Treatment of Non-infectious Intermediate and Posterior Uveitis Associated Macular Edema With Intravitreal Methotrexate

Study Overview
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Brief Summary
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BACKGROUND: Uveitis comprises of a group of diseases associated with inflammation of the eye that can lead to vision loss. Some people with uveitis also have macular edema (swelling of the retina at the back of the eye). Uveitis and macular edema are treated with medications and sometimes surgery, but treatment does not always prevent vision loss. Previous research has shown that injections of methotrexate into the eye of people with eye disease other than uveitis can help relieve the inflammation, or swelling, that causes macular edema and can slow visual loss. However, it has not yet been approved as a treatment for macular edema associated with uveitis. OBJECTIVES: To evaluate the safety and effectiveness of methotrexate injections as a treatment for macular edema associated with uveitis. ELIGIBILITY: Individuals at least 18 years of age who have been diagnosed with uveitis and macular edema in at least one eye. DESIGN: This study requires at least nine visits to the National Eye Institute study clinic over a period of 6 months (24 weeks). Participants will be screened with a physical and ophthalmic examination, medical history, blood and urine tests, and additional eye and other tests as needed. Participants will receive a methotrexate injection in a selected treatment eye. After the injection, participants will receive antibiotic eye drops to place in the eye three times a day for the 3 days following the injection, leucovorin (folic acid) drops to place in the eye four times a day for 1 week following the injection, and a dose of folic acid to be taken by mouth the day after the injection. Participants who tolerate the initial injection may continue to receive injections in their study eye every month for 6 months. After 6 months, participants who show improvement from the injections may be evaluated to receive additional injections every 4 to 8 weeks until researchers end the study.

Detailed Description
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OBJECTIVE: The study objective is to investigate the safety, tolerability and potential efficacy of intravitreal injections of methotrexate as a possible treatment for chronic macular edema secondary to panuveitis, posterior or intermediate uveitis. STUDY POPULATION: Five participants with chronic macular edema associated with panuveitis, posterior or intermediate uveitis will be initially enrolled. However, up to an additional two participants may be enrolled to account for participants who withdraw from the study prior to reaching Week 12. Eligibility criteria include macular edema in the study eye, which has not been responsive to conventional immunosuppressive therapy in the past three months, or the participant experienced a recurrence of macular edema while on conventional immunosuppressive therapy. STUDY DESIGN: In this single-center, prospective, uncontrolled, unmasked, Phase I/II clinical trial, intravitreal injections of methotrexate at a dose of 400 μg per 100 μL will be administered. There will be an induction phase and a pro re nata (PRN) phase. During the induction phase, participants will receive injections at baseline and Weeks 4, 8, 12, 16 and 20 in their study eye unless contraindicated. Additional safety visits will occur at Weeks 1 and 2. Beginning at Week 24, participants who agree to remain in the study will undergo evaluation for injection in the study eye PRN every 4-8 weeks. These participants will be followed for 4-8 weeks after the last enrolled participant completes his/her Week 24 visit. OUTCOME MEASURES: The primary outcome is the number of participants who meet the definition of treatment success within 12 weeks from baseline. Treatment success is defined as achieving at least a 1-step decrease in the LogScore scale for central macular thickness. Secondary outcomes include changes in Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), changes in excess retinal thickening, changes in macular thickness, changes in intraocular inflammation on clinical exam, changes in leakage as seen on fluorescein angiography (FA), changes in autofluorescence patterns seen on fundus autofluorescence (FAF) imaging and observation of dose reductions of systemic immunosuppression or steroids. Safety outcomes include the number and severity of adverse events, systemic and ocular toxicities, electrophysiologic changes assessed by full-field electroretinography (ERG) and number of withdrawals.

