Orbital Radiotherapy in Grave's Ophthalmopathy 1 Week vs 2 Weeks: A Phase II Randomized Controlled Trial (OraGO-1 Trial)
Phase: PHASE3
Conditions: Thyroid Associated Ophthalmopathy
Sponsor: Janjira Petsuksiri

 
 
 
 
 
 
 
 
Orbital Radiotherapy in Graves’ Ophthalmopathy for 1 week versus 2 weeks: 
 
A Phase II Randomized Controlled Trial (ORaGO-1 Trial) 
 
 
(NCT number N/A) 
SiCOA 208/2024 
Siriraj IRB Protocol Approval Date: March 15, 2024 
 
Date of updated document: April 27 2024 
 
 
 
 
 
 
 
                                                                                            Janjira Petsuksiri, M.D. 
Faculty of Medicine Siriraj Hospital, Mahidol University  
2 Wanglang Rd., Bangkok, Thailand 
                                                                                             janjira.pet@mahidol.ac.th 
 
 

OraGo-1 Trial 
 
Backgrounds 
 
Graves' ophthalmopathy (GO) is an autoimmune disease primarily affecting orbital fibroblasts. The severity of GO 
is classified as mild, moderate to severe, or sight-threatening by the European Group of Graves' Orbitopathy 
(EUGOGO), based on subjective and objective criteria. Moderate to severe GO presents with specific signs, 
including eyelid retraction, soft tissue involvement, and exophthalmos. Disease activity is assessed using the 
Clinical Activity Score (CAS), with active GO defined as CAS ≥ 3. Treatment typically begins with intravenous 
methylprednisolone (IVMP), with orbital radiotherapy (RT) considered as a second-line option for non-responsive or 
intolerant patients. Low Dose Radiotherapy (LD-RT) is hypothesized to exert anti-inflammatory, anti-proliferative, 
and immunomodulatory effects. Studies have shown efficacy of combined LD-RT and IVMP in improving clinical 
severity. Concerns regarding long-term side effects and treatment access exist. Various RT dosing regimens have 
been explored, with differing effects on ocular symptoms (1-8). Our study aims to reduce radiation doses by 
minimizing fractions, aiming to maintain effectiveness while enhancing patient quality of life. 
 
Study Objectives 
This phase II prospective randomized controlled trial aims to compare standard orbital radiotherapy fractionation 
(2 Gy per fraction, 1 fraction per day, total 20 Gy over 2 weeks) with reduced-dose orbital radiotherapy (2 Gy per 
fraction, 1 fraction per day, total of 10 Gy over 1 week) in combination with intravenous methylprednisolone (IVMP) 
for patients with active Grave’s ophthalmopathy. 
 
Primary Objective 
To assess the non-inferiority of outcomes in terms of the proportion of patients transitioning from active (CAS > 4) 
to inactive eye disease (CAS <3) with a CAS drop > 2 points following orbital radiotherapy combined with IVMP, 
comparing standard dose and reduced-dose orbital radiotherapy. 
 
Secondary Objectives 
1. To compare the change in volume of extra-ocular muscles and retrobulbar fat after orbital radiotherapy, 
comparing standard with reduced-dose orbital radiotherapy 
2. To evaluate the efficacy in reducing diplopia, by measuring the difference in prism deviation in primary gaze 
after standard and reduced-dose orbital radiotherapy 
3. To assess differences in quality of life, using the Graves' ophthalmopathy quality of life (GO-QOL) scores (Thai 
version) after standard and reduced-dose orbital radiotherapy.  

OraGo-1 Trial 
 
4. To compare the incidence of the RTOG radiation toxicities after standard and reduced-dose orbital 
radiotherapy. 
5. To examine other ophthalmologic evaluations including visual acuity (VA) and visual fields (VF) between 
standard dose and reduced-dose orbital radiotherapy. 
 
 
Inclusion criteria 
1. Patient with active moderate to severe thyroid eye disease with a CAS > 4 with/ without diplopia before 
starting IVMP 
2. Patient with poor response to 3 doses of IVMP (CAS drop < 1) or CAS score > 3 after 3 doses of IVMP 
3. Patients with diplopia after 3 doses of IVMP 
4. Patients with Graves' Ophthalmopathy who have maintained euthyroidism for a minimum of three months. 
5. Non-pregnant adults (aged 35 years or older 
 
Exclusion criteria 
1. Individuals with severe hypertension or diabetic retinopathy 
 
All patients required full written informed consent. 
 
