**5. Clinical Studies in DME**

The evidence for much of the guidelines on DME management has been gathered from clinical trials that have provided information on the safety and efficacy of different therapeutic options, investigated the systemic associations in patients diagnosed with DME, and considered newer and better therapies. This section will provide an overview of DME trials and emphasize the most important findings. Emphasis will be placed on those pharmacotherapies in current use (especially intravitreal injectable drugs).

As mentioned earlier, VEGF plays a central role in the pathogenesis of DME by increasing vascular permeability and blood flow in the setting of microvascular damage secondary to prolonged hyperglycemia. Therefore, intravitreal anti-VEGF has become the standard of care in the treatment of several forms of DME. In many cases, DME can be reversed, and this is associated with sustained improvements in vision. Several RCT have provided data and evidence for the use of intravitreal anti-VEGFs.

Ranibizumab (Lucentis, Genentech, South San Francisco, CA, USA) has been described earlier. It has a molecular weight of approximately 48 kilodaltons as it lacks an Fc region, unlike Bevacizumab. It is prepared in *Escherichia coli* with tetracycline in the nutrient medium. Due to its relatively small size, Ranibizumab penetrates the deeper layers of the retina, including the RPE and choroid.

Ranibizumab was the first anti-VEGF approved by the US Food and Drug Administration (FDA) for the treatment of DME and DR at a dose of 0.3 mg monthly. Also, the 0.5 mg dose has been used for treating DME. The 0.3 mg is as effective as the 0.5 mg. Also, the higher dose was found to confer no additional benefit compared to the 0.3 mg but was associated with more fatalities at three years (i.e., 6.4% compared to 4.4% with 0.3 mg monthly). Furthermore, at three years reported stroke rate was 4.8% and 2%; and adverse thromboembolic events (ATE) were 10.4% and 10.8% with monthly 0.5 mg and 0.3 mg Ranibizumab, respectively. Because of these systemic risks, the FDA approved the 0.3 mg dose of Ranibizumab instead of the 0.5 mg dose. However, a reduced dose is not available for other available anti-VEGF, i.e., Bevacizumab or Aflibercept. It is, however, essential to consider that the occurrence of these systemic adverse events is not uncommon after prolonged diabetes.

RISE and RIDE: These were two landmark trials. RISE was A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus. RIDE was A Study of Ranibizumab Injection in Subjects Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus [137]. These studies compared *Current Management of Diabetic Macular Edema DOI: http://dx.doi.org/10.5772/intechopen.100157*

two doses of Ranibizumab with sham injections and confirmed the superiority of intravitreal Ranibizumab compared to sham injections. The study investigated using monthly Ranibizumab at two doses (0.5 and 0.3 mg) to treat DME. At month 24, the study results showed that 98% of patients-maintained vision with 0.3 mg monthly intravitreal injections, 34–45% of patients gained at least three lines (15 letters); and mean BCVA gain was 10.9 to 12.5 letters. Significantly higher numbers in the Ranibizumab arm gained >15 letters at month 24 compared to sham ie 44.8% vs. 18.1% in RISE; P < 0.0001, and 33.6% vs. 12.3%; P < 0.0001 in RIDE. Only 45–49% of patients needed macular laser compared with 91–94% in the control group. Also, there was no additional effect with the use of the higher strength 0.5 mg Ranibizumab when compared with the 0.3 mg dose.

In the RISE and RIDE extension phase, patients in the sham control group could cross over and receive monthly Ranibizumab injections in the 3rd year. The 36-month outcomes demonstrated that the rapid and sustained response of Ranibizumab in DME is further maintained for an additional 3rd year of continued monthly treatment. In addition, the group with delayed initiation of Ranibizumab therapy gained fewer letters compared to groups initially randomized to receive Ranibizumab (+4.7 vs. +10.6 letters in the 0.3 mg Ranibizumab arm). This finding suggests that chronic retinal edema (for an average of 4.5 years before Ranibizumab therapy) may result in irreversible loss of vision, and therefore prudent to initiate Ranibizumab therapy earlier. The RISE and RIDE study has become a vital landmark study against which other studies investigating more recent intravitreal pharmacotherapies have been compared.