Official Title
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Treatment of Non-infectious Panuveitis, Intermediate and Posterior Uveitis Associated Macular Edema With Intravitreal Methotrexate

Conditions
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Non-infectious Intermediate and Posterior Uveitis

Intervention / Treatment
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* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Participant must be 18 years of age or older. Participant must understand and sign the protocol's informed consent document. Participant is willing to comply with the study procedures and return for all study visits. Participant has chronic macular edema secondary to non-infectious panuveitis, posterior or intermediate uveitis in at least one eye (the study eye) that has: not been responsive to conventional immunosuppressive therapy in the past 3 months; OR recurred while on conventional immunosuppressive therapy. Participant has central macular thickness of ≥ 270 microns in the study eye. Participant has visual acuity of 20/400 or better (≥ 19 ETDRS letters) in the study eye. Female participants of childbearing potential must not be pregnant or breast-feeding, must have a negative serum pregnancy test at screening and must be willing to undergo serum pregnancy tests throughout the study. Both female participants of childbearing potential (see Appendix 1 for definition) and male participants able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse or must agree to practice two acceptable methods of contraception throughout the course of the study and for six months after the last study medication injection. Acceptable methods of contraception include: hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring), intrauterine device, barrier methods (diaphragm, condom) with spermicide, or surgical sterilization (tubal ligation). EXCLUSION CRITERIA: Participant is in another investigational study and actively receiving investigational therapy for macular edema. Participant has evidence of infectious panuveitis, posterior or intermediate uveitis in either eye. Participant is expected to need ocular surgery in the study eye during the course of the trial. Participant had intraocular surgery in the study eye within the past 90 days. Participant had an injection of bevacizumab or ranibizumab within the past four weeks in the study eye. Participant had an injection of triamcinolone within the past six weeks in the study eye. Participant has a systemic condition that, in the opinion of the investigator, would preclude participation in the study. Participant has significant cataract or media opacity in the study eye that makes posterior segment visualization difficult as determined by investigator. Participant has a confirmed positive serologic and/or molecular test for HIV-1/2.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methotrexate<br>400 μg/100 μL injection | Drug: Methotrexate<br>* 400 μg/100 μL monthly injections for the first 3 months, then as needed per the treatment criteria<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Meet the Definition of Treatment Success Within 12 Weeks From Baseline. | Treatment success is defined as achieving at least a 1-step decrease in the LogScore scale for central macular thickness. A decrease of at least 1-step on the logOCT scale, where Change in logOCT=log(follow-up thickness/200) - log(baseline thickness/200) is considered clinically significant. A 1-step decrease is equivalent to at least a 20% improvement of central macular thickness and represents greater than twice the variability of retinal thickness measurements (approximately 25-30 µ). Examples of OCT measurements with their corresponding LogScore, where LogScore=10xlogOCT are as follows: LogScore 0 = OCT 200 µm, LogScore 1 = OCT 250 µm, LogScore 2 = OCT 320 µm, LogScore 3 = OCT 400 µm, LogScore 4 = OCT 500 µm, LogScore 5 = OCT 640 µm, LogScore 6 = OCT 800 µm, LogScore 7 = OCT 1000 µm | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Optical Coherence Tomography (OCT) Excess Retinal Thickening in the Study Eye at 4 Weeks Compared to Baseline | Excess retinal thickening was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 4 | 
| Change in Optical Coherence Tomography (OCT) Excess Retinal Thickening in the Study Eye at 8 Weeks Compared to Baseline | Excess retinal thickening was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 8 | 
| Change in Optical Coherence Tomography (OCT) Excess Retinal Thickening in the Study Eye at 12 Weeks Compared to Baseline | Excess retinal thickening was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 12 | 
| Change in Optical Coherence Tomography (OCT) Excess Retinal Thickening in the Study Eye at 16 Weeks Compared to Baseline | Excess retinal thickening was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 16 | 
| Change in Optical Coherence Tomography (OCT) Excess Retinal Thickening in the Study Eye at 20 Weeks Compared to Baseline | Excess retinal thickening was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 20 | 
| Change in Optical Coherence Tomography (OCT) Excess Retinal Thickening in the Study Eye at 24 Weeks Compared to Baseline | Excess retinal thickening was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 24 | 
