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

Uveitis Clinical Trial

— RUBI  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02929251
• Other study ID #: P150945 2016-002284-34
• Status: Recruiting
• Phase: Phase 2
• First received: October 7, 2016
• Last updated: December 7, 2017
• Start date: June 28, 2017
• Est. completion date: May 2019

Study information

• Verified date: December 2017
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: David Saadoun, MD PHD
• Phone: 142178009
• Email: david.saadoun[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: May 2019
• Est. primary completion date: May 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

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

2. 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

3. 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

4. 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

5. Best corrected visual acuity (BCVA) by ETDRS of 20/20 to 20/400 (approximately 85 to 20 letters) in the study eye

6. Best corrected visual acuity (BCVA) by ETDRS of 20/20 or better in the fellow eye (approximately 20 letters)

7. Stable dose for two weeks prior to inclusion of topical corticosteroids and/or NSAIDs

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

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

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

11. For female subjects of child-bearing age, a negative serum pregnancy test

12. 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:

1. Infectious uveitis, masquerade syndromes, or uveitis due to causes other than non infectious uveitis disease (idiopathic uveitis is permitted)

2. Isolated anterior uveitis

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

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

5. 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

6. Monocular patient

7. Active tuberculosis or history of untreated tuberculosis

8. Known positive syphilis serology, HIV antibody, hepatitis B surface antigen or anti-nucleocapsid antibody of hepatitis B virus, and/or hepatitis C antibody.

9. 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.

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 to Inclusion

• 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 103/mm3

• Platelet count < 80 x 103/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

• 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.

16. 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

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

Related Conditions & MeSH terms

• Biotherapy
• Uveitis

Intervention

Drug:
• Anakinra
Anakinra (100 mg/day subcutaneously) (n=40) for 16 weeks
• Tocilizumab
Tocilizumab (162 mg/7 days subcutaneously) (n=40) for 16 weeks.
• Adalimumab
Adalimumab (40mg/14 days subcutaneously) (n=40) for 16 weeks

Locations

Country	Name	City	State
France	Hopital La Pitié Salpetriere	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Mean change from baseline in Vitreous Haze	Mean change from baseline in Vitreous Haze	Week 4, 8, 12, 16, 24
Secondary	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
Secondary	Mean change from baseline in BCVA (ETDRS letters score)		Week 4, 8, 12, 16, 24
Secondary	Mean change from baseline in central retinal thickness measured with Optical Coherence Tomography (OCT)		Week 4, 8, 12, 16, 24
Secondary	Percentage of patients with Central Retinal Thickness (CRT) <300 microns		Week 4, 8, 12, 16, 24
Secondary	Percentage of patients without retinal vessel leakage on fluorescein angiography		Week 4, 8, 12, 16, 24
Secondary	Percent meeting targets = 0.1 mg/day prednisone		week 16
Secondary	Mean change in prednisone dose		Week 4, 8, 12, 16, 24
Secondary	Mean dose of prednisone		week 16
Secondary	Cumulative dose of prednisone		week 16
Secondary	Time to response onset		week 16
Secondary	Time to relapse of uveitis		week 30
Secondary	Number of relapse of uveitis		week 30
Secondary	Underlying systemic disease	Complete remission of extra opthalmologic sign of Behcet disease or sarcoidosis	week 4, 8, 12, 16, 24
Secondary	Percentage of adverse event		week 4, 8, 12, 16, 24
Secondary	Percentage of serious adverse event		week 4, 8, 12, 16, 24
Secondary	time to treatment failure		week 30