A study on combination therapy of methotrexate and steroid eye drops for scleritis

JRCT ID: jRCTs051230023

Registered date:19/05/2023

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Scleritis
• Date of first enrollment: 14/08/2023
• Target sample size: 10
• Study type: Interventional

Intervention(s)

Perform examinations and treatments in the following order.
(1) Steroid eye drops (betamethasone sodium phosphate eye drops)
1-2 drops at a time, 4 or more times a day (up to 8 times a day) for up to 8 weeks
1-2 drops once, 4 times a day for up to 8 weeks
1-2 drops once, 3 times a day for up to 12 weeks
1-2 drops at a time, 2 times a day No use period set
Thereafter, the frequency of instillation was gradually reduced and discontinued. In principle, if the Standardized grading system for scleritis score is 0.5 or less, consider reducing the frequency of eye drops. If a clear clinical improvement in scleritis is observed, the frequency of eye drops may be reduced at the discretion of the attending physician. Rescue treatment (such as systemic administration of steroids: details are described in [Treatment of recurrent and treatment-resistant cases]) should be performed if symptoms do not improve even after the maximum administration period. In principle, at the time of recurrence, therapy with only eye drops will not be given.
Adjuvant therapy: For local steroid injections [dexamethasone conjunctival injection (1.65 mg 1A) or triamcinolone subcapsular injection (20 mg)], as adjuvant therapy, if no improvement in symptoms is observed after 4 weeks, It can be administered.

2. Oral MTX in parallel with steroid eye drops
Oral administration of MTX is started at 4 mg/week. Thereafter, the dose is increased by 4 mg/week every 4 weeks and then maintained at 12 mg/week. If the effect is insufficient (such as when the scleritis score does not reach 0), increase the dose to 16 mg/week. In addition, when adverse reactions occur, MTX should be reduced or discontinued. Weekly MTX dose once or divided into 2 doses at 12-hour intervals administer orally. One full weekly dose is possible, but not more than 8 mg/week per dose.

Usually administered for one year. After that, it gradually decreases and ends in 3-6 months.

Patients should be examined every 2 weeks for 1 month after the start of treatment, and then followed up at intervals of 1-3 months.

Treatment of recurrent and treatment-resistant cases
In patients with recurrence or resistance to the therapy, systemic steroid administration can be performed as rescue treatment at the discretion of the attending physician. If uveitis is also present along with scleritis, treatment with immune modulate therapy (cyclosporine) or biologics (adalimumab) should be considered depending on the therapeutic response to steroid therapy.

Outcome(s)

Primary Outcome

Treatment success at 24 weeks after protocol treatment
Definition: Treatment success: Treatment success is defined as the fulfillment of the following two items
1 Based on the standardized grading system for scleritis, scleritis score, transition to inactivity, scleritis score 0 or 0.5, with betamethasone instillation less than or equal 2 times per day without recurrence after starting the study drug administration
2 Not receiving rescue therapy

Secondary Outcome

Efficacy evaluation items
Treatment success at 36 weeks and 48 weeks
Time to treatment success
Score by Standardized grading system for scleritis (at each time point of 2, 4, 8, 16, 20, 24, 36, 48 weeks)
Definitions: At each visit, a 4-quadrant (nasal, temporal, superior, and inferior) anterior segment photo is performed, and the scleritis score is determined by the attending physician based on the images. Judgment adopts the scleritis score of the most severe quadrant. At the end of the study, the obtained images are masked before and after and scored by a third party (scleritis score) to confirm the rate of agreement with the clinical judgment of the attending physician.
Modified treatment success at 24, 36, and 48 weeks
Definition: Modified treatment success: Scleritis is improved to inactive (scleritis score 0 or 0.5) and maintained with oral sterodi less than or equal 7.5 mg per day or betamethasone instillation less than or equal 2 times per day after starting the study drug administration
Time to modified treatment success
Course of anterior chamber inflammation (cell and flare) according to Standardization of Uveitis Nomenclature (SUN) classification (at each time point of 0, 2, 4, 8, 16, 20, 24, 36, 48 weeks)
Presence or absence of posterior eye inflammation
Course (haze) of vitreous inflammation according to the Standardization of Uveitis Nomenclature (SUN) classification when posterior segment inflammation occurs (at each time point of 0, 2, 4, 8, 16, 20, 24, 36, 48 weeks)

Presence or absence of rescue treatment
With rescue treatment
Type of rescue treatment
Reason for rescue (recurrence/number of treatment-resistant cases/others)
Time from initiation of treatment (day 1) to need of rescue treatment
Time from initiation of rescue treatment to remission
Presence or absence of adjuvant therapy, the content of adjuvant therapy, number of times of adjuvant therapy
Definition: Recurrence: Cases where the score by the Standardized grading system for scleritis once decreased to 0.5 or less, but the score increased to 1 or more after the next VISIT.
Treatment resistance: Cases in which the score according to the Standardized grading system for scleritis has never decreased to 0.5 or less even after 4 or more daily steroid instillations for 8 weeks.
Total instillation period until the end of instillation

Corrected visual acuity and change from screening (at 2, 4, 8, 12, 16, 20, 24, 36, and 48 weeks)
Intraocular pressure and changes from screening (at each time point of 4, 12, 24, 36, and 48 weeks)
Presence or absence of macular edema (24 and 48 weeks only)
Evaluate the non-target eyes in cases of binocular scleral inflammation in the same way as above.

Safety evaluation items
Drug discontinuation (MTX, steroid eye drops)
Occurrence of diseases, etc., during the observation period
Definition: Presence or absence of illness related to protocol treatment. If the same subject has suffered from the same condition several times, we will pick up one of the worst severity.
Development of glaucoma or ocular hypertension
Development of cataract
Development of an eye infection
Development of systemic infection
The onset of gastrointestinal symptoms
Development of liver dysfunction
Development of renal dysfunction
Development of interstitial pneumonia
Development of encephalopathy (including leukoencephalopathy)
Other complications developing or worsening

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: <= 70age old
• Gender: Both

Include criteria

(1) Patients aged between 18 and 70 at the time of informed consent
(2) Patients with active inflammation in the sclera
Patients with idiopathic non-necrotizing scleritis with a scleritis score of 1 or higher who have a history of steroid eye drops for 2 weeks or more and subsequently have recurrence or prolonged inflammation
(3) Males and females who agree to use contraception before and during administration of this drug and for 3 months after discontinuation of this drug, or males and females who are medically judged to be infertile
(4) Patients who have shown the consent of agreement with the written informed consent by their own free will after receiving a sufficient explanation for participating in this study.

Exclude criteria

Patients who correspond to any of the following are excluded from the study.
1. Patients with only posterior or episcleritis of scleritis
2. Patients with infectious scleritis
3. Patients with severe renal dysfunction (judged by following states)
Patients receiving dialysis or glomerular filtration rate (GFR) <30 mL/min/1.73m2
4. Patients already taking immunosuppressants or corticosteroids at the time of enrollment
5. Patients who appear to be immunosuppressed (e.g., congenital immune deficiency, HIV infection, etc)
6. Patients who are pregnant, lactating, or may be pregnant
7. Patients with malignant tumors
8. Patients who have undergone intraocular surgery or glaucoma surgery in the past, excluding cataract surgery, or who are expected to require surgery during this clinical study
9. Patients who have a history of hypersensitivity to methotrexate or betamethasone eye drop
10. Patients with significant hematological/lymphatic disorders
(1) Patients have a history of myelodysplastic syndrome, aplastic anemia, or blood-cell aplasia
(2) Patients have been diagnosed or treated for lymphoproliferative disease within the past 5 years
(3) Patients with leukopenia or thrombocytopenia: following criteria should be used for the judgment, and the presence of other complications should be also considered: 1) White blood cell count < 3,000/mm3, 2) Platelet count < 50,000/mm3
11. Patients with liver dysfunction
(1) Hepatic dysfunction AST>60 (U/L) or ALT>84 (U/L)
(2) Complication of acute/chronic active viral hepatitis B or C
(3) Liver cirrhosis
(4) Other severe liver dysfunction.
12. Patients with severe respiratory disorders (refer to the following criteria for judgment)
(1) Presence of hypoxemia SpO2<93% in room air (equivalent to PaO2<70 Torr)
(2) Restrictive disorder with % VC < 80% in pulmonary function test
(3) Presence of advanced pulmonary fibrosis in chest X-ray imaging
13. Patients with severe infections
14.In addition to the above, the drug is contraindicated for target diseases (systemic diseases: myelosuppression, pleural effusion, ascites. ocular diseases: corneal epithelial erosion or ulcer, viral conjunctival corneal disease, tuberculous eye disease, fungal eye disease, or purulent eye disease, ocular tuberculosis.)
15. Other patients who are judged to be inappropriate as research subjects by the principal investigator or co-investigator

Related Information

• Primary Sponsor: Matsumiya Wataru