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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Uveitis
• Intervention / Treatment: Drug: Adalimumab; Drug: Methotrexate; Drug: Adalimumab+Methotrexate

• Study Type: Interventional
• Enrollment (Estimated): 192
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Luis Rodriguez Rodriguez; Phone Number: 7560 +0034-91330300; Email: lrrodriguez@salud.madrid.org

Study Locations

• Spain
  • A Coruña, Spain
    • Not yet recruiting
    • Complejo Hospitalario Universitario A Coruña
    • Contact: JOSE A PINTO TASENDE
  • Alicante, Spain
    • Recruiting
    • Hospital General Universitario de Alicante
    • Contact: MARIA DE LA VEGA JOVANI CASANO
  • Baracaldo, Spain
    • Recruiting
    • Hospital Universitario Cruces
    • Contact: ALEJANDRO FONOLLOSA CALDUCH
  • Las Palmas De Gran Canaria, Spain
    • Not yet recruiting
    • Hospital Universitario de Gran Canaria Doctor Negrín
    • Contact: FELIX M FRANCISCO HERNANDEZ
  • León, Spain
    • Not yet recruiting
    • Complejo Asistencial Universitario de Leon
    • Contact: MIGUEL CORDERO COMA
  • Madrid, Spain
    • Recruiting
    • Hospital Universitario La Paz
    • Contact: MARIA DIANA PEITEADO LOPEZ
  • Madrid, Spain
    • Not yet recruiting
    • Hospital Universitario 12 de Octubre
    • Contact: ALFREDO JAVIER GARCIA GONZALEZ
  • Madrid, Spain
    • Recruiting
    • Hospital Universitario Infanta Leonor
    • Contact: LETICIA LOJO OLIVEIRA
  • Madrid, Spain
    • Recruiting
    • Hospital Clinico San Carlos
    • Contact: Luis Rodriguez Rodriguez
  • Madrid, Spain
    • Recruiting
    • Hospital Universitario Fundacion Jimenez Diaz
    • Contact: ESTER CARREÑO SALAS
  • San Sebastián De Los Reyes, Spain
    • Not yet recruiting
    • Hospital Universitario Infanta Sofía
    • Contact: SANTIAGO MUÑOZ FERNANDEZ
  • Santa Cruz De Tenerife, Spain
    • Not yet recruiting
    • Complejo Hospitalario Universitario de Canarias
    • Contact: MARIA BEATRIZ RODRIGUEZ LOZANO
  • Valencia, Spain
    • Recruiting
    • Hospital Universitario Doctor Peset
    • Contact: LUCIA MARTINEZ-COSTA PEREZ
  • Valladolid, Spain
    • Not yet recruiting
    • Instituto Universitario de Oftalmología Aplicada
    • Contact: LIDIA COCHO ARCHILES

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Methotrexate	Drug: Methotrexate; Inicial dose 15mg/week increasing up to 25 mg/week
Active Comparator: Adalimumab	Drug: Adalimumab; At the Baselin visit adalimumab 80 mg subcutaneous loading dose followed a week later by 40 mg every-other-week starting at Week 1.
Experimental: Adalimumab+Methotrexate	Drug: Adalimumab+Methotrexate; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	week 16
EuroQol-5D at each study visit	We will use the EuroQol-5D (0-100, the higher the better quality of life) to compare the change in health-related quality of life between treatment strategies.	Baseline, weeks 16 and 52.
Visual Functioning Questionnaire-25 (VFQ-25)	We will use the VFQ-25 (0-100, the higher the better quality of life) to compare the change in visual-related quality of life between treatment strategies	Baseline, weeks 16 and 52.
Hospital Anxiety and Depression Scale; HADS	We will use the HADS (0-21 for either anxiety or depression, the higher the more severe anxiety/depression symptoms) to compare the change in anxiety and depression sympthoms between treatment strategies quality of life, anxiety and depression) between treatment strategies	Baseline, weeks 16 and 52.
Clinical components of the Good Clinical Response variable	Presence of non active chorioretinal lesions; active retinal vascular inflammation; macular edema; ACC; vitreous haze; and loss of CVA secondary to inflammation	Baseline, weeks 16 and 52.
Time to inflammatory relapse.	time from visit 16 weeks until end of the study, loss of follow-up or appearance of at least one ocular inflammatory manifestation, in those individuals achieving a Good Clinical Response.	week 16.
Best corrected visual acuity (BCVA)	We will use the BCVA between treatment strategies	Baseline, weeks 16 and 52.
Anti-ADA antibodies (AAA).	Presence of anti-ADA antibodies (AAA) in subjects receiving this study drug.	Weeks 15, 27 and 51.
Cost-efficacy	Direct and indirect cost, and Incremental Cost Effectiveness Ratios	Week 52.
Safety: adverse events.	Ocurrence of adverse events.	Baseline, weeks 16 and 52.

Collaborators and Investigators

• Sponsor: Hospital San Carlos, Madrid
• Investigators: Principal Investigator: Luis Rodriguez Rodriguez, Fundación para la Investigacion Biomédica del Hospital Clínico San Carlos

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2022
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): October 1, 2025

Study Registration Dates

• First Submitted: March 9, 2021
• First Submitted That Met QC Criteria: March 12, 2021
• First Posted (Actual): March 15, 2021

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 20, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Eye Diseases; Uveal Diseases; Uveitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Tumor Necrosis Factor Inhibitors; Adalimumab; Methotrexate
• Other Study ID Numbers: Co-THEIA

Plan for Individual participant data (IPD)

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

IPD Plan Description

Data obtained through this study may be provided to qualified researchers with academic interest in uveitis. Data or samples shared will be coded, and donated to a Registered Biobank and made available under legal requirement. Approval of the request and execution of all applicable agreements are prerequisites to the sharing of data with the requesting party.

Regarding dissemination, in order to communicate the clinical trial progress and findings to a broad group of stakeholders, we will elaborate a Dissemination plan which will include production of materials adapted to scientific meetings, scientific publications, patients, and other stakeholders. A summary of the final version of the study protocol will be made available through the Spanish Clinical Trial Registry (REEC) and Clinicaltrials.gov database. The promoter will be the only with access to the participant-level data, following the regulation on data protection.

• IPD Sharing 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.
• IPD Sharing 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).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; CSR

Drug and device information, study documents

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