Anti-VEGF Therapy for Acute Thyroid Eye Disease

NCT04311606 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: 2019P000939
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

The primary objective of this clinical trial is to assess the safety and tolerability of sub-tenon aflibercept in combination with either saline or hyaluronidase (HA) in patients with acute Thyroid Eye Disease (TED) as assessed by the incidence and severity of adverse events from baseline to day 45. Participants will undergo clinical examinations and receive three injections of aflibercept with saline, aflibercept with hyaluronidase, or hyaluronidase.

Conditions

Thyroid Eye Disease

Keywords

VEGF

Outcome Measures

Primary Outcomes (1)

• Primary Outcome: Safety

  To assess the safety and tolerability of sub-tenon aflibercept in combination with either saline or hyaluronidase (HA) in patients with acute Thyroid Eye Disease (TED) as assessed by the incidence and severity of adverse events

  45 days

Secondary Outcomes (12)

• Secondary Outcome: Safety

  Baseline to day 90

• Secondary Outcome: Change in Clinical Activity

  1-90 days

• Secondary Outcome: Change in Ocular Muscle

  1-90 days

• Secondary Outcome: Change in Proptosis measured by exophthalmometry

  1-90 days

• Secondary Outcome: Change in Proptosis by CT scan

  1-90 days

Study Arms (3)

Saline and aflibercept

EXPERIMENTAL

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

Drug: Sub-tenon injection of saline followed by a sub-tenon injection of aflibercept

Hyaluronidase and aflibercept

EXPERIMENTAL

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

Drug: Sub-tenon injection of hyaluronidase (HA) followed by a sub-tenon injection of aflibercept

Hyaluronidase alone

PLACEBO COMPARATOR

Group 3: Sub-tenon injection of HA injection alone

Drug: Sub-tenon injection of hyaluronidase (HA) alone

Interventions

Sub-tenon injection of saline followed by a sub-tenon injection of aflibercept DRUG

The study will randomly assign a total of eight subjects into this treatment arm to receive a sub-tenon injection of saline followed by injection of 4 mg aflibercept (total volume 1.1 ml) in the worse eye. Injections will be given three times: on day 1, day 14 and day 28. Subjects will be followed until day 90.

Also known as: Group 1

Saline and aflibercept

Sub-tenon injection of hyaluronidase (HA) followed by a sub-tenon injection of aflibercept DRUG

The study will randomly assign a total of eight subjects into this treatment arm to receive a sub-tenon injection of hyaluronidase (HA) followed by injection of 4 mg aflibercept (total volume 1.1 ml) in the worse eye. Injections will be given three times: on day 1, day 14 and day 28. Subjects will be followed until day 90.

Also known as: Group 2

Hyaluronidase and aflibercept

Sub-tenon injection of hyaluronidase (HA) alone DRUG

The study will randomly assign a total of eight subjects into this treatment arm to receive a sub-tenon injection of hyaluronidase (HA) injection alone (total volume 1.1 ml) in the worse eye. Injections will be given three times: on day 1, day 14 and day 28. Subjects will be followed until day 90.

Also known as: Group 3

Hyaluronidase alone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Minimum of 18 years-old
• Active Thyroid Eye Disease
• Clinical Activity Score (CAS) between 3 and 5, inclusive
• Phakic and pseudophakic eyes are allowed in the study.
• Willing and able to provide written informed consent after the nature of the study has been explained, and prior to any research-related procedures
• Willing and able to comply with clinic visits and study-related procedures
• Only one eye will be enrolled. The worse eye (demonstrating any of these features:
• 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.

You may not qualify if:

• History of orbital, strabismus, or eyelid surgery or orbital radiation
• Optic neuropathy or other vision-threatening signs
• Patients currently on systemic or topical steroids. If they received steroids in the past, they would require a 6 week washout period and the cumulative dose of steroids must be less than 1 gram of methylprednisolone (or equivalent). During the washout period we will contact patients by phone weekly to monitor their safety and address any concerns they may have related to no longer taking steroids .
• Patients who have taken teprotumumab (Tepezza.)
• Patients who have received intraocular anti-VEGF medications within 1 year of screening
• Patients who have a history of receiving systemic anti-VEGF
• Presence of other retinal vascular diseases (diabetic retinopathy, vein occlusion) that could affect the VEGF levels within the eye
• History of stroke or prior myocardial infarction
• Known hypersensitivity to aflibercept
• Infectious conjunctivitis, keratitis, or endophthalmitis of either eye
• Presence of a glaucoma shunting or filtration device that is subconjunctival
• Previous participation in any studies of investigational drugs within 1 month preceding Day 0
• Any clinically significant acute or chronic medical condition that would preclude participation in a clinical study
• Pregnant or breast-feeding women
• Sexually active men\* or women of childbearing potential\*\* who are unwilling to practice adequate contraception during the study (adequate contraceptive measures include stable use of oral contraceptives or other prescription pharmaceutical contraceptives for 2 or more menstrual cycles prior to screening; intrauterine device \[IUD\]; bilateral tubal ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly)

