title: Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial.
abstract: Non-infectious uveitis is a potentially sight-threatening ocular disorder caused by chronic inflammation and its complications. Therapeutic success is limited by systemic adverse effects associated with long-term corticosteroid and immunomodulator use if topical medication is not sufficient to control the inflammation. We aimed to assess the efficacy and safety of adalimumab in patients with inactive, non-infectious uveitis controlled by systemic corticosteroids.
  
  
  
  We did this multicentre, double-masked, randomised, placebo-controlled phase 3 trial at 62 study sites in 21 countries in the USA, Canada, Europe, Israel, Australia, and Latin America. Patients (aged ≥18 years) with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by 10-35 mg/day of prednisone were randomly assigned (1:1), via an interactive voice and web response system with a block size of four, to receive either subcutaneous adalimumab (loading dose 80 mg; biweekly dose 40 mg) or placebo, with a mandatory prednisone taper from week 2. Randomisation was stratified by baseline immunosuppressant treatment. Sponsor personnel with direct oversight of the conduct and management of the study, investigators, study site personnel, and patients were masked to treatment allocation. The primary efficacy endpoint was time to treatment failure, a multicomponent endpoint encompassing new active inflammatory chorioretinal or inflammatory retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, and visual acuity. Analysis was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov number NCT01124838.
  
  
  
  Between Aug 10, 2010, and May 14, 2015, we randomly assigned 229 patients to receive placebo (n=114) or adalimumab (n=115); 226 patients comprised the intention-to-treat population. Median follow-up time was 155 days (IQR 77-357) in the placebo group and 245 days (119-564) in the adalimumab group. Treatment failure occurred in 61 (55%) of 111 patients in the placebo group compared with 45 (39%) of 115 patients in the adalimumab group. Time to treatment failure was significantly improved in the adalimumab group compared with the placebo group (median not estimated [>18 months] vs 8·3 months; hazard ratio 0·57, 95% CI 0·39-0·84; p=0·004). The 40th percentile for time to treatment failure was 4·8 months in the placebo group and 10·2 months in the adalimumab group. No patients in either group had opportunistic infections (excluding oral candidiasis and tuberculosis). No malignancies were reported in the placebo group whereas one (1%) patient in the adalimumab group reported non-serious squamous cell carcinoma. The most common adverse events were arthralgia (12 [11%] patients in the placebo group and 27 [23%] patients in the adalimumab group), nasopharyngitis (16 [17%] and eight [16%] patients, respectively), and headache (17 [15%] patients in each group).
  
  
  
  Adalimumab significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in patients with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by systemic corticosteroids. No new safety signals were observed and the rate of adverse events was similar between groups. These findings suggest that adalimumab is well tolerated and could be an effective treatment option in this patient population. An open-label extension study (NCT01148225) is ongoing to provide long-term safety data for adalimumab in patients with non-infectious uveitis.
  
  
  
  AbbVie.
authors.affiliation: Ocular Imaging Research and Reading Center (OIRRC), Omaha, NE, USA. Electronic address: quan.nguyen@unmc.edu.
authors.forename: Quan Dong
authors.initials: QD
authors.lastname: Nguyen
authors.affiliation: Rush University Medical Center, Chicago, IL, USA.
authors.forename: Pauline T
authors.initials: PT
authors.lastname: Merrill
authors.affiliation: Duke University, Durham, NC, USA.
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Jaffe
authors.affiliation: University of Bristol, Bristol Eye Hospital, Bristol, UK; National Institute for Health Research (NIHR) Biomedical Research Centre, London, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Dick
authors.affiliation: Wake Forest Baptist Medical Center, Winston-Salem, NC, USA.
authors.forename: Shree Kumar
authors.initials: SK
authors.lastname: Kurup
authors.affiliation: Lions Medical Eye Bank of Eastern Virginia, Eastern Virginia Medical School and Virginia Eye Consultants, Norfolk, VA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Sheppard
authors.affiliation: Austral University, Buenos Aires, Argentina.
authors.forename: Ariel
authors.initials: A
authors.lastname: Schlaen
authors.affiliation: Moorfields Eye Hospital and University College London, Institute of Ophthalmology, London, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Pavesio
authors.affiliation: Arcispedale Santa Maria Nuova IRCCS, Reggio Emilia RE, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Cimino
authors.affiliation: University Hospitals Leuven, Leuven, Belgium.
authors.forename: Joachim
authors.initials: J
authors.lastname: Van Calster
authors.affiliation: AbbVie Deutschland, Ludwigshafen, Germany.
authors.forename: Anne A
authors.initials: AA
authors.lastname: Camez
authors.affiliation: AbbVie, North Chicago, IL, USA.
authors.forename: Nisha V
authors.initials: NV
authors.lastname: Kwatra
authors.affiliation: AbbVie, North Chicago, IL, USA.
authors.forename: Alexandra P
authors.initials: AP
authors.lastname: Song
authors.affiliation: AbbVie Deutschland, Ludwigshafen, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Kron
authors.affiliation: AbbVie, North Chicago, IL, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Tari
authors.affiliation: Université Paris Descartes, Hôpital Cochin, Paris, France.
authors.forename: Antoine P
authors.initials: AP
authors.lastname: Brézin
mesh_terms: D000208:Acute Disease; D000068879:Adalimumab / Q000627:therapeutic use*; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002908:Chronic Disease; D018572:Disease-Free Survival; D004311:Double-Blind Method; D019317:Evidence-Based Medicine; D006801:Humans; D008875:Middle Aged; D017211:Treatment Failure; D016896:Treatment Outcome; D014605:Uveitis / Q000188:drug therapy* / Q000517:prevention & control*
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D000068879:Adalimumab