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)

NCT03847272 | Terminated Phase 2

• 1 other identifier: BIELEFELD Janssen-PHRC N 2017
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 2

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.

Conditions

Patients With Newly Diagnosed Active NISU

Outcome Measures

Primary Outcomes (2)

• Percentage of remission

  Through study completion, an average of 30 months

• Percentage of patients free of relapse between week 6 and week 24

  Through study completion, an average of 30 months

Study Arms (1)

Patients

EXPERIMENTAL

Drug: prednisone and ustekinumab treatment; Other: Ophthalmologic examination; Other: Questionnaires; Biological: Blood samples

Interventions

prednisone and ustekinumab treatment DRUG

Treatment with prednisone and ustekinumab (90 mg subcutaneously at inclusion (W0), W4 and W16)

Patients

Ophthalmologic examination OTHER

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

Patients

Questionnaires OTHER

VFQ-25 and SF-36

Patients

Blood samples BIOLOGICAL

Additional blood samples for immunomonitoring

Patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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
• 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
• History of congenital or acquired immunodeficiency (e.g. common variable immunodeficiency disease).
• History of prior treatment with ustekinumab

Sponsors & Collaborators

• Centre Hospitalier Universitaire Dijon: lead

Study Sites (2)

CH Avignon

Avignon, 84902, France

Location

CHU Dijon Bourgogne

Dijon, 21000, France

Location

MeSH Terms

Interventions

Prednisone; Surveys and Questionnaires; Blood Specimen Collection

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Data Collection; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 15, 2019
• First Posted: February 20, 2019
• Study Start: August 1, 2019
• Primary Completion: October 25, 2023
• Study Completion: October 25, 2023
• Last Updated: January 12, 2024

Record last verified: 2024-01

Locations

FR (2)