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

Study Overview
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Brief Summary
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RUBI, is the first prospective randomized, head to head study, comparing Adalimumab to either anakinra, or tocilizumab in refractory Non Infectious Uveitis (NIU). There is no firm evidence or randomized controlled trials directly addressing the best biologic agent in severe and refractory NIU. NIU can cause devastating visual loss and up to 20% of legal blindness. Corticosteroids and immunosuppressants failed to demonstrate sustainable remission over 70 % of refractory/relapsing severe uveitis. The incidence of blindness in NIU has been dramatically reduced in the recent years with the use of biologics, raising the question of whether these compounds should be used earlier in the treatment of severe non infectious uveitis. Contrasting with immunosuppressors, biotherapies act rapidly and are highly effective in steroid's sparing thus preventing occurrence of cataract and/or glaucoma. Despite a strong rationale, these compounds are not yet approved in uveitis, which guarantees the innovative nature of this study that aims selecting or dropping any arm when evidence of efficacy already exists.

Official Title
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Multicentre, Randomized, Multi-arm Trial Comparing the Efficacy and Safety of Adalimumab, Anakinra and Tocilizumab in Subjects With Non-infectious Refractory Uveitis RUBI: Refractory Uveitis BIotherapies

Conditions
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Uveitis, Biotherapy

Intervention / Treatment
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* Drug: Anakinra
* Drug: Tocilizumab
* Drug: Adalimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written, informed consent prior to the performance of any study specific procedures Diagnosis of non-infectious intermediate, posterior-, or pan-uveitis in at least one eye fulfilling the International Study Group Classification Criteria (Standardization of Uveitis Nomenclature [SUN] criteria) of posterior, or pan- uveitis confirmed by documented medical history Currently uncontrolled uveitic disease. Uncontrolled uveitic disease is defined as fulfilling of the two following criteria at Inclusion: Active inflammatory chorioretinal and/or inflammatory retinal vascular lesions OR Vitreous haze grade >1+ according to the SUN National Eye Institute (NEI) Scoring for Vitreous Haze Are receiving prednisone ≥10 mg/day (or equivalent dose of another corticosteroid) and at least 1 other systemic immunosuppressant, or, . Are receiving IFNalpha or, To be intolerant to immunosuppressant Best corrected visual acuity (BCVA) by ETDRS of 20/20 to 20/400 (approximately 85 to 20 letters) in the study eye Best corrected visual acuity (BCVA) by ETDRS of 20/20 or better in the fellow eye (approximately 20 letters) Stable dose for two weeks prior to inclusion of topical corticosteroids and/or NSAIDs Male or female , Age >= 18 years at Inclusion Weight 40 - 120 kg (88.2 - 264 lbs) at Inclusion Chest X-ray results (postero-anterior and lateral) within 12 weeks prior to Inclusion with no evidence of active Tuberculosis, active infection, or malignancy For female subjects of child-bearing age, a negative serum pregnancy test For subjects with reproductive potential, a willingness to use contraceptive measures adequate to prevent the subject or the subject's partner from becoming pregnant during the study. Adequate contraceptive measures include hormonal methods used for two or more cycles prior to Screening (e.g., oral contraceptive pills, contraceptive patch, or contraceptive vaginal ring), barrier methods (e.g., contraceptive sponge, diaphragm used in conjunction with contraceptive foam or jelly, or condom used in conjunction with contraceptive foam or jelly), intrauterine methods (IUD), sterilization (e.g., tubal ligation or a monogamous relationship with a vasectomized partner), and abstinence. Exclusion Criteria: Infectious uveitis, masquerade syndromes, or uveitis due to causes other than non infectious uveitis disease (idiopathic uveitis is permitted) Isolated anterior uveitis Presence of cataract or posterior capsular opacification so severe that an assessment of the posterior segment of either eye is inadequate or impossible Contraindication to mydriasis in either eye or presence of posterior synechiae in the study eye such that mydriasis is inadequate for posterior segment examination Intraocular pressure ≥ 25 mmHg by Goldmann tonometry or advanced glaucoma (e.g., cup-to-disc ratio > 0.9, split fixation on visual field, or need for > 3 intraocular pressure lowering medications to keep Intra Ocular Pressure (IOP) < 22 mmHg) in either eye Monocular patient Active tuberculosis or history of untreated tuberculosis Known positive syphilis serology, HIV antibody, hepatitis B surface antigen or anti-nucleocapsid antibody of hepatitis B virus, and/or hepatitis C antibody. History of malignancy within 5 years prior to Inclusion other than carcinoma in situ of the cervix or adequately treated, non-metastatic squamous or basal cell carcinoma of the skin. History of severe allergic or anaphylactic reactions to monoclonal antibodies Infectious disease: Fever or infection requiring treatment with antibiotics within 3 weeks prior to Inclusion History of recurrent infection or predisposition to infection Known immunodeficiency History of multiple sclerosis and/or demyelinating disorder Laboratory values assessed during Inclusion: Hemoglobin < 8g/dL White Blood Cell Count (WBC) < 2.0 x 103/mm3 Platelet count < 80 x 103/mm3 Glomerular filtration rates (GFR) <30ml/min. Transaminases > 3 times upper normal value Use of the following systemic treatments during the specified periods: Any other previous systemic biologic therapy Any prior treatment with tocilizumab, anakinra, or anti Tumor Necrosis Factor (TNF) Treatment with any systemic alkylating agents within 12 months prior to Inclusion or between Inclusion and Day 0 (e.g., cyclophosphamide, chlorambucil) Any live (attenuated) vaccine within 3 months prior to Inclusion; recombinant or killed virus vaccines are permitted. Live seasonal flu and H1N1 vaccines are permitted ≥ 2 weeks prior to Inclusion. Use of the following ocular treatments during the specified periods: Previous anti Vascular Endothelial Growth Factor (VEGF) intravitreal therapy within 3 months prior to Inclusion, or anticipated use during the study period Treatment with dexamethasone intravitreal implant [Ozurdex®]) within 6 months prior to Inclusion Intravitreal corticosteroids within 3 months prior to Inclusion. Previous Subtenon's corticosteroid injections are permitted if administered at least 2 months prior to Inclusion Stage III and IV New York Heart Association (NYHA) cardiac insufficiency

