Anti-VEGF Therapy for Acute Thyroid Eye Disease (AcTED)

Anti-VEGF Therapy for Acute Thyroid Eye Disease (AcTED Study)

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.

Study Overview

• Status: Recruiting
• Conditions: Thyroid Eye Disease
• Intervention / Treatment: Drug: Sub-tenon injection of saline followed by a sub-tenon injection of aflibercept; Drug: Sub-tenon injection of hyaluronidase (HA) followed by a sub-tenon injection of aflibercept; Drug: Sub-tenon injection of hyaluronidase (HA) alone

Detailed Description

The study is a double-blinded exploratory investigation to evaluate use of sub-tenon injected HA or saline followed by sub-tenon injection of 4 mg aflibercept for the treatment of acute thyroid disease. The study will prospectively and sequentially enroll a total of twenty-four patients who meet the study enrollment criteria and will be randomized to one of three treatment arms:

1. Group 1: Sub-tenon's injection of saline followed by injection of 4 mg aflibercept (total volume 1.1 ml) in the worse eye
2. Group 2: Sub-tenon's injection of HA followed by injection of 4mg aflibercept (total volume 1.1 ml) in the worse eye
3. Group 3: HA injection alone (total volume 1.1 ml) in the worse eye

Study subjects will receive bi-weekly sub-tenon injections on day 1, day 14 and day 28 for a total of 3 treatments. Subjects will be followed for an additional 62 days (until the 90-day visit) after the last injection.

At the time of enrollment, patients will undergo a full ophthalmologic examination including external photography, a 30-2 automated Humphrey visual field, intraocular pressure, ocular motility and alignment, calculation of the CAS score, smoking status, measurement of blood pressure, a pre-treatment CT scan, and laboratory work-up (including plasma testing of TSI, thyroglobulin antibodies, thyroid peroxidase antibodies, cytokine levels (IL-6, IL-8, IFN-g, TNF-a, IL-1B, TGF-B) and a baseline measurement of systemic VEGF levels). The CAS is a 7-point clinical activity score and includes 1 point for the presence of each of the following: Redness of eyelids, spontaneous pain, pain when moving the globe, redness of conjunctiva, swelling of plica and/or caruncle, swelling of eyelid, and chemosis.

Careful clinical monitoring will follow initial injection including a complete re-evaluation on day 4 (CAS, motility exam, photos, patient questionnaire, measurement of blood pressure, and repeat thyroid antibody and cytokine levels). Patients will be re-evaluated in the same way on day 14, day 28, day 45, and day 60. A post-treatment CT scan will be obtained at day 45. A long-term follow-up visit will occur at day 90.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Nahoung Grace Lee, MD; Phone Number: 617-572-5550; Email: Grace_Lee@MEEI.HARVARD.EDU
• Study Contact Backup: Name: Yuki A Wiland, BS; Phone Number: 617-573-6060; Email: yuki_wiland@meei.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Mass Eye and Ear
      • Contact: Stacey M Ellender, PhD; Phone Number: 617-573-6060
      • Sub-Investigator: Jonathan Lu, MD
      • Sub-Investigator: Carolina Chiou, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Minimum of 18 years-old
2. Active Thyroid Eye Disease
3. Clinical Activity Score (CAS) between 3 and 5, inclusive
4. Phakic and pseudophakic eyes are allowed in the study.
5. Willing and able to provide written informed consent after the nature of the study has been explained, and prior to any research-related procedures
6. Willing and able to comply with clinic visits and study-related procedures
7. 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.

