Efficacy, Safety and Costs of Methotrexate, Adalimumab, or Their Combination in Non-infectious Non-anterior Uveitis

NCT04798755 | Unknown Phase 3

• 1 other identifier: Co-THEIA
• Study Type: interventional
• Target: 192
• Locations: 1 country
• Sites: 14

Brief Summary

Introduction: Non-infectious uveitis (NIUs) include a heterogeneous group of sight-threatening conditions. NIUs can be highly disabling and be associated with a profound impact in the quality-of-life (QoL) and wellbeing. Their correct management sometimes requires the use of immunosuppressive drugs (ISDs), which can be prescribed in monotherapy or in combination. Several observational studies have provided evidence that the use of ISDs in combination could be more effective than and as safe as their use in monotherapy. However, a direct comparison between these two treatment strategies has not been carried out yet. Methods and analysis: The Combination THerapy with mEthotrexate and adalImumAb for uveitis (CoTHEIA) study is a phase III, multicenter, prospective, randomized, single-blinded with masked outcome assessment, parallel three arms with 1:1:1 allocation, active-controlled, superiority study design, comparing the efficacy, safety and cost-effectiveness of methotrexate (MTX), adalimumab (ADA), or their combination in non-infectious non-anterior uveitis. The duration of the treatment and follow-up will last up to 52 weeks. The complete and maintained resolution of the ocular inflammation will be assessed by masked evaluators (primary outcome). In addition to other secundray measures of efficacy (QoL, visual acuity, costs) and safety, we will identify subjects' subgroups with different treatment responses by developing prediction models based on machine learning techniques using genetic and proteomic biomarkers.

Conditions

Uveitis

Outcome Measures

Primary Outcomes (1)

• Good Clinical Response

  Complete resolution of the ocular inflammatory signs, achieved within the first 16 weeks of the study, and maintained until week 52; no treatment failure due to safety or intolerability.

  52 weeks

Secondary Outcomes (10)

• Good Clinical Response

  week 16

• EuroQol-5D at each study visit

  Baseline, weeks 16 and 52.

• Visual Functioning Questionnaire-25 (VFQ-25)

  Baseline, weeks 16 and 52.

• Hospital Anxiety and Depression Scale; HADS

  Baseline, weeks 16 and 52.

• Clinical components of the Good Clinical Response variable

  Baseline, weeks 16 and 52.

Study Arms (3)

Adalimumab

ACTIVE COMPARATOR

Drug: Adalimumab

Methotrexate

ACTIVE COMPARATOR

Drug: Methotrexate

Adalimumab+Methotrexate

EXPERIMENTAL

Drug: Adalimumab+Methotrexate

Interventions

Methotrexate DRUG

Inicial dose 15mg/week increasing up to 25 mg/week

Methotrexate

Adalimumab DRUG

At the Baselin visit adalimumab 80 mg subcutaneous loading dose followed a week later by 40 mg every-other-week starting at Week 1.

Adalimumab

Adalimumab+Methotrexate DRUG

Adalimumab: at the Baseline visit 80 mg subcutaneous loading dose followed a week later by 40 mg every-other-week starting at Week 1. Methotrexate:Inicial dose 15mg/week increasing up to 25 mg/week

Adalimumab+Methotrexate

Eligibility Criteria

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

You may qualify if:

• 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:
• Active chorioretinal or retinal vascular lesion, AND/OR
• Presence of macular edema by optical coherence tomography (OCT:thickness \>350 μm AND cysts or intraretinal fluid), AND/OR
• ≥ 2+ anterior chamber cells (ACC; SUN criteria4) , AND/OR
• ≥ 2+ vitreous haze (National Eye Institute \[NEI\]113/SUN criteria4).
• Subjects with active eye inflammation at Baseline visit, defined by the presence of at least 1 of the following parameters in either eye:
• Active chorioretinal or retinal vascular lesion, AND/OR
• Presence of macular edema by OCT (thickness \>350 μm AND cysts or intraretinal fluid), AND/OR
• ≥ 1+ ACC, AND/OR
• ≥ 1+ vitreous haze.
• Subjects meeting at least ONE of the following criteria:
• 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
• Subjects with registered local/systemic corticosteroid refractory uveitis in the previous 180 months before Baseline visit, defined as:

You may not qualify if:

• Subjects with confirmed or suspected infectious uveitis, including ocular histoplasmosis syndrome
• 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; 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).
• \. Central nervous system demyelinating disease

Sponsors & Collaborators

• Hospital San Carlos, Madrid: lead

Study Sites (14)

Complejo Hospitalario Universitario A Coruña

A Coruña, Spain

NOT YET RECRUITING

Hospital General Universitario de Alicante

Alicante, Spain

RECRUITING

Hospital Universitario Cruces

Barakaldo, 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

Related Publications (1)

• Rivas AB, Lopez-Picado A, Calamia V, Carreno E, Cocho L, Cordero-Coma M, Fonollosa A, Francisco Hernandez FM, Garcia-Aparicio A, Garcia-Gonzalez J, Mondejar JJ, Lojo-Oliveira L, Martinez-Costa L, Munoz S, Peiteado D, Pinto JA, Rodriguez-Lozano B, Pato E, Diaz-Valle D, Molina E, Tebar LA, Rodriguez-Rodriguez L; CoTHEIA Study Group. Efficacy, safety and cost-effectiveness of methotrexate, adalimumab or their combination in non-infectious non-anterior uveitis: a protocol for a multicentre, randomised, parallel three arms, active-controlled, phase III open label with blinded outcome assessment study. BMJ Open. 2022 Mar 22;12(3):e051378. doi: 10.1136/bmjopen-2021-051378.

  PMID: 35318229 DERIVED

MeSH Terms

Conditions

Uveitis

Interventions

Methotrexate; Adalimumab

Condition Hierarchy (Ancestors)

Uveal Diseases; Eye Diseases

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Luis Rodriguez Rodriguez

  Fundación para la Investigacion Biomédica del Hospital Clínico San Carlos

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Luis Rodriguez Rodriguez

CONTACT

+0034-91330300; lrrodriguez@salud.madrid.org

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 9, 2021
• First Posted: March 15, 2021
• Study Start: January 12, 2022
• Primary Completion: October 1, 2024
• Study Completion: October 1, 2025
• Last Updated: September 21, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF, CSR
• Time Frame: Data requests can be submitted starting 9 months after article publication and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis.
• Access Criteria: Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA).

Locations

ES (14)