Head-to-Head Comparison of an IGF-1R Inhibitor Versus Intravenous Glucocorticoid for Active Thyroid Eye Disease: Design of a Randomized Clinical Trial

Abstract

Introduction

Thyroid eye disease (TED) is a disfiguring and potentially sight-threatening autoimmune orbital disorder. Intravenous glucocorticoid (IVGC) is the current first-line treatment for active, moderate-to-severe TED but its efficacy in reducing proptosis and diplopia is limited and inconsistent, with high relapse rates. In recent years, inhibitors of the insulin-like growth factor-1 receptor (IGF-1R) have emerged as a novel therapeutic class for TED. Clinical studies have demonstrated that IGF-1R inhibitors can significantly reduce proptosis and improve overall disease activity in patients with active, moderate-to-severe TED. Although both therapies are available, no head-to-head clinical trial has directly compared IGF-1R inhibitors with IVGC. Therefore, this study aims to evaluate the efficacy and safety of an IGF-1R inhibitor compared with IVGC pulse therapy on proptosis in patients with active TED.

Methods

This is a multicenter, randomized, open-label, active-controlled phase 4 trial. Adults with active moderate-to-severe TED and baseline proptosis ≥ 16 mm in the study eye will be enrolled. Participants will be randomized 1:1 to receive either intravenous teprotumumab N01 (10 mg/kg initial dose on day 1, followed by 20 mg/kg at weeks 3, 6, 9, and 12) or IVGC pulse therapy (methylprednisolone 500 mg on day 1 and from week 1 to week 5, followed by 250 mg from week 6 to week 11). After completing the 12-week treatment period, participants will enter an extended treatment and observation phase. The primary outcome measure is the proportion of participants who achieve a ≥ 2-mm reduction in proptosis in the study eye at week 15. Key secondary outcome measures include the change from baseline in proptosis and the overall responder rate in the study eye at week 15.

Planned outcomes

This study plans to enroll approximately 92 participants with active TED. This trial is the first head-to-head clinical study comparing an IGF-1R (Insulin-like growth factor-1 receptor) inhibitor with IVGC. It aims to address the limitations of IVGC, including its uncertain efficacy on proptosis and diplopia, by utilizing a targeted approach to provide more comprehensive clinical evidence for TED treatment.

Trial Registration

ClinicalTrials.gov identifier, NCT07265258 (RESTORE-4).

Supplementary Information

The online version contains supplementary material available at 10.1007/s40123-026-01451-9.

Key Summary Points

This is the first head-to-head trial comparing teprotumumab N01 (an IGF-1R inhibitor) versus intravenous glucocorticoid (IVGC) pulse therapy in patients with active thyroid eye disease (TED).

The primary endpoint is the proptosis responder rate at week 15, chosen to minimize relapse-related bias, align with clinical practice, and allow timely crossover for steroid-nonresponsive participants.

Blinding is not feasible due to fundamental differences in dosing regimens (every-3-week vs. weekly infusions) and mandatory concomitant medications required in the IVGC group.

The crossover design is both ethically justified (providing prompt alternative therapy for IVGC non-responders/relapsers) and scientifically valuable (generating efficacy data on teprotumumab N01 in the refractory population).

Independent ophthalmology outcome assessors remain masked to treatment assignment; proptosis is measured using a standardized Hertel exophthalmometer, and orbital MRI is included as an endpoint with masked central reading.

Final baseline characteristics (age, gender, CAS, diplopia severity, etc.) will be fully reported upon study completion, and the investigators maintain scientific independence.

Introduction

Thyroid eye disease (TED), also known as Graves' orbitopathy (GO), is a disfiguring and potentially sight-threatening autoimmune inflammatory disorder of the orbit and represents the most common orbital disease in adults [1]. It is frequently associated with Graves' disease, affecting approximately 25–58% of these patients [2]. The clinical manifestations of TED encompass a broad spectrum, including eyelid retraction, proptosis, periorbital edema and erythema, diplopia (double vision), and vision loss due to dysthyroid optic neuropathy (DON) or corneal breakdown in severe cases [3]. Beyond its impact on appearance and visual function, TED exerts a profoundly negative effect on patients' psychological well-being and quality of life [4].

