Clinical Trials in Oculoplastics

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Article initiated by:

Jainam Shah, Gagandeep Mudhar, Jason Zheng, Sachin Pathuri, Dina Abdelsalam, Nagham Al-Zubidi, MD, Andrew Go Lee, MD, Bruce Becker, MD

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Jainam Shah, Gagandeep Mudhar, Jason Zheng, Sachin Pathuri, Nagham Al-Zubidi, MD, Andrew Go Lee, MD, Dina Abdelsalam, Bruce Becker, MD

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This article reviews the evolving landscape of clinical trials in oculoplastics, with a particular focus on thyroid eye disease (TED), where rigorous randomized studies have shifted clinical practice by demonstrating measurable improvements in proptosis, inflammation, and quality of life. By summarizing major clinical trials, real-world outcomes, safety data, and current evidence gaps across oculoplastic conditions, this review aims to help ophthalmologists and researchers integrate high-level clinical trial data into decision-making while highlighting key areas for future research as the field continues to advance.

Overview

Clinical trials in Oculoplastics have reshaped the management of thyroid eye disease (TED) over the past decade. Teprotumumab introduced a medical therapy capable of reversing proptosis-a domain previously managed primarily with surgery-while earlier investigations with corticosteroids, mycophenolate, and radiotherapy laid the groundwork for immunosuppressive strategies. This article reviews major randomized trials in the field of Oculoplastics, including OPTIC, OPTIC-X, MINGO, and CIRTED, along with real-world data, safety outcomes, guideline frameworks, and evolving practice patterns.

Trial Design and Common Endpoints

Thyroid Eye Disease (TED) studies typically assess:

1. Proptosis reduction (mm): ≥2 mm is clinically significant.
2. Clinical Activity Score (CAS): 0–1 indicates inactive disease.
3. Diplopia grading: Assesses motility impairment.
4. GO-QoL (Graves' Ophthalmopathy Quality of Life questionnaire): Measures functional and appearance-related quality of life.
5. Composite outcomes: Integrate structural and inflammatory domains.

These measures are standardized through EUGOGO (European Group on Graves' Orbitopathy) guidelines.

Major Randomized Controlled Trials in Thyroid Eye Disease

OPTIC Trial (Teprotumumab vs Placebo)

Objective

To evaluate whether teprotumumab improves proptosis, inflammation and quality of life in active, moderate-to-severe TED.

Design  

Phase 3, multicenter, double-masked RCT comparing teprotumumab with placebo over 24 weeks.

Main Outcome Measures  

Proptosis response, CAS reduction, diplopia improvement, GO-QoL change and safety.

Results  

Teprotumumab showed large and consistent improvements across TED domains. Mean proptosis reduction was −2.82 mm in the treatment group compared with −0.54 mm in the placebo group, with 83% achieving a ≥2 mm response. CAS scores fell rapidly, and by Week 24, 59% of treated patients had CAS 0–1 versus 21% of placebo. Diplopia improved in 68% of treated patients, and several achieved complete resolution. GO-QoL functional and appearance subscores improved significantly. Soft-tissue inflammation, eyelid retraction, and orbital congestion improved across subdomains. Reported adverse events were generally mild to moderate, including muscle spasms, and hearing changes.

Adverse events were generally mild to moderate, most commonly muscle spasms (32%), alopecia (20%), nausea (15%), diarrhea (15%), fatigue (12%) and hearing symptoms (10%).

Conclusions  

Teprotumumab offers a transformative shift in treating active, moderate-to-severe TED because it consistently improves both inflammatory activity and true orbital anatomy. The magnitude of proptosis reduction, diplopia improvement, and GO-QoL gains in OPTIC exceeds what has historically been achievable with corticosteroids or radiotherapy. Importantly, the improvement in proptosis, an anatomic feature previously thought to require surgery, redefined what medical therapy can accomplish in TED. Although adverse effects such as muscle spasms and hearing changes require monitoring, the overall therapeutic effect is broad, rapid, and clinically

Clinical Pearl

Teprotumumab provides an anatomical improvement similar to surgical decompression while simultaneously controlling inflammation - a unique profile among TED therapies.

OPTIC-X Extension Study

Objective

To evaluate durability of response and benefit of retreatment in patients from the OPTIC and Phase 2 trials.

Design  

Open-label extension involving 112 participants previously treated with or eligible for teprotumumab with follow-up to 72 weeks.

Main Outcome Measures  

1. Sustained proptosis response
2. CAS stability
3. Diplopia persistence
4. GO-QoL durability
5. Additional therapy requirements

Results  

Among prior responders, mean proptosis reduction was −3.33 mm at Week 24 and remained −2.68 mm at Week 72. CAS remained low in over 90% of responders. Diplopia improvements persisted in 88.6% of patients. GO-QoL gains were maintained, averaging 15–18 points at long-term follow-up. Retreatment benefited patients who relapsed or had incomplete responses, producing additional millimeters of proptosis improvement. Only 17% required any other TED therapy over the 72-week period, and decompression was needed in only 2.8%.

Conclusions  

OPTIC-X demonstrates that teprotumumab's clinical benefits extend far beyond the initial treatment window, with most patients maintaining substantial proptosis reduction, low inflammatory scores, and improved diplopia at more than one year. Retreatment proved effective for patients who relapsed or had incomplete responses, reinforcing the durability and flexibility of IGF-1R blockade as a therapeutic strategy. The low rate of additional interventions, especially surgical decompression, highlights that teprotumumab meaningfully shifts long-term management by reducing procedural burden. OPTIC-X supports the idea that teprotumumab can induce a sustained remission-like state in many patients.

Clinical Pearl

Retreatment is reasonable for partial improvement or relapse, and most responders maintain long-term stability after a single course.

MINGO Trial (IV Methylprednisolone ± Mycophenolate)

Objective  

To determine whether adding mycophenolate mofetil enhances the efficacy of IV methylprednisolone in active TED.

Design  

Randomized, observer-masked trial.

Main Outcome Measures:

1. CAS improvement
2. Relapse rates
3. Safety

Results  

The combination regimen outperformed steroids alone. By week 24, 71% of patients receiving both IVMP and mycophenolate met overall response criteria compared with 53% receiving IVMP alone. CAS reduction was greater in the combination arm (−4.2 vs −3.2), and relapse occurred less frequently (21% vs 34%). Quality-of-life scores improved more robustly in the combination group.

Conclusions  

The MINGO trial shows that adding mycophenolate mofetil meaningfully improves the stability and durability of responses achieved with intravenous methylprednisolone alone. Reduced relapse, lower treatment failure rates, and more consistent improvement across soft-tissue and eyelid parameters help justify its use as a preferred steroid-sparing agent when biologic therapy is not available. While proptosis changes remain limited, consistent with traditional immunosuppressive treatments, MMF contributes to a more predictable and sustained disease course. MINGO clarifies the modern role of IVMP plus MMF as the most evidence-supported nonbiologic regimen for moderate, active TED.

Clinical Pearl  

IVMP plus mycophenolate is the most evidence-supported non-biologic immunosuppressive regimen for moderate-to-severe active TED.

CIRTED Trial (Radiotherapy + Azathioprine + Prednisolone)

Objective  

To determine whether adding radiotherapy or azathioprine improves outcomes in active TED treated with prednisolone.

Design  

Multicenter, double-blind, factorial RCT.

Main Outcome Measures

1. A binary composite clinical outcome score at 48 weeks, which required improvement in at least one major criterion (diplopia, eye movement, or proptosis) or two minor criteria (lid aperture, soft tissue involvement, visual acuity, or patient-judged improvement).
2. The ophthalmopathy index at 48 weeks, quantifying change in ocular deformity and visual dysfunction.
3. Clinical Activity Score (CAS) at 12 weeks, designated as a co-primary outcome to assess early disease activity.

Results  

Across all groups, disease activity steadily declined on corticosteroids, with median CAS improving from 5 at baseline to 3 by week 12 and 2 by week 48 (p<0.0001). Azathioprine demonstrated borderline statistical benefit on the composite clinical outcome (adjusted OR 2.56, p=0.05). Radiotherapy did not improve the primary endpoint but offered selective motility benefits. Total Eye Score improved from 15.1 to 9.36 at week 48 (p<0.0001), and GO-QoL scores increased across all domains.

Conclusions  

CIRTED clarifies the targeted but limited benefits of radiotherapy and azathioprine when used alongside corticosteroids. Radiotherapy offers meaningful improvement in restrictive motility problems, while azathioprine helps maintain steroid-induced gains and reduces treatment failure. However, neither treatment produces significant proptosis change or structural remodeling, emphasizing the limitations of historical TED therapy. CIRTED helps contextualize why biologic therapies have become essential: they address the deeper anatomic drivers of disease, not just inflammation or motility. The trial underscores how RT and AZA fit into the contemporary therapeutic landscape—useful in select scenarios but not comprehensive solutions.

Clinical Pearl  

CIRTED reflects the limits of pre-biologic therapy: inflammation can improve, but proptosis rarely does.

Additional Clinical Evidence in Thyroid Eye Disease

Real-World Outcomes for Teprotumumab

Real-world data reinforce the effectiveness of teprotumumab while highlighting practical considerations. In a multicenter cohort of patients with long-standing, low-activity TED, teprotumumab achieved a proptosis response in 61.9% of treated patients compared with 25% of placebo-treated patients. GO-QoL visual function improved by a mean of 12.15 points versus 5.73 with placebo, and appearance scores improved numerically. Hyperglycemic events occurred in 14.6% of patients receiving teprotumumab, emphasizing the need for metabolic monitoring during therapy.

Clinical Pearl

Teprotumumab retains efficacy even in chronic, low-activity TED, but metabolic surveillance is essential.

Safety and Adverse Effects

Hearing Changes

Audiometric studies document that a subset of patients receiving teprotumumab develop measurable sensorineural threshold shifts. Symptoms include tinnitus, subjective muffled hearing, and autophony. Though most cases are mild, some persist beyond treatment completion.

Clinical Pearl  

Baseline and interval audiometry should be considered for patients with pre-existing hearing loss or new symptoms during therapy.

Hyperglycemia

A prospective cohort of 42 patients found that 83.3% experienced a rise in HbA1c of at least 0.1% and 30.9% had a rise of at least 0.5%. Mean increases were greatest in diabetics (1.3%), followed by prediabetics (0.7%).

Clinical Pearl  

Hyperglycemia typically emerges early and is most pronounced in patients with pre-existing metabolic disease.

Immunomodulators and Steroid-Sparing Therapies

Mycophenolate Meta-analysis

Although early data for mycophenolate mofetil (MMF) in TED were mixed, more rigorous analyses indicate that when combined with intravenous methylprednisolone, mycophenolate improves clinical outcomes compared with corticosteroid monotherapy. One meta-analysis confirmed both higher overall response rates and lower relapse with mycophenolate-based regimens compared with corticosteroids alone.

The MINGO trial evaluated IV methylprednisolone alone versus IV methylprednisolone plus mycophenolate in patients with active, moderate-to-severe disease and found superior composite response rates at 24 weeks with the combination regimen. While evidence remains limited by small sample sizes, these results support the additive immunosuppressive effect of mycophenolate in reducing clinical activity and preventing early relapse. 

Clinical Pearl  

Mycophenolate is among the most studied non-biologic immunosuppressants in TED. When used adjunctively with corticosteroids, it may enhance disease control and potentially reduce steroid exposure.

Rituximab

Rituximab, a B-cell depleting monoclonal antibody targeting CD20, has demonstrated benefit in inflammatory inactivation in TED. Studies and data show that rituximab improves inflammatory inactivation and reduces relapse, though effects on proptosis and motility are modest. Across other cohort studies and smaller trials, rituximab reduces clinical activity score (CAS) and decreases autoantibody titers, although results are inconsistent, and definitive large-scale randomized data are lacking. Comparisons with other biologics suggest rituximab improves inflammatory measures but does not reliably produce meaningful proptosis or diplopia improvements. Cost, variable efficacy, and lack of head-to-head trials limit its routine use.  

Clinical Pearl  

Rituximab is most useful in highly inflammatory presentations with a need for steroid-sparing, but its role remains secondary given variable structural effects.

Tocilizumab

Tocilizumab, an interleukin-6 receptor antagonist, has been evaluated in steroid-resistant active TED. In steroid-resistant TED, tocilizumab significantly reduced CAS and improved several inflammatory parameters. A double-blind randomized controlled trial comparing tocilizumab versus placebo demonstrated that a greater proportion of patients receiving tocilizumab achieved meaningful reductions in CAS at 16 weeks, though effects on proptosis and motility were modest. Observational case series further support these anti-inflammatory effects, but studies to date are small and follow-up limited. Larger, long-term RCTs are needed to clarify both efficacy and safety.

