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A Multicenter Phase 2 Single-arm Proof-of-concept Trial to Assess the Efficacy and Safety of Ustekinumab in Association With Prednisone for the Treatment of Non-infectious Severe Uveitis (NISU) (USTEKINISU)

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ClinicalTrials.gov Identifier: NCT03847272
Recruitment Status : Recruiting
First Posted : February 20, 2019
Last Update Posted : April 13, 2021
Information provided by (Responsible Party):
Centre Hospitalier Universitaire Dijon

Brief Summary:

Uveitis is characterized by inflammation of the uvea, which is the middle portion of the eye. The greatest challenge for the treatment of uveitis is patients who have inflammation involving the posterior segment, either primarily in the vitreous (intermediate uveitis), the choroid or retina (posterior uveitis), or involving the entire eye (panuveitis). The term "uveitis" denotes a heterogeneous collection of diseases including infections, systemic immune-mediated diseases like sarcoidosis, and immune-mediated syndromes confined to the eye like sympathetic ophthalmia. Despite the progress in recent decades, uveitis and the related intraocular inflammation are comparable to diabetes or macular degeneration as a cause of lost quality-adjusted life years due to visual morbidity, and as such are a significant public health problem. The Standardization of Uveitis Nomenclature Working Group Guidelines recommend the use of corticosteroids as the first-line therapy for patients with active uveitis. However, long-term corticosteroid treatment can cause serious systemic and ocular side effects, such as hypertension, diabetes, osteoporosis, cataract, and glaucoma that limit its use in the treatment of uveitis. Alternatively, immunomodulatory therapy (IMT) drugs are given as steroid-sparing agents and have shown good clinical results for both systemic diseases and ocular inflammatory diseases. Given the side effects of chronic corticosteroid therapy and better understanding of the mechanisms of autoimmune-mediated uveitis, the aim of the treatment for patients with noninfectious uveitis is steroid-free remission with IMT. While uveitis is a heterogeneous disease with polygenic and environmental factors, most forms of immune-mediated uveitis are thought to be due to an imbalance between regulatory mechanisms that inhibit the immune system and inflammatory mechanisms, which have evolved to rid the body of infectious organisms, but which can result in immune-mediated, often chronic disease if they are activated outside the context of the immediate infection. The pathophysiology of non-infectious uveitis involves the rupture of peripheral tolerance, resulting in auto-aggressive Th1 or Th17 lymphocytes reaching the eye. L-12 and IL-23 are two key cytokines involved in Th1 and Th17 polarization in uveitis, respectively. Furthermore, these two cytokines share a common subunit (p40). Ustekinumab, a humanized anti-p40 monoclonal antibody, is able to target both IL-12 and IL-23 pathways, thus disrupting Th1 and Th17 immune responses.

Decreasing the dose as well as the duration of treatment with GC is of particular importance in uveitis, and ustekinumab, which selectively inhibits Th1 and Th17 pathways in the inflammatory cascade, could provide a ideal additional therapy for non-infectious severe uveitis (NISU) to reach this objective.

Therefore, in the present study, we propose to evaluate the efficacy and safety of ustekinumab for the treatment of NISU.

Condition or disease Intervention/treatment Phase
Patients With Newly Diagnosed Active NISU Drug: prednisone and ustekinumab treatment Other: Ophthalmologic examination Other: Questionnaires Biological: Blood samples Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 29 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter Phase 2 Single-arm Proof-of-concept Trial to Assess the Efficacy and Safety of Ustekinumab in Association With Prednisone for the Treatment of Non-infectious Severe Uveitis (NISU)
Actual Study Start Date : August 1, 2019
Estimated Primary Completion Date : January 2025
Estimated Study Completion Date : January 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Steroids

Arm Intervention/treatment
Experimental: Patients Drug: prednisone and ustekinumab treatment
Treatment with prednisone and ustekinumab (90 mg subcutaneously at inclusion (W0), W4 and W16)

Other: Ophthalmologic examination
Best corrected visual acuity (BCVA) testing, Slit Lamp Exam, tonometry, dilated indirect ophthalmoscopy, optical coherence tomography (OCT), Fluorescein angiography and Indocyanin green angiography

Other: Questionnaires
VFQ-25 and SF-36

Biological: Blood samples
Additional blood samples for immunomonitoring

Primary Outcome Measures :
  1. Percentage of remission [ Time Frame: Through study completion, an average of 30 months ]
  2. Percentage of patients free of relapse between week 6 and week 24 [ Time Frame: Through study completion, an average of 30 months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion criteria:

  • Patients with newly diagnosed active NISU: evidence of activity within the 3 months prior to the screening visit as per:

    • VH (visual haze) ≥ 4 on the Miami 9-step scale (or VH >1+ according to SUN classification)
    • and/or macular edema on OCT (Central retinal thickness ≥ 300 microns)
    • and/or other signs of intraocular inflammation (e.g. perivascular sheathing of retinal vessels or leakage of retinal vessels on fluorescein angiography (FA)).
  • Patients judged to be in good health as determined by the Principal Investigator based upon the results of medical history, laboratory profile, physical examination, chest x-ray (CXR), and a 12-lead electrocardiogram (ECG) performed during Screening.
  • For men and women of childbearing age, effective contraception must be used by the patient and/or his/her partner throughout the duration of treatment with ustekinumab and until 23 weeks after the end of treatment. Breastfeeding is allowed 23 weeks after the end of treatment. Women considered without risk of pregnancy are those with :

    • combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
    • progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
    • intrauterine device (IUD)
    • intrauterine hormone-releasing system ( IUS)
    • bilateral tubal occlusion
    • vasectomised partner
    • sexual abstinence
    • or those surgically sterile (bilateral oophorectomy or hysterectomy).
    • or at least one year of menopause (amenorrhea for at least 12 months)
  • Patients over 18 years of age
  • Affiliation to a the French health insurance system
  • Patients who have given their consent

Exclusion criteria:

  • Surgery scheduled within 12 months
  • Patients with dementia
  • Non-compliant patients
  • Weight <45 kg or > 100 kg
  • Patients under ward of court, tutelage or legal guardianship
  • Pregnant or breast-feeding women

Exclusion criteria related to uveitis:

  • 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 ≥ 25mmHg 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 IOP < 22 mmHg) in either eye
  • Monocular patient
  • Sarcoidosis-related uveitis

Exclusion criteria related to ustekinumab:

  • History of congenital or acquired immunodeficiency (e.g. common variable immunodeficiency disease).
  • History of prior treatment with ustekinumab
  • Hypersensitivity to ustekinumab, one of its excipients or another human or murine monoclonal antibody or latex
  • Evidence of active infection at the time of baseline visit, or other Infectious contraindication to ustekinumab
  • Neoplasia < 5 years, (except for in situ cervical cancer and skin carcinoma with R0 resection)
  • Active tuberculosis or sign of latent tuberculosis (based on a history of untreated contact, a history of opacity of more than 1 cm in diameter on the chest x-ray, or an in vitro test positive[Quantiferon® or T-spot-TB®]). A history of TB disease or latent TB whose treatment was completed is not an exclusion criteria, regardless the Quantiferon® or T-spot-TB® is positive or not.
  • Known positive laboratory test for syphilis serology, HIV antibody, hepatitis B surface antigen or anti-nucleocapsid antibody of hepatitis B virus, and/or hepatitis C antibody.
  • History of multiple sclerosis and/or other demyelinating disorders
  • Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the Baseline Visit or oral anti-infectives within 14 days prior to the Baseline Visit.
  • Screening laboratory and other analyses showing any of the following abnormal results:

    • AST, ALT > 1.75 × upper limit of the reference range;
    • WBC count < 3.0 × 109/L;

Other treatments:

  • Corticosteroids

    • History of ≥3 systemic corticosteroid therapies (topical or inhaled treatments allowed) for another disease (e.g. asthma) within the last 6 months before screening visit
    • Dexamethasone intravitreal implant less than 6 months prior to study
  • Patients receiving (or having stopped for less than 6 months or 5 elimination half-lives) an immunosuppressive or immunomodulatory drug or biotherapy:

    • anti TNF-α,
    • tocilizumab,
    • abatacept,
    • anakinra,
    • methotrexate,
    • azathioprine,
    • ciclosporine,
    • cyclophosphamide,
    • dapsone
    • or corticosteroid pulses
  • Live vaccine administered within 30 days preceding inclusion
  • Hypersensibility to fluorescein and indocyanin green

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03847272

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Contact: Philip Bielefeld 0629470887 bielefeldphilip@gmail.com

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CH Avignon Recruiting
Avignon, France, 84902
Contact: Philip Bielefeld    0629470887    bielefeldphilip@gmail.com   
CHU Dijon Bourgogne Recruiting
Dijon, France, 21000
Contact: Thomas ROGIER    0380293773    thomas.rogier@chu-dijon.fr   
Sponsors and Collaborators
Centre Hospitalier Universitaire Dijon
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Responsible Party: Centre Hospitalier Universitaire Dijon
ClinicalTrials.gov Identifier: NCT03847272    
Other Study ID Numbers: BIELEFELD Janssen-PHRC N 2017
First Posted: February 20, 2019    Key Record Dates
Last Update Posted: April 13, 2021
Last Verified: April 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Uveal Diseases
Eye Diseases
Anti-Inflammatory Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Dermatologic Agents