According to current guidelines and expert consensus, IVGC therapy, administered either as monotherapy or in combination with other immunosuppressants, remains the first-line treatment for patients with active, moderate-to-severe TED, particularly when significant inflammatory activity is present without marked proptosis or diplopia [1, 5–7]. The standard regimen typically consists of weekly intravenous methylprednisolone over 12 weeks: 500 mg for the first six infusions, followed by 250 mg for the subsequent six. While IVGC is effective in reducing orbital soft-tissue inflammation, its efficacy in improving proptosis and diplopia is often limited and inconsistent, with response rates varying considerably across studies [8]. Furthermore, IVGC therapy is associated with a high relapse rate following discontinuation [9]. These limitations underscore the urgent need for novel therapeutic strategies that can offer more robust, durable, and comprehensive control of these debilitating manifestations.

The IGF-1R has been identified as a pivotal mediator in the pathogenesis of TED. Overexpressed on orbital fibroblasts (OFs) and immune cells, IGF-1R forms a functional complex with the thyrotropin receptor, synergistically promoting orbital inflammation, adipogenesis, and tissue remodeling [10, 11]. The development of teprotumumab (TEPEZZA^®) [12, 13], a monoclonal antibody targeting IGF-1R, marked a breakthrough in TED management. As endorsed by the American Thyroid Association and the European Thyroid Association consensus, teprotumumab is now recommended as a preferred therapy, if available, in patients with active, moderate-to-severe TED with significant proptosis and/or diplopia [6, 14].

Teprotumumab N01 (SYCUME^®, R&D code: IBI311), developed by Innovent Biologics, Inc. (Suzhou, China), is a recombinant, fully human monoclonal antibody directly against IGF-1R. It shares an identical amino acid sequence with teprotumumab but features a modified liquid formulation for more convenient clinical administration. Given its favorable safety profile and significant efficacy in reducing proptosis and improving disease activity in Chinese patients with active, moderate-to-severe TED in its pivotal study (RESTORE-1, NCT05795621) [15], teprotumumab N01 was granted marketing authorization in China in March 2025 and is now widely used in patients with TED.

Although both IVGC and IGF-1R inhibitors are recommended in current guidelines, no head-to-head clinical trial has directly compared their efficacy and safety. While indirect comparisons and meta-analyses have suggested that IGF-1R inhibitors therapy may offer superior outcomes, particularly in proptosis reduction [16, 17], definitive evidence remains lacking [7, 9]. Therefore, a direct, well-controlled comparison between teprotumumab N01 and standard IVGC therapy is essential to generate comprehensive clinical evidence and to establish the role of teprotumumab N01 within the evolving treatment paradigm of TED.

Based on this rationale, we designed this head-to-head phase 4 clinical trial (RESTORE-4, NCT07265258) to directly compare the efficacy and safety of IGF-1R inhibitors versus IVGC therapy in participants with active TED. Herein, we describe the study design for RESTORE-4.

Methods

Study Design

RESTORE-4 is a multicenter, randomized, open-label, active-controlled phase 4 clinical trial conducted in participants with active TED. This trial will be carried out across approximately 20 study sites in China.

Approximately 92 eligible participants will be randomized on day 1 in a 1:1 ratio to either the teprotumumab N01 group or the IVGC group. Randomization will be stratified by the presence or absence of diplopia at baseline (Gorman Diplopia Score ≥ 1 vs. 0). The trial consists of three stages: a 4-week screening period, a 12-week treatment period (day 1 to week 12), and an extended treatment and observation period (week 13 to week 48). The primary endpoint will be assessed at week 15, with the total duration of the study spanning approximately 1 year. Due to the substantial differences in dosing regimens between teprotumumab N01 and IVGC (including frequency and duration), and the mandatory concomitant medications required in the IVGC group to mitigate steroid-induced risks, blinding is not feasible; therefore, this trial will employ an open-label design. Although the trial follows an open-label design, ophthalmologists serving as independent outcome assessors will remain masked to treatment assignments throughout the trial to mitigate potential assessment bias. Specifically, these assessors will have no access to the randomization list or any participant-level treatment information, and will only perform ophthalmic examinations to assess efficacy and safety. The randomization and treatment assignment will be managed by a randomization and trial supply management (RTSM) system, with an unblinded third-party statistician responsible for generating the allocation sequence. This unblinded statistician will not be involved in any outcome assessment or primary statistical analysis.

This trial has a unique two-phase treatment design, including an initial treatment period (day 1 to week 12) followed by an extended treatment and observation period (week 13 to week 48), with treatment regimens specified by group below (Fig. 1).

Fig. 1.

