Comparing Methotrexate and Adalimumab for Non-infectious Uveitis

Efficacy, Safety and Cost-effectiveness of Methotrexate, Adalimumab, or Their Combination in Non-infectious Non-anterior Uveitis: a Randomized, Parallel 3 Arms, Active-controlled, Phase 3 Open Label With Blinded Outcome Assessment Study

This study is testing whether methotrexate, adalimumab, or a combination of both can help people with non-infectious uveitis reduce eye inflammation and improve their overall well-being.

Quick facts

• Phase: PHASE3
• Study type: Interventional
• Enrollment: 192 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Hospital San Carlos, Madrid (other)
• Drugs / interventions: denosumab, natalizumab, rituximab, efalizumab, prednisone, adalImumAb, mEthotrexate
• Locations: 14 sites (A Coruña and 13 other locations)
• Trial ID: NCT04798755 on ClinicalTrials.gov

What this trial studies

This phase III clinical trial aims to evaluate the efficacy, safety, and cost-effectiveness of methotrexate, adalimumab, and their combination in treating non-infectious uveitis. It is a multicenter, randomized, single-blinded study with three treatment arms, where participants will be assigned to one of the three interventions. The study will assess the outcomes based on the reduction of eye inflammation and overall patient well-being. The trial seeks to provide direct comparisons between monotherapy and combination therapy for better management of this sight-threatening condition.

Who should consider this trial

Good fit: Ideal candidates for this study are adults aged 18 and older diagnosed with non-infectious intermediate, posterior, or pan-uveitis who have experienced at least one flare of active eye inflammation in the past 180 days.

Not a fit: Patients with infectious uveitis or those who do not meet the inclusion criteria for active eye inflammation may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to more effective treatment options for patients suffering from non-infectious uveitis, potentially improving their quality of life.

How similar studies have performed: Previous observational studies have suggested that combination therapies may be more effective, but this is the first direct comparison of these treatment strategies.

Eligibility criteria

Inclusion Criteria:

1. Subjects diagnosed with non-infectious intermediate-, posterior-, or pan-uveitis in at least one eye;
2. Adult patients (≥18 years);
3. Subjects with at least one flare of active eye inflammation in the previous 180 days before Baseline visit, defined by the presence of at least 1 of the following parameters in either eye:

   1. Active chorioretinal or retinal vascular lesion, AND/OR
   2. Presence of macular edema by optical coherence tomography (OCT:thickness \>350 μm AND cysts or intraretinal fluid), AND/OR
   3. ≥ 2+ anterior chamber cells (ACC; SUN criteria4) , AND/OR
   4. ≥ 2+ vitreous haze (National Eye Institute \[NEI\]113/SUN criteria4).
4. Subjects with active eye inflammation at Baseline visit, defined by the presence of at least 1 of the following parameters in either eye:

   1. Active chorioretinal or retinal vascular lesion, AND/OR
   2. Presence of macular edema by OCT (thickness \>350 μm AND cysts or intraretinal fluid), AND/OR
   3. ≥ 1+ ACC, AND/OR
   4. ≥ 1+ vitreous haze.
5. Subjects meeting at least ONE of the following criteria:

   1. Subjects with known chronic condition necessitating GCs-sparing immunosuppressive treatment: Behçet's disease with posterior segment involvement, multifocal choroiditis with panuveitis, serpiginous choroidopathy, birdshot retinochoroidopathy, diffuse retinal vasculitis, Vogt-Koyanagi-Harada with bullous serous retinal and/or choroidal detachments, sympathetic ophthalmia. No prior therapy is required for these patients. AND/OR
   2. Subjects with registered local/systemic corticosteroid refractory uveitis in the previous 180 months before Baseline visit, defined as:

      * Presence of active inflammation after 4 weeks of high-dose (1mg/kg prednisone equivalent) corticosteroid treatment, resulting in an incomplete response (there was an amelioration, but there is still inflammation); AND/OR, Presence of active inflammation 4 weeks after a regional corticosteroid injection; AND/OR,
      * Treatment with oral corticosteroids resulting in a reduction of inflammation, followed by relapse \[increase in ≥1 grade in ACC or vitreous haze or a change of non-active to active lesions (including chorioretinal or retinal vascular lesion and/or macular edema)\] when GCs was tapered; AND/OR,
      * Presence of active inflammation after a long-acting corticosteroid intramuscular injection administered between 4 weeks to 180 days before the Baseline visit); AND/OR, Active inflammation after treatment with \>10mg/day oral prednisone for at least the past 90 days before Baseline.
6. If female, subject is:

   1. Not of childbearing potential: at least 1 year or more since the final menstrual period or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy);
   2. Of childbearing potential and willing to use an acceptable method of contraception during the study period (i.e. pharmacologics, devices, barrier methods) or abstinence, and for 150 days after the last dose of study drugs;
   3. Not pregnant or breastfeeding
7. Subject has a negative tuberculosis skin test (PPD test or equivalent) and nonpathological Chest X-ray (CXR; Posterior-anterior and lateral view) at Screening or in the previous 90 days before Baseline visit. If the subject has a positive PPD test (or equivalent), has had a past ulcerative reaction to PPD placement and/or a CXR consistent with prior tuberculosis (TB) exposure, the subject must initiate, be currently receiving or have documented completion of a course of prophylactic anti-TB therapy
8. Subjects able and willing to provide written informed consent and to comply with the study protocol.
9. Do not participate in another clinical trial.