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Adalimumab<br>Adalimumab (40mg/14 days subcutaneously) (n=40) for 16 weeks | Drug: Adalimumab<br>* Adalimumab (40mg/14 days subcutaneously) (n=40) for 16 weeks<br>|
| Experimental: Anakinra<br>Anakinra (100 mg/day subcutaneously) (n=40) for 16 weeks | Drug: Anakinra<br>* Anakinra (100 mg/day subcutaneously) (n=40) for 16 weeks<br>|
| Experimental: Tocilizumab<br>Tocilizumab (162 mg/7 days subcutaneously) (n=40) for 16 weeks. | Drug: Tocilizumab<br>* Tocilizumab (162 mg/7 days subcutaneously) (n=40) for 16 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with at least 2-step reduction in Vitreous Haze (according to Miami 9-step Scale) and with a dose <= 0.1 mg/Kg/day of prednisone (or equivalent oral corticosteroid) | Percentage of patients with at least 2-step reduction in Vitreous Haze (according to Miami 9-step Scale) and with a dose <= 0.1 mg/Kg/day of prednisone (or equivalent oral corticosteroid) | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change from baseline in Vitreous Haze | Mean change from baseline in Vitreous Haze | Week 4, 8, 12, 16, 24 | 
| Percentage of patients with anterior chamber score = 0 or at least 2-step reduction in score (Tyndall and flare according to the Standardization of Uveitis Nomenclature (SUN) classification) |  | Week 4, 8, 12, 16, 24 | 
| Mean change from baseline in BCVA (ETDRS letters score) |  | Week 4, 8, 12, 16, 24 | 
| Mean change from baseline in central retinal thickness measured with Optical Coherence Tomography (OCT) |  | Week 4, 8, 12, 16, 24 | 
| Percentage of patients with Central Retinal Thickness (CRT) <300 microns |  | Week 4, 8, 12, 16, 24 | 
| Percentage of patients without retinal vessel leakage on fluorescein angiography |  | Week 4, 8, 12, 16, 24 | 
| Percent meeting targets ≤ 0.1 mg/day prednisone |  | week 16 | 
| Mean change in prednisone dose |  | Week 4, 8, 12, 16, 24 | 
| Mean dose of prednisone |  | week 16 | 
| Cumulative dose of prednisone |  | week 16 | 
| Time to response onset |  | week 16 | 
| Time to relapse of uveitis |  | week 30 | 
| Number of relapse of uveitis |  | week 30 | 
| Underlying systemic disease | Complete remission of extra opthalmologic sign of Behcet disease or sarcoidosis | week 4, 8, 12, 16, 24 | 
| Percentage of adverse event |  | week 4, 8, 12, 16, 24 | 
| Percentage of serious adverse event |  | week 4, 8, 12, 16, 24 | 
| time to treatment failure |  | week 30 |