Efficacy and Safety of Methotrexate, Methotrexate Disodium, and Adalimumab in Non-Infectious Non-Anterior Uveitis: A Phase 3 Randomized Study

Trial ID: 2024-513123-17-00
Sponsor: Fundacion Para La Investigacion Biomedica Del Hospital Clinico San Carlos

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Diseases & Conditions

Uveitis

Objectives

The primary objective of this study is to compare the proportion of patients with **non-infectious uveitis** achieving a Good Clinical Response by week 16, which is maintained at every study visit until week 52. This objective is clinically relevant as it evaluates the sustained efficacy of treatment strategies over a significant period, providing insights into long-term management of the condition.

Secondary objectives include:

Comparing the clinical components of the Good Clinical Response variable between treatment strategies.
Comparing the proportion of patients achieving a Good Clinical Response by week 16.
Comparing several Patient Reported Outcomes Measures, including health- and vision-related quality of life, anxiety, and depression, between treatment strategies.
Comparing the time to relapse after week 16 between treatment strategies.
Comparing the evolution of the activity disease score in patients with uveitis (UVEDAI) between treatment strategies.
Assessing the safety of each treatment strategy.
Assessing the cost-utility and cost-effectiveness from both a Health System and a Societal perspective of the combination therapy and the ADA monotherapy compared with MTX given alone.
Identifying genetic and proteomic multiomic biomarkers associated with clinical manifestations, diagnosis, and drug response to each treatment strategy, and building a public access biobank for future studies in uveitis.
Generating deep learning models based on convolutional neural networks to automatically quantify image biomarkers related to clinical manifestations, diagnosis, and pharmacological response.

Participants

The clinical trial focuses on **non-infectious uveitis** and includes both male and female participants. The study population comprises adult patients aged 18 years and older. Participants are required to have been diagnosed with non-infectious intermediate, posterior, or pan-uveitis in at least one eye. The trial does not involve a vulnerable population. Participants were selected based on their medical history, specifically those with at least one flare of active eye inflammation in the previous 180 days before the baseline visit. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants. Key inclusion criteria include the presence of active eye inflammation at the baseline visit and the ability to provide written informed consent. Participants must not be involved in another clinical trial. The trial ensures that female participants of childbearing potential use an acceptable method of contraception during the study period. Additionally, participants must have a negative tuberculosis skin test and a non-pathological chest X-ray at screening or within the previous 90 days before the baseline visit.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy**, safety, and cost-effectiveness of **methotrexate**, **adalimumab**, or their combination in patients with non-infectious uveitis. This study is a multicenter, randomized, parallel 3-arm, active-controlled, phase 3 open-label trial with blinded outcome assessment. The trial aims to compare the proportion of patients achieving a Good Clinical Response by week 16, maintained through to week 52. The trial is expected to conclude by September 2025, with recruitment having commenced in September 2021.

Participants will be randomly assigned to one of three treatment arms: methotrexate, adalimumab, or a combination of both. The trial will involve a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as a diagnosis of non-infectious intermediate, posterior, or pan-uveitis in at least one eye, and active eye inflammation at baseline. The trial will include regular follow-up visits to monitor the participants' response to treatment and any adverse effects. The end-of-study visit will assess the long-term outcomes and overall effectiveness of the treatments.

The expected duration of participant involvement is up to 52 weeks, with conditions for early termination including non-compliance with the study protocol, withdrawal of consent, or the occurrence of significant adverse events. The primary endpoint is the proportion of patients achieving a Good Clinical Response between the combination therapy arm and the single immunosuppressive drug arms. Secondary endpoints include changes in visual function, cost-effectiveness ratios, and the evolution of disease activity indices during follow-up. The trial is conducted under strict ethical guidelines, ensuring that all participants provide informed consent and are monitored for safety throughout the study.

Treatment

The clinical trial involves the administration of **METHOTREXATE**, a chemical compound used as an experimental medication. It is provided in the form of a solution for injection in a pre-filled syringe. The administration route is **intramuscular**, with a maximum daily dose of 20 mg and a total maximum dose of 1040 mg over a treatment period of 52 weeks. The medication is not formulated for pediatric use, and participant compliance will be monitored throughout the study to ensure adherence to the dosing schedule.

Another experimental medication used in the trial is **METHOTREXATE DISODIUM**, also a chemical compound. This medication is administered orally in tablet form. The maximum daily dose is 25 mg, with a total maximum dose of 1300 mg over the same 52-week treatment period. As with the other formulations, this medication is not intended for pediatric use, and compliance monitoring will be conducted to ensure proper adherence to the prescribed dosing regimen.

Additionally, the trial includes the use of **ADALIMUMAB**, a structurally diverse substance classified as an immunoglobulin. It is administered as a solution for injection in a pre-filled syringe, with the route of administration being **intramuscular**. The maximum daily dose is 80 mg, with a total maximum dose of 1040 mg over the 52-week treatment period. This medication is also not formulated for pediatric use, and participant compliance will be closely monitored to ensure adherence to the dosing schedule.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data. The study is designed to evaluate the efficacy, safety, and cost-effectiveness of these medications, either individually or in combination, for the treatment of non-infectious non-anterior uveitis. The trial aims to compare the proportion of patients achieving a good clinical response by week 16, maintained through week 52.

