Treatment FOr Corticosteroid Dependent UveitiS (FOCUS)

Randomized Controlled Multicenter Study Comparing Efficacy and Safety of Adalimumab to That of Mycophenolate Mofetil in Steroid Dependent Non-infectious Uveitis

FOCUS is the first prospective randomized study comparing standard of care (mycophenolate mofetil) to adalimumab in recently active non infectious uveitis (NIU) with steroid dependency. There is no firm evidence or randomized trials that compared classical immunosuppressive compounds to biological agents; or identified the best treatment in this condition. The burden of NIU has been reduced with the use of immunosuppressive agents and biologics, raising the question of which of these compounds should be preferentially used in recently active NIU with steroid dependency.

Study Overview

• Status: Not yet recruiting
• Conditions: Non Infectious Uveitis
• Intervention / Treatment: Drug: Adalimumab; Drug: Mycophenolate Mofetil

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jérôme Lambert, Pr; Phone Number: +33142499742; Email: jerome.lambert@u-paris.fr
• Study Contact Backup: Name: Bahram BODAGHI, Pr; Phone Number: +33142163728; Email: bahram.bodaghi@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Provide written, informed consent prior to the performance of any study-specific procedures
2. ≥18 years of age
3. Diagnosis of non-infectious intermediate, posterior-, or pan-uveitis in at least one eye fulfilling the International Study Group Classification Criteria (Standardization of Uveitis Nomenclature [SUN] criteria) of posterior, or pan- uveitis confirmed by documented medical history

4. Recent activity of Non Infectious Uveitis as defined by the presence of at least 1 of the following parameters in either eye within the 3 months prior to inclusion visit despite >7mg/day of oral prednisone:

   • Active chorioretinal or retinal vascular lesion
   • Presence of macular edema by optical coherence.
   • ≥ 2+ anterior chamber cells (Standardization of Uveitis Nomenclature [SUN] criteria)
   • ≥ 2+ vitreous haze (National Eye Institute [NEI]/SUN criteria)
5. Chest X-ray (postero-anterior and lateral) or CT-scanner results within 12 weeks prior to inclusion with no evidence of active Tuberculosis, active infection, or malignancy

6. A potential subject with a positive interferon-gamma release assay (IGRA) (e.g., QuantiFERON®-TB Gold or T-spot TB® Test) at inclusion is eligible if:

   1. Her/his chest X-ray does not show evidence suggestive of active tuberculosis disease
   2. And there are no clinical signs and symptoms of pulmonary and/or extra-pulmonary tuberculosis disease.
   3. And these subjects with a latent tuberculosis infection who have not already received a prophylactic tuberculosis treatment must agree in advance to complete such a treatment course.
7. For female subjects of child-bearing potential: a negative pregnancy test at inclusion

8. For subjects with reproductive potential, a willingness to use contraceptive measures adequate to prevent the subject or the subject's partner from becoming pregnant during the study and 3 months and 5 months after stopping therapy for Mycophenolate mofetil (MMF) and adalimumab, respectively, unless sterility is confirmed. The simultaneous use of two complementary methods of contraception is preferable. Methods which may be considered as highly effective methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods (according to Clinical Trial Falicitation Group (CTFG) recommendations). Such methods include:

   For Female subjects :

   1. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation 1:

      • oral
      • intravaginal
      • transdermal

   2. progestogen-only hormonal contraception associated with inhibition of ovulation:

      • oral
      • injectable
      • implantable
   3. intrauterine device (IUD)
   4. intrauterine hormone-releasing system (IUS)
   5. bilateral tubal occlusion
   6. vasectomised partner
   7. sexual abstinence (In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject).