Withdrawal criteria 
1. Graves' Ophthalmopathy with the potential to cause vision-threatening complications. 
2. Severe complications, such as severe eye inflammation (Grade 3-4) or severe skin complications (Grade 
3-4), as defined by RTOG criteria, or instances of complicating infections necessitating additional 
treatment. 
3. Instances of intolerance will be treated according to the intention-to-treat principle. 
4. Patients experiencing complications due to receiving IVMP. 
 
 
 
 
 
 
 

OraGo-1 Trial 
 
Sample size calculation 
 
The Standard improvement of eye symptoms, as reported in the literature, ranges from 62-85 % after treatment 
(6,8). During the protocol development phase, a one-sided approach was defined. The non-inferiority margin was set 
at 23%, providing 80% statistical power with a one-side α of 0.023. The total sample size calculated by Stata 
(College Station, TX, USA) was 136 eyes (68 eyes in each arm) and shown below. Considering an expected 15% 
loss follow-up rate, the estimated sample size would be 136 eyes (68 eyes per arm). 
 
 
 
 
 
 
 
 
 
 
 
The research project is scheduled to span a total of 4 years, covering the entire project duration. The data 
collection period will also extend over this 4 year, and the researchers affirm the initial schedule.  
Throughout the project, data for all N participants will be consistently gathered until the predetermined 
sample size is attained.  
 
 
 
 
 
 
 
 
 
 
 

OraGo-1 Trial 
 
Statistical analysis plan 
Primary outcome; 
The proportion of changes from active to inactive eye disease. 
              - Proportion of CAS drop > 2 (Before IVMP – week 24th (end of study) 
              - Using the Chi-squared test 
  Secondary outcomes 
Using a mixed model or analyzed as repeated measurements over various time points.  
The comparison of mean changes between the treatment groups will be conducted using the t-test.  
- The measurement of the volume of extra-ocular muscles (9) and retro bulbar fat 
- Assessment of diplopia (the difference in prism deviation in primary gaze) 
- Assessment of Graves’ ophthalmopathy Quality of life (Thai version) (11) scores 
-  Summation of radiation side effects scores (RTOG criteria) (10) 
- Visual acuity (VA) and visual fields (VF) (mean deviation of Humphrey visual field) 
 
 
 
 
 
 
 
 
 
 
 
 
 

OraGo-1 Trial 
 
Study Flow 
 
week 0 
 
- Diagnosis of Active moderate to severe Graves’ 
ophthalmopathy 
- Preparation of patients for the commencement of 
systemic high-dose corticosteroid therapy 
- Blood for CBC BUN Cr Electrolyte Anti-
HIV 
- CAS Score  
- Eye examination 
- QOL  
week 1 
1st IVMP  
- administration of 500 mg IVMP 
 
week 2 
2nd IVMP  - administration of 500 mg IVMP 
 
week 3 
3rd IVMP 
- administration of 500 mg IVMP 
 
Week 4 
4th IVMP  - administration of 500 mg IVMP 
- Evaluation of inclusion and exclusion criteria. 
- RT consultation  
After the completion of three doses of 
steroids. 
- CAS Score  
- Eye examination 
week 5 
5th IVMP  - administration of 500 mg IVMP 
- Re-evaluation of inclusion and exclusion criteria. 
- CT SIMULATION for RT planning  
- RT planning  
- Measure volume/diameter of extra-
ocular muscles and retrobulbar fat 
week 6 
6th IVMP  - administration of 500 mg IVMP 
- Randomization before starting radiation therapy  
 
- CAS Score  
- Eye examination 
- QOL 
- Acute/Late RT Side effects 
week 7 
7th IVMP  - administration of 250 mg IVMP 
- RT completion ARM short course: 10 Gy/5F  
 
- CAS Score  
- Eye examination 
- Acute/Late RT Side effects. 
week 8 
8th IVMP  - administration of 250 mg IVMP 
- RT completion ARM standard course: 20 Gy/10F  
 
