Clinical Studies in Glaucoma: The What, How and Why

Landmark clinical studies, such as the Early Manifest Glaucoma Trial (EMGT) and the Ocular Hypertension Treatment Study (OHTS) established the relevance and importance of IOP management in glaucoma and there have been countless studies since.

However, some argue that clinical studies are often expensive, time consuming, and not representative of real-life data. So, are they worthwhile and should patients get involved?

Clinical studies involve human subjects, and there are two main types: interventional or observational.

Interventional studies aim to find out more about a particular intervention, or treatment. Participants are typically randomised into different treatment groups, and the outcomes of each treatment group are compared.

Observational studies aim to find out what happens to the participants in different situations. The researchers observe the participants, but don’t influence what treatments the participants receive.

All clinical studies are carefully designed and reviewed and are required to obtain ethical approval before they can take place. Most interventional trials are also registered with United States National Library of Medicine (clinicaltrials.gov) or the Australian Clinical Trials Registry (www.australianclinicaltrials.gov.au).

There are four phases of interventional trials:

• Phase I studies usually test new drugs for the first time in a small group of people to evaluate a safe dosage range and identify side effects.
• Phase II studies test treatments that have been found to be safe in phase I but now need a larger group of human subjects to further evaluate safety, and to determine efficacy (whether a treatment is effective or not).
• Phase III studies are conducted on larger populations, and often in different regions and countries, to assess the efficacy of interventions compared to another intervention or standard-of-care, and to monitor adverse events. They are often the step right before a new treatment is approved.
• Phase IV studies take place after country approval to monitor the effectiveness of the intervention and assess its safety in a wider population over a longer timeframe.

Clinical trials provide the highest quality data on the efficacy (or lack thereof ) of a treatment or procedure.

within 20 years of glaucoma diagnosis, one in three people are unilaterally blind… and one in seven are bilaterally blind, despite treatment

In the Levels of Evidence Pyramid (Figure 1), meta-analyses or systematic reviews are considered to provide the best quality evidence for medical studies. A systematic review synthesises the results from all available studies on a particular health topic, answering a specific research question by collecting and evaluating all research evidence that fits the reviewer’s selection criteria; it is filtered information as the data is collated and integrated.

Of the evidence, randomised controlled trials (RCTs), of which most interventional studies are, are ranked the highest level of the unfiltered information. Most RCTs randomly assign subjects to either an experimental group or a control group; the control group receives a placebo, sham, or standard-of care intervention, while the experimental group receives the intervention being studied. Randomising subjects is effective at removing bias, thus increasing the validity of the research. RCTs are frequently masked so that neither the subjects (single masked), nor the clinicians (double masked), nor the researchers (triple masked) know in which group the subjects are placed. This is done to further reduce potential bias.

The first published glaucoma clinical trial was listed in Pubmed in 19612 and the first registered glaucoma clinical trial on the US National Library of Medicine dates to 1978. The classic landmark glaucoma trials are familiar to most ophthalmic clinicians; studies such as the Collaborative Normal Tension Glaucoma Study (CNTGS), Collaborative Initial Glaucoma Study (CIGTS), Advanced Glaucoma Intervention Study (AGIS), as well as the aforementioned EMGT and OHTS. These trials have been fundamental in our understanding of glaucoma and guide our management to this day.

In recent years, the Tube versus Trabeculectomy Study (TVT), the Selective Laser Trabeculoplasty versus Eyedrops for First Line Treatment of Ocular Hypertension and Glaucoma Trial (LiGHT), and the Effectiveness of Early Lens Extraction for the treatment of Primary Angle Closure Glaucoma (EAGLE) are some of the clinical trials that have significantly impacted our approach to glaucoma management. Apart from clinical trials, numerous aspects of glaucoma are evaluated in clinical observational studies, including diagnostic tests, monitoring tools, and behavioural factors.

