatory processes involving the activation of resident immune cells of the retina called microglia is likely to contribute. Minocycline inhibits the activation of microglia which produce inflammatory factors implicated in GA development. The objective of this study is to investigate the safety and possible efficacy of oral minocycline in patients with GA.

Study Population: Forty-five participants with unilateral or bilateral GA associated with AMD will be enrolled. However, up to an additional 15 participants may be enrolled to replace participants who may withdraw from the study prior to reaching the Month 33 visit.

Design: This is a multi-center, prospective, single-arm, Phase II study to evaluate minocycline as a potential treatment to decrease the rate of worsening of GA associated with AMD.

Participants will undergo a nine-month run-in phase prior to receiving investigational product (IP). During this run-in phase, participants will have a total of four pre-treatment visits. Following the run-in phase, beginning at Month 9, participants will receive an oral dose of 100 mg of minocycline twice daily for 36 months. There will be a common termination date, which will take place when the last recruited participant has received 36 months of treatment. Participants who were recruited in the earlier part of the study will continue treatment and be followed every six months until the common termination date. However, participants may complete participation in the study as early as Month 45, at the discretion of the investigator.

Outcome Measures: The primary outcome is the rate of change in area of GA based on grading by an external Reading Center of fundus autofluorescence (FAF) images in the assigned study eye. The primary outcome will compare the rates of GA area expansion as determined on FAF images before and following the initiation of IP until 24 months of treatment. Secondary outcomes will compare differences in rates of change in best-corrected visual acuity (BCVA), low-luminance VA, area of GA based on FAF (using a different statistical approach compared to primary outcome) and fundus photography. The exploratory outcome will compare the difference in the rate of change in macular sensitivity as measured using microperimetry. This outcome was originally a secondary outcome when the clinical trial participants were enrolled, since these represent visual function data corresponding closely to areas affected by geographic atrophy. Hence, changes in microperimetry data over time might be well placed to support changes in structural data over time, as geographic atrophy lesions undergo enlargement. In the original Statistical Analysis Plan, the intention was that "Macular sensitivity, as measured on microperimetry, will be evaluated in a similar manner as BCVA", (i.e., Mean rate of change in BCVA during the treatment phase will be compared to the mean rate of change in BCVA during the run-in phase using Student s paired t-test ). However, microperimetry data (represented by multiple numerical values, one for each anatomical location, at each time-point) are much more complex than BCVA data (represented by a single numerical value at each time-point). The originally proposed statistical treatment is therefore not suitable. In addition, the study team is not aware of any established methods accepted by the community for analyzing microperimetry data, unlike the situation for BCVA. Indeed, the microperimetry acquisition pattern used in GA MIN is unique and was developed specifically for this trial. It therefore needs its own dedicated set of statistical analyses (which may need several iterations), rather than pre-specified and widely accepted analyses that could be detailed in advance in the Statistical Analysis Plan. For these reasons, although the original intention was for the microperimetry data to represent a secondary outcome measure, it is better suited to an exploratory outcome measure. Safety outcomes will include the number and severity of adverse events (AEs). Ocular safety outcomes will be indicated by changes in VA, ocular surface changes, intraocular inflammation and any other ocular changes not consistent with the natural progression of GA.