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

2. 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

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

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

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

8. 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

9. 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)

10. 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

11. Ocular pulse pressure

12. 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

14. 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?

16. 16

17. 17

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

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

23. 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?

25. 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?

26. 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

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

28. Data acquisition

29. Data analysis

30. (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%

31. 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%

32. 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%

33. 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

34. 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?

35. 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?

36. 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?

37. 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

38. 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

39. 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?!

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