Cyclophosphamide vs. Infliximab for Refractory Idiopathic Scleritis (CIRIS)

  • STATUS
    Recruiting
  • End date
    Jul 24, 2024
  • participants needed
    50
  • sponsor
    Hospices Civils de Lyon
Updated on 24 January 2021

Summary

This study will evaluate the Efficacy and Safety of Infliximab versus Cyclophosphamide in Subjects with Idiopathic Refractory Scleritis.

The term scleritis describes a chronic inflammation that involves the outermost cost and skeleton of the eye. Scleritis is classified anatomically as either anterior or posterior based on the principal location of the inflammation. Thirty to forty percent of scleritis cases are associated with systemic autoimmune conditions including rheumatoid arthritis and granulomatosis with polyangiitis. Infectious causes including herpes virus and varicella zoster account for 5 to 10% of patients. The remaining 50% of cases are classified as idiopathic.

CIRIS, is the first prospective randomized, head to head study, comparing infliximab to cyclophosphamide in refractory idiopathic scleritis. There is no firm evidence or randomized controlled trials directly addressing the best biologic agent in severe and refractory idiopathic scleritis. If left untreated or insufficiently treated, scleritis can progress to peripheral ulcerative keratitis, uveitis and glaucoma. Visual loss occurs in approximately 10% of patients with anterior scleritis and in up to 75% of patients with posterior scleritis. The incidence of burden in ocular inflammation (uveitis and scleritis) has been dramatically reduced in the recent years with the use of biologics, raising the question of whether these compounds should be used earlier in the treatment of severe non infectious scleritis. Contrasting with other immunosuppressors, cyclophosphamide and infliximab act rapidly and are highly effective in steroid's sparing.

Despite a strong rationale, these compounds are not yet approved in idiopathic refractory scleritis, which guarantees the innovative nature of this study that aims selecting or dropping any arm when evidence of efficacy already exists.

Details
Condition Idiopathic Refractory Scleritis
Treatment cyclophosphamide, Infliximab
Clinical Study IdentifierNCT03088293
SponsorHospices Civils de Lyon
Last Modified on24 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Provide written informed consent prior to the performance of any study-specific procedures
Male or female, subject aged > or = 18 at Screening
Weight 40 - 120 kg at Screening
Diagnosis of anterior idiopathic scleritis or anterior and posterior idiopathic scleritis at least one eye. Scleritis is classified anatomically as anterior based on the principal location of the inflammation. Clinically, anterior scleritis can be divided into diffuse, nodular or necrotizing types
Active disease: Currently uncontrolled scleritis disease. Uncontrolled scleritis disease is defined as (at least) a 2 in sclera inflammation, according to the grading system defined by Sene for sclera inflammation (gradings from 0 to 4)
Refractory disease: At screening, subjects must be receiving oral corticosteroids (>10 mg/day prednisone equivalent and <80 mg/day) and at least one other immunosuppressive for more than 4 months (azathioprine, methotrexate, mycophenolate mofetyl, cyclosporine, leflunomide) or be intolerant to such immunosuppressive therapies
Topical corticosteroids and/or NSAIDs are permitted provided the dose regimen has been stable for 2 weeks prior to Screening and remains stable throughout the study. Topical treatment for cycloplegia is permitted
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\. Chest X-ray results (postero-anterior and lateral) within 12 weeks prior
to the randomization visit with no evidence of active Tuberculosis, active
infection, or malignancy
\. For female subjects of child-bearing age, a negative serum pregnancy test
A woman is considered of childbearing potential, i.e. fertile, following
menarche and until becoming post-menopausal unless permanently sterile
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy
and bilateral oophorectomy. A postmenopausal state is defined as no menses for
months without an alternative medical cause. A high follicle stimulating
hormone (FSH) level in the postmenopausal range may be used to confirm a post-
menopausal state in women not using hormonal contraception or hormonal
replacement therapy. However in the absence of 12 months of amenorrhea, a
single FSH measurement is insufficient (definition of the Clinical Trial
Facilitation Group)
\. For subjects with reproductive potential, a willingness to use adequate
contraceptive measures to prevent the subject or the subject's partner from
becoming pregnant during the study. For women in period of childbearing
adequate contraceptive measures include hormonal methods used for two or more
cycles prior to Screening and 6 months after the last dose treatment should be
used (e.g., oral contraceptive pills, contraceptive patch, or contraceptive
vaginal ring), barrier methods (e.g., contraceptive sponge, diaphragm used in
conjunction with contraceptive foam or jelly, or condom used in conjunction
with contraceptive foam or jelly), intrauterine devices (IUD), sterilization
(e.g., tubal ligation or a monogamous relationship with a vasectomized
partner), and abstinence. For men who are sexually active with a women in
period of childbearing adequate contraceptive measures from screening to 6
months after the last dose treatment should be used (For men: barrier methods
(condom used in conjunction with contraceptive foam or jelly), sterilization
(vasectomy) and abstinence. For his partner: hormonal methods (e.g., oral
contraceptive pills, contraceptive patch, or contraceptive vaginal ring)
barrier methods (e.g., contraceptive sponge, diaphragm used in conjunction
with contraceptive foam or jelly), intrauterine devices (IUD), sterilization
(e.g., tubal ligation))
\. A negative QuantiFERON-Tuberculosis (TB) test result or, in the event
that their QuantiFERON-TB test result at Screening is positive, all subjects
must agree to complete an INH treatment course of at least 6 months
\. Affiliated to the French social security system

