Rituximab (RTX) Therapy in Steroid Resistant Patients or Patients Relapsing After Intravenous Steroids With Active TAO
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 38
- 试验地点
- 5
- 主要终点
- Clinical Activity Score (a Composite Measure of Ophthalmological Signs and Symptoms)
研究概览
简要总结
Thyroid Associated Ophthalmopathy is condition affecting the eyes of about 10% of patients with Graves disease. Its combination of protrusion affecting the looks of the patient and pain is often severely affecting the quality of life among these patients.
The standard treatment for this illness today is intravenous glucocorticoids together with methotrexate. The purpose of this study is to evaluate the effect of rituximab on patients that do not respond to or relapse after conventional therapy.
详细描述
Diffuse autoimmune hyperthyroidism or Graves' disease (GD) is a common condition mainly affecting women with 2-3% prevalence The increased production of thyroid hormones in GD is driven by autoantibodies directed against the thyroid stimulating hormone (TSH) receptor (TRab). In most cases, this autoimmunity will also affect other tissues, above all the orbital tissue by mechanisms not fully understood -Thyroid Associate Ophthalmopathy (TAO). Symptoms and signs can be mild (grittiness, dry eyes, periorbital swollen, chemosis, redness)-moderate (double eye vision, exophthalmia or severe (optic nerve compression, corneal ulcers). Serious-moderate ocular engagement in TAO is seen in approximately 10% of patients with GD.
Not only has the hyperthyroidism a marked impact on mental health, but the presence of TAO has an additional negative impact on the well-being of these patients, even many years after successful treatment of the hyperthyroidism. It has been suggested that smoking and stress are negative prognostic factors for the course of TAO indicating that a vicious circle. MRI may detect earlier changes than CT that can be used to predict the course of TAO.
The aims of treatment are to retain euthyroidism which can be achieved by anti thyrostatic drugs (ATD), radioiodine treatment or surgery (where patients are pre-treated with ATD) and to avoid TAO as long as possible. If moderate-severe TAO occurs, high dose if intravenous glucocorticoids (GC) are the gold standard considering the side effects. However, many patients are non-steroid responders and for them no treatment except for acute orbital decompression, retro bulbar irradiation and later reconstructive surgery can be offered. When patients relapse immediately after steroids often per oral steroids are given although not recommended from the literature.
Rituximab (RTX) is a mouse-human chimeric antibody designed towards pre B and mature B lymphocytes and that blocks B-cells activation without affecting the regenerating of B cells from stem cells or the plasma cells immunoglobulin production. TAO is a B- lymphocyte mediated disease and in two studies RTX inhibits the active phase of TAO. In a study by Khanna et al a positive effect from RTX is observed in six steroid resistant patients with TAO with a decrease of the inflammation in the orbit, even though no effect on strabismus or proptosis was observed. In another study by Salvi et al , RTX treatment is compared with steroids as a first line treatment for TAO and after 30 weeks of follow up in an unrandomised study design. RTX decreased the activity and severity significantly compared to the steroid group. No relapse was observed in the RTX group but in the steroid group (10%). In the RTX all patients improved, but in the steroid group only 65%. There were more side-effects in the steroid group.
Selection criteria All patients with indication for i.v GC will be evaluate for the study. The patients are recruited consecutively from the region as we are a tertial referral center and iv steroids for TAO is not given on local hospitals..
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •◦Man or woman between 18-70 years TAO with CAS of ≥ 4 (less than 3 months).
- •Euthyroid for at least 6 weeks
排除标准
- •Dysthyroid optic neuropathy (DON)
- •Ulcerative Keratitis
- •Previous treatment with steroids for TAO (do not include prophylaxis for TAO in connection with radio iodine treatment)
- •Previous Treatment with Rituximab (MabThera®)
- •Positive Hepatitis B or C serology.
- •Receipt of a live vaccine within 4 weeks prior RTX+MTX to randomization
- •History of recurrent significant infection or history of recurrent bacterial infections
- •Patient who may not attend to the protocol according to the investigators opinion.
- •Pregnancy or lactation
- •Significant cardiac, including significant or uncontrolled arrhythmia, or pulmonary disease (including obstructive pulmonary disease).
- •Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
- •Concomitant malignancies or previous malignancies.
- •Previous active tuberculosis
- •Alcoholism
- •Alcoholic related liver disease or other chronical liver disease
- •Bone marrow depression with leukopenia, thrombocytopenia or significant anemia
- •Rheumatoid or other significant pulmonary disease
- •Allergy to the active substance or any other substance in the medications or murine proteins
- •Active, severe infections (such as tuberculosis, sepsis or opportunistic infections)
- •Patients with severe immunosuppression
- •Severe cardiac failure or severe uncontrolled heart disease
研究组 & 干预措施
Non-responder RTX+MTX
Patients with moderate-severe TAO with an inflammatory CAS of ≥ 4 that do not respond to iv GC (deltaCAS <2 compared to baseline after 4 weeks of iv GC ) or do relapse (deltaCAS ≥2 and total CAS ≥4) after steroid treatment compared to previous CAS measurement at 12 weeks. Rituximab (1000 mg iv with 2 weeks in between) is combined with methotrexate (15-20 mg once a week) to minimize the risk of antibody developement. MTX is always combined with RTX and is never given as a monotherapy in this study.
rituximab and methotrexate
干预措施: Rituximab (Drug)
Relapse RTX+MTX
Patients that respond to iv GC (Methylprednisolone iv) but relapse after 6 weeks will be randomised to either RTX+MTX or per oral GC (po GC+MTX) rituximab and methotrexate
干预措施: Rituximab (Drug)
Relapse po GC+MTX
Patients that respond to iv GC but relapse after 6 weeks will be randomised to either RTX+MTX or per oral GC (po GC+MTX) This is the conventional therapy arm.
methotrexate and methylprednisolone
干预措施: peroral methylprednisolone and Methotrexate (Drug)
Methylprednisolone iv
All patients in the study have a 4 weeks period of 500 mg methylprednisolone iv/week. Depending of the response patients are classified as non- responders (and are given RTX and MTX) or responders. The responders continue with intravenous infusion of Methylprednisolone 500 mg /week in 2 weeks and thereafter 250 mg iv/week in 6 weeks.
干预措施: Iv Methylprednisolone (Drug)
结局指标
主要结局
Clinical Activity Score (a Composite Measure of Ophthalmological Signs and Symptoms)
时间窗: At 4,12,18 and 68 weeks
Clinical activity score (CAS) according to Mouritz et al and the consensus statement from European Group of Graves orbitopathy (EUGOGO). It consists of 10 items (1. Spontaneous retrobulbar pain, 2. Pain on eye movements, 3. Eyelid erythema, 4. Conjunctival injection, 5. Chemosis, 6. Swelling of the caruncle, 7. Eyelid edema or fullness, 8. Change in motility,9. Change in vision acuity,10.Change in proptosis). One point is given to each item, if present. CAS is the sum of single scores, ranging from 0 (no activity) to 10 (maximal activity).
次要结局
未报告次要终点