   For male subjects :

   1. use of condoms
   2. vasectomy (with documentation of azoospermia)
   3. sexual abstinence
9. Affiliated to a social security system

Exclusion Criteria:

1. Infectious uveitis, masquerade syndromes (idiopathic uveitis is permitted)
2. Isolated anterior uveitis
3. Monocular patient
4. Active tuberculosis
5. Positive HIV serology or Hepatitis C Virus (HCV) Hepatitis B Virus (HBV) Ag test
6. History of malignancy within 5 years prior to Inclusion other than carcinoma in situ of the cervix, non-metastatic squamous or basal cell carcinoma of the skin.
7. History of severe allergic or anaphylactic reactions to monoclonal antibodies, mycophenolate mofetil, rifampicin, isoniazid or fluorescein
8. Infection requiring treatment with intravenous antibiotics within 3 weeks prior to inclusion
9. History of multiple sclerosis and/or demyelinating disorder

10. Laboratory values assessed during inclusion:

    • Hemoglobin < 8g/dL
    • Whole Blood Count (WBC) < 2.0 x 103/mm3
    • Platelet count < 80 x 103/mm3
    • Glomerular filtration rates (GFR) <30ml/min.
    • Transaminases > 3 times upper normal value

11. Use of the following systemic treatments during the specified periods:

    • Treatment with any systemic alkylating agents within 12 months prior to inclusion (e.g., cyclophosphamide, chlorambucil)
    • Any live (attenuated) vaccine within 4 weeks prior to inclusion.
12. Stage III and IV New York Heart Association (NYHA) cardiac insufficiency
13. Pregnancy or breastfeeding
14. Under legal protection
15. Participation in another interventional study involving human participants or in the exclusion period

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Adalimumab	Drug: Adalimumab; Adalimumab (80mg at day 0, then 40mg/14 days from W1 to W35 subcutaneously)
Active Comparator: Mycophenolate mofetil	Drug: Mycophenolate Mofetil; 2 g/day orally for 36 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment failure rate	Treatment failure is defined by any of the following in at least one eye: new active, inflammatory chorioretinal or retinal vascular lesions;; worsening of Best Corrected Visual Acuity (BCVA) by>3 lines; Score from 20/10 (best vision) to 20/2400 (worst vision).; 2- step increase in anterior chamber cell grade and/or in vitreous haze relative to baseline. Anterior chamber cells scored from 0 (None) to 4+ (intense: fibrin or plastic aquerous) and Vitreous haze Scored from 0 (<1 cell in field) to +4 (>100 cells in field); absence of steroid discontinuation between week 13 and week 19 (as per protocol); or any additional immunosuppressive drug or injectable steroids	At week 36