Exclusion Criteria:

1. History of orbital, strabismus, or eyelid surgery or orbital radiation
2. Optic neuropathy or other vision-threatening signs
3. 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 .
4. Patients who have taken teprotumumab (Tepezza.)
5. Patients who have received intraocular anti-VEGF medications within 1 year of screening
6. Patients who have a history of receiving systemic anti-VEGF
7. Presence of other retinal vascular diseases (diabetic retinopathy, vein occlusion) that could affect the VEGF levels within the eye
8. History of stroke or prior myocardial infarction
9. Known hypersensitivity to aflibercept
10. Infectious conjunctivitis, keratitis, or endophthalmitis of either eye
11. Presence of a glaucoma shunting or filtration device that is subconjunctival
12. Previous participation in any studies of investigational drugs within 1 month preceding Day 0
13. Any clinically significant acute or chronic medical condition that would preclude participation in a clinical study
14. Pregnant or breast-feeding women
15. 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)
16. History of hyaluronidase (HA) injection after the diagnosis of thyroid eye disease
17. Taking part in other research studies in the past 12 months that have involved radiation exposure
18. Participated in other research studies in the past 12 months that required radiologic imaging (particularly CT scans and not MRIs)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Saline and aflibercept; 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; 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.; Other Names: Group 1
Experimental: Hyaluronidase and aflibercept; 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; 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.; Other Names: Group 2
Placebo Comparator: Hyaluronidase alone; Group 3: Sub-tenon injection of HA injection alone	Drug: Sub-tenon injection of hyaluronidase (HA) alone; 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.; Other Names: Group 3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary 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	Baseline to day 90
Secondary Outcome: Change in Clinical Activity	Change in clinical activity as measured by a 2 point decrease on the clinical activity score (CAS)	1-90 days
Secondary Outcome: Change in Ocular Muscle	Change in extra ocular muscle diameter as measured by computed tomography (CT) scan	1-90 days
Secondary Outcome: Change in Proptosis measured by exophthalmometry	Change in proptosis as measured by Hertel exophthalmometry	1-90 days
Secondary Outcome: Change in Proptosis by CT scan	Change in proptosis as measured by CT scan	1-90 days
Secondary Outcome: Change in Ocular Alignment	Change in degree of ocular misalignment during physical exam	1-90 days
Secondary Outcome: Change in Ocular Motility	Change in limitation in ocular motility as measured with physical examination	1-90 days
Secondary Outcome: Change in Visual Function	Change in visual function as determined by automated Humphrey visual field	1-90 days
Secondary Outcome: Change in Pain/Discomfort Reported by Subjects	Change in subjective score of pain/discomfort based upon patient Graves' Ophthalmopathy Quality of Life (GO-QOL) questionnaire	1-90 days
Secondary Outcome: Change in Eyelid Retraction/Position	Change in eyelid retraction/position as measured by the mm of inferior and superior scleral show on physical examination	1-90 days
Secondary Outcome: Change in Vision measured by ETDRS BCVA	Change in vision as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA)	1-90 days
Secondary Outcome: Change in Vision measured by Ishihara color test	Change in vision as measured by Ishihara color test	1-90 days

Collaborators and Investigators

• Sponsor: Massachusetts Eye and Ear Infirmary
• Collaborators: Regeneron Pharmaceuticals
• Investigators: Principal Investigator: Nahoung Grace Lee, MD, Investigator

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 2, 2020
• Primary Completion (Anticipated): September 30, 2025
• Study Completion (Anticipated): January 1, 2027

Study Registration Dates

• First Submitted: March 12, 2020
• First Submitted That Met QC Criteria: March 16, 2020
• First Posted (Actual): March 17, 2020

Study Record Updates

• Last Update Posted (Actual): March 20, 2023
• Last Update Submitted That Met QC Criteria: March 16, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: VEGF
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Genetic Diseases, Inborn; Eye Diseases, Hereditary; Graves Disease; Exophthalmos; Orbital Diseases; Goiter; Hyperthyroidism; Eye Diseases; Graves Ophthalmopathy; Thyroid Diseases; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Aflibercept
• Other Study ID Numbers: 2019P000939

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Participant Data will be shared at end of study, after the last participant has had his or her last visit.
• IPD Sharing Time Frame: January 2026
• IPD Sharing Access Criteria: Email Request to PI
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No