clinical research in glaucoma clinical research in... · glaucoma study clinical pearls 1....

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Clinical Research in Glaucoma

J. James Thimons, O.D., FAAO

Chairman, National Glaucoma Society

www.nationalglaucomasociety.org

Ocular Hypertension Treatment Study (OHTS)Primary Goals

Evaluate the safety and efficacy of topical ocular hypotensive medication in delaying or preventing the development of POAG in individuals with elevated IOP

Identify baseline demographic andclinical factors that predict whichparticipants will develop POAG

The OHTS Exclusion Criteria

VA worse than 20/40 in either eyePrevious intraocular surgery other than uncomplicated CE with PCIOLDiabetic retinopathyOther disease capable of causing VF loss/ ON damage

Patient found eligible for OHTS• Eligible untreated IOPs on 2 visits

• 2 sets of normal & reliable HVFs per VFRC• Optic discs judged normal by ODRC

MedicationTopical treatment to lower IOP 20%

and IOP < 24 mm Hg

ObservationNo topical treatment to lower IOP

Randomization

Reproducible Abnormality3 consecutive visual fields and/or 2 consecutive sets of optic disc photographs

as determined by masked readers at ODRC or VFRC

MonitoringHumphrey 30-2 q6 months

Stereoscopic disc photos annually

POAGVisual field and/or optic disc changes attributed to

POAG by masked Endpoint Committee

Adjust therapy if target not met

Medicationn=817

Observationn=819

Native American 0.1% 0.4%

Asian 0.5% 1.2%

African American 25.0% 25.0%

Hispanic 2.9% 4.3%

Caucasian 70.6% 68.4%

Other 1.0% 0.7%

Baseline Characteristics by Randomization GroupSelf-designated Race

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Primary POAG Endpoints*Log Rank P-value <0.001, Hazard Ratio 0.40, 95% CI (0.27, 0.59)

*through 8 Nov 2001

Pro

porti

on P

OA

G

Medication Observation

Months

At 5 yrs, 4.4% of treated group and 9.5% observation group developed glaucoma

First POAG Endpoint (n=125)

Includes all subjects in medication and observation group

Treatment perhaps less protectivein African Americans

African Americans12.7% POAG endpoints in observation group

6.9% POAG endpoints in medication group

Hazard Ratio 0.54

P value for interaction 0.26

Others10.2% POAG endpoints in observation group

3.6% POAG endpoints in medication group

Hazard Ratio 0.34

Significant Baseline Factors Predicting Progression to POAG

Univariate AnalysisAgeBlack raceMale genderHeart diseaseIncreased IOPThinner CCTGreater PSDHorizontal C/D ratioVertical C/D ratio

Multivariate Analysis

AgeIOPCCTPSDVertical C/D ratio

POAG Endpoints by Central Corneal Thicknessand Baseline IOP (mmHg) in Observation Group*

Baseline IOP (mmHg)

Central Corneal Thickness (microns)

* through 8 Nov 2001

< 23.75

>23.75 to < 25.75

>25.75

< 555 >555 to < 588 >58817% 9% 2%

12% 10% 7%

36% 13% 6%

Vertical C/D Ratio

Central Corneal Thickness (microns)* through 8 Nov 2001

< 0.30

>0.30 to <0.50

>0.50

< 555 >555 to < 588 >588

15% 1% 4%

26% 16% 4%

22% 16% 8%

POAG Endpoints by Central Corneal Thicknessand Baseline Vertical C/D Ratio in Observation Group*

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PURPOSE: To determine the relationship between office IOP and peak IOP

METHODS (Study One)1:42 patients with OAGTreated with 3 different IOP lowering eye drops 24 hr IOP values obtained in sitting position with Goldmann applanation tomography at 3 hr intervals

METHODS (Study Two)2:103 patients with OAG (including 35 untreated)24 hr IOP values obtained at 2 hr intervals using a pneumatometer, in sitting and supine positions during the diurnal/wake period and in the supine position during the nocturnal/sleep period

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Peak IOP Outside Office Hours

1.Nakakura S, et al. J Glaucoma 2007; 16(2): 201‐204.2.Mosaed S, et al. Am J Ophthalmol. 2005; 139: 320‐324.

