Tocilizumab in Active Moderate-severe Graves' Orbitopathy

• Status: Recruiting
• Trial end date: 2023-12-18
• Target enrollment: 0
• Participant gender: All

Summary

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)

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
• Collaborators: Azienda Ospedaliera "Sant'Andrea"; Azienda Ospedaliero, Universitaria Pisana; Istituto Auxologico Italiano; Mauriziano Umberto I Hospital
• Treatments: Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Pharmaceutical Solutions; Prednisolone; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate

Criteria

Inclusion Criteria:

1. Written informed consent

2. Male or female, 18-75 years old

3. 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

4. GO at first diagnosis or at the time of relapse of no more than 9 months' duration.

5. 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activity score 4/10 assessed at the end of the screening period) untreated or previously treated with i.v. steroids withdrawn for at least 3 months.

6. 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.

7. Patients will also be allowed to stay on propranolol treatment for the control of tachycardia.

Exclusion Criteria:

1. Patients with sight-threatening Graves' orbitopathy (severe keratopathy, compression optic neuropathy and inflammatory optic neuropathy).

2. Treatment with any biological therapy at any time.

3. Previous oral or intravenous corticosteroid treatment in the last three months except for oral steroid not exceeding a cumulative dose of 1 gr.

4. Plasmapheresis within 90 days prior to Day 0.

5. Treatment with intravenous immunoglobulin.

6. Azathioprine more than 100 mg/day within 30 days before screening.

7. Administration of live vaccines given within 30 days prior to administration of (Day 0) or concurrently with tocilizumab (during study).

8. Splenectomy.

9. Subjects at risk of bleeding that threatens a vital organ.

10. History of a major organ transplant or hematopoietic stem cell/marrow transplant.

11. 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.

12. 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 0.

13. Pregnancy.

14. 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

15. Breast feeding.

16. Previous history of intestinal ulceration or diverticulitis or diverticular disease.

17. Known unstable coronary artery disease.

18. Significant cardiac arrhythmias.

19. Severe congestive heart failure.

20. Other serious chronic illness (including nervous system disease, pulmonary disease including obstructive pulmonary disease, renal disease).

21. Active infection.

22. History of recurrent clinically significant infection or recurrent bacterial infections.

23. History of sarcoidosis.

24. Primary or secondary immunodeficiency.

25. History of IgE-mediated or non-IgE-mediated hypersensitivity.

26. Positive PPD or quantiferon without documentation of treatment for TB infection.

27. Denied consent to HIV testing.

28. Previous orbital radiotherapy

29. HBsAg positive test.

30. HBcAb positive test, regardless of HBsAb status, will undergo HBV DNA which, if positive, will be excluded.

31. Hepatitis C antibody positive test at screening.

32. Positive test for Human Immunodeficiency Virus (HIV) antibody at screening or historically.

33. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) greater or equal to 1.5x upper limit of normal (ULN).

34. Alkaline phosphatase and bilirubin>1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is<35%).

35. Grade 3 / 4 IgG deficiency and IgA deficiency (IgA < 10mg/dL).

36. 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.

37. Major depression.

38. 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.

39. Current drug or alcohol abuse or dependence.

40. White blood cells < 3.0 x 109/L (3000/mm3)

41. Absolute neutrophil count (ANC) < 2.0 x 109/L (2000/ mm3)

42. Absolute lymphocyte count < 0.5 x 109/L (500/ mm3)

43. Platelet count <100 x 109/L

44. Serum creatinine > 1.4 mg/dl (124 µmol/L) in female patients and > 1.6 mg/dl (141 µmol/L) in male patients

45. Hemoglobin <85 g/L (8.5 g/dL; 5.3 mmol/L)

46. Demyelinating disorders

47. Treatment with Methotrexate