Why Ginkgo Biloba in Normal Tension Glaucoma Failed to Replicate?

Summary

A prospective, randomized, placebo-controlled crossover clinical trial published in Investigative Ophthalmology & Visual Science evaluated whether Ginkgo biloba extract (GBE) could improve existing visual field damage or contrast sensitivity in newly diagnosed Chinese patients with normal-tension glaucoma (NTG). Thirty-five patients were randomized to receive either GBE followed by placebo or placebo followed by GBE, with each treatment phase lasting four weeks and separated by an eight-week washout period.

Twenty-eight patients completed the study and were included in the final analysis. The investigators found no statistically significant effect of GBE on visual field mean deviation (MD) or contrast sensitivity. GBE also produced no significant change in intraocular pressure, blood pressure, or heart rate. The study therefore did not confirm the visual benefit reported by an earlier randomized trial in Italian patients.

The authors concluded that, in this group of newly diagnosed Chinese NTG patients, four weeks of GBE treatment did not improve visual field function or contrast sensitivity. They emphasized that the evidence surrounding GBE remains contradictory and that larger, longer clinical trials are needed.

Key Takeaways

·       This was a prospective, randomized, placebo-controlled crossover clinical trial in Chinese patients with normal-tension glaucoma.

·       Thirty-five patients were randomized; 28 patients (80%) completed the study.

·       Patients received Ginkgo biloba extract at 40 mg three times daily, for a total of 120 mg/day.

·       Each treatment period lasted four weeks and was separated by an eight-week washout period.

·       The primary outcomes were change in visual field mean deviation (MD) and contrast sensitivity.

·       GBE did not significantly improve visual field MD compared with placebo (treatment difference −0.10 dB; 95% CI −0.72 to 0.51; P = 0.730).

·       GBE did not significantly change contrast sensitivity at any of the five spatial frequencies tested.

·       IOP did not change significantly with GBE: mean 15.1 mm Hg before treatment versus 14.8 mm Hg after treatment (P = 0.657).

·       Blood pressure and heart rate also did not change significantly.

·       No adverse events were reported during the GBE treatment phase; two participants reported adverse events during placebo treatment and withdrew.

·       The study had 80% power to detect an MD effect as large as the benefit previously reported by Quaranta et al.

·       The authors identified the relatively small sample and four-week treatment period as important limitations.

Why Is This Study Important?

Normal-tension glaucoma is a form of glaucoma in which measured IOP remains within the statistically normal range, yet the optic nerve and visual field can still sustain progressive damage. Because lowering IOP does not fully explain all NTG progression, investigators have explored therapies that might improve ocular blood flow or provide neuroprotective effects.

Ginkgo biloba extract has attracted interest because experimental and clinical studies have suggested possible effects on ocular blood flow, oxidative stress, platelet-activating factor, and neuronal survival. Earlier studies had produced encouraging but inconsistent findings. In particular, a randomized crossover study by Quaranta and colleagues reported significant improvement in visual field MD after one month of oral GBE, while Lee et al. later reported slower visual field progression in a retrospective long-term study.

The 2014 Guo study was important because it provided a randomized clinical trial in China specifically designed to test whether GBE could improve preexisting visual field defects and contrast sensitivity in NTG. It therefore provided a higher-quality test of the hypothesis than several earlier uncontrolled or retrospective studies.

What Is Ginkgo Biloba Extract?

Ginkgo biloba extract is derived from Ginkgo biloba leaves and has been investigated for circulatory, antioxidant, and potential neuroprotective effects. The study used GBE tablets containing 40 mg per dose, administered three times daily.

The rationale for studying GBE in NTG included reports that it may increase ocular blood flow and possible neuroprotective effects on retinal ganglion cells. These mechanisms were hypotheses motivating the trial; this study did not directly measure ocular blood flow or demonstrate a neuroprotective mechanism.

Study Design

Type of Study

·       Prospective clinical trial

·       Randomized

·       Placebo-controlled

·       Crossover design

·       Double-masked treatment assignment

·       Two four-week treatment periods separated by an eight-week washout

Who Participated?