Peak IOP Outside Office Hours

• 67% of peak IOP occurs outside office hours2

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Times at which maximum and minimum IOP occurred in a 24-

hr period1:

Time of maximum IOP in 24‐hourTime of minimum IOP in 24‐hour

8

Num

ber o

f eyes

2819

10

40

30

20

10

03am‐6am

9am‐12pm

3pm‐6pm

9pm‐12am

2010 12

23

1.Nakakura S, et al. J Glaucoma 2007; 16(2): 201‐204.2.Mosaed S, et al. Am J Ophthalmol. 2005; 139: 320‐324.

Study 1 Study 2

PURPOSE: To characterize the 24 hr pattern of IOP in untreated patients

METHODS:24 untreated patients with newly diagnosed glaucomatous optic discs and/or abnormal visual fields24 hr IOP values obtained with a penumatonometer at 2 hr intervals, in the sitting and supine position during the diurnal/wake period and in the supine position during the nocturnal/sleep period

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IOP is Higher at Night

Liu JH et al. Invest Ophthalmol Vis Sci. 2003; 44: 1586‐1590.

IOP is Higher at NightHigher nocturnal supine IOP than diurnal sitting IOP (healthy and OAG)Supine IOP higher than sitting IOP, regardless of time of day

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Habitual IOP of healthy eyes

IOP

(m

m H

g)

Habitual IOP of glaucomatous eyes

3:3

0 A

M

3:3

0 P

M5:3

0 P

M7:3

0PM

9:3

0 P

M11:3

0 P

M1:3

0 A

M

5:3

0 A

M7:3

0AM

9:3

0 A

M11:3

0AM

1:3

0 P

M

252423222120191817161514

26

Clock Time

n=24

Nocturnal

Supine

Diurnal Sitting

Diurnal SittingNocturnal

Supine

Diurnal Sitting

Diurnal Sitting

Clock Time 1:3

0 P

M

IOP

(m

m

Hg

)

252423222120191817161514

263:3

0 A

M

3:3

0 P

M

5:3

0 P

M

7:3

0 P

M

9:3

0 P

M11:3

0 P

M

1:3

0 A

M

5:3

0 A

M7:3

0AM

9:3

0 A

M

11:3

0 A

M

n=24

Liu JH et al. Invest Ophthalmol Vis Sci. 2003; 44: 1586‐1590.

*Error bars = SEM

Collaborative Normal Tension Glaucoma Study

Methods One eye per each of 145 subjects with NTG was randomized either to 30% IOP reduction or to no treatment (control) Randomization criteria included documented progression of field defects, new disc hemorrhage, or field defects that threatened fixation


Treatment for IOP reduction: medication (excluding beta- blockers or alpha2 adrenal receptor agonists due to concerns of vasoactivity), ALT, or filtration surgery

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Survival analysis: time to visual field progression Findings At 5 years, treated patients showed overall survival of 80% compared with 40% in controls (P=.0018) The beneficial results of IOP reduction were found only when the impact of cataracts on visual field progression (caused mainly by filtration surgery) was removed

The Collaborative Normal-Tension Glaucoma StudyClinical Pearls

1. Therapeutic intervention (30% IOP reduction) helped prevent visual field progression. However, one must adjust for the development of cataracts, which occur commonly after filtration surgery, to detect the therapeutic benefit of IOP reduction.

The Collaborative Normal-Tension Glaucoma Study

Clinical Pearls2. 30% IOP reduction was achieved in 57%

of patients receiving medical therapy with or without argon laser trabeculoplasty (ALT), which underscores the importance of conservative therapy. Since beta-blockers, alpha2 agonists, and prostaglandin analogs were not used in the study, currently available medical agents may achieve IOP reduction in a greater percentage of patients.


3. Approximately 50% of eyes without a history of progression did not progress by 7 years when untreated. However, if progression has been documented in the past, future progression is highly likely, and IOP reduction is recommended.


4. Confirmatory visual fields are essential for verifying suspected progression. For both visual function as well as structural tests, it is important to confirm suspected progression.


5. Disc hemorrhage is a strong, negative prognostic sign; other risk factors include migraine and female gender.

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Diurnal Fluctuations in IOP: Independent Risk Factor?

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Asrani S, et al. J Glaucoma 2000; 9: 134‐142.

PURPOSE: To study the risk associated with diurnal IOP variations in patients with OAG

METHODS:• 64 patients with OAG and IOP below 25 mm Hg (over 5 year

follow‐up)• Patients successfully performed tonometry with a self‐tonometer

5 times a day for 5 days• Baseline status and time to progression of visual field loss

identified from clinical charts• Level and variability of diurnal IOP characterized and risk of

progression analyzed using a nonparametric time‐to‐event model

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1.0

5.76

Higher Quartile of Home IOP Range

Lower Quartile ofHome IOP Range

Relativ

e risk of disease

progression with

in 5 years

Hazard ratio between higher quartile and lower quartile for “Range in Home IOP” was 5.7

Diurnal Fluctuations Correlate with Visual Field Progression

Asrani S, et al. J Glaucoma 2000; 9: 134‐142.