| Change in Optical Coherence Tomography (OCT) Central Macular Thickness in the Study Eye at 4 Weeks Compared to Baseline | Central-subfield macular thickness was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 4 | 
| Change in Optical Coherence Tomography (OCT) Central Macular Thickness in the Study Eye at 8 Weeks Compared to Baseline | Central-subfield macular thickness was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 8 | 
| Change in Optical Coherence Tomography (OCT) Central Macular Thickness in the Study Eye at 12 Weeks Compared to Baseline | Central-subfield macular thickness was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 12 | 
| Change in Optical Coherence Tomography (OCT) Central Macular Thickness in the Study Eye at 16 Weeks Compared to Baseline | Central-subfield macular thickness was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 16 | 
| Change in Optical Coherence Tomography (OCT) Central Macular Thickness in the Study Eye at 20 Weeks Compared to Baseline | Central-subfield macular thickness was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 20 | 
| Change in Optical Coherence Tomography (OCT) Central Macular Thickness in the Study Eye at 24 Weeks Compared to Baseline | Central-subfield macular thickness was assessed by spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA), a non-invasive imaging technique that uses long-wavelength light to capture micrometer-resolution cross-sectional images from biological tissue. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 24 | 
| Changes in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Study Eye at 4 Weeks Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 4 | 
| Changes in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Study Eye at 8 Weeks Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 8 | 
| Changes in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Study Eye at 12 Weeks Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 12 | 
| Changes in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Study Eye at 16 Weeks Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 16 | 
| Changes in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Study Eye at 24 Weeks Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 24 | 
| Changes in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Study Eye at 20 Weeks Compared to Baseline | Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 20 | 
| Number of Participants Presenting No Change in the Area of Leakage in the Study Eye as Seen on Fluorescein Angiography (FA) Imaging at Week 12 as Compared to Baseline | Fluorescein angiography (FA) images were obtained via a standard digital imaging system (OIS, Sacramento, CA). Three retinal specialists independently graded the area of late fluorescein leakage (at approximately 10 minutes) in each eye using a region-of-interest tool in an image analysis software package (NIH ImageJ, Bethesda, MD). The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 12 | 
| Number of Participants Presenting No Change in the Area of Leakage in the Study Eye as Seen on Fluorescein Angiography (FA) Imaging at Week 24 as Compared to Baseline | Fluorescein angiography (FA) images were obtained via a standard digital imaging system (OIS, Sacramento, CA). Three retinal specialists independently graded the area of late fluorescein leakage (at approximately 10 minutes) in each eye using a region-of-interest tool in an image analysis software package (NIH ImageJ, Bethesda, MD). The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 24 | 
| Number of Participants Presenting the Same Autofluorescence Patterns in the Study Eye as Seen on Fundus Autofluorescence (FAF) Imaging at Week 12 as Observed at Baseline | Fundus autofluorescence patterns were assessed using fundus autofluorescence (FAF) imaging, a non-invasive technique that uses a confocal scanning ophthalmoscope to detect naturally-fluorescing lipofuscin. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 12 | 
| Number of Participants Presenting the Same Autofluorescence Patterns in the Study Eye as Seen on Fundus Autofluorescence (FAF) Imaging at Week 24 as Observed at Baseline | Fundus autofluorescence patterns were assessed using fundus autofluorescence (FAF) imaging, a non-invasive technique that uses a confocal scanning ophthalmoscope to detect naturally-fluorescing lipofuscin. The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the choice of study eye in cases of bilateral disease selection criteria outlined in the eligibility criteria. | Baseline and Week 24 | 
| Number of Participants Experiencing a Complete Resolution of Fluid as Seen on OCT at Any Time During the Study Period |  | Baseline and Week 74 | 
| Observation of Dose Reduction of Systemic Immunosuppression or Steroids Over the Course of the Study Period | This study terminated early due to lack of recruitment; therefore, we chose not to report due to insufficient data. | Baseline and Week 74 | 
| Cytokine Analysis on Aqueous Samples to Assess Whether Intravitreal Injection of Methotrexate Affects Aqueous Inflammatory Cytokine Levels | This study terminated early due to lack of recruitment; therefore, we chose not to report due to insufficient data. | Baseline and Week 74 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Uveitis, Macular Edema, Methotrexate