Efficacy and Safety of Tocilizumab in Patients With Active Moderate-to-Severe Corticosteroid-Resistant Thyroid Eye Disease: Open, Prospective, Observational Study
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 32
- 试验地点
- 2
- 主要终点
- Disease improvement
研究概览
简要总结
The aim of this study is to evaluate the efficacy and safety of Tocilizumab as second/third line treatment in patients with Active Moderate-to-Severe Corticosteroid-Resistant Thyroid Eye Disease.
详细描述
Graves' Orbitopathy (GO) is an autoimmune disease that involves orbital tissues, leading to temporary or permanent damage to the eye. Although GO is a rare condition, it negatively affects the quality of life in the majority of patients. In the majority of european centers, high-dose intravenous glucocorticoid (GCs) therapy remains the first-line treatment in patients with active, moderate-to-severe GO. However, GCs are effective in only 45-60% of patients, with a high probability of diseases relapse (10-40%) or disease progression to dysthyroid optic neuropathy (up to 10%). Due to limited efficacy of GCs, unpredictable relapses and progression of GO, the management of GO remains a challenge.
A few studies have demonstrated that interleukin-6 (IL-6) blockade with tocilizumab (TCZ) is effective in GC-refractory GO. However, the long-term outcomes of TCZ remain scarce.
Therefore, the investigators are planning to assess the therapy with Tocilizumab, regarding clinical outcomes and adverse events. The investigators plan to include a total of 30 patients with active, moderate-to-severe, corticosteroid-resistant GO over a period of approximately 4 years.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent
- •Male or female, 18-80 years old
- •Patients with active (Clinical Activity Score ≥ 3 in 7-item scale) and moderate-to-severe GO, diagnosed according to the EUGOGO guidelines, after the completion of MP pulse treatment, WITH
- •o Deterioration of GO (in 1 or 2 eyes) when two of the following occurred:
- •increase in palpebral aperture by at least 2 mm;
- •deterioration in CAS by at least 2 points (7-point CAS)
- •increase in exophthalmos by at least 2 mm;
- •worsening of diplopia (appearance or change in the degree)
- •worsening in ocular motility by 8o
- •o Incomplete response in both eyes to intravenous methylprednisolone pulse therapy; defined changes smaller than previously defined in any of the mentioned parameters.
- •Euthyroid for at least 6-8 weeks (serum free hormone concentrations within 30% of normal range) on either anti-thyroid medications (tyonamides) to control hyperthyroidism or L-thyroxine for replacement therapy for hypothyroidism.
- •Negative pregnancy test in women of fertile age.
- •All female patients of fertile age must use a reliable contraceptive method to prevent pregnancy during the study period, and at least during a period of six months following the last dose of the investigational medicinal product.
排除标准
- •Signs of sight-threatening TED (severe keratopathy, optic neuropathy)
- •Pregnant or breastfeeding woman or woman planning to become pregnant during the study
- •Patients who could need treatment with radioactive iodine or thyroidectomy during the study
- •Treatment with any biological therapy at any time.
- •Active infection.
- •History of recurrent clinically significant infection or recurrent bacterial infections.
- •Positive quantiferon without documentation of treatment for tuberculosis (TB) infection or documentation of no need for such therapy.
- •Required management of infections, as follows: currently on any suppressive therapy for a chronic infection, hospitalization for treatment of infection within 60 days before Day 0, use of parenteral antibiotics within 60 days before Day 0, use of oral antibiotics within 30 days before Day
- •History of intestinal ulceration or diverticulitis
- •Patients with a history of chronic liver disease or liver disorders: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) above 5 times upper limit of normal (ULN)
- •HBsAg positive test.
- •HBcAb positive test, regardless of HBsAb status, will undergo HBV DNA which, if positive, will be excluded. HbcAb positive, HbsAg negative patients with undetectable HBV DNA will receive antiviral prophylaxis throughout the immunosuppressive therapy.
