Randomized Trial Comparing Efficacy of Adalimumab, Anakinra and Tocilizumab in Non-infectious Refractory Uveitis

Inclusion Criteria:

1. Provide written, informed consent prior to the performance of any study specificprocedures

2. Diagnosis of non-infectious intermediate, posterior-, or pan-uveitis in at least oneeye fulfilling the International Study Group Classification Criteria (Standardization of Uveitis Nomenclature [SUN] criteria) of posterior, or pan-uveitis confirmed by documented medical history

3. Currently uncontrolled uveitic disease. Uncontrolled uveitic disease is defined asfulfilling one of the two following criteria at Inclusion:

• Active inflammatory chorioretinal and/or inflammatory retinal vascular lesionsand/or macular edema (CRT ≥300 microns) OR

• Vitreous haze grade ≥4 on the Miami 9-step scale (or VH >1+ according toSUN/NEI classification)

4. a. Patient who are receiving prednisone ≥10 mg/day and <80mg/day (or equivalent doseof another corticosteroid) at stable dose 30 days prior to the first study drugadministration on Day 0 and who received at least 1 other systemic immunosuppressant (All systemic immunosuppressants must have been discontinued 30 days prior to thefirst study drug administration on Day 0), or, b. Patient who received IFN alpha (All systemic immunosuppressants must have been discontinued 30 days prior to thefirst study drug administration on Day 0), or, c. To be intolerant toimmunosuppressant

5. Best corrected visual acuity (BCVA) by ETDRS ≥ to 20/400 in either eye

6. Stable dose for two weeks prior to inclusion of topical corticosteroids and/orNSAIDs

7. Male or female , Age >= 18 years at Inclusion

8. Weight 40 - 120 kg (88.2 - 264 lbs) at Inclusion

9. Chest X-ray or thoracic CT scan results (postero-anterior and lateral) within 12weeks prior to Inclusion with no evidence of active Tuberculosis, active infection,or malignancy

10. For female subjects of child-bearing age, a negative serum or urine pregnancy test

11. For subjects with reproductive potential, a willingness to use contraceptivemeasures adequate to prevent the subject or the subject's partner from becomingpregnant during the study and 3 and 5 months after stopping therapy for roactemraand adalimumab, respectively. Birth control methods which may be considered ashighly effective methods that can achieve a failure rate of less than 1% per yearwhen used consistently and correctly are considered as highly effective birthcontrol methods (according to CTFG recommendations). Such methods include :

• combined (estrogen and progestogen containing) hormonal contraceptionassociated with inhibition of ovulation 1:

• oral

• intravaginal

• transdermal

• progestogen-only hormonal contraception associated with inhibition of ovulation 1:

• oral

• injectable

• implantable

• intrauterine device (IUD)

• intrauterine hormone-releasing system ( IUS)

• bilateral tubal occlusion

• vasectomised partner

• sexual abstinence (In the context of this guidance sexual abstinence isconsidered a highly effective method only if defined as refraining fromheterosexual intercourse during the entire period of risk associated with thestudy treatments. The reliability of sexual abstinence needs to be evaluated inrelation to the duration of the clinical trial and the preferred and usuallifestyle of the subject).

12. A QuantiFERON®-Tuberculosis (TB) test within 6 months prior to Screening

Exclusion Criteria:

1. Infectious uveitis, masquerade syndromes (idiopathic uveitis is permitted)

2. Isolated anterior uveitis

3. Presence of cataract or posterior capsular opacification so severe that anassessment of the posterior segment of either eye is inadequate or impossible

4. Contraindication to mydriasis in either eye or presence of posterior synechiae inthe study eye such that mydriasis is inadequate for posterior segment examination

5. Intraocular pressure ≥ 25 mmHg by Goldmann tonometry or advanced glaucoma in eithereye

6. Monocular patient

7. Active tuberculosis

8. Known positive syphilis serology, HIV antibody, hepatitis B surface antigen and/oranti-nucleocapsid antibody of hepatitis B virus and/or Hepatitis C virus, within 1month prior to inclusion.

9. History of malignancy within 5 years prior to Inclusion other than carcinoma in situof the cervix or adequately treated, non-metastatic squamous or basal cell carcinomaof the skin.

10. History of severe allergic or anaphylactic reactions to monoclonal antibodies

11. Infectious disease:

• Fever or infection requiring treatment with antibiotics within 3 weeks prior toInclusion

• History of recurrent infection or predisposition to infection

12. Known immunodeficiency

13. History of multiple sclerosis and/or demyelinating disorder

14. Laboratory values assessed during Inclusion:

• Hemoglobin < 8g/dL

• White Blood Cell Count (WBC) < 2.0 x 10^3/mm3

• Platelet count < 80 x 10^3/mm3

• Glomerular filtration rates (GFR) <30ml/min.

• Transaminases > 3 times upper normal value

15. Use of the following systemic treatments during the specified periods:

• Any other previous systemic biologic therapy

• Treatment with any systemic alkylating agents within 12 months prior toInclusion or between Inclusion and Day 0 (e.g., cyclophosphamide, chlorambucil)

• Any live (attenuated) vaccine within 3 months prior to Inclusion

16. Use of the following ocular treatments during the specified periods:

• Previous anti Vascular Endothelial Growth Factor (VEGF) intravitreal therapy (applied to both eyes) within 3 months prior to Inclusion, or anticipated useduring the study period

• Treatment with dexamethasone intravitreal implant [Ozurdex®]) within 6 monthsprior to Inclusion

• Intravitreal corticosteroids within 3 months prior to Inclusion. PreviousSubtenon's corticosteroid injections are permitted if administered at least 2months prior to Inclusion

17. Stage III and IV New York Heart Association (NYHA) cardiac insufficiency