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)

  • STATUS
    Recruiting
  • End date
    Jan 22, 2025
  • participants needed
    29
  • sponsor
    Centre Hospitalier Universitaire Dijon
Updated on 22 April 2021

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.

Details
Condition Patients With Newly Diagnosed Active NISU
Treatment Questionnaires, blood samples, Ophthalmologic examination, prednisone and ustekinumab treatment
Clinical Study IdentifierNCT03847272
SponsorCentre Hospitalier Universitaire Dijon
Last Modified on22 April 2021

Eligibility

Yes No Not Sure

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-
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
Clear my responses

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