Schematic diagram of the trial design. D day, W week, C cycle, IVGC intravenous glucocorticoid, TED thyroid eye disease, CAS Clinical Activity Score, DON dysthyroid optic neuropathy, EOS end of study

During the treatment period, participants in the teprotumumab N01 group will receive intravenous infusions every 3 weeks (Q3W) for a total of five doses, comprising 10 mg/kg on day 1, followed by 20 mg/kg at weeks 3, 6, 9, and 12. Participants in the IVGC group will receive weekly intravenous infusions of methylprednisolone for 12 doses, specifically 500 mg on day 1 and from week 1 to week 5, followed by 250 mg from week 6 to week 11.

During the subsequent extended treatment and observation period (week 13 to week 48), the teprotumumab N01 group will receive three additional doses of 20 mg/kg at weeks 15, 18, and 21, with observational follow-up visits at weeks 24, 30, 36, 42, and 48. In contrast, the IVGC group will undergo observational follow-up visits at weeks 15, 18, 21, and 24. Participants in the IVGC group who experience disease deterioration between week 15 and week 24, as determined by the investigator, will have the option to cross over to receive teprotumumab N01 treatment or withdraw from the study. The crossover treatment will start with a 10 mg/kg dose at the C1 visit, followed by up to seven doses of 20 mg/kg from C2 to C8 visits, Q3W. Disease deterioration is defined as either: (a) Development of DON or severe exposure keratopathy in either eye; or (b) Worsening of TED in either eye as evidenced by at least two of the following criteria: i. increase in proptosis of ≥ 2 mm from baseline; ii. increase in Clinical Activity Score (CAS) of ≥ 2 from baseline; iii. increase in lid aperture of ≥ 2 mm from baseline; iv. worsening of diplopia by ≥ 1 grade from baseline; v. reduction in ocular motility of ≥ 8°in any direction from baseline; vi. decrease in best-corrected visual acuity (BCVA) by ≥ 1 line from baseline.

At week 24, participants in the IVGC group will undergo disease assessment. Those demonstrating a poor or partial response to IVGC therapy will be eligible for crossover treatment with teprotumumab N01, administered from C1 to C8 visits according to the previously defined dosing regimen. Criteria for crossover treatment include: (i) proptosis ≥ 18 mm in either eye; (ii) absence of proptosis response (i.e., < 2 mm reduction from baseline) in either eye; (iii) failure to achieve a CAS of 0 or 1 in either eye; (iv) presence of diplopia. Participants who do not meet any of these criteria will continue into observational follow-up through week 48.

Given the potential effects of glucocorticoids on the gastrointestinal tract, electrolyte balance, and bone metabolism, participants receiving IVGC treatment need to concurrently take the following medications: pantoprazole sodium enteric-coated capsules (40 mg once daily) and potassium chloride sustained-release tablets (0.5 g twice daily), both administered for 12 weeks. Additionally, calcium carbonate D3 tablets (600 mg calcium and 125 IU vitamin D3 per tablet, once daily) and calcitriol capsules (0.5 μg once daily) are used for a total of 24 weeks. The above-mentioned concomitant medications shall be supplied uniformly by the sponsor, and participants are required to document their medication intake in the diary card provided by the sponsor.

Sample Selection

The study key inclusion and exclusion criteria are detailed in the Supplementary Table 1. In brief, eligible participants will be male or female aged 18–80 years (inclusive), with a body weight between 45 and 100 kg (inclusive) at screening. They must have a diagnosis of active moderate-to-severe TED at both screening and baseline, which is defined by a CAS ≥ 3 (on the 7-item scale) in the study eye, symptoms of active TED in the study eye within 12 months prior to screening, and the presence of at least two of the following criteria: eyelid retraction ≥ 2 mm, moderate or severe soft-tissue involvement, proptosis of ≥ 3 mm above the upper limit of normal, or inconstant or constant diplopia (Gorman Diplopia Score of 2 or 3). Additionally, all participants must have a baseline proptosis measurement of ≥ 16 mm in the study eye.

Key exclusion criteria comprise significant clinical improvement between screening and baseline (defined as a reduction in CAS by ≥ 2 points or a decrease in proptosis by ≥ 2 mm), sight-threatening complications (DON or corneal breakdown), planned or prior orbital surgery or radiotherapy for TED, uncontrolled thyroid function (free triiodothyronine or free thyroxine levels exceeding 50% above or below the normal reference range of the local laboratory at screening) [1, 18, 19], uncontrolled diabetes mellitus (HbA1c ≥ 8.0% at screening), prior treatment for TED with glucocorticoids ( cumulative dose ≥ 1 g methylprednisolone equivalent), or prior use of biologics targeting IGF-1R, CD-20, IL-6R, or any other investigational therapies for TED. Participants with specific preexisting medical conditions, abnormal physical examination findings, or laboratory abnormalities that could contraindicate use of any of the study drugs, interfere with data interpretation, or in the opinion of the investigator would render the participants at high risk for treatment complications, including hearing impairment, uncontrolled systemic infections, inflammatory bowel disease, severe osteoporosis, Cushing's disease, etc., will also be excluded. A comprehensive list of prohibited medications and therapies before and during the study is provided in the Supplementary Table 2.

Given that diplopia is a key indicator of disease severity and functions as a baseline stratification factor, the proportion and severity of diplopia at baseline will be carefully controlled. At least 70% of participants are expected to have diplopia at baseline, with at least 50% exhibiting either inconstant or constant diplopia (Gorman Diplopia Score ≥ 2). One eye per participant will be designated as the study eye. At baseline (day 1), if both eyes are eligible for inclusion, the eye with greater disease severity will be selected. In cases of discordance between CAS and proptosis, priority will be given to the eye with more pronounced proptosis. Only the study eyes will be used for assessment of the primary outcome.

Measurements

The key trial endpoints are presented in Table 1. The primary endpoint is the proptosis response rate in the study eye at week 15, defined as the percentage of participants achieving ≥ 2 mm reduction from baseline in proptosis without ≥ 2 mm increase in the contralateral eye (measured by Hertel exophthalmometer). Week 15 was chosen as the primary timepoint based on previous registrational trials of teprotumumab N01. By this time, approximately 70% of participants had already achieved a meaningful proptosis response [20].

Table 1.

Key trial endpoints

Primary endpoint

Proptosis response rate in the study eye at week 15 (defined as the percentage of participants achieving ≥ 2 mm reduction from baseline in proptosis without ≥ 2 mm increase in the contralateral eye [Note: Unless otherwise specified, proptosis in this study is measured using a Hertel exophthalmometer])

Key secondary endpoints

Change in proptosis from baseline in the study eye at week 15

Overall response rate in the study eye at week 15 (defined as a simultaneous reduction of ≥ 2 mm in proptosis and ≥ 2 points in CAS in the study eye, without worsening in the contralateral eye [worsening defined as an increase in CAS of ≥ 2 or an increase in proptosis of ≥ 2 mm])

Other secondary endpoints

The endpoints for assessing additional efficacy in improving proptosis include: the change from baseline in proptosis of the study eye as measured by magnetic resonance imaging (MRI) at week 15; the proptosis response rate and the change from baseline in proptosis of the study eye at weeks 24 and 48; the proportion of participants with an improvement of ≥ 4 mm in proptosis of the study eye at weeks 15, 24, and 48; and the time to first proptosis response in the study eye through week 24

The endpoints for assessing the impact on the overall response rate include: the overall response rate at weeks 24 and 48; the proportion of participants achieving a significant overall response (defined as a reduction of ≥ 3 points in CAS and ≥ 3 mm in proptosis of the study eye, without worsening in the contralateral eye) at weeks 15, 24, and 48; and the time to first overall response through week 24

The endpoint for assessing the impact on the composite response rate is the composite response rate in the study eye at weeks 15, 24, and 48 (defined as the percentage of participants meeting at least two of the following four criteria without worsening in the contralateral eye: (a) reduction in palpebral fissure width ≥ 2 mm; (b) decrease of ≥ 1 point in the five-item CAS; (c) reduction in proptosis ≥ 2 mm; (d) improvement in ocular motility ≥ 8°)

The endpoints for assessing the impact on CAS include the percentage of participants with a CAS of 0 or 1 in the study eye and the change from baseline in CAS at weeks 15, 24, and 48, as well as the time to first achievement of a CAS of 0 or 1 in the study eye through week 24

The endpoints for assessing the efficacy in improving diplopia include the diplopia response rate (defined as the percentage of participants with an improvement of ≥ 1 grade in the Gorman Diplopia Score) and the complete resolution rate (defined as the percentage of participants with a Gorman Diplopia Score of 0), as well as the change from baseline in the diplopia score at weeks 15, 24, and 48; and the time to first diplopia response and first complete resolution of diplopia through week 24

The endpoint for assessing the efficacy in improving ocular motility and eyelid retraction is the change from baseline in ocular motility and palpebral fissure width of the study eye at weeks 15, 24, and 48

The endpoint for assessing the efficacy in improving the contralateral eye includes the change from baseline in proptosis, proptosis response rate, overall response rate, change from baseline in CAS, the proportion of participants achieving a CAS of 0 or 1, and the treatment response rate at weeks 15, 24, and 48

The endpoint for assessing the impact on the Graves’ Ophthalmopathy Quality of Life (GO-QoL) questionnaire is the change from baseline in the total score, as well as in the visual functioning and appearance subscale scores, at weeks 15, 24, and 48

The endpoint for assessing the safety and tolerability is the number, incidence, severity, and relationship to the study drug/treatment of all ocular and systemic adverse events (AEs), treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs), and serious adverse events (SAEs)

Key secondary endpoints included the change in proptosis from baseline in the study eye at week 15 and the overall response rate (defined as a simultaneous reduction of ≥ 2 mm in proptosis and ≥ 2 points in CAS in the study eye, without corresponding worsening in the contralateral eye) of the study eye at week 15.

Safety will be comprehensively evaluated throughout the study via monitoring and collection of adverse events (AEs), concomitant medications, and a series of assessments, including comprehensive ophthalmic examinations: routine assessments (BCVA, measurement of palpebral fissure width/height, pupillary examination, color vision assessment, intraocular pressure, slit-lamp examination, fundus examination, external ocular photography, and visual field testing), along with evaluation of the degree of ocular motility restriction, diplopia, proptosis, and CAS; together with vital signs, systemic physical examinations, laboratory tests (including hematology, blood biochemistry, urinalysis, fasting blood glucose, HbA_1C, coagulation function, thyroid function, pathogen screening, and tuberculosis screening), and electrocardiograms (ECGs). In addition, for female participants of childbearing potential, a serum pregnancy test will be performed during screening, and urine pregnancy tests will be performed prior to drug administration at all subsequent visits. To exclude individuals with hearing impairment and to monitor potential auditory changes, pure-tone audiometry will be performed at screening and throughout the study. Furthermore, to exclude participants with severe osteoporosis and to assess changes in bone mineral density, bone mineral density will be measured (e.g., dual-energy X-ray absorptiometry scans) at screening and at specified intervals during the study.

All AEs will be recorded throughout the study and coded using the Medical Dictionary for Regulatory Activities terms. AEs severity will be graded according to standardized criteria: mild (symptoms cause noticeable discomfort but do not interfere with daily activities), moderate (symptoms cause sufficient discomfort to reduce or impact daily functioning), or severe (symptoms result in the inability to perform normal daily activities or work).

Based on the clinical experience with IGF-1R inhibitor, adverse events of special interest (AESIs) include infusion-related reactions (both immediate and delayed), hypoacusis, and hyperglycemia. Hypoacusis is defined as an increase of ≥ 15 dB in the average threshold of pure tone audiometry (bone conduction) at a minimum of two consecutive test frequencies (0.5, 1, 2, and 4 kHz) in at least one ear compared to the baseline. Hyperglycemia is defined by any of the following criteria during treatment: HbA_1C ≥ 6.5% with an increase of > 0.5% from baseline, or addition of new antihyperglycemic medications to the existing regimen, or a > 10% dose escalation of existing antihyperglycemic medication. Additionally, potential risks and AEs associated with glucocorticoid treatment will be closely monitored throughout the study.

Planned Outcomes

The primary and key secondary endpoints are detailed in the Measurements section. In brief, the primary endpoint is the proptosis response rate at week 15; key secondary endpoints include change in proptosis and overall response rate at week 15. Safety outcomes include AEs, with special interest in infusion-related reactions, hypoacusis, and hyperglycemia.

Data Collection

All study data will be collected by trained investigators using prespecified Case Report Forms. Source documents will be retained according to local regulations. The final database will be locked prior to statistical analysis.

Data Analysis

Approximately 92 participants will be randomized in a 1:1 ratio to teprotumumab N01 or IVGC, providing > 90% power at a two-sided alpha level of 0.05 to detect superiority of teprotumumab N01 over IVGC, assuming a week 15 proptosis response rate of 70% for teprotumumab N01 (based on teprotumumab N01 preliminary data [20]) and 36% for IVGC (a meta-analysis estimate from three studies [21–23]). The detailed results of this meta-analysis are presented in Table 2.

Table 2.

