Tocilizumab in Active Moderate-severe Graves' Orbitopathy

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)

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

Randomized, single blind (ophthalmologist), controlled study, IIb phase. The study will be conducted in 5 National centres dedicated to the management of Graves' orbitopathy

The present study will randomize GO patients, euthyroid for at least 6-8 weeks, to two treatments:

1. Tocilizumab weight adjusted, 8 mg/kg, 1 intravenous infusion every four weeks (+/- 72 hours) for 12 weeks
2. Methylprednisolone, 500 mg infusion weekly (+/- 48 hours) for 6 weeks, followed by 250 mg infusion weekly (+/- 48 hours) for another 6 weeks

The enrollment period is approximately 24 months

3.Phases of the study

* Screening phase (-4/-2 to 0 weeks): involves 1 to 2 visits
* Treatment phase (0 to 12 weeks): assessments at baseline and every 4 weeks
* Observation phase (12 to 24 weeks): assessments every 6 weeks
* Follow up (24 to 48 weeks): assessments every 12 weeks

Data from week 24 are used to determine primary and secondary endpoints

4.Definition of improvement, worsening or no change of the secondary end point criteria\*

1. Improvement, when at least two of the following outcome measures improve in one eye, without deterioration in any of the measure in either eyes: a) reduction in palpebral aperture by at least 3 mm; b) reduction in any of the class 2 signs of NOSPECS by at least 2 grades; c) reduction of proptosis by at least 2 mm; d) improvement of ≥8 degrees in any duction or in diplopia (Gorman score); e) improvement in CAS by at least 2 points
2. Worsening, when optic neuropathy or two of the following occur: a) increase in palpebral aperture by at least 3 mm; b) increase in any of the class 2 signs of NOSPECS by at least 2 grades; c) increase of proptosis by at least 2 mm; d) deterioration of ≥8 degrees in any duction or in diplopia (Gorman score); e) worsening in CAS.
3. No change, when there are no changes or changes smaller than the above defined parameters

5. Study population

5.1 Withdrawal Rules

1. Should patients become affected with any of the conditions outlined as exclusion criteria during the study period or follow-up, they will be withdrawn from the study
2. Should patients require administration of any of the medications listed in the exclusion criteria, according to prohibited medication rules, they will be withdrawn from the study.
3. Other reasons for study withdrawal are:

   1. refusal of continuing the study medication after having commenced it.
   2. diagnosis of major cardiovascular diseases or neoplasia once treatment has started.
4. If patients present with a severe complication of GO, i.e. progression to dysthyroid optic neuropathy due to unresponsiveness to treatment, they will be considertreatment failure and will undergo urgent surgical orbital decompression.

Patients have the right to voluntarily withdraw from the study at any time for any reason. In addition, the investigator has the right to withdraw a patient from the study at any time. Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements as determined by the investigator or Sponsor

Every effort should be made to obtain information on patients who withdraw from the study. The primary reason for withdrawal from the study should be documented on the appropriate eCRF. If a patient requests to be withdrawn from the study, this request must be documented in the source documents and signed by the investigator. Patients who withdraw from the study will not be replaced.

5.2 Study Arms

Arm 1: 32 patients with active moderate-severe GO treated with i.v. tocilizumab

Arm 2: 32 patients with active moderate-severe GO treated with i.v. methylprednisolone.

5.3 Study Medications and Dosing Regimen

Tocilizumab, the IMP-test, will be supplied and distribute by Roche packed and labelled.

Upon delivery to the site, site personnel should check for damage and verify proper identity, quantity, integrity of seals and temperature conditions. Site personnel should report any deviations or product complaints to the study monitor upon discovery.

For information on the formulation and handling of tocilizumab see the SmPC and Investigator's Brochure

Methylprednisolone is the IMP-comparator,

For information on the formulation, packaging, and handling of MP, see the SmPC.

Arm 1. Tocilizumab: i.v. infusion of, weight adjusted, 8 mg/kg of TCZ every four weeks (+/- 72 hours) for 12 weeks.

Arm 2. Methylprednisolone (MP): i.v. infusion of 500 mg of MP weekly (+/- 48 hours) for 6 weeks, followed by i.v. infusion of 250 mg of MP one a week (+/- 48 hours) for 6 weeks

5.4 Study duration

Duration of the study: 3 years (2 years for enrollment and one year for follow up)

5.5 Study Discontinuation

The Sponsor has the right to terminate this study at any time. Reasons for terminating the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a potential health hazard to patients

Patient enrollment is unsatisfactory

The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.

5.6 Site Discontinuation

The Sponsor has the right to close a site at any time. Reasons for closing a site may include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have been fulfilled)

6. Statistical considerations and sample size calculation A sample size of 64 patients is planned to provide at least an 80% power if 32 patients per treatment arm were included for an anticipated (improvement) responder rate of 68% in steroid and 95% in tocilizumab treated patients, with a two-tail significance of 0.05.

No patients stratification is planned The calculation is based on the available literature on the significant decrease of the after rituximab and steroid therapy and after tocilizumab and placebo.

64 patients with active GO will be enrolled and an interim analysis of results will be carried out after the first 32 patients (16 in arm 1 and 16 in arm 2) will reach the 24 week endpoint.

All enrolled patients receiving at least one dose of study medication and withdrawing from the study for any reason will be analyzed as non-responder in an ITT population for the 24 weeks primary endpoint.

Statistical Analysis: repeated measures ANOVA and Spearman or Pearson rank test for clinical activity and severity scores; Wilcoxon rank sum test to assess differences between treatment groups; chi-square for response and relapse rates.

An interim analysis of results will be carried out after the first 16 enrolled patients in both arms reach 24 week point), in order to eventually plan for another study perhaps employing s.c. TCZ .

Eligibility 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