From June 2010 through December 2011, investigators identified 50 consecutive patients with newly diagnosed NTG. Ten were referred from a tertiary glaucoma clinic at the Zhongshan Ophthalmic Center and 40 came from a routine general physical-examination cohort in Lingtou, southern China.

Patients were eligible if they were at least 30 years old, had visual field damage consistent with glaucoma, corresponding optic nerve changes, maximum IOP of 20 mm Hg in both eyes during daytime measurements, open angles, and no systemic neurologic or ocular condition that could explain the visual field defect.

Patients were excluded if they had previously used GBE, had central corneal thickness below 500 μm, best-corrected visual acuity worse than 6/60, a history of IOP above 21 mm Hg, unreliable visual field testing, or inability to provide informed consent.

·       50 potential patients identified

·       3 excluded because they were already taking GBE

·       12 declined participation

·       35 patients randomized

·       28 patients completed the study and were included in the final analysis

·       Mean age of analyzed participants: 63.7 ± 6.5 years

Randomization and Treatment

After diagnosis, each patient was assigned a target IOP representing a 30% reduction from baseline and was started on conventional topical IOP-lowering treatment as directed by a glaucoma specialist.

Participants were then randomized to one of two sequences:

·       Group A: GBE for four weeks → eight-week washout → placebo for four weeks.

·       Group B: placebo for four weeks → eight-week washout → GBE for four weeks.

The GBE preparation was Ginaton (Dr. Willmar Schwabe GmbH & Co. KG), 40 mg per capsule, taken three times daily. The placebo capsules were identical in appearance and contained fructose and starch. Patients and investigators were masked to treatment assignment.

How Did Researchers Measure the Outcomes?

Visual Field Testing

Visual fields were measured using the Humphrey Visual Field Analyzer II with the 24-2 Swedish Interactive Testing Algorithm (SITA) Standard program. Because the participants were newly diagnosed and visual field performance can improve with experience, the investigators obtained three reliable visual field tests at baseline and at least two tests at each subsequent visit.

The primary visual field outcome was mean deviation (MD), a summary measure of the degree to which the patient's visual field differs from an age-matched normal reference. More negative MD values generally indicate greater visual field loss.

Contrast Sensitivity

Contrast sensitivity was assessed using the Functional Acuity Contrast Test (FACT) chart at five spatial frequencies: 1.5, 3, 6, 12, and 18 cycles per degree. Testing was performed before and after each treatment phase under standardized office illumination.

Contrast sensitivity is clinically relevant because glaucoma can impair the ability to detect low-contrast objects even when standard visual acuity remains relatively good.

Other Measurements

·       IOP was measured by Goldmann applanation tonometry every two hours from 8 AM to 4 PM.

·       Systolic and diastolic blood pressure were measured at each study visit.

·       Heart rate was recorded.

·       Visual acuity and refraction were assessed.

·       Central corneal thickness was measured at baseline.

·       Ocular examinations and patient-reported adverse events were recorded at each visit.

Results

Visual Field Mean Deviation

The primary visual field outcome did not improve significantly with GBE. When the two treatment periods were pooled, the mean change in MD before versus after GBE was 0.11 dB (95% CI −0.79 to 0.60; P = 0.777), compared with 0.21 dB for placebo (95% CI −0.59 to 0.19; P = 0.297).

The difference between GBE and placebo was −0.10 dB (95% CI −0.72 to 0.51; P = 0.730). In other words, the observed difference was small and not statistically significant.

Contrast Sensitivity

GBE also failed to produce a significant improvement in contrast sensitivity. The study evaluated five spatial frequencies: 1.5, 3, 6, 12, and 18 cycles per degree. No significant difference in change over time was found at any frequency, whether the treatment periods were examined separately or pooled.

This was the first study, according to the authors, to specifically evaluate the effect of GBE on contrast sensitivity in glaucoma patients.

