Phase III Study in Refractory Behcet's Disease (SHIELD)

A 24 Week Multicenter, Randomized, Double-masked, Placebo Controlled Study to Assess the Difference in the Rate of Recurrent Exacerbations in Behçet¿s Patients With Posterior or Panuveitis Treated With AIN457 vs Placebo Adjunctive to Standard-of-care Immunosuppressive Therapy

The purpose of this pivotal trial is to evaluate subcutaneous (SQ) AIN457 as an adjunctive therapy to reduce the rate of exacerbations of posterior uveitis or panuveitis secondary to Behçet's disease during the 24 weeks of study therapy as compared to standard of care alone.

Study Overview

• Status: Completed
• Conditions: Behcet Disease
• Intervention / Treatment: Drug: Placebo; Drug: AIN457

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Phase 3

Contacts and Locations

Study Locations

• Egypt
  • Alexandria, Egypt
    • Novartis Investigative Site
• France
  • Grenoble, France, 38043
    • Novartis Investigative Site
• Germany
  • Dessau-Rosslau, Germany, 06847
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Muenster, Germany, 48145
    • Novartis Investigative Site
• Greece
  • Athens, Greece, GR 156 69
    • Novartis Investigative Site
  • Ioannina, Greece, 45500
    • Novartis Investigative Site
  • Larisa, Greece, GR 41110
    • Novartis Investigative Site
  • Patras, Greece, 26500
    • Novartis Investigative Site
  • GR
    • Athens, GR, Greece, 115 27
      • Novartis Investigative Site
    • Heraklion - Crete, GR, Greece, 711 10
      • Novartis Investigative Site
    • Ioannina, GR, Greece, 455 00
      • Novartis Investigative Site
    • Larissa, GR, Greece, 41110
      • Novartis Investigative Site
• Hong Kong
  • Hongkong, Hong Kong
    • Novartis Investigative Site
• India
  • Angamaly, India, 683572
    • Novartis Investigative Site
  • New Delhi, India, 110 029
    • Novartis Investigative Site
  • Tamil Nadu
    • Chennai, Tamil Nadu, India, 600006
      • Novartis Investigative Site
    • Madurai, Tamil Nadu, India, 625020
      • Novartis Investigative Site
• Israel
  • Afula, Israel, 18101
    • Novartis Investigative Site
  • Nahariya, Israel, 22100
    • Novartis Investigative Site
  • Ramat Gan, Israel, 52621
    • Novartis Investigative Site
  • Tel-Aviv, Israel, 64239
    • Novartis Investigative Site
• Italy
  • AN
    • Ancona, AN, Italy, 60126
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20132
      • Novartis Investigative Site
• Jordan
  • Amman, Jordan, 11195
    • Novartis Investigative Site
  • Irbid, Jordan, 22110
    • Novartis Investigative Site
• Korea, Republic of
  • Korea
    • Seoul, Korea, Korea, Republic of, 120-752
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 110 744
      • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 308433
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08035
    • Novartis Investigative Site
  • Barcelona, Spain
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Barcelona, Catalunya, Spain, 08028
      • Novartis Investigative Site
• Switzerland
  • Bern, Switzerland, 3012
    • Novartis Investigative Site
  • Lausanne, Switzerland, 1003
    • Novartis Investigative Site
• Taiwan
  • Lin-Ko, Taiwan, 33305
    • Novartis Investigative Site
• Tunisia
  • Monastir, Tunisia, 5019
    • Novartis Investigative Site
  • Sfax, Tunisia
    • Novartis Investigative Site
  • Tunis, Tunisia
    • Novartis Investigative Site
• Turkey
  • Altindag / Ankara, Turkey, 06590
    • Novartis Investigative Site
  • Ankara, Turkey, 06100
    • Novartis Investigative Site
  • Ankara, Turkey, 06490
    • Novartis Investigative Site
  • Istanbul, Turkey, 34093
    • Novartis Investigative Site
  • Istanbul, Turkey, 34303
    • Novartis Investigative Site
  • Izmir, Turkey, 35380
    • Novartis Investigative Site
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21205-2005
      • Novartis Investigative Site
  • Texas
    • Arlington, Texas, United States, 76012
      • Novartis Investigative Site
    • Houston, Texas, United States, 77025
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with Behçet's disease and with a history of recurrent uveitis in a least one eye.