Clock Time

Hab

itual IO

P (m

m Hg)

Sitting Supine Sitting

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Timolol: Nocturnal IOP

Liu JH, et al. Am J Ophthalmol. 2004; 138: 389-395.

N=18Error bars = SEM

Effect of Travoprost on Diurnal and Nocturnal IOP

Measured in the usual “habitual position” of the patients during those time periods

– Diurnal period –sitting

– Nocturnal period –supine

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Sit AJ, et al. Am J Ophthalmol. 2006; 141(6): 1131‐1133.

NOCTURNAL/SLEEP

DIURNAL/WAKEDIURNAL/WAKE28

262422

20

1816

14

3:30

PM

5:30

PM

7:30

PM

9:30

PM

11:30 PM

1:30

AM

3:30

AM

5:30

AM

7:30

AM

9:30

AM

11:30 AM

1:30

PM

Hab

itual IO

P (m

mHg)

Clock TimeBaseline “On Treatment”

Error bars = SEM

Early Manifest Glaucoma Trial

Compared the effect of immediately lowering the IOP vs no treatment or later treatment, on the progression of newly detected open-angle glaucoma

Heijl A. et al. Arch Ophthalmol. 2002;120:1268-1279

EMGT Participants

255 open angle glaucoma patientsAges 50-80 (median 68 years)Early glaucomaMild VF loss (median MD, –4dB)Median IOP of 20


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EMGT

Excluded from trial–Patients with IOP greater than 30

mmHg–Patients with advanced VF loss


EMGT - Interventions

Subjects randomized to either–Argon Trabeculoplasty + Betaxolol

(n=129)OR

–No initial treatment (n=126)

HVF 30-2 and IOP q 3 months for 10 yearsOptic nerve photos every 6 months


EMGT – progression criteria

Visual field progression–Computer based criteria–Defined as the same 3 or more test

point locations showing significant deterioration from baseline in the glaucoma change probability maps on 3 consecutive tests


EMGT – progression criteria

Optic disc progression–Determined by masked graders–Used flicker chronoscopy plus side-by

side photographs


EMGT- Results

Median follow-up of 6 years (range 51-103 months)Excellent retention (only 6 patients lost to follow-up for reasons other than death)On average, tx reduced IOP by 5.1mm Hg or 25%25% IOP reduction was maintained throughout follow-up

Leske MC et al. Arch Ophthalmol. 2003 Jan;121(1):48-56.

EMGT- Results

53 % of subjects progressedProgression–45 % of treated patients progressed

(58/129)–62% of untreated patients progressed

(78/126)–Statistically significant (P=.007)–This progression difference was evident

at 11 months and increased steadily over time

Leske MC et al. Arch Ophthalmol. 2003 Jan;121(1):48-56.

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EMGT- Results

In multivariate analyses, progression risk was halved by treatmentProgression risk decreased by about 10% with each mm of HG of IOP reduction from baseline to the first follow-up visitProgression risk increased by about 10 % with each mm of HG of IOP increase from baseline at first follow-up visitLeske MC et al. Arch Ophthalmol. 2003 Jan;121(1):48-56.

EMGT- Summary

Factors Increasing Risk of Progression–Higher baseline IOP–Exfoliation–Bilateral disease–Older age–Worse MD on visual field–Presence of disc hemorrhageLeske MC et al. Arch Ophthalmol. 2003 Jan;121(1):48-56.

PGAs: Effects on Circadian IOP

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PURPOSE: To compare 24 hr reduction in IOP with latanoprost, travoprost and bimatoprost in patients with OAG and ocular hypertension (OH)

DESIGN: Randomized, double‐masked, crossover studyPARTICIPANTS: 24 OAG and 20 OH patientsMETHODS: • Patients treated with randomized cross‐over sequence of

latanoprost, travoprost and bimatoprost for 1 month each, with 30 day washout in between

• 24 hr tonometric curves were recorded at baseline (prior to each treatment) and after each treatment period in seated and supine positions

• Baseline and post‐treatment IOP measured at 3:00, 6:00, 9:00 AM and noon and 3:00, 6:00, 9:00 PM and midnight

Orzalesi N, et al. Ophthalmology 2006; 113: 239‐246.