- CAS Score  
- Eye examination 
- Acute/Late RT Side effects 
week 9 
9th IVMP  - administration of 250 mg IVMP 
 
week 10 
10th IVMP  - administration of 250 mg IVMP 
 

OraGo-1 Trial 
 
week 11 
11th IVMP  - administration of 250 mg IVMP 
 
week 12 
12th IVMP - administration of 250 mg IVMP 
Stop IVMP 
 
week 13-14 
- 
- 
- 
week 15 
 
1st Follow up 
- CAS Score  
- Eye examination 
- QOL 
- Acute/Late RT Side effects 
week 16-23 
- 
- 
- 
week 24 
END of the 
study 
 
 
  
 
2nd Follow up 
CT SIMULATION (Non-contrast) 
- CAS Score  
- Eye examination 
- QOL 
- Measure volume/diameter of 
extraocular muscles and retro bulbar fat 
- Acute/Late RT Side effects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

OraGo-1 Trial 
 
References 
1. Hoang, T. D., Stocker, D. J., Chou, E., & Burch, H. B. (2022). 2022 Update on Clinical Management of Graves 
Disease and Thyroid Eye Disease. Endocrinology and Metabolism Clinics of North America, 51(2), 287–304. 
https://doi.org/10.1016/j.ecl.2021.12.004 
2. Miguel, I. S., Arenas, M., Carmona, R., Rutllán, J., Medina-Rivero, F., & Lara, P. C. (2018). Review of the treatment 
of Graves’ ophthalmopathy: The role of the new radiation techniques. Saudi Journal of Ophthalmology, 32(2), 139–
145. https://doi.org/10.1016/j.sjopt.2017.09.003 
3. Bartalena, L., Kahaly, G. J., Baldeschi, L., Dayan, C., Eckstein, A., Marcocci, C., Marinò, M., Vaidya, B., & 
Wiersinga, W. M. (2021). The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines 
for the medical management of Graves’ orbitopathy. European Journal of Endocrinology, 185(4), G43–G67. 
https://doi.org/10.1530/eje-21-0479 
4. Marcocci, C., Bartalena, L., Bogazzi, F., Bruno-Bossio, G., Lepri, A., & Pinchera, A. (1991). Orbital radiotherapy 
combined with high dose systemic glucocorticoids for Graves' ophthalmopathy is more effective than radiotherapy 
alone: results of a prospective randomized study. Journal of endocrinological investigation, 14(10), 853–860. 
https://doi.org/10.1007/BF03347943 
4. Royò, L. T., Redondo, G. A., Pianetta, M. Á., & Prat, M. A. (2020). Low-dose radiation therapy for benign 
pathologies. 
Reports 
of 
Practical 
Oncology 
& 
Radiotherapy, 
25(2), 
250–254. 
https://doi.org/10.1016/j.rpor.2020.02.004 
5. Abdus-Salam, A. A., Olabumuyi, A. A., Jimoh, M. A., Folorunso, S. A., & Orekoya, A. A. (2020). The role of radiation 
treatment in the management of inflammatory musculoskeletal conditions: a revisit. Radiation Oncology Journal, 
38(3), 151–161. https://doi.org/10.3857/roj.2020.00178 
6. Weissmann, T., Lettmaier, S., Donaubauer, A., Bert, C., Schmidt, M., Kruse, F. E., Ott, O. J., Hecht, M., Fietkau, 
R., Frey, B., & Putz, F. (2021). Low- vs. high-dose radiotherapy in Graves’ ophthalmopathy: a retrospective 
comparison of long-term results. Strahlentherapie Und Onkologie. https://doi.org/10.1007/s00066-021-01770-9 
7. Johnson, K., Wittig, A., Loesch, C., Esser, J., Sauerwein, W., & Eckstein, A. (2009). A retrospective study on the 
efficacy of total absorbed orbital doses of 12, 16 and 20 Gy combined with systemic steroid treatment in patients 
with Graves’ orbitopathy. Graefes Archive for Clinical and Experimental Ophthalmology, 248(1), 103–109. 
https://doi.org/10.1007/s00417-009-1214-3 
8. Kahaly, G. J., Rösler, H., Pitz, S., & Hommel, G. (2000). Low- versus High-Dose Radiotherapy for Graves’ 
Ophthalmopathy: A randomized, single blind trial. The Journal of Clinical Endocrinology and Metabolism, 85(1), 
102–108. https://doi.org/10.1210/jcem.85.1.6257 

