Clinical trial NCT02929251: Randomized Trial Comparing Efficacy of Adalimumab, Anakinra and Tocilizumab in Non-infectious Refractory Uveitis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Uveitis
Biotherapy
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2016-10-11
Enrollment: 112
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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 one of the two following criteria at Inclusion:

   * Active inflammatory chorioretinal and/or inflammatory retinal vascular lesions and/or macular edema (CRT ≥300 microns) OR
   * Vitreous haze grade ≥4 on the Miami 9-step scale (or VH \>1+ according to SUN/NEI classification)
4. a. Patient who are receiving prednisone ≥10 mg/day and \<80mg/day (or equivalent dose of another corticosteroid) at stable dose 30 days prior to the first study drug administration on Day 0 and who received at least 1 other systemic immunosuppressant (All systemic immunosuppressants must have been discontinued 30 days prior to the first study drug administration on Day 0), or, b. Patient who received IFN alpha (All systemic immunosuppressants must have been discontinued 30 days prior to the first study drug administration on Day 0), or, c. To be intolerant to immunosuppressant
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/or NSAIDs
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 12 weeks 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 contraceptive measures adequate to prevent the subject or the subject's partner from becoming pregnant during the study and 3 and 5 months after stopping therapy for roactemra and adalimumab, respectively. Birth control methods which may be considered as highly effective methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods (according to CTFG recommendations). Such methods include :

    * combined (estrogen and progestogen containing) hormonal contraception associated 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 is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle 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 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 in either eye
6. Monocular patient
7. Active tuberculosis
8. Known positive syphilis serology, HIV antibody, hepatitis B surface antigen and/or anti-nucleocapsid antibody of hepatitis B virus and/or Hepatitis C virus, within 1 month prior to inclusion.
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 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 to Inclusion 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 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

Primary outcomes:
measure: 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)
timeFrame: Week 16
Secondary outcomes:
measure: Mean change from baseline in Vitreous Haze
timeFrame: Week 4, 8, 12, 16, 24
measure: 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)
timeFrame: Week 4, 8, 12, 16, 24
measure: Mean change from baseline in BCVA (ETDRS letters score)
timeFrame: Week 4, 8, 12, 16, 24
measure: Mean change from baseline in central retinal thickness measured with Optical Coherence Tomography (OCT)
timeFrame: Week 4, 8, 12, 16, 24
measure: Percentage of patients with Central Retinal Thickness (CRT) <300 microns
timeFrame: Week 4, 8, 12, 16, 24
measure: Percentage of patients without retinal vessel leakage on fluorescein angiography
timeFrame: Week 4, 8, 12, 16, 24
measure: Percent meeting targets ≤ 0.1 mg/day prednisone
timeFrame: week 16
measure: Mean change in prednisone dose
timeFrame: Week 4, 8, 12, 16, 24
measure: Mean dose of prednisone
timeFrame: week 16
measure: Cumulative dose of prednisone
timeFrame: week 16
measure: Time to response onset
timeFrame: week 16
measure: Time to relapse of uveitis
timeFrame: week 30
measure: Number of relapse of uveitis
timeFrame: week 30
measure: Underlying systemic disease
timeFrame: week 4, 8, 12, 16, 24
measure: Percentage of adverse event
timeFrame: week 4, 8, 12, 16, 24
measure: Percentage of serious adverse event
timeFrame: week 4, 8, 12, 16, 24
measure: time to treatment failure
timeFrame: week 30
Other outcomes:
Locations:
city: Bobigny
country: France
facility: Hopital Avicenne - CRC
city: Bobigny
country: France
facility: Hopital Avicenne - Ophtalmologie
city: Bobigny
country: France
facility: Hopital Avicenne- Médecine interne
city: Bordeaux
country: France
facility: Hopital Pellegrin
city: Bordeaux
country: France
facility: Hopital Saint André - Médecine interne
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand - Hopital Gabriel Montpied - Médecine interne
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand - Hopital Gabriel Montpied - Ophtalmologie
city: Dijon
country: France
facility: CHU Dijon Bourgogne -Ophtalmologie
city: Dijon
country: France
facility: CHU Dijon Bourgogne Médecine Interne et Maladies Systémiques - Médecine 2 / SOC 2
city: Lyon
country: France
facility: HCL - Hôpital de la Croix Rousse - Médecine interne
city: Lyon
country: France
facility: HCL - Hôpital de la Croix Rousse - Ophtalmologie
city: Nancy
country: France
facility: CHRU de Nancy - Médecine interne
city: Nancy
country: France
facility: CHRU de Nancy
city: Paris
country: France
facility: Hopital la pitié salpetriere - Médecine interne 1
city: Paris
country: France
facility: CHNO des Quinze Vingt - Médecine interne
city: Paris
country: France
facility: CHNO des Quinze Vingt - Ophtalmologie
city: Paris
country: France
facility: CHNO des Quinze Vingt
city: Paris
country: France
facility: Hopital Pitié Salpetriere
city: Paris
country: France
facility: Hopital Rotchild - Médecine interne
city: Paris
country: France
facility: Hopital Rotchild - Ophtalmologie
city: Paris
country: France
facility: Hôpital de la pitié salpêtrière - Ophtalmologie
city: Rennes
country: France
facility: CHRU de Rennes Hopital Sud Médecine interne
city: Rennes
country: France
facility: CHU Rennes - Hopital Ponchaillou - Ophtalmologie
city: Rouen
country: France
facility: CHU Rouen - Hopital Charles Nicolle - Ophtalmologie
city: Rougé
country: France
facility: CHU Rouen - Hopital Charles Nicolle - Médecine interne
city: Toulouse
country: France
facility: CHU TOULOUSE - HOPITAL PIERRE PAUL RIQUET - Ophtalmologie
city: Toulouse
country: France
facility: CHU Toulouse - Hopital Rangueil
Study officials:
affiliation: APHP
name: David Saadoun, MD PHD
role: PRINCIPAL_INVESTIGATOR
References: