Clinical trial NCT06693856: Multi-center Prospective Clinical Study on Glucocorticoid Pulse Therapy for Graves' Ophthalmopathy (GO)
Official title: A Prospective, Multicenter, Randomized Controlled Clinical Study on the Efficacy and Safety of Different Methylprednisolone Pulse Therapy Regimens for the Treatment of Graves' Ophthalmopathy
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: NA
Conditions: Graves Ophthalmopathy
Keywords: Graves ophthalmopathy, methylprednisolone, therapy regimens
Lead sponsor: Shanghai Changzheng Hospital
Sponsor class: OTHER
First posted: 2024-11-18
Enrollment: 120
Sex: ALL
Minimum age (years): 25
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study plans to include newly diagnosed, active, moderate to severe Graves' ophthalmopathy patients, divided into a high-dose group (methylprednisolone 500mg, D1-3, once every 4 weeks) and a low-dose group (methylprednisolone 1mg/kg, D1-3, once every 4 weeks), with a treatment duration of 24 weeks to compare the efficacy and safety of the two groups. Additionally, this study will extend the follow-up to 48 weeks to observe the recurrence rate after treatment in both groups, exploring the heterogeneity of the active course of Graves' ophthalmopathy.

Detailed description: Graves' ophthalmopathy (GO) is an organ-specific autoimmune disease closely related to the thyroid gland, typically manifested by proptosis, eyelid swelling, eye pain, and double vision. Mild GO may resolve with the control of hyperthyroidism, while moderate to severe GO can severely damage vision and require more aggressive treatment. Glucocorticoids are the first-line treatment for moderate to severe, active GO, and intravenous methylprednisolone is more effective than oral glucocorticoids. The 2021 clinical practice guidelines of the European Group on Graves' Orbitopathy (EUGOGO) recommend that the optimal dosage regimen for methylprednisolone is once a week for 12 weeks, with a cumulative dose of 4.5 grams. For the most severe cases, a higher cumulative dose of up to 8 grams can also be used as monotherapy.

Starting from the 1990s, the Endocrinology Department of Shanghai Changzheng Hospital began to admit patients with Graves' ophthalmopathy and initiated immunosuppressive pulse therapy, accumulating nearly 1000 cases of GO, making it the hospital with the most patients with Graves' ophthalmopathy in Shanghai and even nationwide. The monthly pulse therapy regimen has a high treatment response rate, a low relapse rate, and good safety. However, there are still a series of unresolved issues with glucocorticoid pulse therapy for Graves' ophthalmopathy. Firstly, the optimal cumulative dose of methylprednisolone has not been established. Secondly, the active course of Graves' ophthalmopathy varies greatly among individuals, with reports ranging from a few months to several years, and the pulse therapy has not yet been individualized. Thirdly, there is a significant difference in individual sensitivity to glucocorticoids; the fixed high-dose administration of methylprednisolone at 500mg per session lacks sufficient evidence. Calculating the single-dose administration based on body weight or surface area may be more reasonable.

The efficacy and safety of different dosage regimens of methylprednisolone pulse therapy for Graves' ophthalmopathy will be further explored. This study plans to include newly diagnosed, active, moderate to severe Graves' ophthalmopathy patients, divided into a high-dose group (methylprednisolone 500mg, D1-3, once every 4 weeks) and a low-dose group (methylprednisolone 1mg/kg, D1-3, once every 4 weeks), with a treatment duration of 24 weeks to compare the efficacy and safety of the two groups. Additionally, this study will extend the follow-up to 48 weeks to observe the recurrence rate after treatment in both groups, exploring the heterogeneity of the active course of Graves' ophthalmopathy.

Eligibility criteria: Inclusion Criteria:

1. Voluntarily accept the study and sign the informed consent form.
2. Age between 25 and 70 years old at the time of enrollment, both males and females are eligible.
3. Newly diagnosed Graves' ophthalmopathy, moderate to severe active patients. The criteria for moderate to severe GO are: ① eyelid retraction ≥2mm; ② moderate to severe involvement of orbital soft tissues; ③ proptosis ≥20mm; ④ periodic or persistent diplopia. Meeting one of the above four criteria is sufficient.

   The criteria for active GO are: CAS score ≥4 points. Scoring criteria: ① spontaneous retro-ocular pain; ② pain on eye movement; ③ conjunctival congestion; ④ eyelid congestion; ⑤ chemosis of the conjunctiva; ⑥ swelling of the caruncle; ⑦ eyelid edema. One point is recorded for each of the above seven symptoms if present, and zero if absent.
4. The onset of Graves' ophthalmopathy does not exceed 12 months, and those who have not been treated with glucocorticoids or other immunosuppressive agents.
5. Women of childbearing age must use effective contraceptive measures.
6. At the time of screening, hyperthyroidism in the study subjects should be basically controlled. Thyroid function should be normal or only mildly abnormal, defined as FT4 and FT3 levels within 50% of the upper and lower limits of the normal range. Mild thyroid dysfunction should be corrected as much as possible, and a normal thyroid function state should be maintained throughout the clinical trial period.

Exclusion Criteria:

1. Pregnant women, women who are breastfeeding, or women planning to become pregnant during the trial period.
2. Severe cardiac diseases such as myocardial infarction, unstable angina, and chronic heart failure.
3. Known liver diseases, or alanine transaminase (ALT) levels more than 1.5 times the upper limit of normal.
4. Chronic kidney disease, or serum creatinine \>135 umol/L (\>1.5 mg/dL).
5. Individuals with diabetes, and HbA1c \>9.0%.
6. Individuals with a history of alcohol abuse or drug use.
7. Subjects with a white blood cell count \<4.0×10\^9/L, or a platelet count \<80×10\^9/L.
8. Significant anemia (hemoglobin levels \<110 g/L in males, \<100 g/L in females).
9. Patients with psychiatric disorders, or those who are non-cooperative.
10. Individuals with optic nerve involvement requiring orbital decompression surgery. Defined as a decrease in vision by more than two lines in the past six months, or new visual field defects, or color vision deficiencies.
11. Corneal ulcers, contraindications for glucocorticoid treatment.

Primary outcomes:
measure: Overall Response Rate, ORR
timeFrame: From enrollment to the end of treatment at 24 weeks
Secondary outcomes:
measure: CAS and proptosis
timeFrame: From enrollment to the end of treatment at 24 weeks
measure: Clinical Activity Score
timeFrame: From enrollment to the end of treatment at 24 weeks
measure: proptosis
timeFrame: From enrollment to the end of treatment at 24 weeks
Other outcomes:
measure: Recurrence Rate, RR
timeFrame: From enrollment to the end of treatment at 48 weeks
Locations:
city: Shanghai
country: China
facility: Shanghai Changzhen Hospital
state: Shanghai
city: Shanghai
country: China
facility: Shanghai Changhai Hospital
state: Shanghai
city: Shanghai
country: China
facility: Shanghai Longhua Hospital
state: Shanghai
Study officials:
affiliation: Shanghai Changzheng Hospital
name: Zou JJ Professor
role: PRINCIPAL_INVESTIGATOR
References: