Clinical Trials Making Sense of the Jargon

With so many clinical trials reported in the medical media, it can be difficult to decide which we should be interested in – or in fact whether we should be interested in any of them at all.

Clinical trials are often searching for answers to the same clinical questions that your patients might ask of you. For example; in diabetic maculopathy, how many eye injections are needed for improvement? How safe is anti-VEGF treatment? And what will happen if treatment is delayed?

…clinical studies, are often searching for answers to the same clinical questions that your patients might ask of you

TRIAGING A STUDY

To understand clinical trials and studies, we first need to appreciate what they are attempting to report. Here it can be helpful to put them into a particular category.

Common categories include:

1. A head-to-head comparison between treatments/drugs (usually focused on a key outcome i.e., achieving dryness on ocular coherence tomography (OCT) in age related macular degeneration (AMD).
2. Safety – what are the adverse effects of a new drug and how likely is your patient to suffer from this adverse effect?
3. Efficacy – outside of a head-to-head comparison, how effective is this drug or management protocol in achieving a desired outcome?

If you can triage a study into one of these categories, then you’re at a good starting point to better understand its purpose.

STUDY THEME

Understanding the ‘theme’ or premise of a study is important.

You need to ask yourself, what is this study aimed at? The giveaway is often in the title – i.e., early diagnosis or treatment. Remember the theme isn’t necessarily the subject, i.e., AMD, but rather an investigation into an aspect of the subject, i.e., does a particular anti-VEGF, which achieves a dry retina, improve vision in patients with AMD?

The theme will set the tone of the study, further reading will determine whether you can agree with the outcomes, and, if they are plausible (and most importantly), if they are relatable to your patient demographic.

Let’s discuss the clinical trials and studies that are quite commonly referenced using the following three themes and clinical questions as an example.

Theme 1. Investigating an aspect of diagnosis or treatment and how this impacts on visual outcomes,

Theme 2. The safety of a drug, and

Theme 3. The efficacy of a treatment regimen.

Theme 1. Investigating an aspect of diagnosis or treatment and how this impacts on visual outcomes. 

DRCRnet Protocol V² 

Questions asked: In patients with diabetic macular oedema (DME), when is the ideal time to start treatment in these patients? What impact will this have on their visual outcome? 

The DRCR network investigates a number of aspects of diabetes within well-executed clinical trials.

Trials labelled ‘Protocol V’ addressed whether patients, who had DME but good vision, should receive treatment with anti-VEGF injections. The randomised clinical trial employed three different management strategies:

1. Observation,
2. Laser treatment, and
3. Anti-VEGF (Aflibercept).

At the two year follow-up, there was no observable difference in visual outcomes in the patients in the three groups. The average visual acuity (VA) at two years was found to be 6/6 in 77% in the anti-VEGF (Aflibercept) treated group, 71% in the laser treated group and 66% in the observation group. This data suggested that it is generally safe to initially observe patients with DME who have good vision.

However, these conclusions need to be viewed with caution due to the following implications:

• The study did not take into account DME with >400μm central thickness on OCT, therefore it is unclear if observation alone is beneficial in these patients,
• The study did not look at the impact of the three management strategies on quality of life. This will undoubtedly affect people who have DME and are living alone or working full time and are unable to attend frequent eye review, and
• The study did not report outcomes past two years.

The ALTAIR Study³ 

Question asked: How frequently are intravitreal injections required in AMD to maintain vision? 

One of the most challenging aspects of treating patients with macular degeneration is the frequency of ongoing intravitreal injections. The ALTAIR study looked at a number of dosing regimens using aflibercept anti-VEGF injections. The study found that patients receiving this treatment, with a minimal interval of eight weeks and a maximum of 16 weeks, improved and maintained functional and anatomical outcomes over 96 weeks. This is sobering as it may allow clinicians to extend patient injection intervals, thus reducing the treatment burden.

Again, there are potential limitations to be aware of:

• The study was designed, conducted and sponsored by the pharmaceutical company Bayer, and
• All patients were treatment naive in this study; whether the results would be similar in patients who have been previously treated is unknown.

FLUID Study⁴ 

Question asked: What is the visual impact of fluid on an OCT in AMD patients? 

In recent times there has been controversy as to whether achieving a ‘dry’ macula on an OCT in a patient with AMD improves vision. The FLUID study was a two-year multicentre randomised clinical trial of eyes with AMD treated with ranibizumab. It tested whether the presence of subretinal fluid (SRF) on OCT achieved the same visual gains as absence of SRF. In summary, the study found that patients treated with ranibizumab with SRF <200μm on OCT achieved the same vision as those without SRF.

This is a landmark finding in AMD management, challenging previous conventional management strategies of treating to achieve a ‘dry’ macular on OCT.

Theme 2. Drug Safety 

Association of intravitreal anti-VEGF with risk of stroke, myocardial infarction and death in patients with AMD.⁵ 

Question asked: How safe are anti-VEGF injections? 

Adverse events related to intravitreal anti-VEGF, in particular thromboembolic phenomenon, have attracted much controversy. This population-based, retrospective cohort study focused on these potential risks. The five-year risk of stroke, myocardial infarction (MI), and death were assessed in patients compared with controls using statistical analysis. Results revealed that intravitreal anti-VEGF therapy for exudative AMD was not associated with increases in the risk of stroke, MI, or death compared with no therapy in patients with or without AMD.