CERA STUDIES UNDERWAY

The Centre for Eye Research Australia (CERA) in Melbourne is a world-leading research institution, ranked fourth in the world among ophthalmology research institutions (source: Centre for World University Rankings). Numerous clinical studies are conducted at CERA every year on a range of eye diseases. The clinical studies currently taking place in glaucoma range from an observational study on imaging to surgical interventional studies. They are as follows:

PRODIGIES: Prediction and Detection of Glaucoma Progression Evaluation Study
Background
It has been shown that within 20 years of glaucoma diagnosis, one in three people are unilaterally blind (as defined by the World Health Organization) and one in seven are bilaterally blind, despite treatment.² A key contributor to this is the difficulty of accurately predicting the risk of glaucoma progression to enable more intensive initial treatment and surveillance of those at highest risk.³ Previous attempts to develop predictive models using current clinical data^4,5 have been described as being “unsuitable for clinical practice”.⁶ In addition, it is challenging to accurately detect whether disease progression is occurring within a short timeframe. For instance, clinically important rates of progression (between -0.5 to -1.0 dB/year in visual field mean deviation) can only be detected after between approximately 3.5 to 5.5 years of twice-yearly testing.⁷ This represents a significant missed opportunity for treatment escalation at an earlier time point to prevent irreversible vision loss.

Study Design
CERA is thus undertaking a prospective, longitudinal, observational study to examine whether novel imaging techniques can be used to transform the prediction and detection of glaucoma progression. This study is led by Assoc Prof Zhichao Wu, Principal Investigator and Head of Clinical Biomarkers Research Unit at CERA.

Participants in this study will be examined at six-monthly intervals for up to 24 months, with both standard clinical assessments and novel imaging techniques that will allow the identification of imaging biomarkers that are associated with the rate of neuroretinal tissue loss and visual function decline in eyes with glaucoma. This study will also enable an assessment of whether novel imaging techniques can be used to enable the accurate detection of glaucoma progression within a six-month period, rather than requiring nearly six years of twice-yearly visual field testing.⁷

Significance
This study has the potential to transform how we manage individuals with glaucoma through personalised risk prediction, which will allow accurate identification of those at high-risk of losing vision to target for more intensive treatments and monitoring. It could also help overcome the challenge of detecting glaucoma progression within a short timeframe, so that appropriate changes can be made to treatments to prevent further irreversible vision loss as early as possible.

Furthermore, these new imaging techniques could also help expedite the discovery of new therapies, by helping identify high-risk individuals to target for trials, and providing more effective tools to determine the effectiveness of new therapies.

Vitamin B3 in Glaucoma Study
Background

personalised risk prediction… will allow accurate identification of those at high-risk of losing vision to target for more intensive treatments and monitoring

Glaucoma is a progressive optic neuropathy that results in gradual dysfunction and death of retinal ganglion cells (RGCs) and their axons. There is evidence that RGCs sustain significant metabolic stress in glaucoma but maintain the capacity to recover function.

Current methods of glaucoma treatment all target the lowering of IOP. Yet elevated IOP is only one risk factor and many with glaucoma do not have elevated IOP (48% of newly diagnosed glaucoma subjects in EMGT).

This implant has the potential to provide a clinician-administered, long-acting ocular antihypertensive that reduces the medication burden

There is evidence that mitochondrial dysfunction is associated with open angle glaucoma susceptibility. Mitochondria are the powerhouse of our cells. Nicotinamide is known to improve mitochondrial function and may be protective against ongoing damage of RGCs in individuals with open angle glaucoma.

Study Design
This is a multicentre, placebo-controlled, double-masked randomised-controlled trial investigating whether adding high dose nicotinamide (a form of vitamin B3) can help to slow the rate of progression on visual fields as well as demonstrate an improvement in retinal function captured by the electroretinogram (ERG). Participants will remain in the trial for two years and will continue their current glaucoma treatment during the study. This international trial is led by CERA investigators Dr Flora Hui and Professor Keith Martin and is also taking place in Sweden and Singapore.

Significance
If demonstrated to be effective, this simple tablet would be the first therapy that specifically targets retinal ganglion cells.

ONL1204
Background
ONL Therapeutics has developed a new therapy based on protecting retinal cells from Fragment Apoptosis Stimulator-receptor (Fas)-mediated cell death.

In preclinical studies, this drug has been demonstrated to protect several retinal cell types and is currently being studied in three clinical indications: rhegmatogenous retinal detachment, geographic atrophy secondary to age-related macular degeneration, and open angle glaucoma. It is administered as an intravitreal injection. Similar to the Vitamin B3 study, this is a neuroprotective trial specifically targeting apoptosis and promoting survival of RGCs, independent of IOP-based pathways.

