Anti-VEGF Therapy for Thyroid Eye Disease

(AcTED Trial)

Overseen By Yuki A Wiland, BS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts Eye and Ear Infirmary

Must not be taking: Steroids, Teprotumumab, Anti-VEGF

Disqualifiers: Stroke, Myocardial infarction, others

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 6 weeks

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a potential new treatment for individuals with active Thyroid Eye Disease (TED), which can cause eye bulging and vision issues. The study tests the safety of a drug called aflibercept (an anti-VEGF therapy), administered with either saline or hyaluronidase, to evaluate its effectiveness and safety. Individuals with active TED who are not currently on steroids might be suitable candidates for this trial. Participants will receive one of three treatments and will be monitored for side effects over approximately six weeks. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

If you are currently taking systemic or topical steroids, you will need to stop and have a 6-week period without them before joining the trial. The protocol does not specify other medications, so it's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that aflibercept is generally well-tolerated by patients. One study found that it improved vision in people with age-related macular degeneration without causing serious side effects, suggesting its safety for use in eye conditions.

Hyaluronidase, another treatment in this trial, has also been researched for eye conditions. One study found it effective and safe for treating periorbital myxedema, a condition linked to thyroid eye disease.

Since this trial is in its early stages, it primarily focuses on safety. While earlier research has shown promise for these treatments, more data is needed to confirm their safety for thyroid eye disease. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for thyroid eye disease because they utilize aflibercept, which targets vascular endothelial growth factor (VEGF). Unlike traditional treatments like corticosteroids and orbital decompression surgery, which manage symptoms and inflammation, aflibercept works by inhibiting VEGF, potentially reducing abnormal blood vessel growth and swelling. Additionally, the use of sub-tenon injections offers a new delivery method that may provide localized treatment with fewer side effects. This novel approach could offer a more targeted treatment with quicker and more effective results.

What evidence suggests that this trial's treatments could be effective for Thyroid Eye Disease?

In this trial, participants will receive various treatments to manage Thyroid Eye Disease (TED). Studies have shown that aflibercept, one of the treatments in this trial, can improve vision and reduce eye swelling in conditions like age-related macular degeneration. Researchers believe aflibercept could also benefit TED patients by reducing swelling and inflammation. Another treatment option in this trial is hyaluronidase, which research has effectively used to treat swelling around the eyes in TED. The trial will also explore combining aflibercept with hyaluronidase, potentially providing better results by addressing different aspects of the eye disease. Although research is ongoing, these treatments show promise for managing TED symptoms. ^{3 6 7 8 9}

Who Is on the Research Team?

Nahoung Grace Lee, MD

Principal Investigator

Investigator

Are You a Good Fit for This Trial?

This trial is for adults over 18 with active Thyroid Eye Disease, showing moderate symptoms. Participants must be able to consent and follow the study plan. Only one eye will be treated, preferably the worse one or non-dominant if equal. Exclusions include prior eye surgeries or treatments, other retinal issues, heart attack or stroke history, aflibercept allergy, infections in the eye area, certain device implants in the eye, recent participation in other drug studies or radiation exposure research.

Inclusion Criteria

Only one eye will be enrolled. The worse eye (demonstrating worse HVF results, worse restricted motility, worse visual acuity, worse edema, worse proptosis, worse eyelid retraction) will be enrolled. If both eyes are equivalent, we will enroll the non-dominant eye.

I have been diagnosed with active Thyroid Eye Disease.

Your clinical activity score is between 3 and 5.

Exclusion Criteria

I am sexually active and not willing to use birth control during the study.

Pregnant or breast-feeding women

I have an eye infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive three injections of aflibercept with saline, aflibercept with hyaluronidase, or hyaluronidase alone

6 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Aflibercept
• Hyaluronidase

Trial Overview The trial tests safety and tolerability of aflibercept injections for acute Thyroid Eye Disease when combined with saline or hyaluronidase (HA), compared to HA alone. Over a period leading up to day 45 from baseline, participants receive three injections while undergoing clinical examinations to monitor adverse events.

How Is the Trial Designed?