Travoprost AppearsConsistent Peak to Trough

Peak-to-trough loss:

• Bimatoprost = 38%

• Latanoprost = 26%

• Travoprost = 14%

40

60%% of p

eak IOP redu

ction

(@ 12 hr)

Time

65%70%75%

80%85%90%95%

100%

9:00am

3:00pm

9:00pm

12 hours post dose = peak IOP reduction 24 hours post dose = trough IOP reduction

TravoprostLatanoprostBimatoprost

Orzalesi N, et al. Ophthalmology 2006; 113: 239‐246.

Collaborative Initial Glaucoma Treatment Study

On ongoing study to determine if newly diagnosed open-angle glaucoma is better treated with initial medical therapy or immediate filtration surgeryDifferent study design:– Patient satisfaction and quality of life are determining

factors in deciding patient care; enrolled patients interviewed before being assigned treatment then re-interviewed every 3-6 months

– Allows referring ophthals to remain primary caretaker; routine biannual visits conducted at clinical center

CIGTS: Subjects

Eligibility criteria–25-75 years old–Newly diagnosed glaucoma as

determined by elevated IOP, glaucomatous optic disc damage and VF loss

–Must not have received any previous glaucoma treatment for longer than 14 days

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CIGTS: Subjects

607 patients enrolled at 14 centersOf the 607 patients enrolled:

90.6% had primary open angle glaucoma 4.6% pigmentary glaucoma4.8% pseudoexfoliative glaucoma

Subjects randomized to surgery or stepped medical therapy

CIGTS: Subjects

Medications: typically BB followed in order by other monotherapy, dual therapy, triple therapy, quad therapy, ALT, Trab, meds, trab+MMC, medsSurgical treatment arm: patients underwent immediate trab and, with documented failure, proceed to ALT, then conclude with medications

CIGTS: Subjects

Patients rather than eyes were randomized to the two treatment arms if both eyes were eligible (the treatment course for both eyes is the same and was determined in randomization)

CIGTS: Design

Advance through regimens if VF progression or failure to reach IOP target occursTarget defined on basis of baseline IOP and degree of field damageCriteria for failure stricter if VF worse

CIGTS: Results at 5 years

Quality of life: Surgical vs. Medical–Main outcomes were Visual Activities

Questionnaire and Symptom and Health Problem Checklist

–A significantly greater level of symptoms present in surgical patients over 5 years, especially those localized to the eye (such as feeling something in the eye)

Ophthalmology 2001; 108: 1954-65

CIGTS: Results

Quality of life: Surgical vs. Medical–The medical group reported a variety of

systemic symptoms that were not consistent over time, but were clearly different from the symptoms reported by the surgical group


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CIGTS: Results

Quality of life: Surgical vs. Medicine–The self-reported visual function of

surgical patients was marginally (5%) worse than medically treated patients over 5 years

–No difference in fear of blindness: both groups decline from 50%-25% over 5 years


CIGTS: Results

Clinical Results: Surgery vs. Medicine–Average pressure in the medically

treated group 17-18 mmHg–Pressure in the surgical group was 3

points lower (14-15)


CIGTS: Results

Clinical Results: Surgery vs. Medicine–VF loss did not differ over 5 years

between treatment groups–VA was better for medically treated

group over much of the study, but by 4 years, was no different than the surgical group

–Number progressing in both groups was low (15%)Ophthalmology 2001; 108: 1943-53

CIGTS: Results

Clinical Results: Surgery vs. Medicine–THREE TIMES THE RATE of cataract in

the surgical group

CIGTS: Results

With pressure-lowering significantly better in the surgical group, why were their outcomes not superior?–More aggressive use of better currently

available meds–Cataract rates higher in surgery group;

could mask visual field outcomes

Glaucoma & Pregnancy

BJO 2009; JD Ho: 244 pregnant women treated for glaucoma analyzed for birth weight1,952 age matched controlsNo significant difference between women on BB’s vs: no TxHerndon, L: D/C Brimonodine several weeks before d/t risk of apnea

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Advanced Glaucoma Intervention Study

AGIS

AGIS

How effective is IOP lowering in preserving VF?Is there an “ideal” IOP that provides maximum benefit in reducing or eliminating pressure-related component of damage?

AGIS

Patients enrolled 1988-1992591 patients789 eyes8 years of follow upRandomized to ALT or Trab first for COAG patients inadequately controlled with medsMain result: no difference between the two groups

AGIS

Evaluated 2 tx sequences in medically uncontrolled COAG patients

Patients randomized to either ALT or Trabeculectomy first.