Exclusion Criteria

medical contraindication to administer experimental drugs: Cyclophosphamide (urinary obstruction, bladder inflammation) or Infliximab (moderate or severe heart failure, classe III /IV classification NYHA)/low dose Methotrexate (chronic respiratory insufficiency); and non-experimental drugs (10 % phenylephrine instillation, prednisone, paracetamol, polaramine, folic acid and uromitexan)
Infectious scleritis, posterior idiopathic scleritis or scleritis related to systemic diseases (i.e. granulomatosis with polyangiitis, rheumatoid arthritis, lupus, relapsing chondritis, etc)
Blindness or very low visual acuity (<1/20) of the no study eye
Active tuberculosis or history of untreated tuberculosis
Known positive syphilis serology, HIV antibody, . Positive serology for hepatitis B or C virus is not considered as non-inclusion criteria. These tests should be performed during the screening, and in case of positive result the opinion of a hepatologist will be requested
History of malignancy within 5 years prior to Screening other than carcinoma in situ of the cervix or adequately treated, non-metastatic squamous or basal cell carcinoma of the skin
History of severe allergic or anaphylactic reactions to monoclonal antibodies. Hypersensitivity known to cyclophosphamide, to infliximab, to other murine proteins, to methotrexate or to any of the excipients
Infectious disease
Fever or infection requiring treatment with antibiotics within 3 weeks prior to Screening or between Screening and Day 0
History of recurrent infection or predisposition to infection
Known immunodeficiency
History of multiple sclerosis and/or demyelinating disorder
Laboratory values assessed during Screening
Hemoglobin <8.5 g/dL
WBC <3.0 x 103/mm3
Platelet count <100 x 103/mm3
Glomerular filtration rates (GFR) <30 ml/min
AST/ALT >1.5 x upper limit of normal (ULN)
Absolute Neutrophil Count <2.0 x 103/mm3
Absolute Lymphocyte Count <0.5 x 103/mm3
Use of the following systemic treatments during the specified periods
Any other previous systemic biological therapy, including anti-TNF
Treatment with any systemic alkylating agents within 12 months prior to Screening or between Screening and Day 0 (e.g., cyclophosphamide, chlorambucil)
Any live (attenuated) vaccine within 3 months prior to Screening or between Screening and Day 0; recombinant or killed virus vaccines are permitted. Live seasonal flu and H1N1 vaccines are permitted 2 weeks prior to Screening
Participation to another interventional research
Inability to understand information concerning the protocol
Pregnant or lactating women
Patient under guardianship
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