Efficacy

The efficacy of the clinical trial will be assessed by evaluating the proportion of patients achieving a **Good Clinical Response** by week 16, which is maintained at every study visit until week 52. The primary endpoint focuses on comparing this proportion between the combination therapy arm and the single immunosuppressive drug arms. Secondary endpoints include the proportion of patients achieving a Good Clinical Response by week 16 between study arms, changes from baseline in the VFQ-25, and the evolution of the UVEDAI during follow-up. Additional secondary endpoints involve the time to inflammatory relapse between groups, defined as the time from the 16-week visit until the end of the study, loss of follow-up, or the appearance of specific inflammatory markers in individuals achieving a Good Clinical Response by the 16-week visit.

Measurements will be collected at specified timepoints, including baseline, week 16, and subsequent follow-up visits. The study will utilize validated scales and patient-reported outcomes to assess changes in visual function and quality of life, such as the VFQ-25 and EQ-5D. The presence of anti-ADA antibodies will be evaluated at baseline, week 15, week 27, and the final evaluation visit, comparing the ADA monotherapy and combination arms. The analysis will also consider direct and indirect costs, as well as Incremental Cost Effectiveness Ratios, to assess the cost-effectiveness of the treatments. The trial is designed to provide a comprehensive evaluation of the efficacy of methotrexate, adalimumab, and their combination in treating non-infectious non-anterior uveitis.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subjects diagnosed with non-infectious intermediate-, posterior-, or pan-uveitis in at least one eye
Adult patients (≥18 years)
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: a. Active chorioretinal or retinal vascular lesion, AND/OR b. Presence of macular edema by optical coherence tomography (OCT: thickness >350 μm when measured with spectralis or >340 μm when measured with Cirrus or TopCon, AND cysts or intraretinal fluid), AND/OR c. ≥ 2+ anterior chamber cells (ACC; SUN criteria4) , AND/OR d. ≥ 2+ vitreous haze (National Eye Institute [NEI]113/SUN criteria).
Subjects with active eye inflammation at Baseline visit, defined by the presence of at least 1 of the following parameters in either eye: a. Active chorioretinal or retinal vascular lesion, AND/OR b. Presence of macular edema by OCT (thickness >350 μm when measured with spectralis or >340 μm when measured with Cirrus or TopCon AND cysts or intraretinal fluid), AND/OR c. ≥ 1+ ACC, AND/OR d. ≥ 1+ vitreous haze.
Subjects meeting at least ONE of the following criteria: a. Subjects with known chronic condition necessitating GCs-sparing immunosuppressive treatment: 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 b. Intermediate uveitis fulfilling the following characteristics:  Bilateral disease, AND,  Low visual acuity (best corrected visual acuity <0.5) OR  Bilateral macular involvement, defined as presence of macular edema (as defined in Inclusion Criteria 3, subpoint (b)), macular atrophy, and/or macular scarring. No prior therapy is required for these patients. AND/OR c. Subjects with registered local/systemic corticosteroid refractory uveitis in the previous 180 days months before Baseline visit, defined as:  Presence of active inflammation after 4 weeks of high-dose (1mg/kg prednisone equivalent, see equivalence Table 6) 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.
If female, subject is: a. 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); b. 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; For the purpose of this clinical trial, 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 12 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. c. Not pregnant or breastfeeding
Subject has a negative tuberculosis skin test (PPD test or equivalent) and non-pathological 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
Subjects able and willing to provide written informed consent and to comply with the study protocol.
Do not participate in another clinical trial

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Exclusion Criteria

Subjects with confirmed or suspected infectious uveitis, including ocular histoplasmosis syndrome
Subject diagnosed with or with suspected Behçet’s disease
Subjects with previous intolerability, safety issues according to investigator criteria, AND/OR previous failure to control ocular or other inflammation with MTX
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);
Subjects with previous exposure to synthetic immunosuppressive therapy (such as mycophenolate or cyclosporine) other than corticosteroids in the past 6 months before Baseline
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
Chronic hypotony (IOP < 5 mm Hg for in the last 3 months and/or in the baseline visit) in both eyes
Subjects receiving local GCs: a. Fluocinolone acetonide implant (Iluvien®) in the previous 3 years before Baseline; b. Dexametasona implant (Ozurdex®) in the previous 6 months before Baseline; c. Removal of a GC implant in the previous 30 days before Baseline Visit; d. Intra or periocular GC injections in the previous 8 weeks before Baseline Visit;
Subjects receiving intravitreal anti-VEGF therapy: a. Ranibizumab or bevacizumab in the previous 45 days before Baseline Visit; b. Aflibercept in the previous 60 days before Baseline Visit;
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
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
Subjects with active malignancy considered by the Site’s Investigator, and confirmed or suspected ocular masquerade syndromes
Subjects with systemic autoimmune disease or ocular condition (besides uveitis) anticipated to dictate treatment course, as considered by the Site’s Investigator
Subjects with 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
Subjects with systemic active or chronic recurring infections, such as active TB (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 (see “Study Procedures” section)), 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., listeriosis and histoplasmosis)
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
Subjects with clinically significant abnormal screening laboratory results as evaluated by the Site’s Investigator (at screening/baseline or in the previous 4 weeks).
Central nervous system demyelinating disease: a. Subjects with history of Central nervous system demyelinating disease AND/OR b. Magnetic Resonance Imaging (MRI) findings suggestive of a demyelinating disease: All subjects with intermediate uveitis or panuveitis that have signs of intermediate uveitis (e.g., presence or history of snowbanking or snowballs) must have a brain MRI within 90 days prior to the Baseline visit.