Co-Theia (Combination Therapy with Methotrexate and Adalimumab for Uveitis): Efficacy, Safety and Cost-Effectiveness of Methotrexate, Adalimumab, or Their Combination in Non Infectious Non Anterior Uveitis: a Multicenter, Randomized, Parallel 3 Arms, Active-Controlled, Phase 3 Open Label with Blinded Outcome Assessment Study.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion Para La Investigacion Biomedica Del Hospital Clinico San Carlos

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Eye Diseases [C11]

Trial duration

12 Jan 2022 → 26 Nov 2025

Decision date (initial)

2024-04-15

Transition trial

Yes

Low-intervention

Yes

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-513123-17-00

EudraCT number

2020-000130-18

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To compare the proportion of patients achieving a Good Clinical Response by week 16 that is maintained in every study visit until week 52

Secondary objectives 9

1. To compare the clinical components of the Good Clinical Response variable between treatment strategies (see section 12.1 for a complete list of the components)
2. To compare the proportion of patients achieving a Good Clinical Response by week 16
3. To compare several Patient Reported Outcomes Measures (health- and vision-related quality of life, anxiety and depression) between treatment strategies
4. To compare the time to relapse after week 16 between treatment strategies
5. To compare the evolution of the activity disease score in patients with uveitis (UVEDAI) between treatment strategies
6. To assess the safety of each treatment strategy
7. To assess the cost-utility and cost-effectiveness from both a Health System and a Societal perspectives of the combination therapy and the ADA monotherapy compared with MTX given alone
8. To identify genetic and proteomic multiomic biomarkers (including genetic, transcriptomic, proteomic, epigenetic and metabolomic) associated with clinical manifestations, diagnosis and drug response to each treatment strategy. In addition, we will carry out a substudy with the objective of building a public access biobank with peripheral blood derived samples to carry out future studies in uveitis.
9. To generate deep learning models based on convolutional neural networks to automatically quantify image biomarkers related to clinical manifestations, diagnosis and pharmacological response.

Conditions and MedDRA coding

Non-infection uveitis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

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: 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).
4. 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.
5. 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.
6. 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
7. 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
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 18

1. Subjects with confirmed or suspected infectious uveitis, including ocular histoplasmosis syndrome
2. Subject diagnosed with or with suspected Behçet’s disease
3. Subjects with previous intolerability, safety issues according to investigator criteria, AND/OR previous failure to control ocular or other inflammation with MTX
4. 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);
5. Subjects with previous exposure to synthetic immunosuppressive therapy (such as mycophenolate or cyclosporine) other than corticosteroids in the past 6 months before Baseline
6. 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
7. Chronic hypotony (IOP < 5 mm Hg for in the last 3 months and/or in the baseline visit) in both eyes
8. 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;
9. 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;
10. 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
11. 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
12. Subjects with active malignancy considered by the Site’s Investigator, and confirmed or suspected ocular masquerade syndromes
13. 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 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
15. 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)
16. 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
17. Subjects with clinically significant abnormal screening laboratory results as evaluated by the Site’s Investigator (at screening/baseline or in the previous 4 weeks).
18. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of patients achieving a Good Clinical Response between the combination therapy arm and the single immunosuppressive drugs arms.

Secondary endpoints 13

1. Proportion of patients achieving a Good Clinical Response by week 16, between study arms
2. Change from baseline of the VFQ-25 between groups
3. Direct and indirect cost, and Incremental Cost Effectiveness Ratios
4. Proportion of patients achieving each of the clinical component of the primary efficacy outcome, between study arms
5. Proportion of patients achieving each clinical component of the Good Clinical Response by week 16, between study arms
6. Evolution of the UVEDAI during follow-up
7. Proportion of patients achieving the primary efficacy outcome based on the commercial brand of ADA prescribed
8. Proportion of patients achieving the primary efficacy outcome based on the use of iv GC during the screening period
9. Evolution of the EQ-5D during follow-up
10. Change from baseline of the HADS between groups
11. Time to inflammatory relapse between groups, defined as the time from visit 16 weeks until end of the study, loss of follow-up or appearance of at least one of the following, in those individuals achieving a Good Clinical Response by visit 16 week
12. Evolution of the BCVA during follow-up
13. Proportion of patients developing anti-ADA antibodies (AAA) at Baseline, week 15, 27 and the FET visit, between the ADA monotherapy and the combination arm.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion Para La Investigacion Biomedica Del Hospital Clinico San Carlos

Sponsor organisation

Fundacion Para La Investigacion Biomedica Del Hospital Clinico San Carlos

Address

Calle Del Profesor Martin Lagos

City

Madrid

Postcode

28040

Country

Spain

Scientific contact point

Organisation

Fundacion Para La Investigacion Biomedica Del Hospital Clinico San Carlos

Contact name

Investigator coordinator

Public contact point

Organisation

Fundacion Para La Investigacion Biomedica Del Hospital Clinico San Carlos

Contact name

Investigator coordinator

Locations

1 EU/EEA country · 21 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications