Table 2.

Key RCTs on novel treatment approaches of GO

Therapeutics [ref.]	Mechanism of action	Study design/patient population	Key outcomes	Results (intervention vs. control group)
MMF [48]	Dual antiproliferative effect on both B and T cells	• Single-center RCT • 174 euthyroid patients with active moderate-to-severe GO • MMF 1 g daily vs. GC therapy (both for 24 weeks)	Primary • Response rates at weeks 12 and 24 (improvement in ≥3 parameters of the composite index without deterioration in any objective parameters)	• Week 12: 79 vs. 51% Week 24: 91 vs. 68%
MPS [49]	Dual antiproliferative effect on both B and T cells	• Multicenter RCT • 164 euthyroid patients with active moderate-to-severe GO • MPS 720 mg daily (24 weeks) plus weekly IVGC (12 weeks) vs. weekly IVGC (12 weeks) alone	Primary • Response rate at week 12 (improvement in ≥2 parameters of the composite index without deterioration in any parameters); relapse rates at weeks 24 and 36 Post hoc • Response rate at week 24 • Sustained response at week 36 • GO-QoL scales	• No significant difference between groups • 71 vs. 53% • 67 vs. 43% • No significant difference between groups
RTX [61]	B cell depletion	• Single-center RCT • 32 euthyroid patients with active moderate-to-severe GO • RTX (i.v. 2 g/500 mg) vs. weekly IVGC (12 weeks with cumulative dose 7.5 g)	Primary • Decrease in CAS of ≥2 points or disease inactivation (CAS <3) at week 24 Secondary • Improvement in severity signs (NOSPECS class, proptosis and lid width, eye motility) • GO reactivation • Percentage of patients requiring surgical procedures after 12 months • GO-QoL scales	• 100 vs. 69% • Better ocular motility in RTX group • 0 vs. 33% • 33 vs. 75% • Visual functioning scores improved significantly in RTX group only
RTX [62]	B cell depletion	• Single-center RCT • 25 euthyroid patients with active moderate-to-severe GO • RTX (i.v. 2 g) vs. placebo	Primary • Decrease in CAS (assessed as a continuum and separately as an improvement by ≥2 points) at week 24	• No significant difference between groups in both primary and all secondary outcomes
TCZ [80]	Anti-IL-6R MAb	• Multicenter RCT • 32 euthyroid patients with GC-resistant active moderate-to-severe GO • TCZ (i.v. 8 mg/kg once every 4 weeks for 4 doses) vs. placebo	Primary • Decrease in CAS of ≥2 points at week 16 Secondary/post hoc • Decrease in CAS of ≥2 points at week 40 • CAS <3 at weeks 16 and 40 • Disease severity • GO-QoL scales	• 93 vs. 59% • 87 vs. 59% • Week 16: 87 vs. 35% Week 40: 80 vs. 47% • No significant improvement of proptosis and diplopia in the TCZ group • More patients in the TCZ group reported improvement in GO-QoL (47 vs. 35%)
TPT [94, 95]	Anti-IGF-1R-blocking MAb	• Two multicenter RCTs • 170 euthyroid patients with active moderate-to-severe GO in total • TPT (once every 3 weeks for 8 i.v. infusions; first dose 10 mg/kg, remaining 7 doses 20 mg/kg)	• Overall responders (reduction of ≥2 points in CAS and reduction of ≥2 mm in proptosis) at week 24 • CAS of 0 or 1 • Reduction of ≥2 mm in proptosis • Diplopia response • GO-QoL scales	• 73 vs. 14% • 62 vs. 22% • 77 vs. 15% • 68 vs. 27% • TPT group reported higher scores and greater improvement in overall visual functioning and appearance scores

CAS, clinical activity score; GC, glucocorticoid; GO, Graves' orbitopathy; GO-QoL, Graves' orbitopathy-specific quality of life; i.v., intravenous; IGF-1R, insulin-like growth factor 1 receptor; IL-6R, interleukin 6 receptor; IVGC, intravenous glucocorticoid; MAb, monoclonal antibody; MMF, mycophenolate mofetil; MPS, mycophenolate sodium; RCT, randomized controlled trial; RTX, rituximab; TCZ, tocilizumab; TPT, teprotumumab.