• Documented evidence of >2 recurrent exacerbations of either intermediate uveitis, posterior uveitis or panuveitis in the study eye within the past 6 months (this could include the current exacerbation for patients having an acute exacerbation at screening). Exacerbations fulfilling the study inclusion criteria must have one or more of the following recorded in the patients patients medical record for each recurrent exacerbation:

  • >2+ vitreous haze with <2+ anterior chamber cell grade (intermediate or posterior uveitis) or >2+ vitreous haze with >2+ anterior chamber cell grade (panuveitis)
  • presence of retinal infiltrates or vasculitis or hemorrhages
  • documented >10 ETDRS letter or 2 line Snellen decrease in visual acuity attributed to ocular inflammation secondary to the recurrent exacerbation of Behçet's disease.

• Requirement for either of the following immunosuppressive therapies for at least 3 of the past 6 months for the treatment of or to prevent an exacerbation of ocular inflammation related to Behçet's disease:

  • Prednisone or equivalent >10 mg daily
  • The need for at least >1 periocular injection or >1 intravitreal corticosteroid injection in the study eye within the past 6 months (the last injection must have not been given within 6 weeks of screening)
  • Treatment with cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, mycophenolic acid or methotrexate either as monotherapy or in combination with or without steroids. (Patients treated at any time with chlorambucil or cyclophosphamide are not eligible for the study.)
• Patients not meeting the above specified criteria for immunomodulatory therapies are eligible for enrollment if they are intolerant to systemic immunomodulatory therapy as determined by the study investigator.

Exclusion Criteria:

• Subjects with infectious uveitis, uveitis due to other causes than Behçet's disease, or uveitis of unknown etiology.
• Less severe (i.e. anterior) uveitis associated with Behçet's disease.

Ocular treatments

• Treatment with intravitreal anti-VEGF agents administered to the study eye within 3 months prior to study screening.
• Treatment with any injected or implantable corticosteroid releasing device (i.e., flucinolone acetonide implant, Retisert®) in the study eye within the last 3 years.
• Intraocular surgery or laser photocoagulation in the study eye within the last 6 weeks prior to screening except for a diagnostic vitreous or aqueous tap with a small-gauge needle.

Systemic conditions or treatments

• Treatment with any live or live-attenuated vaccine (including vaccine for varicella-zoster virus or measles) within 2 months prior to screening.
• Any systemic biologic therapy (e.g. interferon, infliximab, daclizumab, etanercept, or adalimumab) given intravenously or subcutaneously within 3 months prior to screening and no prior treatment with AIN457.
• Any prior treatment with systemic alkylating agents (cyclophosphamide, chlorambucil).

