Download Clinical Trials in Glaucoma

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Clinical Trials in Glaucoma
Chair: John G. Flanagan
Presenters: Anders Heijl, Paul Palmberg, Murray Fingeret
Abstract: This course presents an overview of recent clinical trials in glaucoma, and
their influence on current evidence based standards of practice for the diagnosis and
management of the glaucomas. Particular attention is given to the Early Manifest
Glaucoma Trial, OHTS (and OHTsII), CIGTS, and the European Glaucoma Prevention
Study.
Learning Objectives:
1. To review recent clinical trials in glaucoma.
2. To present the influence of recent clinical trials on evidence based standards of
practice for the diagnosis of glaucoma
3. To present the influence of recent clinical trials on evidence based standards of
practice for the management of glaucoma
Principles of glaucoma management influenced by:
- Clinical experience
- Randomized clinical trial
- Basic science research
- Cross-sectional studies
- Longitudinal studies
Well-designed clinical trial
- Adequate sample size
- Detect difference between groups
- Defined eligibility criterion
- Random assignment
- Masked, valid measurements
- Data collection
- Independent data and safety monitoring committee
Glaucoma Clinical Trials Completed
1. Scottish glaucoma trial-1988
2. Early Trabeculectomy Vs. Conventional Management
3. The Moorfields Primary Treatment Trial- 1986
4. Early Trabeculectomy Vs. Conventional Management
5. Glaucoma Laser Trial (GLT)
6. Glaucoma Laser Trial Follow-up Study (GLTFS)
7. Fluorouracil Filtering Surgery Study (FFSS)
8. Advanced Glaucoma Intervention Study (AGIS)
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a. ALT Vs. Trabeculectomy in uncontrolled eyes on maximally tolerated
medical therapy (MTMT)
9. Normal Tension Glaucoma Study (NTGS)
10. Ocular Hypertension Treatment Study (OHTS)
11. Early Manifest Glaucoma Trial (EMGT)
Glaucoma Clinical Trials Currently in Follow-Up Stages
1. Ocular Hypertension Treatment Study II (OHTS II)
2. Collaborative Initial Glaucoma Treatment Study (CIGTS)
3. European Glaucoma Prevention Study (EGPS)
Early Manifest Glaucoma Trial (EMGT)
 Efficacy of therapy in open angle glaucoma
- Little literature on effect of therapy in POAG
 Subjects w documented glaucomatous damage enrolled
 NEI funded study being performed in Sweden using US resources
 Eligibility
- POAG, NTG, Exfoliative Glaucoma
- IOP up to 35 mm Hg
- Optic nerve and/or VF changes
 2 treatment groups with 25% IOP reduction
- Observation
- Betoptic S w ALT
- No Specific IOP lowering
 Enrollment started 10/92
- Still in enrollment phase
- 255 individuals 126 control group vs. 129 in treatment group
 Examinations q. 3 months
- Follow optic nerve stereo photos
- Follow 30-2 VF
• read by independent reading centers
 Follow-up for at least 6 years
Anticipated Impact on Glaucoma Management
 Challenge to concept of reducing IOP to treat OAG
 Impact of study depends on results
- IOP reduction helps- confirms obvious
- No difference between groups
• study becomes controversial
• require additional studies to confirm results
• require us to reassess long-standing beliefs
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Results after 6 years of follow-up:
1. 45% treatment group vs. 62% control group progressed
2. Change occurred later in treatment group
3. For every 1 mm Hg reduction, risk reduces 10%
The Ocular Hypertension Treatment Study (OHTS)
 Is medical therapy of ocular hypertension beneficial?