RESOLVE: Safety and Efficacy of Ranibizumab in Diabetic Macular Edema With Center Involvement. This trial compared Ranibizumab versus sham in DME patients with BCVA of 20/40–20/160. It showed a better mean gain in letters with Ranibizumab than sham (10.3 letters gain versus a loss of 1.4 letters respectively). The patients were given three monthly injections, followed by PRN injections over a 12-month followup. A rescue laser could be performed if needed. CMT reduction was also more with Ranibizumab compared to sham. This study also suggested that Ranibizumab treatment was superior to laser (7.8 ETDRS letters gained versus −1.7 ETDRS letters lost).

READ-2: Ranibizumab for Edema of the mAcula in Diabetes-2). This study was A phase II, RCT to compare Ranibizumab alone (group 1), the focal laser alone (group 2), and combination of laser and Ranibizumab (group 3), i.e., randomized patients 1:1:1 to receive 0.5 mg Ranibizumab, laser, or both. Inclusion criteria were BCVA of 20/40–20/320 and CSMT of 250microns. The study demonstrated a BCVA gain of 7.4 letters in the RBZ arm at three months compared to 0.5 letters in the laser arm.

Change in mean BCVA in ETDRS letters at six months for the three groups was +7.24, −0.43, and + 3.8, respectively. However, at 24 months, it was demonstrated that Ranibizumab alone or in combination was superior to laser alone in DME.

READ-3 study (compared regular versus high dose RBZ) was a double-masked, multicenter RCT that evaluated two doses of RBZ (0.5 mg versus 2 mg). The study outcome showed that 2 mg RBZ (high dose) did not show any additional benefits over 0.5 mg dose at the primary endpoint at month 6 (+7.01 in the 2 mg group vs. +9.43 letters in the 0.5 mg group; P = 0.161).

RESTORE: A Twelve-Month Study to Assess the Efficacy and Safety of Ranibizumab (Intravitreal Injections) in Patients with Visual Impairment Due to Diabetic Macular Edema and a 24 month open-label extension study. It was a phase 3 RCT that was designed to compare RBZ with laser therapy. At 12 months, BCVA gain was highest in the RBZ monotherapy arm at the primary endpoint (+6.1 vs. +0.8 letters in the laser arm; P < 0.001).

REVEAL: A phase 3 RCT comparing Ranibizumab with laser. At the 12-month study endpoint, RBZ monotherapy was superior to laser since there was a gain of +5.9 letters in the Ranibizumab monotherapy arm vs. +1.4 letters in the laser arm;

P < 0.001. In addition, RESTORE and REVEAL studies showed that combining Ranibizumab with laser did not improve the BCVA.

LUCIDATE: Lucentis (Ranibizumab) in Diabetic Macular Oedema: Compared macular laser with Ranibizumab or combination in DME. This study further showed that in addition to improvements in BCVA and CMT, treatment of patients with center involving DME with monthly Ranibizumab was associated with an improvement in contrast threshold, retinal sensitivity on microperimetry amplitudes, and implicit times on electrophysiology.

With the use of several studies, the DRCR network answered questions relating to the effectiveness and timing of intravitreal pharmacotherapy use, combination therapy, and retinal laser photocoagulation to treat DR and DME. An example of such a study is Protocol T.

PROTOCOL-T of DRCR.net: Compared Ranibizumab, Bevacizumab and Aflibercept in DME. While the FDA had approved Ranibizumab and Aflibercept, the use of Bevacizumab was off-label. The study results revealed improvement in vision from baseline to one year with all three drugs. Improvement was most significant with Aflibercept (+13 letters) than Ranibizumab (+11 letters) or Bevacizumab (+10 letters), a statistically significant mean difference of 2–3 letters at one year. This difference appeared to be driven by baseline vision. Half of the



#### *Current Management of Diabetic Macular Edema DOI: http://dx.doi.org/10.5772/intechopen.100157*


*AFL: Aflibercept, BEVA: Bevacizumab, DEXA: Dexamethasone, FA: Flucinolone Acetonide, RBZ: Ranibizumab, PRN: Pro re nata, T&E: Treat and Extend, RCT: Randomized Controlled Trial.*

#### **Table 1.**

*Summary of Anti-VEGF and Steroid for DME studies.*

study participants had BCVA of 20/40 or 20/32. The mean letter score improvement in these patients was +8.3 with Ranibizumab, +8.0 with Aflibercept, and + 7.5 with Bevacizumab (each pairwise comparison p > 0.5).