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AIN457C 300 mg every 2 week dosage regimen; AIN457 300 mg was administered in 2 subcutaneous (s.c.) injections of 150 mg each. every 2 weeks	Drug: AIN457
Experimental: AIN457C 300 mg monthly dosage regimen; AIN457 300 mg was administered in 2 subcutaneous (s.c.) injections of 150 mg e	Drug: AIN457
Placebo Comparator: Placebo; Placebo was administered in 2 s.c. injections every 2 weeks	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Recurrent Ocular Exacerbations in the Study Eye During 24 Weeks by Treatment		Baseline to week 24
Rate of Recurrent Ocular Exacerbations in the Study Eye During 24 Weeks by Treatment	Patients number of occurences during a 24 week period.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline for Composite Immunosuppressive Medication Score at Week 24 by Treatment (Full Analysis Set)	For each corticosteroid medication, dose of the corticosteroid was first converted to a prednisone-equivalent dose. To determine the prednisone equivalent dose, the corticosteroid dose was multiplied by a conversion factor. . The total prednisone equivalent dose was calculated as the sum of the prednisone equivalent doses of all corticosteroids. Consequently, the total converted prednisone equivalent dose was used to obtain the immunosuppressive score. The key secondary efficacy variable was the change in total post-baseline immunosuppressive medication score from baseline.The score is actually the prednisoone equivalents taken by patient as calculated by conversion table. A reduction in prenisone or prenisone equivalents is a positive outcome. An increase in the number of prednisone equivalents suggests that the treatment is not efficacious or that there is disease progression. A score of 0 would be the lowest ( no steriods taken) and the upper limit is indeterminate.	24 weeks
To Determine the Effect of AIN457 on Macular Edema and Visual Acuity in Patients With Posterior Segment Uveitis Secondary to Behçet's Disease as Determined by Optical Coherence Tomography.	Optical coherence tomography (OCT) is amedical imaging technique that uses light to capture micrometer-resolution, three-dimensional images from within optical scattering media (e.g., biological tissue). OCT is based on low-coherence interferometry, typically employing near-infrared light. The use of relatively long wavelength light allows it to penetrate into the scattering medium. OCT is a noninvasive procedure that uses optical interferometry to visualize the structures within the retina. Following dilation of the pupil, a light source operating at 850nm provides probe illumination which is split and detected with and without the refraction of the retinal tissues. Cross-sectional imaging is accomplished in 1.3 second by acquiring a sequence of interferometric A-scans. A false color tomogram of optical reflectivity is produced by the computer. Central foveal thickness will be the primary variable derived from OCT. A increase in thickness could translate to disease progression.	baseline, and wk 24 (end of study)
To Establish the Impact of AIN457 on Quality of Life of Posterior Segment Uveitis Patients Secondary to Behçet's Disease Refractory to Systemic Immunomodulatory Therapy as Measured by National Eye Institute Visual Function Questionaire-25 and Euroqol.	The VFQ-25 is a reliable and valid 25-item version of the 51-item National Eye Institute Visual Function Questionnaire (NEI-VFQ). It is especially useful in settings such as clinical trials, where interview length is a critical consideration. Scores range from 0 to 100, with higher scores indicating better visual function.	screening, and wk 24 (end of study)
To Observe the Effect of AIN457 on the Systemic Non-ocular Manifestations of Behçet's Disease in Patients With Posterior Segment Uveitis Requiring Systemic Immunosuppression as Measured by the Bechet's Disease Current Activity Form.	The BDCAF scores oral and genital ulceration, skin, joint and gastrointestinal involvement, presence of fatigue and headache according to the duration of symptoms. The presence and type of large-vessel and central nervous system (CNS) involvement are documented. Eye activity was deemed present if there was a history of blurring of vision or if the eye was painful or red. . The BDCAF score was calculated by adding the score of each index and ranged between 0 and 12 A reduction in score signifies a lessening of the disease.	baseline and wk 24 (end of study)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Dick AD, Tugal-Tutkun I, Foster S, Zierhut M, Melissa Liew SH, Bezlyak V, Androudi S. Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials. Ophthalmology. 2013 Apr;120(4):777-87. doi: 10.1016/j.ophtha.2012.09.040. Epub 2013 Jan 3.

Study record dates

Study Major Dates

• Study Start: October 1, 2009
• Primary Completion (Actual): July 1, 2010
• Study Completion (Actual): July 1, 2010

Study Registration Dates

• First Submitted: October 13, 2009
• First Submitted That Met QC Criteria: October 14, 2009
• First Posted (Estimate): October 15, 2009

Study Record Updates

• Last Update Posted (Estimate): August 31, 2015
• Last Update Submitted That Met QC Criteria: August 13, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: uveitis; Behçet's disease,; intermediate uveitis; panuveitis; posterior uveitis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Eye Diseases; Genetic Diseases, Inborn; Stomatognathic Diseases; Mouth Diseases; Uveitis, Anterior; Panuveitis; Uveitis; Uveal Diseases; Vasculitis; Hereditary Autoinflammatory Diseases; Skin Diseases, Genetic; Skin Diseases, Vascular; Behcet Syndrome; Physiological Effects of Drugs; Immunologic Factors; Antibodies, Monoclonal
• Other Study ID Numbers: CAIN457C2303; 2009-011237-27 (EudraCT Number)