Sponsors & Collaborators

• Regeneron Pharmaceuticals: collaborator
• Massachusetts Eye and Ear Infirmary: lead

Study Sites (1)

Mass Eye and Ear

Boston, Massachusetts, 02114, United States

Location

Related Publications (8)

• Wong LL, Lee NG, Amarnani D, Choi CJ, Bielenberg DR, Freitag SK, D'Amore PA, Kim LA. Orbital Angiogenesis and Lymphangiogenesis in Thyroid Eye Disease: An Analysis of Vascular Growth Factors with Clinical Correlation. Ophthalmology. 2016 Sep;123(9):2028-36. doi: 10.1016/j.ophtha.2016.05.052. Epub 2016 Jul 14.

  PMID: 27423310 BACKGROUND

• Smith TJ, Kahaly GJ, Ezra DG, Fleming JC, Dailey RA, Tang RA, Harris GJ, Antonelli A, Salvi M, Goldberg RA, Gigantelli JW, Couch SM, Shriver EM, Hayek BR, Hink EM, Woodward RM, Gabriel K, Magni G, Douglas RS. Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med. 2017 May 4;376(18):1748-1761. doi: 10.1056/NEJMoa1614949.

  PMID: 28467880 BACKGROUND

• Min L, Vaidya A, Becker C. Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy. Eur J Endocrinol. 2011 Feb;164(2):303-7. doi: 10.1530/EJE-10-0833. Epub 2010 Nov 18.

  PMID: 21088057 BACKGROUND

• Kajdaniuk D, Marek B, Niedziolka-Zielonka D, Foltyn W, Nowak M, Sieminska L, Borgiel-Marek H, Glogowska-Szelag J, Ostrowska Z, Drozdz L, Kos-Kudla B. Transforming growth factor beta1 (TGFbeta1) and vascular endothelial growth factor (VEGF) in the blood of healthy people and patients with Graves' orbitopathy--a new mechanism of glucocorticoids action? Endokrynol Pol. 2014;65(5):348-56. doi: 10.5603/EP.2014.0048.

  PMID: 25301484 BACKGROUND

• Bock F, Onderka J, Dietrich T, Bachmann B, Kruse FE, Paschke M, Zahn G, Cursiefen C. Bevacizumab as a potent inhibitor of inflammatory corneal angiogenesis and lymphangiogenesis. Invest Ophthalmol Vis Sci. 2007 Jun;48(6):2545-52. doi: 10.1167/iovs.06-0570.

  PMID: 17525183 BACKGROUND

• Mourits MP, Koornneef L, Wiersinga WM, Prummel MF, Berghout A, van der Gaag R. Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: a novel approach. Br J Ophthalmol. 1989 Aug;73(8):639-44. doi: 10.1136/bjo.73.8.639.

  PMID: 2765444 BACKGROUND

• Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ, Lawitts JA, Benjamin L, Tan X, Manseau EJ, Dvorak AM, Dvorak HF. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med. 2002 Dec 2;196(11):1497-506. doi: 10.1084/jem.20021244.

  PMID: 12461084 BACKGROUND

• Cursiefen C, Maruyama K, Jackson DG, Streilein JW, Kruse FE. Time course of angiogenesis and lymphangiogenesis after brief corneal inflammation. Cornea. 2006 May;25(4):443-7. doi: 10.1097/01.ico.0000183485.85636.ff.

  PMID: 16670483 BACKGROUND

MeSH Terms

Conditions

Graves Ophthalmopathy

Interventions

Single Person

Condition Hierarchy (Ancestors)

Eye Diseases, Hereditary; Eye Diseases; Graves Disease; Exophthalmos; Orbital Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Goiter; Thyroid Diseases; Endocrine System Diseases; Hyperthyroidism; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Marital Status; Family Characteristics; Demography; Population Characteristics; Socioeconomic Factors

Study Officials

• Nahoung Grace Lee, MD

  Investigator

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Masking Details: Double-masked
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Physician

Model Details: Three groups as follows: Group 1: Sub-tenon's injection of saline followed by sub-tenon injection of aflibercept Group 2: Sub-tenon's injection of hyaluronidase (HA) followed by sub-tenon injection of aflibercept; and Group 3: Sub-tenon injection of HA injection alone

Study Record Dates

• First Submitted: March 12, 2020
• First Posted: March 17, 2020
• Study Start: November 2, 2020
• Primary Completion: December 17, 2024
• Study Completion: December 17, 2024
• Last Updated: December 31, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: January 2026
• Access Criteria: Email Request to PI

Locations

US (1)