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

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

Background:

Age-related macular degeneration (AMD) is the main reason older people lose their vision. It affects the macula, the center of the retina needed for sharp, clear vision. Researchers want to see if an antibiotic can help people with an advanced form of AMD, Geographic Atrophy (GA).

Objective:

To see if minocycline is safe for people with GA and if it helps preserve their vision.

Eligibility:

People age 55 and older who have GA in at least one eye.

Design:

Participants will be screened with physical exam, medical history, blood tests, and eye exam.

Participants will take minocycline. They will take 1 pill twice a day for at least 3 years.

Participants will have a minimum of 11 study visits. (But they are not every 3 months.). At each visit, participants will have a medical history. They may have:

Blood tests.

Eye exam. Vision, eye pressure, and eye movements will be checked. The pupils may be dilated. The inside of the eyes may be photographed.

Their thyroid gland felt while they swallow.

Microperimetry. They will sit in front of a computer and press a button when they see a light on the screen.

Fluorescein angiography. An intravenous line (IV) will be placed in an arm vein. A dye called fluorescein will be placed in the IV and travel through the veins to the blood vessels in the eyes. A camera will take pictures of the dye as it flows through the eye blood vessels.

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.

• INCLUSION CRITERIA:

To be eligible, the following inclusion criteria must be met, where applicable:

• Participant must be 55 years of age or older.

• Participant must understand and sign the protocol s informed consent document.

• Participant must have evidence of early or intermediate AMD as defined by characteristic presence of drusen and/or pigmentary changes.

• Participant must be able to swallow capsules.

• Participant must have normal renal function and liver function or have mild abnormalities not above grade 1 as defined by the Common Terminology Criteria for Adverse Events v4.0 (CTCAE).

• Participant must agree to minimize exposure to sunlight or artificial ultraviolet (UV) rays and to wear protective clothing, sunglasses and sunscreen (minimum sun protection factor (SPF) 15) if s/he must be out in the sun.

• Any female participant of childbearing potential (see Appendix 1 for definition) must have a negative pregnancy test at screening and be willing to undergo pregnancy tests throughout the study.

• Any female participant of childbearing potential (see Appendix 1 for definition) and any male participant able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent* from intercourse or must agree to practice two acceptable methods of contraception throughout the course of the study and for at least one week after investigational product (IP) discontinuation. Acceptable methods of contraception include:

  1. hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring),

  2. intrauterine device,

  3. barrier methods (diaphragm, condom) with spermicide, or,

  4. surgical sterilization (hysterectomy or tubal ligation).

     • Abstinence is only acceptable when it is the participant s preferred and usual lifestyle choice. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

EXCLUSION CRITERIA:

A participant is not eligible if any of the following exclusion criteria are present.

• Participant is actively receiving study therapy in another investigational study.
• Any female participant of childbearing potential (see Appendix 1 for definition) that is pregnant, breast-feeding or planning to become pregnant during the study.
• Participant is expected to be unable to comply with study procedures or follow-up visits.
• Participant is on ocular or systemic medications known to be toxic to the lens, retina or optic nerve (e.g., ethambutol, chloroquine, or hydroxychloroquine).
• Participant has a condition that would preclude participation in the study (e.g., unstable medical status including blood pressure and glycemic control) by interfering with the participant s ability to engage in the required protocol evaluation and testing and/or comply with study visits.
• Participant has a history of chronic renal failure requiring dialysis or kidney transplant.
• Participant has a history of chronic hepatitis or liver failure.
• Participant has a history of thyroid cancer.
• Participant has an allergy or hypersensitivity to minocycline or any drug in the tetracycline family.
• Participant is currently taking minocycline or another tetracycline medication.
• Participant is taking any medication that could adversely interact with minocycline such as methoxyflurane.
• Participant has a prior history of idiopathic intracranial hypertension.

STUDY EYE ELIGIBILITY CRITERIA:

The participant must have at least one eye meeting all inclusion criteria and none of the exclusion criteria listed below.

STUDY EYE INCLUSION CRITERIA:

• The study eye must have greater than 1/2 disc area (approximately 1 mm(2)) of GA compatible with dry AMD. GA is defined as one or more well-defined and often circular patches of partial or complete depigmentation of the RPE, typically with exposure of underlying choroidal blood vessels. Even if much of the RPE appears to be preserved and large choroidal vessels are not visible, a round patch of RPE partial depigmentation may be classified as early GA. The GA in the study eye must be able to be photographed in their entirety, and it must not be contiguous with any areas of peripapillary atrophy, which can complicate area measurements.
• The total area of GA lesions combined should be less than 7.0 MPS disc areas (DA) (17.78 mm(2)) as evident on FAF imaging.
• The VA of the study eye should be greater than or equal to19 E-ETDRS letters (i.e., 20/400 or better).
• The study eye must have clarity of ocular media and degree of pupil dilation sufficient to permit adequate fundus photographs.

STUDY EYE EXCLUSION CRITERIA:

• Current evidence of choroidal neovascularization (CNV) as determined by the treating physician or a history of treatments for CNV

• Evidence of retinal atrophy due to causes other than atrophic AMD.

• Current evidence or history of ocular disorders in the study eye that in the opinion of the investigator confounds study outcome measures, including (but not limited to):

  1. non-proliferative diabetic retinopathy involving 10 or more hemorrhages or microaneurysms, or active proliferative diabetic retinopathy
  2. Branch or central retinal vein or artery occlusion
  3. Macular hole
  4. Pathologic myopia
  5. Uveitis
  6. Pseudovitelliform maculopathy

• History of vitreoretinal surgery.

• Need for ocular surgery during the course of the study.

• Recent history of lens removal (less than 3 months) or Yttrium Aluminum Garnet (YAG) laser capsulotomy (less than 1 month).