Deven Tuli MS

Glaucoma Consultant, New Delhi

Glaucoma Trials (Medical)

Clinical Trials: Glaucoma

Deven TuliMS

Early Manifest Glaucoma TrialEarly Manifest Glaucoma Trial1 (EMGT) was reported in 2002 in the background of the controversy of ‘What happens to those glaucoma suspects/ early glaucoma patients that are not treated?’

The aim of the EMGT was to compare the effect of immediate medical therapy to lower intraocular pressure (IOP) versus no or delayed treatment in patients with newly diagnosed glaucoma.

Methods

Inclusion subjects: Newly diagnosed open angle glaucoma that show some early visual field loss.

Treatment was with topical beta-blocker followed by LTP (Argon laser trabeculoplasty).

Outcome was progression on Humphrey Visual Field or Optic Nerve Head changes.

EMGT Results

In the Treatment group: 58/129 (45%) Progressed vs. 78/126 (62%) in the Control group highlighting the clear benefit of treatment (Figure 1).

EMGT Follow Up data reported in 20092 showed

• Progression in 60% of Treatment Group and 76% of Observation Group.

• Rate of Progression was very low (Mean Rate on field -0.4 dB/yr) though to be noted, rate was highly variable (some progressed much more rapidly).

The Risk factors for progression noted were:

• Older age,

• IOP >21mmHg,

• Thinner CCT,

• Low ocular perfusion pressure,

• Exfoliation,

• Bilateral disease,

• Disc hemorrhages.

What we learn from the study• First study to clearly demonstrate benefits of treatment

with IOP reduction.

• High rate of progression (up to 60%) even in treatment group showing IOP lowering (by 25%) was not enough in all situations. The concept of target pressure ought to be followed in practise, where more advanced damage means lower the IOP needed to salvage the residual vision/ field.

• Patients with Exfoliative Glaucoma tend to have higher rate of progression thus warranting more aggressive treatment and follow up.

Figure 1: EMGT result

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Clinical Trials: Glaucoma

Collaborative Normal Tension Glaucoma Study (CNTGS)3

Aim

• Does IOP play a role in the pathogenesis of NTG?

• Does treatment serve any benefit?

Methods

Study Eligibility

• Have NTG (optic disc abnormalities & visual field defects characteristic of glaucoma).

• Between 20-90 years of age.

• After ten IOP readings: Average IOP below 20 mmHg, no reading above 24 mmHg.

• Three reliable visual fields within 1 month.

• 4-week wash out of any current medications.

Study Design

• Patients randomized to treatment and observation arms.

• Treatment goal was to lower IOP by 30%

• Treatment included medication and surgery (Beta-blockers and alpha agonists excluded).

Results

• Progression 35% in control arm vs 12% in treatment arm. Mean IOP was 16.0 mmHg in control vs 10.6 mmHg in treatment arm (Figure 2).

• Lowering IOP reduces the risk of progression and related vision loss in Normal-Tension Glaucoma.

Risk Factors in NTG

• Migraine and other possible vasospastic or vascular dysregulation disorders.

• Disc hemorrhage.

• Female gender.

• Racial heritage.

CNTG: What the study taught us:• IOP does have a role in disease progression in NTG

patients.

• Treat those with progressive or advanced NTG aggressively: 30-50% IOP reduction. This much reduction is definitely possible currently with Prostaglandin analogues and other drugs, and trabeculectomy with anti-fibrotics.

Ocular Hypertension Treatment Study 20024

Aim

Compare the effect of stepped treatment vs. careful observation for the onset of visual field and/or optic nerve damage in ocular hypertension (OHT).

Methods

Subjects:

• IOP = 24-32 mmHg (study eye).

• Normal ONH and Humphrey Visual Field.

Treatment

• Topical meds to goal of 18 mmHg or 20% reduction.

Monitoring

• Visual Fields every 6 months.

• Disc photos annually.

Results

• At 5 years follow up, the incidence of POAG was 9.5% in the no treatment OHT cohort vs 4.4% in the treatment group. (Nearly 50% reduction) (Figure 3).

• Baseline Predictive Factors for the Development of POAG:

• Age.

• IOP.

• Central Corneal Thickness CCT (first study to show the importance of thin cornea in glaucoma).

• Vertical C/D Ratio of optic nerve.

• Pattern Standard Deviation PSD on visual field.

• African-Americans - Higher Risk.

What the study taught us• Treatment of OHT reduces Risk of Progression and is

safe.Figure 2: CNGTS result

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Clinical Trials: Glaucoma

• Early diagnosis of glaucoma requires three (3) visual fields.

• Disc Hemorrhages increase risk of developing POAG but are often missed on clinical exam (detected best on colored fundus photos).

• Thin cornea undermeasures IOP and is an independent risk factor for glaucoma.

• OHTS did not find an association between Diabetes and Glaucoma.

OHTS Phase 2: 20105

Rationale

• OHTS Phase 1 provides proof of concept: medication reduces the incidence of POAG.

• OHTS Phase 1 does not indicate when medication should begin.

• OHTS Phase 1 does not indicate if all OHT patients should receive early medication.

Methods

• Medication Group N = 694 : Medication is continued in the Medication group.

• OHTS Phase 2, N = 672 Medication is Initiated in the Observation group (After 7.5 years of observation, participants originally randomized to observation group start medication). This creates: Delayed treatment group (treated for 5.5 years).

• Initial treatment group: Medication group treated for median of 13 years from the beginning. This allowed comparing incidence of POAG in initial treated vs delayed treated (at final 13 years follow up).

• Median Time to Develop POAG:

Observation Group 6.0 years versus Medication Group 8. 7 years (P ≤ .001).

What OHTS Phase 2 taught usDelaying Treatment of OHT

1. Increased cumulative incidence of POAG at 13 years (22% vs 16%).

2. More eyes with structural and functional damage (8% vs 5%).

3. More participants with bilateral disease (6% vs 4%).

4. Shorter time to develop POAG (6.0 vs 8.7 years).

OHTS Summary • Patients continue to develop glaucoma throughout

their life. The risk of developing POAG continued over at least a 13 year follow-up in this study.

• Most OHT patients are at low risk. Most low risk OHT patients can be followed without medication.

• Delaying treatment for 7.5 years resulted in only a small absolute increase in POAG in low risk participants.

• Starting treatment of POAG at diagnosis has no major negative effect on prognosis over 5 years but is likely beneficial over the longer 13 year time period.

• High Risk OHT patients may benefit from more frequent examinations and early treatment.

• There are safe and effective treatment options for most ocular hypertensive patients.

References1. Heijl A et al. Early member glaucoma trials Arch Ophthalmol. Oct

2002;120:1268-79.

2. Heijl A, Bengtsson B, Hyman L, Leske MC, for the EMGT Group. Natural history of open-angle glaucoma. Ophthalmology. 2009;116:2271-6. Predictors of Progression

3. Collaborative Normal Tension Study Group. Am J Ophthalmol. 1998;126:487-97.

4, Kass MA, Heuer DK, Higginbotham EJ, et al.: The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002; 120:701–713.

5. Kass MA, Gordon MO, Gao F, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JK, Miller JP, Parrish RK, Wilson MR; Ocular Hypertension Treatment Study Group. Arch Ophthalmol. 2010; 128:276-87.

Figure 3: OHTS result