Transcript protecting_the_cells_in_the_eyex

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
– 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
Black subjects (n=4674)
15
White subjects (n=5770)
10
5
Sommer et al (1991)
0
0
10
14
18 22
26
IOP (mmHg)
30
34
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?
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?
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
UKGTS
ANSWERS
(mean 10 fastest
locations)
MD
Placebo
-3.92 (3.10)
0.03 (-2.09, 1.72)
Treatment
-3.01 (2.59)
0.57 (-1.59, 2.16)
0.03%
17%
Placebo
-3.12 (2.59)
-0.22 (-1.04, 0.71)
Treatment
-2.47 (2.25)
0.05 (-0.77, 0.95)
<0.01%
2%
Placebo
-2.48 (2.26)
-0.18 (-0.93, 0.38)
Treatment
-1.93 (1.87)
0.18 (-0.43, 0.75)
<0.01%
0.1%
Placebo
-2.18 (2.13)
-0.17 (-0.60, 0.24)
Treatment
-1.69 (1.76)
0.17 (-0.29, 0.50)
<0.01%
0.5%
N = 437
6 months
p
12 months
p
18 months
p
24 months
p
Sample size calculations
ANSWERS
PLR
Rate
reduction
Slope
(UKGTS
latanoprost
arm):
mean (sd)
Target
slope with
neuroprotective
treatment
Sample size
(per arm)
Slope
(UKGTS
latanoprost
arm):
mean (sd)
Target
slope with
neuroprotective
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%
-2.47 (2.25)
-1.98 (2.25)
444
-6.58 (6.37)
-5.27 (6.37)
497
30%
-2.47 (2.25)
-1.73 (2.25)
195
-6.58 (6.37)
-4.61 (6.37)
220
Assumptions:
Patients in reference group on latanoprost
Observation period 12 months
Power 90%
P 5%
Pilot study
ANSWERS
Slope (UKGTS
latanoprost
arm):
mean (sd)
Target slope
with neuroprotective
treatment
10%
-2.47 (2.25)
-2.22
20%
-2.47 (2.25)
-1.98
30%
-2.47 (2.25)
-1.73
Improvement
Assumptions:
Patients in reference group on latanoprost
Observation period 12 months
Power 80%
P 10%
Sample size
(per arm)
115
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?