Exclusion Criteria:

1. Subjects with confirmed or suspected infectious uveitis, including ocular histoplasmosis syndrome
2. Subjects with previous intolerability, safety issues according to investigator criteria, AND/OR previous failure to control ocular or other inflammation with MTX
3. Subjects with previous exposure to any biological therapy at any time (excluding intravitreal anti-vascular endothelial growth factor \[anti-VEGF\] therapy and denosumab), including those with that have a potential or known association with progressive multifocal leukoencephalopathy (i.e. natalizumab, rituximab or efalizumab);
4. Subjects with previous exposure to synthetic immunosuppressive therapy (such as mycophenolate or cyclosporine) other than corticosteroids in the past 6 months before Baseline;
5. Subjects with chronic structural eye damage considered by the Site's

Investigator to:

a. Interfere with the measurement of any of the study outcomes, AND/OR b. Cause eye damage regardless of the inflammatory process, AND/OR c. Prevent the normalization of the eye structures; 6. Chronic hypotony (IOP \< 5 mm Hg for in the last 3 months and/or in the baseline visit) in both eyes; 7. Subjects receiving local GCs 8. Subjects receiving intravitreal anti-VEGF therapy 9. Subjects with a history of prior intraocular surgery within 30 days prior to the Baseline visit, AND/OR any planned eye surgery within the next 52 weeks from Baseline Visit 10. Subjects with best spectacle-corrected visual acuity (BCVA) worse than 20/400 (ETDRS logMAR \> 1.34) in the better eye during the screening or at Baseline visit 11. Subjects with active malignancy considered by the Site's Investigator, including lymphoma, leukemia, non-melanoma skin cancer, and confirmed or suspected ocular masquerade syndromes 12. Subjects with systemic autoimmune disease or ocular condition (besides uveitis) anticipated to dictate treatment course, as considered by the Site's Investigator 14. Subjects with systemic active or chronic recurring infections, such as active TB, syphilis, or hepatitis B or C, at Screening visit or in the previous 90 days before Baseline visit; AND/OR a history of invasive infection (e.g., listeriosisand histoplasmosis); 15. Subjects with history of moderate to severe congestive heart failure (NYHA class III or IV), recent cerebrovascular accident (6 months) and any other condition which, in the opinion of the Site's Investigator, would put the subject at risk by participation in the study 16. Subjects with clinically significant abnormal screening laboratory results as evaluated by the Site's Investigator (at screening/baseline or in the previous4 weeks).

17. Central nervous system demyelinating disease

Where this trial is running

A Coruña and 13 other locations

• Complejo Hospitalario Universitario A Coruña — A Coruña, Spain (NOT_YET_RECRUITING)
• Hospital General Universitario de Alicante — Alicante, Spain (RECRUITING)
• Hospital Universitario Cruces — Baracaldo, Spain (RECRUITING)
• Hospital Universitario de Gran Canaria Doctor Negrín — Las Palmas De Gran Canaria, Spain (NOT_YET_RECRUITING)
• Complejo Asistencial Universitario de León — León, Spain (NOT_YET_RECRUITING)
• Hospital Clínico San Carlos — Madrid, Spain (RECRUITING)
• Hospital Universitario 12 de Octubre — Madrid, Spain (NOT_YET_RECRUITING)
• Hospital Universitario Fundación Jiménez Díaz — Madrid, Spain (RECRUITING)
• Hospital Universitario Infanta Leonor — Madrid, Spain (RECRUITING)
• Hospital Universitario La Paz — Madrid, Spain (RECRUITING)
• Hospital Universitario Infanta Sofía — San Sebastián De Los Reyes, Spain (NOT_YET_RECRUITING)
• Complejo Hospitalario Universitario de Canarias — Santa Cruz De Tenerife, Spain (NOT_YET_RECRUITING)
• Hospital Universitario Doctor Peset — Valencia, Spain (RECRUITING)
• Instituto Universitario de Oftalmología Aplicada — Valladolid, Spain (NOT_YET_RECRUITING)

Study contacts

• Principal investigator: Luis Rodriguez Rodriguez — Fundación para la Investigacion Biomédica del Hospital Clínico San Carlos
• Study coordinator: Luis Rodriguez Rodriguez

Conditions: Uveitis