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to treatment failure		Up to week 55
Best corrected visual acuity	Snellen score in each eye. Score from 20/10 (best vision) to 20/2400 (worst vision).	At week 4
Best corrected visual acuity	Snellen score in each eye. Score from 20/10 (best vision) to 20/2400 (worst vision).	At week 8
Best corrected visual acuity	Snellen score in each eye. Score from 20/10 (best vision) to 20/2400 (worst vision).	At week 12
Best corrected visual acuity	Snellen score in each eye. Score from 20/10 (best vision) to 20/2400 (worst vision).	At week 16
Best corrected visual acuity	Snellen score in each eye. Score from 20/10 (best vision) to 20/2400 (worst vision).	At week 20
Best corrected visual acuity	Snellen score in each eye. Score from 20/10 (best vision) to 20/2400 (worst vision).	At week 24
Best corrected visual acuity	Snellen score in each eye. Score from 20/10 (best vision) to 20/2400 (worst vision).	At week 30
Best corrected visual acuity	Snellen score in each eye. Score from 20/10 (best vision) to 20/2400 (worst vision).	At week 36
Best corrected visual acuity	Snellen score in each eye. Score from 20/10 (best vision) to 20/2400 (worst vision).	At week 55
Anterior chamber cell grade in each eye	Score from 0 (None) to 4+ (intense: fibrin or plastic aqueous).	At week 4
Anterior chamber cell grade in each eye	Score from 0 (None) to 4+ (intense: fibrin or plastic aqueous).	At week 8
Anterior chamber cell grade in each eye	Score from 0 (None) to 4+ (intense: fibrin or plastic aqueous).	At week 12
Anterior chamber cell grade in each eye	Score from 0 (None) to 4+ (intense: fibrin or plastic aqueous).	At week 16
Anterior chamber cell grade in each eye	Score from 0 (None) to 4+ (intense: fibrin or plastic aqueous).	At week 20
Anterior chamber cell grade in each eye	Score from 0 (None) to 4+ (intense: fibrin or plastic aqueous).	At week 24
Anterior chamber cell grade in each eye	Score from 0 (None) to 4+ (intense: fibrin or plastic aqueous).	At week 30
Anterior chamber cell grade in each eye	Score from 0 (None) to 4+ (intense: fibrin or plastic aqueous).	At week 36
Anterior chamber cell grade in each eye	Score from 0 (None) to 4+ (intense: fibrin or plastic aqueous).	At week 55
Vitreous haze grade in each eye.	Nussenblatt score, Score from 0 (<1 cell in field) to +4 (>100 cells in field)	At week 4
Vitreous haze grade in each eye.	Nussenblatt score, Score from 0 (<1 cell in field) to +4 (>100 cells in field)	At week 8
Vitreous haze grade in each eye.	Nussenblatt score, Score from 0 (<1 cell in field) to +4 (>100 cells in field)	At week 12
Vitreous haze grade in each eye.	Nussenblatt score, Score from 0 (<1 cell in field) to +4 (>100 cells in field)	At week 16
Vitreous haze grade in each eye.	Nussenblatt score, Score from 0 (<1 cell in field) to +4 (>100 cells in field)	At week 20
Vitreous haze grade in each eye.	Nussenblatt score, Score from 0 (<1 cell in field) to +4 (>100 cells in field)	At week 24
Vitreous haze grade in each eye.	Nussenblatt score, Score from 0 (<1 cell in field) to +4 (>100 cells in field)	At week 30
Vitreous haze grade in each eye.	Nussenblatt score, Score from 0 (<1 cell in field) to +4 (>100 cells in field)	At week 36
Vitreous haze grade in each eye.	Nussenblatt score, Score from 0 (<1 cell in field) to +4 (>100 cells in field)	At week 55
Central retinal thickness in each eye from baseline		At week 4
Central retinal thickness in each eye from baseline		At week 8
Central retinal thickness in each eye from baseline		At week 12
Central retinal thickness in each eye from baseline		At week 16
Central retinal thickness in each eye from baseline		At week 20
Central retinal thickness in each eye from baseline		At week 24
Central retinal thickness in each eye from baseline		At week 30
Central retinal thickness in each eye from baseline		At week 36
Central retinal thickness in each eye from baseline		At week 55
Proportion of patients with central macular thickness< 300 microns		At week 4
Proportion of patients with central macular thickness< 300 microns		At week 8
Proportion of patients with central macular thickness< 300 microns		At week 12
Proportion of patients with central macular thickness< 300 microns		At week 16
Proportion of patients with central macular thickness< 300 microns		At week 20
Proportion of patients with central macular thickness< 300 microns		At week 24
Proportion of patients with central macular thickness< 300 microns		At week 30
Proportion of patients with central macular thickness< 300 microns		At week 36
Proportion of patients with central macular thickness< 300 microns		At week 55
Time to optical coherence tomographic (OCT) evidence of macular edema in at least one eye		Up to week 55
National Eye Institute Visual Functioning Questionaire-25 (VFQ-25) composite score	Note after responses converted: 100=Best, 0=Worst possible score	At week 12
National Eye Institute Visual Functioning Questionaire-25 (VFQ-25) composite score	Note after responses converted: 100=Best, 0=Worst possible score	At week 24
National Eye Institute Visual Functioning Questionaire-25 (VFQ-25) composite score	Note after responses converted: 100=Best, 0=Worst possible score	At week 36
Measures of corticosteroid sparing	Percent meeting targets [<0.1 mg/kg/day prednisone], mean change, mean dose at week 55, and cumulative dose	Up to week 55
Cumulative incidence of relapse		Up to week 55
Number of relapses		Up to week 55
Number of clinical manifestations of underlying disease	Depending on the underlying disease	Up to week 55
Frequency and severity of adverse events		Up to week 55
Treatment discontinuation		Up to week 55

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): November 1, 2027

Study Registration Dates

• First Submitted: January 23, 2024
• First Submitted That Met QC Criteria: February 12, 2024
• First Posted (Actual): February 14, 2024

Study Record Updates

• Last Update Posted (Actual): February 14, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Macular oedema; Adalimumab; Non-infectious uveitis; Mycophenolate mofetil; Retinal vascularitis
• Additional Relevant MeSH Terms: Eye Diseases; Uveal Diseases; Uveitis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Tumor Necrosis Factor Inhibitors; Adalimumab; Mycophenolic Acid
• Other Study ID Numbers: APHP211032

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No