- Lack of evidence in current literature
 Eligible
- IOP b/w 24-32 in one eye w at least 21 mm Hg in other eye
 Multicenter trial
 2 treatment groups
- Observation
- Medical regimen- stepped therapy
• reduce IOP at least 20%
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Enroll 1500 individuals
- At least 25% African American with enrollment from 3/94-6/96
Follow for 5+ years- until November 2001
Monitor Visual Field w 30-2 q. 6 months
Monitor Optic nerve w stereo photos q. year
VF and Optic nerve read by independent reading centers
Side studies
- Heidelberg tomograph of optic nerve, short wavelength automated perimetry,
pachymetry
Anticipated Impact on Glaucoma Management
 Importance of IOP as risk factor for glaucoma
- IOP as pathogenesis of glaucoma
 Importance of other risk factors
- Family history, race, others
Results OHTS
1. 4.4% in Tx group vs. 9.5% in control group developed POAG
2. Factors that predict onset of POAG
 thin corneas
 older age
 IOP
 larger horizontal and vertical C/D ratio
 male
 African Americans
Collaborative Initial Glaucoma Treatment Study (CIGTS)
 Compare efficacy in new POAG w initial treatment of Filter Surgery Vs. Medications
- Hypotheses of study
• Surgery yields lower IOP
• More consistent reduction of IOP
• Avoids adverse consequences of long-term meds
• Improve quality of life
 Multicenter, controlled randomized trial with 2 treatment grouops
- Stepped topical medical therapy
- Immediate filtration surgery
• ALT available for both treatment arms
 Enrollment began October 1993 with aim of 600 subjects
 Study Outcomes
- Visual Function
• 24-2 Visual Field and Visual Acuity
- Quality of life telephone survey
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Examinations q.3 mos, 6 mos. and every 6 months thereafter
Anticipated Impact on Glaucoma Management
 Is Surgery a better treatment option for POAG?
 Comparison of quality of life between 2 groups
European Glaucoma Prevention Study (EGPS)
 Objective
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Evaluate efficacy of reducing IOP w dorzolamide tid versus placebo tid to
prevent or delay patients with ocular hypertension from developing POAG
Randomized, double-blinded, controlled clinical trial in 18 European Centers
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Patients age 30 yrs and older
IOP b/w 22-29 mm Hg
Two normal reliable visual fields
Normal optic discs
To be followed for five years, every 6 months
1077 subjects randomized b/w January 1, 1997 and May 31, 1999.
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Mean age 57.03 yrs
54.41% Female
99.9% Caucasian
Mean IOP 23.6 mmHg +/- 1.6
Outcomes- visual field or optic nerve change as noted by masked reading centers
Results sometime in 2004-2005
The Advanced Glaucoma Intervention Study (AGIS)
 Long-term study of clinical course and prognosis of OAG after MTMT failed
 All eyes had elevated IOP on MTMT and glaucomatous damage
 2 treatment groups
- ALT > trabeculectomy > trab (ATT group)
- Trabeculectomy > ALT > trab (TAT group)
 4/88 - 11/92 patients recruited
 789 eyes of 591 subjects
 1/3rd of patients enrolled both eyes
- each eye got different treatment regimen
 During study protocol changed to allow 5-FU or MMC for high risk eyes
 Drainage implants also used after 2 trab failures
 AGIS exam sequence
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6 weeks, 3 months, 6 months and every 6 months thereafter
Study funded until 1997
- follow-up between 4-9 years
Results
1. Blacks respond better to one course of therapy as opposed to whites
ATT vs TAT
2. Results of AGIS 7 show need for lower controlled IOP
3. Group with IOP always below 18 mmHg showed no change over 7-year followup
Anticipated Impact on Glaucoma Management
 Glaucoma management strategies have changed since start of study- 1988
- Types of surgeries, antifibrotic agents
 Long-term course of advanced OAG
- Especially eyes post surgery
 Influence of ALT on Filter Success?
 Influence of prior medications on Filter Success?
 Patient prognostic factors surgical outcomes?
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Normal Tension Glaucoma Study (NTGS)
 Objectives
- How often NTG is progressive?
- Whether reducing IOP by 30% from baseline (w either meds or surgery) preserve
visual function
- How frequently treatment is protective against further damage
 2 treatment groups
- Treatment or No treatment
 202 patients randomized into study
 Only one eye enrolled
- Less involved eye
- None study eye- no oral agents or vasoactive agents
 Whether IOP is a causative factor for NTG
 Incidence and severity of side effects of treatment
 Benefit of medications vs. surgery for NTG
 Attempt to predict which patients will benefit from therapy
Results
1. Treatment reduces failure rate, even when IOP already low
2. Many eyes with therapy failed, though more slowly over time
Anticipated Impact on Glaucoma Management
 Predict which eyes will benefit from therapy
 Demonstrate that some eyes progress despite therapy
 Investigate other etiologies in NTG
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