OraGo-1 Trial 
 
9. Kim, M., Chang, J. H., & Lee, N. K. (2019). Quantitative analysis of extraocular muscle volume and exophthalmos 
reduction after radiation therapy to treat Graves’ ophthalmopathy: A pilot study. European Journal of 
Ophthalmology, 31(2), 340–345. https://doi.org/10.1177/1120672119873841 
10. Cox, J. D., Stetz, J. A., & Pajak, T. F. (1995). Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) 
and the European organization for research and treatment of cancer (EORTC). International Journal of Radiation 
Oncology Biology Physics, 31(5), 1341–1346. https://doi.org/10.1016/0360-3016(95)00060-c 
11. Lumyongsatien, M., Keeratidamkerngsakul, B., Pornpanich, K., Vangveeravong, S., Saonanon, P., 
Wiwatwongwana, D., Mahaisavariya, P., Aryasit, O., & Pongpirul, K. (2019). Development and psychometric 
properties of the Thai Graves’ ophthalmopathy quality of life (GO-QOL) questionnaire. Journal of Patient-Reported 
Outcomes, 4(1). https://doi.org/10.1186/s41687-019-0164-8 
12. Marcocci C, Bartalena L, Bogazzi F, Bruno-Bossio G, Lepri A, Pinchera A. Orbital radiotherapy combined with 
high dose systemic glucocorticoids for Graves’ ophthalmopathy is more effective than radiotherapy alone: results 
of a prospective randomized study. J Endocrinol Invest [Internet]. 1991;14(10):853–60. Available from: 
http://dx.doi.org/10.1007/bf03347943 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

OraGo-1 Trial 
 
 
 
Initial CAS Score item 1-7 
1.Pain or pressure in a periorbital or retroorbital distribution 
▢ YES 
▢ NO 
2.Pain with upward, downward, or lateral eye movement 
▢ YES 
▢ NO 
3.Swelling of the eyelids 
▢ YES 
▢ NO 
4.Redness of the eyelids 
▢ YES 
▢ NO 
5.Conjunctival injection 
▢ YES 
▢ NO 
6.Chemosis 
▢ YES 
▢ NO 
7.Inflammation of the caruncle or plica 
▢ YES 
▢ NO 
Total Score 
____  /7 
Follow up after 1-3 months score items including 8-10 
8. increase of > 2 mm proptosis 
▢ YES 
▢ NO 
9. decrease in uniocular ocular excursion in any one direction of > 8 degrees 
▢ YES 
▢ NO 
10.decrease of acuity equivalent to 1 Snellen line  
▢ YES 
▢ NO 
Total Score 
____  /10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

OraGo-1 Trial 
 
Eye assessment 
Hertel’s Exophthalmometry 
Base  :___________ mm. 
RE ____________ .mm  
LE ____________ .mm 
VA 
Pinhole 
RE ____________. 
RE ____________. 
LE ____________. 
LE ____________. 
RAPD 
RE      Present  /Absent 
LE      Present  /Absent 
Color vision 
RE      Normal  /Abnormal 
LE      Normal  /Abnormal 
Motility 
RE 
Ductions (degrees) 
Restriction 
 
 
 
 
LE 
Ductions (degrees) 
Restriction 
 
Lid retraction 
 
▢ YES 
▢ NO 
Eyelid measurement 
RE 
upper (MRD-1) ___________mm 
(inferior sclera show) ______ mm 
Lagophthalmos ___________mm 
LE 
upper (MRD-1) ___________mm 
(inferior sclera show) ______ mm 
Lagophthalmos ___________mm 
Corneal stain  
RE __________ sec. 
LE __________ sec. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

