PROTECTING CELLS IN THE EYE AT RISK OF DAMGE FROM GLAUCOMA Glaucoma Day: Research into New Treatments Saturday 6th September 2014

Glaucoma causes "The excavation of the disc in glaucoma is not a purely mechanical result of exalted pressure; it is, in part at least, an atrophic condition which, though primarily due to pressure, includes vascular changes and impaired nutrition of the substance of the optic disc which may possibly progress even though all excessive pressure be removed." Priestly Smith, 1879

enlarged optic cup narrowed neuro-retinal rim patchy loss of vision

Glaucoma causes Primary OAG Secondary OAGs Susceptibility factors: ocular systemic genetic environmental ↑ IOP “characteristic neuropathy” glaucoma with subtle differences

Evidence population studies longitudinal cohort studies risk factors for having glaucoma longitudinal cohort studies risk factors for glaucoma progression

Blue Mountains Eye Study Ocular risk factors raised IOP 5x risk myopia 2x risk Systemic factors age: exponential relationship family history 3x risk diabetes 2x risk high blood pressure 1.7x

Intraocular Pressure Prevalence (%) 35 30 25 20 15 10 5 Black subjects (n=4674) White subjects (n=5770) Sommer et al (1991) 10 14 18 22 26 30 34 IOP (mmHg)

Risk of having glaucoma Raised IOP Mechanism? Biomechanical damage to ONH architecture? Reduced ONH perfusion? Which component? Level of IOP (area under time curve) Fluctuation of IOP Long term Diurnal/Nocturnal IOP Ocular pulse pressure

Ocular pulse pressure

Risk of having glaucoma What is it about ethnicity that confers greater susceptibility? Increased genetic risk for raised IOP? Increased susceptibility to raised IOP? Thinner CCT? Larger optic disc? Cardiovascular disease? Lack of access to health care

Risk of having glaucoma Myopia 2-fold risk for mild myopia, 3-fold risk for higher myopia (Blue Mountains) Myopia not related to IOP Mechanism Greater susceptibility to raised IOP Biomechanical?

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Additional mechanisms Neuronal susceptibility factors trophic support altered glial/astrocyte function excitotoxicity mitochondrial function apoptosis control &c, &c

Carelli V et al. Prog Retin Eye Res. 2004;23(1):53-89.

Finding New Treatments Once we find a risk factor, we need to find treatments which influence that risk factor Then we need to see if those treatments work! But how?

Question? The observation period for most trials with visual field outcomes has been in the order of years delays bringing benefit to patients increases cost of drug development fewer potentially beneficial drugs evaluated Do trials need to be this long?

DF Garway-Heath, H Zhu, DP Crabb on behalf of the UKGTS Investigators Observation periods of 1 year for clinical trials of neuroprotective agents in glaucoma are feasible DF Garway-Heath, H Zhu, DP Crabb on behalf of the UKGTS Investigators ARVO Orlando, Florida, 6th May 2014

Trial design considerations Goal: increase precision of the estimate of the outcome reduce variability Data acquisition Data analysis

Data acquisition

Data analysis

(mean 10 fastest locations) UKGTS N = 437 ANSWERS (mean 10 fastest locations) MD 6 months Placebo -3.92 (3.10) 0.03 (-2.09, 1.72) Treatment -3.01 (2.59) 0.57 (-1.59, 2.16) p 0.03% 17% 12 months -3.12 (2.59) -0.22 (-1.04, 0.71) -2.47 (2.25) 0.05 (-0.77, 0.95) <0.01% 2% 18 months -2.48 (2.26) -0.18 (-0.93, 0.38) -1.93 (1.87) 0.18 (-0.43, 0.75) 0.1% 24 months -2.18 (2.13) -0.17 (-0.60, 0.24) -1.69 (1.76) 0.17 (-0.29, 0.50) 0.5%

Sample size calculations ANSWERS PLR Rate reduction Slope (UKGTS latanoprost arm): mean (sd) Target slope with neuro-protective treatment Sample size (per arm) 10% -2.47 (2.25) -2.22 (2.25) 1703 -6.58 (6.37) -5.93 (6.37) 2019 20% -1.98 (2.25) 444 -5.27 (6.37) 497 30% -1.73 (2.25) 195 -4.61 (6.37) 220 Assumptions: Patients in reference group on latanoprost Observation period 12 months Power 90% P 5%

Pilot study Assumptions: Patients in reference group on latanoprost ANSWERS Improvement Slope (UKGTS latanoprost arm): mean (sd) Target slope with neuro- protective treatment Sample size (per arm) 10% -2.47 (2.25) -2.22 20% -1.98 30% -1.73 115 Assumptions: Patients in reference group on latanoprost Observation period 12 months Power 80% P 10%

Summary Factors other than eye pressure influence glaucoma susceptibility, but we don’t know all the factors we don’t know how important the factors are that we do know about there are many possible treatments and interventions, but testing each one requires a clinical trial

What are the important questions? Which lifestyle factors do you think it is most important to investigate as risk factors? Which concern you most that may affect your glaucoma? Examples: diet exercise alcohol smoking yoga others?

What are the important questions? Would you ‘donate’ a blood sample for research into genetic susceptibility for: a study of all patients with glaucoma (a ‘biobank’) a specific study of a few patients looking for a particular gene both the above neither of the above What are you concerns?

What are the important questions? Would you consent to having your routine clinical data being used for research to identify who does well and who does less well with treatment? What are you concerns?

What are the important questions? Clinical trial duration to investigate a new therapy Would you prefer a trial that lasts one year, but involves 6 visits and lots of tests at each visit that lasts 2 years and involves 10 visits and fewer tests at each visit that lasts 5 years and is similar to routine clinical care

What are the important questions? What type of treatment would you prefer? drops that protect the eye an injection into eye once every 6 months that protects the eye a tablet that protects the eye an injection into the skin that protects the eye

What are the important questions? How would you feels about a treatment that involves changing another medication you are taking or changing your lifestyle? For instance, if your blood pressure treatment is making your glaucoma worse, would you be willing to reduce your medication? Blood pressure medication is taken to reduce the risk of stroke and heart attack Would you be willing to give up steak and chips or chocolate?!

What are the important questions? What else do you think is important?