Clinical Pearl  

Tocilizumab is a reasonable second-line biologic for persistent inflammatory disease despite steroids, with most benefits seen in activity rather than structural change.

Selenium

In a RCT of patients with mild active TED conducted in regions with selenium insufficiency, selenium supplementation significantly reduced disease progression and improved both functional and appearance-related GO-QoL scores compared with placebo. Its good safety profile and low cost make selenium appealing as supportive therapy in mild disease, although benefits appear most pronounced in populations with low baseline levels.

Clinical Pearl  

Selenium is safe and inexpensive and may slow progression in mild active TED, especially where deficiency is prevalent.

IGF-1R Pathophysiology

Orbital fibroblasts in TED overexpress insulin-like growth factor-1 receptor (IGF-1R), which forms a signaling complex with the thyroid-stimulating hormone receptor (TSHR). This interaction amplifies pro-inflammatory cytokine production and drives adipogenesis and extraocular muscle expansion, both key disease mechanisms. Teprotumumab, a human monoclonal antibody targeting IGF-1R, disrupts this signaling, underpinning its ability to reduce both inflammation and proptosis, an effect rarely seen with traditional immunosuppression.

Guideline Frameworks

The European Group on Graves’ Orbitopathy and other consensus guidelines provide standardized frameworks for assessing TED severity, scoring activity with CAS, interpreting GO-QoL outcomes, and sequencing therapies from mild to sight-threatening disease. These standardized approaches also guide clinical trial design and endpoint selection, improving comparability across studies and strengthening evidence synthesis.

Surgical Trends

Since the approval of teprotumumab and widespread adoption, retrospective cohorts and registry data show a marked decrease in the frequency and earlier timing of orbital decompression surgeries. Many centers now reserve decompression for residual structural disease after adequate medical therapy or for chronic sequelae, rather than as early intervention during active inflammation, reflecting the medical therapy’s ability to reduce proptosis and soft tissue volume.

Clinical Pearl  

Orbital decompression is increasingly considered a secondary, targeted procedure for residual anatomic defects after optimal medical therapy.

Clinical Trials in Other Oculoplastics Domains

Clinical trial activity in other oculoplastics domains remains limited, with most randomized studies focused on lacrimal interventions and periocular reconstruction. Consequently, much of current practice continues to rely on retrospective and single-center evidence.

For example, trials have compared everting sutures vs. lateral tarsal strip for lower-eyelid entropion, randomized versus secondary approaches in dacryocystorhinostomy for acute dacryocystitis, and scalpel vs. electrocautery skin incision techniques in upper-eyelid blepharoplasty, though these remain rare and cover only a fraction of oculoplastic practice.

Limitations of Current Evidence

Current evidence in oculoplastics is limited by several important potential shortcomings. Many studies, especially surgical and procedural reports, have small sample sizes and are often retrospective or descriptive, which limits statistical power and generalizability. There is also a paucity of long-term follow-up data, making it difficult to assess sustained effectiveness and late complications of interventions. In addition, head-to-head comparisons between biologic therapies are uncommon, and randomized controlled trials remain rare outside of a few focused areas such as lacrimal and periocular surgery.

Future Directions

Although TED has seen transformative randomized trials, evidence from high-quality clinical studies in other oculoplastics domains remains sparse, with most surgical and therapeutic approaches supported mainly by retrospective data or small case series rather than prospective trials. Research gaps noted in the literature include optimal surgical techniques for complex eyelid reconstructions, lacrimal system disorders, and orbital fracture repair, where comparative trials are needed to define best practices and generate evidence-based guidelines. The lack of standardized outcome measures and long-term data further limits the ability to draw clear conclusions across studies and underscores the need for larger, multicenter randomized trials in these areas.

In parallel, innovation in reconstructive materials and biomaterials offers promising avenues for investigation, yet clinical evidence on efficacy and reproducibility is insufficient, and there are no definitive evidence-based recommendations for many emerging technologies. Future clinical trials should therefore prioritize rigorous evaluation of new implants, tissue-engineered constructs, and minimally invasive techniques while incorporating validated functional and patient-reported outcomes. These efforts will help close longstanding evidence gaps in oculoplastics and improve surgical care across eyelid, lacrimal, and orbital disorders.