Given that the patient demographic with AMD is also more prone to thromboembolic events, this study is useful in demonstrating to patients that anti-VEGF treatment does not increase their risk of these events.

Theme 3. Efficacy of a Treatment Regimen 

Hawk and Harrier⁶ 

Question asked: Are there new treatments available to manage exudative AMD? 

Brolucizumab, marketed by Novartis, is a low molecular weight anti-VEGF for the treatment of AMD.

The Hawk and Harrier trial was a double-masked, multicentre, randomised controlled trial comparing the efficacy of brolucizumab to aflibercept.

The results revealed that brolucizumab was non-inferior to aflibercept in terms of visual gains at 12-weekly intervals up to 48 weeks. However, over the last 12 months, the concerns of this new drug surround its safety profile, including vision threatening retinal necrosis and ocular inflammation.⁷ 

Geneva Study: Retinal Vein Occlusions (RVO) and the Use of Dexamethasone Implant (Ozurdex).⁸ 

Question asked: In management of retinal vein occlusions, what are the treatment options and how do they impact visual outcome?

 The use of the implantable corticosteroid, dexamethasone implant (ozurdex), offers an option for the treatment of chronic macular oedema from RVO, which is unresponsive to repetitive anti-VEGF therapy. This review of the current published data of ozurdex highlighted key factors in the use of ozurdex implants for RVO:

• To achieve visual and anatomic outcomes, the reinjection period needs to be less than six months,
• Its safety profile, in particular the risk of complications such as a rise in intraocular pressure (IOP), needs to be carefully monitored, as up to 20% of ozurdex treated patients had an elevation in IOP, and
• Cataract progression in phakic patients is expected, and hence this treatment is favoured for pseudophakic patients.

A READY REFERENCE

Our ability to understand important clinical trials and studies can serve as an invaluable tool in our clinical armamentarium.

Developing a sound practice of understanding the premise of a study, triaging by theme, and evaluating whether the outcomes are valid to one’s patient population, can be of enormous assistance. Furthermore, becoming familiar with the commonly cited retinal studies can prove to be a ready reference to answer a specific clinical question.

Dr Christolyn Rajakulenthiran is a Melbourne trained and based ophthalmologist. Her special interest areas include cataract and laser-assisted cataract surgery and use of presbyopia correcting lenses including multifocal IOLs. Her extensive clinical and research in diabetic eye disease and other retinal vascular disease results in her overseeing the surgical care of many patients presenting with cataract and co-morbid disease. Dr Rajakulenthiran practises at Sunbury Eye Surgeons and Vision Eye Institute Camberwell and Coburg. 

References 

1. Aronson JK. What is a clinical trial? Br J Clin Pharmacol. 2004 Jul; 58(1): 1–3. 
2. Cheung N, Cheung CMG, James S, Wong TY, Management of diabetic macular oedema: new insights and global implications of DRCR protocol V, Eye (2020) 34:999–1002, 
3. Ohji M, Takahashi K, Okada AA,. Kobayashi M, Matsuda Y, Terano Y. for the ALTAIR Investigators , Efficacy and Safety of Intravitreal Aflibercept Treat- and-Extend Regimens in Exudative Age-Related Macular Degeneration: 52- and 96- Week Findings from ALTAIR, Advances in Therapy volume 37, pages1173–1187(2020), 
4. Guymer RH, MBBS, PhD, Markey CM, PhD, McAllister IL, MBBS, PhD, Gillies MC, MBBS, PhD, Hunyor AP, MBBS, Arnold JJ, MBBS,on behalf of the FLUID Investigators , Tolerating Subretinal Fluid in Neovascular Age-Related Macular Degeneration Treated with Ranibizumab Using a Treat-and-Extend Regimen : FLUID Study 24-Month Results , Ophthalmology Volume 126, Number 5, May 2019. 
5. Dalvin LA, MD; Starr MR, MD; AbouChehade JE, MD; Damento GM, MD ; Garcia M, MD; Shah SM, BS; Hodge DO, MS; Meissner I, MD; Bakri SJ, MD; Iezzi R, MD, MS , Association of Intravitreal Anti–Vascular Endothelial Growth Factor Therapy With Risk of Stroke, Myocardial Infarction, and Death in Patients With Exudative Age-Related Macular Degeneration, JAMA Ophthalmology May 2019 Volume 137, Number 5 (Reprint). 
6. Pravin U. Dugel, MD, Adrian Koh, MD, FRCS, Yuichiro Ogura, MD, Glenn J. Jaffe, MD,Ursula Schmidt-Erfurth, MD, David M. Brown, MD, Andre V. Gomes, MD, PhD, James Warburton, MBBS, Andreas Weichselberger, PhD, Frank G. Holz, MD, on behalf of the HAWK and HARRIER Study Investigators , HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration, Ophthalmology 2019 Dec;126(12). 
7. Srinivas Sai A. Kondapalli, Retinal Vasculitis After Administration of Brolucizumab Resulting in Severe Loss of Visual Acuity, JAMA Ophthalmology August 2020. 
8. Garweg JG, Zandi S, Retinal vein occlusion and the use of a dexamethasone intravitreal implant (Ozurdex) in its treatment , Graefes Arch Clin Exp Ophthalmol (2016) 254:1257–1265.