AGIS

ATT or TATSupplemented with medsTarget IOP<18Mean pre-surgery IOP=25

AGIS 7 Report

Analysis of the relationship b/t IOP control and VF loss over the first 6 years of F/U.

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AGIS 7 Report

Patients with IOP<18 on 100% of follow-up exams over 6 years had mean change from baseline VF close to ZERO. (Mean IOP=12.3 over 6 years)Patients with IOP<18 on 50% of follow-up exams showed progression

Am J Ophthalmol 2000;130:429-440

AGIS 7

Does AGIS 7 apply to all patients?AGIS 7: Target IOP=12AGIS specific to COAG. May not be applicable to 2^ G or OHTAll study subjects had surgery (ALT or Trab)

AGIS 7

Average IOP at target following initial intervention had better preservation of VF.Those who did not achieve target IOP during months 6-18 did worse.

Therefore, when IOP is more resistant to surgical or medical tx, outcome is worse

AGIS

AGIS 4: Interaction b/t race and txAGIS 6: Visual function improvement post cataract surgeryAGIS 8: More cataracts post trabAGIS 9: Race-dependent differences in the course of advanced glaucoma.

AGIS

Racial difference (7 year follow-up)–African Americans ATT–White Americans TAT

Before XalatanTrabs without MMCRigid protocol is different today

A message from AGIS and CIGTS

Aggressive IOP-lowering by any means is the best way to protect against further VF loss

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Ocular Surface Disease Prevalence Study

Purpose: To Determine The Prevalence of OSD Symptoms in Glaucoma PatientsMethods:–10 Sites –630 Glaucoma Patients On IOP Lowering

Medication:Patients Completed an OSDI Survey While in The Office

Fechtner R, Budenz D, Godfrey D. Prevalence of ocular surface disease symptoms in glaucoma patients on IOP-lowering medications. Poster presented at: annual meeting of the American Glaucoma Society; March 8, 2008; Washington DC.

OCULAR SURFACE DISEASE INDEXPlease Answer The Following Questions by Checking The Box That Best Represents Your Answer

OCULAR SURFACE DISEASE INDEXPlease Answer The Following Questions by Checking The Box That Best Represents Your Answer

All of the time

Most of the time

Half of the time

Some of the time

None of the time

1 Eyes that are sensitive to light?

4 3 2 1 0

2 Eyes that feel gritty?

3 Painful or sore eyes?

4 Blurred vision?

5 Poor vision?Have problems with your eyes limited you in performing any of the following during the last week:Have problems with your eyes limited you in performing any of the following during the last week:All of

the timeMost of the time

Half of the time

Some of the time

None of the time

N/A

6 Reading?

7 Driving at night?

8 Working with a computer or bank machine (ATM)?

9 Watching TV?Have your eyes felt uncomfortable in any of the following situations during the last week:Have your eyes felt uncomfortable in any of the following situations during the last week:

All of the time

Most of the time

Half of the time

Some of the time

None of the time

N/A

10 Windy conditions?

11 Placed or areas with low humidity (very dry)?

12 Areas that are air conditioned?

Have you experienced any of the following during the last week:Have you experienced any of the following during the last week:

OSDI Severity GradingOSDI Severity Grading

Miller KL, Mink DR, Mathias SD, & Walt JG. Estimating the minimal clinical important difference of the Ocular Surface Disease Index®: Preliminary findings [Abstract]. Abstract obtained from www.isoqol.org/2006AbstractsBook.pdf.

Severe

Total OSDI Score=(Sum of Score for All Questions

Answered) X (25)(Total # of Questions Answered)

Total OSDI Score=(Sum of Score for All Questions

Answered) X (25)(Total # of Questions Answered)

Mild ModerateNormal Severe

0 10 20 30 40 50 60 70 80 90 100Score

0-12 23-3213-220 33-100

OSD Prevalence Study: Results

OSD Prevalence Study: Results

Ranking Normal

Mild Moderate

Severe

Patients 325 134 84 87

Percentage 51.6% 21.3% 13.3% 13.8%

48.4%48.4%Fechtner R, Budenz D, Godfrey D. Prevalence of ocular surface disease symptoms in glaucoma patients on IOP-lowering medications. Poster presented at: annual meeting of the American Glaucoma Society; March 8, 2008; Washington DC.