IOP, Blood Pressure, and Heart Rate

GBE did not significantly affect IOP. Mean IOP was 15.1 ± 2.6 mm Hg before GBE and 14.8 ± 3.3 mm Hg after treatment, a mean difference of 0.28 mm Hg (P = 0.657).

Similarly, there were no significant changes in systolic blood pressure, diastolic blood pressure, or heart rate. This suggests that the absence of a visual benefit could not be explained by a meaningful treatment-related change in these measured systemic or pressure variables.

H3 Adverse Events

No adverse events were reported during the GBE treatment periods. Two participants reported medication-associated events during the placebo phase and withdrew: one experienced gastric discomfort and another developed urticaria. These events occurred during placebo rather than GBE treatment.

What Do the Results Mean?

The main message of the 2014 Guo study is that GBE did not produce a measurable short-term improvement in either standard visual field function or contrast sensitivity in this group of newly diagnosed Chinese NTG patients.

This finding is particularly relevant because the study was randomized and placebo-controlled, making it less vulnerable to some forms of selection bias and placebo effects than earlier retrospective studies. The investigators also had enough statistical power to detect an MD effect as large as the one previously reported by Quaranta and colleagues.

The result does not prove that GBE has no effect on glaucoma under all circumstances. The study tested a specific dose, population, and four-week treatment period. A smaller effect, a delayed effect, or an effect in patients with more advanced disease could potentially have been missed.

Study Strengths

·       Randomized treatment assignment reduced the likelihood that baseline differences explained the treatment result.

·       Placebo-controlled crossover design allowed each treatment sequence to be compared within the study population.

·       Patients and investigators were masked to treatment.

·       The study specifically assessed clinically meaningful functional outcomes: visual field MD and contrast sensitivity.

·       The investigators used repeated visual field testing to reduce the impact of learning effects in newly diagnosed glaucoma.

·       The study had 80% power to detect an MD effect as large as that previously reported by Quaranta et al.

·       A sensitivity analysis suggested that even substantial deterioration among participants who dropped out would not have changed the overall negative conclusion.

Study Limitations

Small Sample Size

Only 35 patients were randomized and 28 completed the study. Although the trial was powered to detect a relatively large effect, it may not have been able to detect a smaller clinically meaningful benefit.

Short Treatment Period

Each GBE exposure lasted only four weeks. The authors acknowledged that four weeks might not be long enough for a therapeutic effect to become apparent, although the earlier Quaranta trial reported a benefit within the same period.

Newly Diagnosed Patients

The participants were newly diagnosed with NTG and had relatively modest baseline visual field damage compared with some earlier studies. Results may therefore not apply to patients with more advanced or long-standing glaucoma.

Crossover Design Considerations

Crossover trials require appropriate handling of possible carryover effects. The investigators found no statistically significant carryover effect, but they acknowledged methodological concerns raised in the literature about the statistical approach used to test for crossover effects.

The Bottom Line

The 2014 Guo randomized clinical trial found no evidence that four weeks of Ginkgo biloba extract improved visual field mean deviation or contrast sensitivity in newly diagnosed Chinese patients with normal-tension glaucoma. GBE also did not significantly change IOP, blood pressure, or heart rate.

This study is an important counterpoint to earlier reports suggesting that Ginkgo biloba could improve visual function or slow glaucoma progression. Its randomized, placebo-controlled design makes the negative result particularly informative, although the small sample and short treatment period leave open the possibility of smaller or longer-term effects.

For patients with NTG, the study does not support using Ginkgo biloba as a proven treatment for improving visual field function. It also does not demonstrate that GBE prevents glaucoma progression. Larger and longer randomized trials would be needed to determine whether GBE has any clinically meaningful role as an adjunctive therapy.

Study Reference

Guo X, Kong X, Huang R, Jin L, Ding X, He M, Liu X, Patel MC, Congdon NG. Effect of Ginkgo Biloba on Visual Field and Contrast Sensitivity in Chinese Patients With Normal Tension Glaucoma: A Randomized, Crossover Clinical Trial. Investigative Ophthalmology & Visual Science. 2014;55:110–116. doi:10.1167/iovs.13-13168.