Group I: Saline and aflibercept Experimental Treatment 1 Intervention

Group 1: Sub-tenon's injection of saline followed by sub-tenon injection of aflibercept

Group II: Hyaluronidase and aflibercept Experimental Treatment 1 Intervention

Group 2: Sub-tenon's injection of hyaluronidase (HA) followed by sub-tenon injection of aflibercept

Group III: Hyaluronidase alone Placebo Group 1 Intervention

Group 3: Sub-tenon injection of HA injection alone

Aflibercept is already approved in United States, European Union for the following indications:

Approved in United States as Eylea for:

• Neovascular (Wet) Age-Related Macular Degeneration (AMD)
• Macular Edema following Retinal Vein Occlusion (RVO)
• Diabetic Macular Edema (DME)
• Diabetic Retinopathy (DR)

Approved in European Union as Eylea for:

• Neovascular (Wet) Age-Related Macular Degeneration (AMD)
• Macular Edema following Retinal Vein Occlusion (RVO)
• Diabetic Macular Edema (DME)
• Diabetic Retinopathy (DR)

Approved in United States as Zaltrap for:

• Metastatic Colorectal Cancer

Who Is Running the Clinical Trial?

Massachusetts Eye and Ear Infirmary

Lead Sponsor

Trials

115

Recruited

15,000+

Regeneron Pharmaceuticals

Industry Sponsor

Trials

690

Recruited

948,000+

Founded

1988

Headquarters

Tarrytown, USA

Known For

Precision medicine

Top Products

Dupixent, EYLEA, Libtayo, Praluent

Leonard Schleifer

Regeneron Pharmaceuticals

Chief Executive Officer since 1988

MD and PhD in Medicine

George Yancopoulos

Regeneron Pharmaceuticals

Chief Medical Officer since 1997

MD from Harvard Medical School

Published Research Related to This Trial

Intravitreal aflibercept significantly improved visual acuity in patients with diabetic macular oedema compared to macular laser photocoagulation and other treatments like bevacizumab and ranibizumab, particularly in those with worse baseline vision, as shown in phase III trials.

Aflibercept was generally well tolerated, making it a promising and effective new treatment option for diabetic macular oedema.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aflibercept: A Review of Its Use in Diabetic Macular Oedema. Keating, GM.[2022]

In a study involving 24 rabbits with chemically induced corneal neovascularization, treatments with aflibercept, betamethasone, or their combination did not significantly reduce neovascularization compared to a control group.

Despite the lack of efficacy in reducing neovascularization, all treatment groups showed lower VEGF levels than the control, suggesting that while these treatments may affect VEGF concentration, they do not effectively reverse the neovascularization process in this model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Subconjunctival Aflibercept and Betamethasone for the Treatment of Formed Corneal Neovascularization in a Rabbit Model. Eiger-Moscovich, M., Livny, E., Sella, R., et al.[2019]

Aflibercept (Eylea) treatment showed positive results in improving visual acuity and resolving macular edema in patients with age-related macular degeneration and other retinal diseases.

The treatment was generally safe, with no major side effects or resistance observed, although some patients experienced recurrences of their conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Preliminary results of treatment with aflibercept]. Blăjan, C., Nicula, D., Rusu, I.[2015]

Aflibercept effectively inhibits vascular endothelial growth factor (VEGF), which is crucial for pathological blood vessel formation, thereby reducing the proliferation of human umbilical vein endothelial cells (HUVEC) in vitro.

The study found that aflibercept maintains its full inhibitory effect for at least 120 hours after being transferred to an injection syringe, which is longer than the manufacturer's specifications suggest.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of aflibercept (EYLEA®) on inhibition of human VEGF in vitro. Schicht, M., Hesse, K., Schröder, H., et al.[2017]

In a study of 30 eyes from 23 patients with diabetic macular edema (DME) who previously received an average of 16 injections of ranibizumab and/or bevacizumab, switching to aflibercept resulted in a significant reduction in central subfoveal thickness, improving from 374 µm to 332 µm after the first aflibercept injection (P < .001).