However, when initial visual acuity was 20/50 or worse, the mean letter improvement was +18.9 with Aflibercept, +14.2 with Ranibizumab and + 11.8 with Bevacizumab (p values: Aflibercept-Bevacizumab <0.001, Aflibercept-Ranibizumab = 0.003, Ranibizumab-Bevacizumab = 0.21) (**Table 1**).

## **6. Variation between clinical trials and real-world outcome using intravitreal injection of pharmacotherapy**

There has been a universal observation of divergence between the outcomes obtained from the use of intravitreal anti-VEGF in the real world and outcomes reported in randomized clinical trials. The visual outcomes and gains in vision observed have been much poorer. This finding has led to investigations into the reason for this difference. Some possible explanations for this observation include that participants are pre-selected using strict selection criteria and are well ahead motivated to complete the treatment schedule in clinical trials. This is not the case in real life, in which the patients have to grapple with significant challenges ranging from financial to demands on time and often have to deal with other comorbidities. These challenges could be of considerable impact on patients from low socio-economic backgrounds. It has also been shown that undertreatment is a common feature in real-world experience and that most patients do not receive the *Current Management of Diabetic Macular Edema DOI: http://dx.doi.org/10.5772/intechopen.100157*

recommended number of intravitreal anti-VEGF. This real-life experience results in a mismatch between real-world visual outcomes and those of major clinical trials. The frequent clinic visits and treatment burden contributes to this discrepancy. To resolve this challenge, a host of pharmaceuticals with extended durability are at different stages of development. Hopefully, some extended durability options may make it to the bedside soon. Some of the extended durability options in the pipeline include intravitreal injections such as Faricimab, OPT-302, and KSI-301. There are implantable devices such as the Port delivery system (PDS) and Vorolanib. Gene therapy options include RGX-314, and ADVM-022. These therapeutics are currently being investigated for AMD, but could apply to DME if approved. It is expected that any therapy that will join the list of already available anti-VEGFs will be required to have the same or better safety data if compared with already available drugs.

## **7. Newer and emerging concepts in DME**

The burden of DME and its impact on vision begs for more efficient care and better outcomes for treatment. This situation has fueled the drive for new concepts in understanding the disease process and alternative treatment.

Some of the new concepts in the understanding of DR and DME include in genetic studies, which aim to understand the variable risk diabetes poses to each person living with the disease. This risk may be affected by the individual's genetic make-up. Also, the role of epigenetics may be an essential factor in determining the response to treatment. Screening for DR and DME will take on a newer feel by introducing artificial intelligence algorithms and software, combined with the advantages of teleophthalmology. This will open up access to more persons who can benefit from screening, including persons in more remote places with limited health and eye care. Home OCT for monitoring of DME will provide information into the clinical evolution of DR and DME and answers to what happens to the eye when patients cannot attend the regular clinics. Home OCT will be an added benefit in reducing the burden of attendance to regular clinics to monitor anti-VEGF therapy. The desire for a reduction in clinic visits is a critical need.

The quest to explore alternative pathogenetic pathways outside the anti-VEGF pathway has resulted in the current progress investigating the Ang-Tie pathways and the Kallikrein pathways. In addition, pharmacotherapies are being developed based on these newer principles.

More innovation will be seen as the years unfold and will significantly benefit treatment outcomes, individualizing DME treatment, and patient satisfaction.

### **8. Conclusion**

It is expected that the number of people living with diabetes will continue increasing, resulting in more patients diagnosed with DR and DME. There is a need to develop more efficient health systems providing holistic care for patients living with diabetes. These systems should provide for the visual needs and consider the psychological and other health needs. Medicare for such patients should ideally be with reduced treatment burden compared to the current situation and preferably fewer hospital visits.

If we succeed in creating these systems, it will positively affect the patients living with diabetes and the society. This will increase the productivity of our DR and DME patients, who then can live a happier and more fulfilling life.
