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临床试验/NCT04876534
NCT04876534Unknown2 期

Multicenter, Randomized, Observer-blind, Controlled Study of the Anti-IL-6 Receptor Antibody Tocilizumab (TCZ) or Methylprednisolone (MP) Treatment in Patients With Active Moderate-severe Graves' Orbitopathy

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico4 个研究点 分布在 1 个国家目标入组 64 人开始时间: 2019年12月18日最近更新:
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适应症
干预措施
相关药物

试验速览

阶段
2 期
入组人数
64
试验地点
4
主要终点
Desease inactivation
研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

To treat patientis with active moderate-severe GO with the anti-IL6 receptor monoclonal antibody tocilizubam with the purpose of assesing the efficacy of therapy on active GO and on the proportion of patiens with inactivation and reactivation of disease (Primary Objective) Effect of therapy on disease progression, improvement of QoL, the degree of residual disease after the inflammatory phase and safety of treatment (Secondary Objective)

详细描述

1 Primary Endpoint:

  1. Proportion of patients with CAS reduction of 3 points or disease inactivation (CAS<4) at 12 and 24 weeks

1.2 Secondary Endpoints:

  1. Proportion of patients improved at 24 weeks as assessed by the EUGOGO composite ophthalmic score (see below paragraph#5)
  2. Improvement of quality of life according to the GO-QoL questionnaire at 12 and 24 weeks.
  3. Safety of tocilizumab therapy in patients with GO compared to Methylprednisolone, evaluated on the basis of the following endpoints: Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5.0,
  4. Changes of serum TSH receptor binding and stimulating antibodies, anti-TPO antibodies and serum concentrations of IL-6 and sIL-6 receptor at 12, 24 and 36 and 48weeks of follow up.
  5. Proportion of patients with disease reactivation (CAS > or =4) during follow-up at 24-48 weeks.
  6. Quantification of signs of residual motility abnormalities by motility tests and orbital imaging
  7. Number of rehabilitative surgical interventions at the end of follow-up

2.Study Design and Methods

研究设计

研究类型
Interventional
分配方式
Randomized
干预模型
Parallel
主要目的
Treatment
盲法
Single (Care Provider)

盲法说明

The ophthalmologist assessing the ophthalmic changes is blinded to the patient's treatment

入排标准

年龄范围
18 Years 至 75 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, 18-75 years old
  • •Women of childbearing potential should use effective contraception (abstinence or use contraceptive methods with a failure rate of <1%) throughout study and for a minimum of 6 months after study drug therapy and must have a negative serum pregnancy test at screening
  • •GO at first diagnosis or at the time of relapse of no more than 9 months' duration.
  • •Patients with moderate-severe active GO (clinical activity score 4/10 assessed at the end of the screening period) untreated or previously treated with i.v. steroids withdrawn for at least 3 months.
  • •Euthyroid for at least 6-8 weeks (serum free hormone concentrations within 20% of normal range), on either anti-thyroid medications (tyonamides) to control hyperthyroidism or L-thyroxine for replacement therapy for hypothyroidism.
  • •Patients will also be allowed to stay on propranolol treatment for the control of tachycardia.