Results of a meta-analysis of three clinical studies of IVGC

Studya	Responders/total N in IVGC group
Salvi M, et al., 2015 [21]	1/16
Kahaly GJ, et al., 2018 [22]	11/39
Lanzolla G, et al., 2021 [23]	35/76

	Pooled IVGC response rate (95% CI)
Meta-analysis result	36% (28.2%, 44.4%)

^aDerived from the ATA and ETA consensus statement: Management of Thyroid Eye Disease: A Consensus Statement by the American Thyroid Association and the European Thyroid Association [6]

The Intent-to-Treat (ITT) population will include all randomized participants. Analyses for this population will be based on the treatment group to which participants were randomly assigned. The ITT population will be used for all baseline characteristic summaries and efficacy endpoint analyses. Final baseline characteristics (age, gender, CAS, diplopia severity, and other relevant characteristics) will be fully reported upon study completion.

The primary estimand is the proptosis response rate in the study eye at week 15. The primary analysis will be based on the Cochran–Mantel–Haenszel (CMH) test, stratified by the randomization factor (baseline diplopia). The Mantel–Haenszel method will be used to calculate the between-group difference in the proptosis response rate and its 95% confidence interval (CI).

Should the primary endpoint be statistically significant, key secondary endpoints of the change from baseline in study eye proptosis at week 15 and the overall response rate in the study eye at week 15 will be tested in sequence to control for type I error rate. The continuous endpoints will be analyzed using a mixed model for repeated measures (MMRM) with treatment, visit, treatment-by-visit interaction, and randomization stratification factor as fixed effects, and baseline as a covariate.

Data after week 15 will be summarized descriptively, with no formal between-group comparisons planned.

Ethical Approval

The study will be conducted in compliance with the ethical principles of the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines, and all applicable Chinese laws and regulations. Written informed consent will be obtained from all participants prior to any study-related procedures, and the study protocol will be approved by institutional review boards before the start of the study..

Discussion

This phase 4 clinical trial is primarily designed to demonstrate the superiority of teprotumumab N01 over standard IVGC therapy in reducing proptosis among patients with active moderate-to-severe TED. In addition, the study will comprehensively compare the efficacy and safety profiles of these two guideline-recommended treatments. As the first head-to-head comparative trial between the two therapies, its findings are expected to provide high-level evidence that will significantly advance clinical practice in TED management.

The rationale for this study is grounded in the well-characterized mechanism of action of teprotumumab N01, supported by robust preclinical and clinical evidence. Teprotumumab N01 functions by specifically binding to IGF-1R, thereby blocking the interaction of ligands IGF-1 and IGF-2 with the receptor and effectively suppressing the activation of downstream signaling pathways [15]. This targeted inhibition interrupts the pathological cascade at its origin by suppressing the activation of OFs and their production of hyaluronic acid and other glycosaminoglycans, mitigating inflammation, and inhibiting the differentiation of OFs into adipocytes or myofibroblasts [10, 11]. Through these mechanisms, teprotumumab N01 holds strong therapeutic potential to reduce disease activity and severity in patients with TED (Fig. 2).

Fig. 2.

Mechanism and outcome comparison: IVGC vs. anti-IGF-1R mAb in thyroid eye disease (TED). IVGC intravenous glucocorticoid, IGF-1R insulin-like growth factor-1 receptor, OF orbital fibroblast, TSHR thyroid-stimulating hormone receptor. Illustrated by the author using Adobe Illustrator

The clinical development program of teprotumumab N01 provides robust evidence for its efficacy and safety. The pivotal registration study demonstrated a significantly higher proptosis response rate in the study eye at week 24 with teprotumumab N01 compared to placebo (85.8% vs. 3.8%, p < 0.0001), comparable to the phase 3 study data for TEPEZZA (83%) [14, 15]. Furthermore, the proportion of participants achieving an overall response, those with a CAS of 0 or 1, and the least-squares mean change from baseline in proptosis in the study eye at week 24 were all significantly greater in the teprotumumab N01 group versus placebo (80.2% vs. 3.6%; 83.5% vs. 16.4%; − 2.85 mm vs. − 0.02 mm, all p < 0.0001) [14]. In terms of the efficacy of IVGC, results varied across studies. According to the available literature, only one small randomized controlled trial (RCT), involving 16 patients with TED, has directly compared IVGC with placebo and reported beneficial outcomes [24]. Most evidence on IVGC efficacy comes from RCTs comparing IVGC with alternative or combination therapies [25–27], which indicate improvement in disease activity in up to 80% of IVGC-treated patients, comparable to outcomes observed with IGF-1R inhibitor [6, 20]. A recent retrospective cohort study utilizing the TriNetX Analytics platform demonstrated that while the overall rate of additional interventions was similar between intravenous methylprednisolone and teprotumumab-treated patients, the intravenous methylprednisolone group required significantly fewer subsequent surgical interventions at both 12 months (3.8% vs. 8.8%) and 18 months (4.8% vs. 10.0%) [28]. However, indirect comparisons suggest that IVGC is less effective in reducing disease severity, particularly in proptosis (0–46%) and diplopia (0–19%), where IGF-1R inhibitors demonstrate superior results [6, 13]. These findings provide a strong rationale for the current study, designed to directly compare teprotumumab N01 with standard IVGC therapy.

The selection of IVGC as the active comparator enables a direct comparison against the current standard of care, ensuring clinical relevance for practice. As recommended by multiple guidelines and consensus [1, 5, 6], a cumulative dose of 4.5 g methylprednisolone over 12 weeks, administered either as monotherapy or in combination with other immunosuppressants, has a certain efficacy in active moderate-to-severe TED, and is well tolerated in most patients. Therefore, it is the most commonly used IVGC regimen for active moderate-to-severe TED. For more severe cases presenting with motility disturbances, diplopia, significant proptosis, or severe soft-tissue involvement, guidelines recommend an intensified regimen with a higher cumulative dose of 7.5 g methylprednisolone over 12 weeks [1, 5]. This dosing strategy is directly derived from comparative studies, which confirmed the additional benefit of higher doses in severe cases while also establishing a concomitantly significant increase in the risk of drug-induced AEs [29]. Other glucocorticoid therapy options, for example, oral administration of glucocorticoids, are less recommended due to higher toxicity and lower efficacy [1, 5].

The proptosis response rate has become a widely accepted primary endpoint in clinical trials of IGF-1R inhibitors since the introduction of TEPEZZA and has received recognition from the FDA [12, 13]. In this trial, setting the proptosis response rate at week 15 as the primary endpoint enables a timely and efficient assessment of treatment efficacy. While response to IVGC therapy usually occurs early, it may be delayed in some patients; hence, partial responders are encouraged to complete the full 12-week treatment course [30]. In this study, a 4-week interval between the end of IVGC therapy (week 11) and the primary assessment (week 15) allows sufficient time for the full therapeutic effect of glucocorticoids to emerge. Nevertheless, IVGC therapy is associated with a high relapse rate, ranging from 21 to 40% within 12 weeks after discontinuation [27]. Regarding the efficacy in proptosis of teprotumumab N01, data from its phase 3 trial indicate a proptosis response rate of approximately 70% at week 15. Although slightly lower than the response observed at week 24, the majority of patients had already achieved clinically meaningful improvement by week 15 [20]. Considering the importance of early efficacy assessment, the timing of peak response, and to capture maximal benefit before potential relapse, week 15 emerges as a scientifically robust and clinically meaningful time point. In addition, week 15 was selected to avoid bias from the relapse of IVGC therapy [27], aligns with clinical practice for assessing sustained response, and allows timely crossover for IVGC-nonresponsive participants, addressing ethical concerns that would arise with a later week 24 endpoint. Furthermore, a comprehensive set of secondary endpoints assessed at predefined intervals, including overall response rate, diplopia, quality of life, and imaging assessments, will characterize the multi-dimensional treatment profile of teprotumumab N01.

A key feature of the study protocol is its two-phase treatment design, including an initial treatment period (day 1 to week 12) followed by an extended treatment and observation period (week 13 to week 48), incorporating a pre-specified crossover strategy for participants in the IVGC group who experience disease progression or an inadequate response to IVGC therapy. This design enables a direct head-to-head comparison between teprotumumab N01 and IVGC during the initial treatment period, while serving both ethical and scientific purposes. Ethically, given the suboptimal response (pooled rate 36% [21–23]) and high relapse rate (21–40% within 3 months after IVGC discontinuation [27]), crossover allows non-responders or relapsed participants to promptly switch to an alternative therapy, thereby avoiding disease deterioration. Scientifically, this design generates much-needed efficacy data on teprotumumab N01 in patients refractory to first-line IVGC, filling a current data gap in the TED treatment landscape regarding second-line/switch therapy strategies. Achievement of the primary endpoint would establish a clear, evidence-based hierarchy between these therapeutic strategies in the management of active TED. The crossover component further enables evaluation of whether patients who are initial non-responders or partial responders to IVGC can benefit from delayed anti-IGF-1R therapy with teprotumumab N01. Furthermore, the follow-up period will yield valuable data on the durability of treatment response, as well as the incidence, timing, and risk of TED relapse over the 1-year trial duration. Collectively, findings from this study are expected to shape the evolving treatment paradigm for TED and inform future updates of clinical practice guidelines.