OSDI Scores in Glaucoma PatientsOSDI Scores in Glaucoma Patients

Number of Meds Taken 1 2 3

N 253 227 114Average OSDI Score

12.9 ±13.1

16.7 ±17.0

19.4 ±18.1

OSD Prevalence Study Multiple Medication ImpactOSD Prevalence Study Multiple Medication Impact

P-Values2

Medications3

Medications

1 Medicatio

n 0.007 0.0012

Medications 0.19

Fechtner R, Budenz D, Godfrey D. Prevalence of ocular surface disease symptoms in glaucoma patients on IOP-lowering medications. Poster presented at: annual meeting of the American Glaucoma Society; March 8, 2008; Washington DC.

Neuro-Protection in Glaucoma

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Are any of the following glaucoma medications neuroprotective?

Beta blockers (timolol)Alpha agonists (brimonidine)Prostaglandins (travatan)Carbonic anhydrase inhibitors (dorzolamide)

Four Criteria Required for a Medication to be Neuroprotective

1. Evidence of receptors on its target tissue2. Adequate penetration into the vitreous and retina at pharmacologic levels3. Evidence that supports a mechanism of action that enhances a neuron’s resistance to injury in animal studies4. Demonstrated neuroprotective activity in human prospective randomized clinical trials

Retinal Receptors

Brimonidine is a highly selective alpha 2 agonistAnimal and human studies show alpha 2 receptors in the retinal ganglion cell

Brimonidine penetration into the Vitreous

Brimonidine is absorbed into pigmented tissue after topical administrationVitreous concentrations with .2% brimonidine in monkey eyes was 82 +/- 45 nM Retina receptors activate with minimal concentrations of 2 nMAnimal and human studies confirm that adequate amounts of brimonidine reach the posterior vitreous to activiate ganglion cell receptors

Brimonidine Animal Studies

Investigative Ophthalmology & Visual Science, Vol 40, 65-73, 1999Alpha2-adrenoreceptor agonists are neuroprotective in a rat model of optic nerve degeneration E Yoles, LA Wheeler and M Schwartz Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel.

Brimonidine and RatsPart I

Partial crush injury to optic nervesTreated with single does of intraperitoneal brimonidine vs timololSecondary degeneration of optic nerve was measured by electrophysiologically and counting ganglion cell axonsBrimonidine treated rats had three times less loss of axons than timolol tx rats

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Brimonidine Animal Studies

(Investigative Ophthalmology and Visual Science. 2001;42:2849-2855.)Neuroprotection of Retinal Ganglion Cells by Brimonidine in Rats with Laser-Induced Chronic Ocular Hypertension Elizabeth WoldeMussie, Guadalupe Ruiz, Mercy Wijono and Larry A. Wheeler From the Department of Biological Sciences, Allergan Inc., Irvine, California.

Brimonidine and RatsPart II

IOP was elevated in rat eyes by laser photocoagulation to episcleral and limbal veinsTimolol, brimonidine or saline was injected subcutaneously after IOP elevationAfter 3 weeks of elevated IOP, GCA loss in control group was 33% loss, vs 26% and 15% loss for brimonidine (.5mg/kg and 1mg/kg) vs 33% loss for timololBelieved that brimonidine may reduce levels of intravitreal glutamate secondary to ischemia in rat models

Human Clinical TrialsPhase I: Usually designed to evaluate safety, determine a safe dosage range, and identify side effects on a small group of patients. Phase II: If Phase I is successful, the trial is then repeated with a larger group to further evaluate its effect and safety. Phase III: Trials are conducted on an ever larger group and are compared with the best current treatment while gathering more information on effect and safety. Phase IV: These studies monitor long-term side effects after the treatment has been marketed.

Human Clinical Trials of Brimonidine Neuroprotection

NAIONFazzone et al. retrospective study of 31 patients with NAION14 patients received brimonidine up to qid after initial episode of AION compared with an age match group of NAIONNo benefit was seen in the brimonidine treated group and there was a trend towards worse visual fields, color vision and visual acuity

BRAION Study

Wilhelm, et al. BRAION studyDouble blind randomized clinical trial comparing brimonidine and placebo for patients with acute AIONNo statistically significant benefit found

Other Human Clinical TrialsNo statistically sig benefit with brimonidine found in fellow eye of patients with Lebers hereditary optic neuropathy. Newman et al,No statistically sig benefit with brimonidine

found in patients with retinal dystrophies Merin et al.Slight benefit found in reducing collateral damage caused by laser photocoagulation in pt with choroidal neovascularization Ferencz et al

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