排除标准

  • •Patients with sight-threatening Graves' orbitopathy (severe keratopathy, compression optic neuropathy and inflammatory optic neuropathy).
  • •Treatment with any biological therapy at any time.
  • •Previous oral or intravenous corticosteroid treatment in the last three months except for oral steroid not exceeding a cumulative dose of 1 gr.
  • •Plasmapheresis within 90 days prior to Day
  • •Treatment with intravenous immunoglobulin.
  • •Azathioprine more than 100 mg/day within 30 days before screening.
  • •Administration of live vaccines given within 30 days prior to administration of (Day 0) or concurrently with tocilizumab (during study).
  • •Splenectomy.
  • •Subjects at risk of bleeding that threatens a vital organ.
  • •History of a major organ transplant or hematopoietic stem cell/marrow transplant.
  • •History of malignant neoplasm within the last 5 years, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.
  • •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
  • •Patients with reproductive potential not willing to use an effective method of contraception throughout study and for a minimum of 6 months after study drug therapy
  • •Breast feeding.
  • •Previous history of intestinal ulceration or diverticulitis or diverticular disease.
  • •Known unstable coronary artery disease.
  • •Significant cardiac arrhythmias.
  • •Severe congestive heart failure.
  • •Other serious chronic illness (including nervous system disease, pulmonary disease including obstructive pulmonary disease, renal disease).
  • •Active infection.
  • •History of recurrent clinically significant infection or recurrent bacterial infections.
  • •History of sarcoidosis.
  • •Primary or secondary immunodeficiency.
  • •History of IgE-mediated or non-IgE-mediated hypersensitivity.
  • •Positive PPD or quantiferon without documentation of treatment for TB infection.
  • •Denied consent to HIV testing.
  • •Previous orbital radiotherapy
  • •HBsAg positive test.
  • •HBcAb positive test, regardless of HBsAb status, will undergo HBV DNA which, if positive, will be excluded.
  • •Hepatitis C antibody positive test at screening.
  • •Positive test for Human Immunodeficiency Virus (HIV) antibody at screening or historically.
  • •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) greater or equal to 1.5x upper limit of normal (ULN).
  • •Alkaline phosphatase and bilirubin>1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is<35%).
  • •Grade 3 / 4 IgG deficiency and IgA deficiency (IgA < 10mg/dL).
  • •History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy including a previous anaphylactic reaction to parenteral administration contrast agents, human or murine proteins or monoclonal antibodies.
  • •Major depression.
  • •Evidence of serious suicide risk including any history of suicidal behaviour in the last 6 months and/or any suicidal ideation in the last 2 months or who in the investigator's judgment, pose a significant suicide risk.
  • •Current drug or alcohol abuse or dependence.
  • •White blood cells < 3.0 x 109/L (3000/mm3)
  • •Absolute neutrophil count (ANC) < 2.0 x 109/L (2000/ mm3)
  • •Absolute lymphocyte count < 0.5 x 109/L (500/ mm3)
  • •Platelet count <100 x 109/L
  • •Serum creatinine > 1.4 mg/dl (124 µmol/L) in female patients and > 1.6 mg/dl (141 µmol/L) in male patients
  • •Hemoglobin <85 g/L (8.5 g/dL; 5.3 mmol/L)
  • •Demyelinating disorders
  • •Treatment with Methotrexate

研究组 & 干预措施

Tocilizumab

Experimental

32 patients with active moderate-severe GO treated with i.v. tocilizumab; Tocilizumab weight adjusted, 8 mg/kg, 1 intravenous infusion every four weeks (+/- 72 hours) for 12 weeks

干预措施: Tocilizumab 20 Mg/mL Intravenous Solution (Drug)

Methylprednisolone

Active Comparator

32 patients with active moderate-severe GO treated with i.v. methylprednisolone; Methylprednisolone, 500 mg infusion weekly (+/- 48 hours) for 6 weeks, followed by 250 mg infusion weekly (+/- 48 hours) for another 6 weeks

干预措施: MethylPREDNISolone Injectable Solution (Drug)

结局指标

主要结局

Desease inactivation

时间窗: at 12 and 24 weeks

Proportion of patients with CAS reduction of 3 points or disease inactivation (CAS\<4) at 12 and 24 weeks

次要结局

  • Desease improvement(24 weeks)
  • Improvement of quality of life(at 12 and 24 weeks)
  • Incident of adverse events in tocilizumab therapy(from 0 to 12 weeks)
  • Immunological changes(at 12, 24 and 36 and 48weeks of follow up)
  • Residual desease(at 48 weeks)
  • Desease relapse(at 24-48 weeks)
  • Rehabilitative therapy(at 48 weeks)

研究者

申办方类型
Other
责任方
Sponsor

研究点 (4)

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