- •Hepatitis C antibody positive test at screening.
- •Positive test for Human Immunodeficiency Virus (HIV) antibody at screening or historically. Denied consent to HIV testing.
- •Absolute neutrophil count (ANC) < 2.0 × 109/L or a platelet count < 100×103/μL
- •Alkaline phosphatase and bilirubin>1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is<35%).
- •Cardiovascular or cerebrovascular disease clinically significant.
- •Other serious chronic illness (including uncontrolled diabetes mellitus, renal disease, pulmonary disease, major depression).
- •History of sarcoidosis.
- •Primary or secondary immunodeficiency.
- •History of IgE-mediated or non-IgE-mediated hypersensitivity.
- •History of reactions or anaphylactic allergic severe human monoclonal antibodies, humanized or murine.
- •Administration of live vaccines given within 30 days prior to administration of (Day 0) or concurrently with tocilizumab (during study).
- •Splenectomy.
- •Current drug or alcohol abuse or dependence.
研究组 & 干预措施
Graves' orbitopathy
Patients with active, moderate to severe TED, without disease improvement after methylprednisolone pulse therapy in an intermediate-dose schedule (starting dose of 0.5 g once weekly for 6 weeks, followed by 0.25 g once weekly for 6 weeks) or high-dose regimens (a starting dose of 0.75 g once weekly for 6 weeks, followed by 0.5 g once weekly for 6 weeks) with or without concomitant radiotherapy.
干预措施: Tocilizumab (Drug)
结局指标
主要结局
Disease improvement
时间窗: at 16, 24 and 48 weeks
Proportion of patients improved at 16, 24 and 48 weeks as assessed by a composite ophthalmic score. A response to treatment will be considered positive in the case of an improvement of at least 2 of the following features in 1 eye, without concomitant deterioration in the other eye: * decrease in eyelid aperture by at least 2 mm measured with a ruler * decrease in proptosis by at least 2 mm measured with Hertel Exophthalmometer * increase in eyelid motility by at least 8° assessed by ophthalmologist or improvement of Bahn-Gorman diplopia score (Grade I - intermittent diplopia, Grade II - Inconstant diplopia, Grade III - Constant diplopia) * decrease in 7-item (spontaneous retrobulbar pain, pain on attempted upward or downward gaze, redness of eyelids, redness of conjunctiva, sweeling of caruncle or plica, swelling of eyelids, swelling of conjunctiva) clinical activity score (CAS) by at least 2 points.
Improvement of quality of life
时间窗: at 16, 24 and 48 weeks
Improvement of quality of life according to the disease-specific quality of life questionnaire in Graves' orbitopathy (GO-QoL) at 16, 24 and 48 weeks. All Go-QoL questions will be scored as 'severely limited' (one point), a 'little limited' (two points), or 'not limited at all' (three points). The questions will be transformed from 0 to 100 by the following formula: total score= (raw score- 8)/16 x100. An improvement in QoL wil be considered, if there will be an increase of 6 or more points on either one (or both) the GO-QoL scales (functioning and appearance);
次要结局
- Disease inactivation(at 16, 24 and 48 weeks)
- Number of participants with treatment-related adverse events as assessed by CTCAE v5.0(from 0 to 16 weeks)
- Number of the rehabilitative surgeries performed after immunosuppressive therapy(at 48 weeks)
- The rate of disease relapse(at 48 weeks)
- Decrease in concentration of thyrotropin receptor antibodies(at 4, 8, 12, 16, 24 and 48 weeks)
- Decrease in proptosis by at least 2 mm assessed using magnetic resonance imaging (MRI)(at 16 weeks)
- Proportion of patients achieving response in specific GO signs and symptoms(at 16, 24 and 48 weeks)
- Decrease in levels of proinflammatory cytokines(at 4, 8, 12, 16, 24 and 48 weeks)
研究者
Tomasz Bednarczuk
Prof
Medical University of Warsaw