Visual acuity also improved after the switch to aflibercept, with a change from logMAR 0.40 (20/50) to logMAR 0.35 (20/45) (P = .044), suggesting that aflibercept may be a beneficial treatment option for patients with persistent DME.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aflibercept for Diabetic Macular Edema in Eyes Previously Treated With Ranibizumab and/or Bevacizumab May Further Improve Macular Thickness. Shah, CP., Heier, JS.[2022]

A study involving 12 patients showed that a single intravitreal injection of ziv-aflibercept for treating choroidal neovascularization due to age-related macular degeneration was safe, with no serious ocular or systemic adverse events reported after 30 days.

While there was only a slight improvement in best-corrected visual acuity after treatment, the absence of significant side effects suggests that ziv-aflibercept could be a viable low-cost alternative for macular disease therapy, especially in resource-limited settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SHORT-TERM SAFETY PROFILE OF INTRAVITREAL ZIV-AFLIBERCEPT. Chhablani, J., Narayanan, R., Mathai, A., et al.[2022]

Aflibercept is a newly approved anti-VEGF drug that effectively suppresses choroidal neovascularization in patients with exudative age-related macular degeneration, showing excellent short-term results in clinical trials.

In pivotal phase 3 trials, aflibercept demonstrated comparable efficacy and safety to ranibizumab while requiring fewer injections, potentially leading to lower overall treatment costs for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aflibercept for age-related macular degeneration: a game-changer or quiet addition? Browning, DJ., Kaiser, PK., Rosenfeld, PJ., et al.[2013]

Aflibercept (Eylea) is an effective anti-VEGF therapy for neovascular age-related macular degeneration (AMD), showing excellent safety and significant benefits in maintaining vision, as demonstrated in randomized trials.

Aflibercept, administered every 8 weeks after an initial loading dose, is clinically equivalent and statistically noninferior to ranibizumab (Lucentis), which is given every 4 weeks, indicating its potential as a more convenient treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal aflibercept for neovascular age-related macular degeneration. Xu, D., Kaiser, PK.[2022]

Citations

1. withpower.com withpower.com/trial/phase-3-graves-ophthalmopathy-10-2020-c9bde

Anti-VEGF Therapy for Thyroid Eye Disease (AcTED Trial) Aflibercept (Eylea) treatment showed positive results in improving visual acuity and resolving macular edema in patients with age-related macular degeneration ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12331743/

Emerging therapeutic approaches in graves' ophthalmopathy Emerging data suggest that early initiation of biologics, particularly teprotumumab, may reduce the need for rehabilitative surgery by reversing ...

3. ophthalmologytimes.com ophthalmologytimes.com/view/regeneron-to-highlight-real-world-efficacy-of-aflibercept-8-mg-eylea-hd-in-wamd-dme-and-dr

Regeneron to highlight real-world efficacy of aflibercept 8 ... Results from PULSAR showed that at weeks 48 and 96, the 2 groups treated with aflibercept 8 mg demonstrated noninferior BCVA gains compared with ...

4. frontiersin.org frontiersin.org/journals/ophthalmology/articles/10.3389/fopht.2023.1295902/full

Emerging therapies in the medical management of thyroid ... In this study, two infusions led to substantial reductions in proptosis and clinical activity scores. No patients treated with VRDN-001 achieve ...

5. delveinsight.com delveinsight.com/blog/4-late-stage-thyroid-eye-disease-treatments

4 Late-Stage Thyroid Eye Disease Treatments These studies demonstrate statistically significant and clinically relevant improvements in various aspects of thyroid eye disease, such as ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04311606

Anti-VEGF Therapy for Acute Thyroid Eye Disease The primary objective of this clinical trial is to assess the safety and tolerability of sub-tenon aflibercept in combination with either saline or ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11182121/

Emerging therapies in the medical management of thyroid ... No patients treated with VRDN-001 achieve completed resolution of diplopia at week six. Moreover, there were no reported serious adverse events, including ...

8. eyeworld.org eyeworld.org/2025/eyeworld-weekly-may-16-2025/

EyeWorld Weekly, May 16, 2025 Breakthrough Therapy designation granted to investigational thyroid eye disease drug candidate · Data supports protection of retinal cells from ...

9. eyewiki.org eyewiki.org/Biologics_for_Thyroid_Eye_Disease

Biologics for Thyroid Eye Disease Thyroid eye disease is a complex entity often requiring both local and systemic treatments. Biologic therapies targeting specific immunologic sites offer a ...