OraGo-1 Trial 
 
Radiological assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT SIMULATION 
RE 
LE 
Extraocular muscle diameters 
- Inferior rectus 
__cm 
- Medial rectus 
__cm 
- Lateral rectus 
__cm 
- Superior group ________cm 
- Inferior rectus _________cm 
- Medial rectus 
__cm 
- Lateral rectus 
__cm 
- Superior group ________cm 
Extraocular muscle volume 
- Inferior rectus__________cm3 
- Medial rectus 
__cm3 
- Lateral rectus__________cm3 
- Superior group_________cm3 
- Inferior rectus _________cm3 
- Medial rectus _________cm3 
- Lateral rectus _________cm3 
- Superior group_________cm3 
Proptosis 
 
 cm 
 
 cm 
Retrobulbar fat volume 
 
 cm3 
 
  cm3 

OraGo-1 Trial 
 
Grave’s Ophthalmopathy Quality of Life (GO-QOL) (Thai version) (Lumyongsatien M 
 
Total score = (raw score – Y)/ (2 x Y) x 100 
Y; number of completed question items  
 
 
 
 
 
 
 
 
0 
(never) 
1 
Seriously 
limited 
2  
A little 
limited 
3 
Not limited 
at all 
Functioning 
 
 
 
 
1. Bicycling 
 
 
 
 
2. Driving 
 
 
 
 
3. Moving around the house 
 
 
 
 
4. Walking outside the house 
 
 
 
 
5. Reading 
 
 
 
 
6. Watching TV 
 
 
 
 
7. Enjoying hobby or pastime 
 
 
 
 
8. Prevented from doing what you want to do 
 
 
 
 
Appearance 
 
 
 
 
9. Changed physical appearance 
 
 
 
 
10. Stared at on the streets 
 
 
 
 
11. People have a negative reaction 
 
 
 
 
12. Influence on self-confidence 
 
 
 
 
13. Social isolation 
 
 
 
 
14. Effect on making friends 
 
 
 
 
15. Reluctance to be photographed 
 
 
 
 
16. Hide or conceal physical changes 
 
 
 
 
Raw score  ______   Total Score ___ /100 

OraGo-1 Trial 
 
 
RTOG Radiation side effects 
 
 
Tissue 
Gr .0 
Gr .1 
Gr .2 
Gr .3 
Gr .4 
Dry eye 
▢ 
None 
▢  Asymptomatic  
clinical or diagnostic 
observations only; 
symptoms relieved 
by lubricants 
▢  Symptomatic  moderate 
decrease in visual acuity 
(best corrected visual acuity 
20/40 and better or 3 lines or 
less decreased vision from 
known baseline) 
 ▢ Symptomatic with 
marked - decrease in 
visual acuity , limiting 
self-care ADL 
 
Eye pain 
▢ 
None 
▢ Mild pain 
 ▢ Moderate pain; limiting 
instrumental ADL 
 ▢ Severe pain; limiting 
self-care ADL 
 
Keratitis 
▢ 
None 
▢ Asymptomatic 
▢Moderate decrease in 
visual acuity (best corrected 
visual acuity 20/40 and 
better or 3 lines or less 
decreased vision from 
known baseline) 
▢Symptomatic with 
marked decrease in 
visual acuity limiting self-
care ADL 
▢Perforation; 
best corrected 
visual acuity of 
20/200 or worse 
in the affected 
eye  
Eyelids 
▢ 
None 
▢Erythema 
▢Loss of eye 
lashes 
▢Tender 
▢Bright erythema 
▢Moist desquamation 
▢ Visual loss 
Conjunctiva 
▢ 
None 
 ▢Mild 
conjunctivitis 
 ▢Moderate conjunctivitis 
 
▢ Visual loss 
Lacrimal gland 
system 
▢ 
None 
▢ Increased 
Tearing  
▢Need artificial tear 
 
▢ Visual loss 
Cornea 
▢ 
None 
▢ Scleral injection 
▢ Keratitis 
▢ Need steroid / ATB 
▢ Server keratitis with 
corneal ulcer 
▢ Visual loss 
IRIS 
▢ 
None 
 
▢ Iritis 
▢ Photophobia 
 
▢ Visual loss 
Skin 
▢ 
None 
▢ Faint erythema, 
mild tight skin  
▢ Bright erythema  /dry 
desquamation, Itchy 
▢ Moist desquamation 
▢ confluent moist 
desquamation , 
Soreness with edema 
▢ Ulceration , 
hemorrhage , 
Necrosis 
Total scores  _____/  34