In summary, this study represents a pivotal step addressing the existing evidence gap between IGF-1R targeted therapy and standard IVGC therapy. The ultimate goal is to provide a more comprehensive and effective treatment alternative for patients with active moderate-to-severe TED.

Strengths and Limitations

The core strength of this study resides in its innovative, head-to-head design, being the first trial to directly compare teprotumumab N01 with the current standard of care, IVGC, rather than relying on indirect comparisons with placebo.

At the same time, we acknowledge that the open-label nature of the study may introduce potential bias in the evaluation of subjective outcomes, such as patient-reported outcomes. However, this risk will be effectively mitigated through the involvement of independent and masked assessors, who have no access to treatment assignment (see Sect. 2 for full details). The primary endpoint is proptosis response measured in millimeters using a Hertel exophthalmometer, which is a highly standardized, relative objective, and quantifiable measurement less susceptible to observer bias. Furthermore, MRI will be used to quantify changes in proptosis, as well as in the anatomy and signal intensity of key orbital tissues, including orbital fat, extraocular muscles, and lacrimal gland. MRI measurements are largely objective and will be evaluated centrally by masked readers, further mitigating detection bias.

Additionally, as thyroid dysfunction is an established independent risk factor for TED severity and progression [31], we applied a ± 50% thyroid function threshold as an exclusion criterion to eliminate participants with severe thyroid dysfunction, ensure baseline homogeneity, minimize confounding from metabolic and immune disturbances, and align with mainstream guidelines recommending stable euthyroidism in all TED patients.

However, the RESTORE-4 trial excludes participants with active, moderate-to-severe TED previously treated with glucocorticoids (cumulative dose ≥ 1 g methylprednisolone equivalent) or biologics, individuals with symptoms of active TED lasting longer than 12 months, and those with progressive, treatable, active TED with low CAS-a phenotype more prevalent in East Asian populations, represented by China [32, 33]. These may limit the generalizability of the findings to these underrepresented groups.

Ethics and Dissemination

Ethical Approval

The study will be conducted in compliance with the ethical principles of the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines, and all applicable Chinese laws and regulations. Written informed consent will be obtained from all participants prior to any study-related procedures, and the study protocol will be approved by institutional review boards before the start of the study.

Dissemination

The results of this trial will be submitted for publication in a peer-reviewed journal. Data sharing will follow the policy stated in the Data Availability statement.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Profs Xianqun Fan and Huifang Zhou will have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Xianqun Fan, Huifang Zhou, Lei Qian, Haiyang Zhang, Jing Sun, Yinwei Li, Junjie Deng, Bingxue Zhu, Shujie Lu. Drafting of the manuscript: Haiyang Zhang, Junjie Deng, Wen Zhang, Han Han-Zhang, Yulia Jin. Critical review of the manuscript for important intellectual content: Xianqun Fan, Huifang Zhou, Lei Qian, Haiyang Zhang, Yazhuo Huang, Shuo Zhang, Sisi Zhong, Junjie Deng, Wen Zhang, Han Han-Zhang. Statistical analysis: Wen Zhang. Obtained funding: Lei Qian. Supervision: Huifang Zhou, Xianqun Fan, Han Han-Zhang, Lei Qian. We would like to express our sincere gratitude to Profs Jianmin Liu and Terry J. Smith for their valuable insights and constructive discussions during the development of the study protocol.

Funding

This study will be funded by Innovent Biologics, Construction of a Precision Diagnosis and Treatment Cohort for Thyroid Eye Disease (JYHX2025049). The journal’s Article Processing Charge and Rapid Service Fee was funded by the Construction of a Precision Diagnosis and Treatment Cohort for Thyroid Eye Disease (JYHX2025049).

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Haiyang Zhang, Jing Sun, Yinwei Li, Yazhuo Huang, Shuo Zhang, Sisi Zhong, Huifang Zhou, and Xianqun Fan have nothing to disclose. Junjie Deng, Bingxue Zhu, Shujie Lu, Wen Zhang, Han Han-Zhang, Yulia Jin, and Lei Qian are employees of Innovent Biologics. The investigators (with Xianqun Fan and Huifang Zhou as the principal investigators) will maintain scientific independence. No other disclosures were reported.

Ethical Approval

The study will be conducted in compliance with the ethical principles of the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines, and all applicable Chinese laws and regulations. Written informed consent will be obtained from all participants prior to any study-related procedures, and the study protocol will be approved by institutional review boards before the start of the study.