Study Design
This is a phase 1b, multicentre, single-masked, randomised, sham-controlled study primarily designed to demonstrate the safety of ONL1204 in individuals with progressive open-angle glaucoma. Eligible individuals will be randomised to receive either an intravitreal ONL1204 injection or sham injection. Participants will be part of the study for approximately 39 weeks.

Significance
This drug has the potential to specifically target RGC apoptosis and prevent cell death through an intravitreal injection.

PolyActiva
Background
Medication nonadherence is a major barrier to treatment success. In glaucoma, this issue is well described.

The reasons behind poor medication adherence can be multiple and varied. Removing the need for frequent self administration has been demonstrated to improve compliance.

Latanoprost is well established as a safe and effective ocular anti-hypertensive and is now generally the first-line medication for glaucoma treatment. A Melbourne-based company, PolyActiva, has developed a long-acting latanoprost implant that can be injected into the anterior chamber of patients with glaucoma to avoid the need for daily eye drop administration.

Study Design
This is a phase 1, multicentre, open-label, comparative study to identify a safe and efficacious dose of Latanoprost Free Acid Sustained Release Ocular Implant in adults with open angle glaucoma. Participants will remain in the study for 26 weeks, or until the implant has biodegraded and the IOP has returned to a normal clinical care range.

Significance
This implant has the potential to provide a clinician-administered, long-acting ocular antihypertensive that reduces the medication burden on patients and improves disease control.

REGISTERING FOR TRIALS

These abovementioned clinical studies are but some of many undertaken worldwide to address major clinical areas of need in the clinical management of glaucoma.

More broadly, clinical studies are a fundamental process in the advancement of medicine. Our understanding and management of glaucoma would not be where it is today without clinical studies.

Such studies cannot take place without the participation of patients, and without the partnership of community-based eye care practitioners to offer potentially eligible individuals an opportunity to contribute to such ongoing advancement. All the studies are performed under rigorous regulations and observation to ensure the safety and wellbeing of the participants.

For further information and to register your or your patients’ interest in becoming involved in any of these trials, please visit: cera.org.au/take-part-in-research/registeryour-interest/.

These abovementioned clinical studies are but some of many undertaken worldwide to address major clinical areas of need in the clinical management of glaucoma

Dr Jennifer C. Fan Gaskin MBChB MD FRANZCO is a Principal Investigator and Head of Ocular Fibrosis Research at CERA, and a Consultant Ophthalmologist at the Royal Victorian Eye and Ear Hospital (RVEEH).

Dr Fan Gaskin’s current research focus is on developing an effective and safe method of controlling postoperative scarring in glaucoma surgery to prevent glaucoma blindness. She is a Director of Australian Vision Research (formerly Ophthalmic Research Institute of Australia), and the Victorian Representative of the Australian and New Zealand Glaucoma Society. She was named a Superstar of STEM by Science and Technology Australia in 2021.

Assoc Prof Zhichao Wu BAppSc(Optom) PhD FAAO FACO is a Principal Investigator and Head of Clinical Biomarkers Research at CERA, and an Honorary Principal Fellow at the University of Melbourne. As a clinician-scientist, his research aims to establish new biomarkers by exploiting technological advances to prevent irreversible vision loss, especially from common eye conditions such as age-related macular degeneration and glaucoma.

References

1. https://openmd.com/guide/levels-of-evidence
2. Luntz M.H., Glaucoma treated with Daranide – A clinical trial. Br J Ophthalmol 1961;45:125-9.
3. Peters D., et al., Life-time risk of blindness in Open-Angle Glaucoma. Am J Ophthalmol. 2013;156(4):724-30.
4. Susanna R., et al., Why do people (still) go blind from glaucoma? Transl Vis Sci Tech. 2015;4(2):1.
5. Ernest P.J., et al. Prediction of Glaucoma Visual Field Progression Using Baseline Clinical Data. J Glaucoma. 2016;25(2):228-35.
6. De Moraes C.G., et al., A validated risk calculator to assess risk and rate of visual field progression in treated glaucoma patients. Invest Ophthalmol Vis Sci. 2012;53(6):2702-7
7. Saunders L.J., et al., The coefficient of determination: what determines a R2 statistic? Invest Ophthalmol Vis Sci. 2012;53(11):6830-2.
8. Wu Z., et al., Frequency of testing to detect visual field progression derived using a longitudinal cohort of glaucoma patients. Ophthalmology. 2017;124(6):786-92.a