A pilot study towards a therapy with prednisolone encapsulated liposomes for the treatment of Graves' Orbitopathy with reduced systemic steroid exposure

1. Male or female ≥ 18 years old.

2. Informed consent.

3. Patients are able and willing to complete the study (12 months follow-up).

4. Active GO, defined as Clinical Activity Score (CAS) ≥ 3.

5. Moderate to severe GO (Bartalena et al. 2016):

Patients without sight-threatening GO whose eye disease has sufficient impact on daily life to justify the risks of immunosuppression (if active) or surgical intervention (if inactive). They usually have two or more of the following: lid retraction ≥ 2 mm, moderate or severe soft-tissue involvement, or exophthalmos ≥ 3 mm above normal for race and gender, inconstant or constant diplopia.

6. Euthyroidism for at least 3 months with antithyroid drugs or following thyroidectomy, or 6 months following radioiodine administration. (Euthyroidism is defined as normal serum free thyroxine, total or free triiodothyronine, and thyrotropin levels below 4 mU/Liter.)

1. Sight threatening GO due to optic neuropathy (decrease of (pinhole) vision, visual field loss, prolonged VEP, diminished colour vision) or severe keratopathy.

2. Any concurrent illness, disability or clinically significant abnormality that may, as judged by the investigator, affect the interpretation of clinical efficacy or safety data or prevent the subject from safely completing the assessments required by the protocol.

3. Current participation in another interventional clinical trial (with subjects having
received an investigational drug within 30 days prior to the baseline visit).

4. Treatment with oral, rectal or injectable (including intra-articular) glucocorticoids within 6 weeks prior to baseline visit. Inhaled glucocorticoids are allowed. Topical steroids are allowed, however subjects should not have received more than 100 gram of a mild to moderate topical corticosteroid cream per week, 50 gram of a potent corticosteroid cream per week or 30 gram of a very potent topical corticosteroid cream per week in the 4 weeks prior to the baseline visit.

5. Patients who are unlikely to adequately comply with the trial¡¯s procedures (due for instance to medical conditions likely to require an extended interruption or discontinuation, history of substance abuse or noncompliance).

6. Women who are lactating, pregnant (positive pregnancy test at screening) or planning to become pregnant during the course of the study.

7. Unwillingness to use reliable and acceptable contraceptive methods untill 3 months after last study medication except for female patients who are surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy) or at least 1 year postmenopausal
8. Uncontrolled Diabetes Mellitus.

9. History of a psychiatric disease (psychosis, depression, mania).

10. History of or active hepatitis or Human immunodeficiency virus.

11. Abnormal hepatic function (ALT/AST or bilirubin > 2 x upper limit of normal) at screening.

12. Abnormal renal function (Blood Urea Nitrogen or creatinine >1.25 x upper limit of normal) at screening.

13. Signs of active infection, requiring systemic treatment.

14. Major surgery within the 60 Days prior to screening or planned surgery during study period.
15. Malignant disease, unless cured.

16. Clinically significant out-of-range values on hematology panel, at discretion of the
Principal Investigator.

17. Poor peripheral venous access (as per Investigator or site personnel opinion).

18. Current substance abuse or alcohol abuse.

19. Contraindications for MRI.