Uveitis
Conditions
Keywords
antimetabolite, noninfectious
Brief summary
In the First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial, the investigators propose to establish which immunosuppressive therapy, methotrexate or mycophenolate mofetil, is more effective as a first-line, corticosteroid-sparing agent for the treatment of non-infectious uveitis in a block-randomized, observer-masked, comparative effectiveness trial.
Detailed description
This is a randomized comparative effectiveness trial to determine which treatment, methotrexate or mycophenolate mofetil, is more effective as first-line corticosteroid-sparing treatment for patients with non-infectious intermediate, posterior and panuveitis requiring corticosteroid-sparing therapy. The primary outcome is treatment success assessed at the 6 month visit (Phase 1, 0-6 months). If patients are a treatment success, they continue on the medication for another 6 months (Phase 1, 6-12 months). Patients who are a treatment failure can crossover to the other medication (Phase 2, 0-6 months).
Interventions
DRUGMycophenolate mofetil
For the first two weeks, an introductory dose of 500 mg twice a day (BID) orally. After two weeks, the dose will be increased to 1.5 g BID.
DRUGMethotrexate
For the first two weeks, an introductory dose of 15 mg/week (7.5mg BID once a week) orally. After two weeks, the dose will be increased to 25 mg/week (12.5mg BID once a week)
DRUGPrednisone
All patients enrolled in the study will be initially taking concomitant oral corticosteroids at 1 mg/kg or 60 mg daily, whichever is less. Initial corticosteroid dose will be continued for 2 to 4 weeks at which point prednisone will be gradually tapered. Prednisone will be tapered to and held at 7.5 mg/day for the first 6 months of the study.
Sponsors
Aravind Eye Hospitals, India
Oregon Health and Science University
Asociación para Evitar la Ceguera en México
Royal Victoria Eye and Ear Hospital
Northwestern University
National Eye Institute (NEI)
King Khaled Eye Specialist Hospital
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* All the following criteria must be met at enrollment: Historical non-infectious intermediate, anterior and intermediate, posterior or panuveitis in at least one eye Active inflammation within the last 180 days, defined by the presence of any of the following (in at least one eye) according to Standardization of Uveitis Nomenclature (SUN) criteria: * ≥ 2+ anterior chamber cells * ≥ 2+ vitreous haze * active retinal or choroidal lesions Active inflammation at enrollment, defined by the presence of any of the following (in at least one eye) according to SUN criteria: * ≥1+ anterior chamber cells and/or * ≥1+ vitreous haze and/or * active retinal/choroidal lesions At least one of the following criteria must be met before or at enrollment: * Active inflammation after 4 weeks of high-dose (1mg/kg prednisone equivalent) corticosteroid treatment or 4 weeks following a regional corticosteroid injection * Treatment with oral corticosteroids resulting in a reduction of inflammation, followed by an increase in inflammation (of at least 1 grade in anterior chamber cells or vitreous haze or a change of non-active to active lesions) when corticosteroid is tapered, in the 180 weeks prior to enrollment * Active inflammation after long-acting corticosteroid injection 4 weeks to 180 days prior to enrollment * Active inflammation after treatment with \>10mg/day oral prednisone for at least the past 90 days prior to enrollment * Known chronic condition necessitating corticosteroid-sparing immunosuppressive treatment: Behcet's disease with posterior segment involvement, multifocal choroiditis with panuveitis, serpiginous choroidopathy, birdshot retinochoroidopathy, diffuse retinal vasculitis, Vogt-Koyanagi-Harada with bullous serous retinal detachments and/or choroidal detachments, sympathetic ophthalmia. No prior therapy required for these patients Willingness to start corticosteroid treatment at 1mg/kg or 60mg a day of prednisone, whichever is less Willingness to limit alcohol consumption Willingness to use an acceptable method of contraception during the study period (i.e. pharmacologic medications, devices, barrier methods) or abstinence. *
Exclusion criteria
Any of the following Any infectious cause of uveitis Prior immunosuppressive therapy other than corticosteroids in the past 12 months Prior intolerability or safety issues with methotrexate or mycophenolate mofetil Prior failure to control ocular or other inflammation using methotrexate or mycophenolate mofetil Prior biologic therapy at any time Media opacity (such as cataract and/or corneal scar) and/or extensive posterior synechiae such that examination of the posterior segment is not possible in both eyes Chronic hypotony (IOP \< 5 mm Hg for \> 3 months) in both eyes Periocular or intravitreal corticosteroid injection in the past 4 weeks Fluocinolone acetonide implant in either eye in \< 3 years Intraocular surgery in \< 30 days, or planning on getting surgery within the next 6 months Best spectacle-corrected visual acuity (BSCVA) of hand motions or worse in better eye \< 16 years of age at enrollment Planning to conceive during the study period, pregnant or breast-feeding (blood or urine pregnancy test for all females, excluding those who are post-menopausal is mandatory)\* Any history of cancer (If a patient has a history of non-melanoma skin cancer they can still be considered for inclusion in this study, provided it is not currently active). Systemic autoimmune disease anticipated to dictate treatment course Abnormal Complete blood count (≤ 2,500 white blood cells and/or ≤ 75,000 platelets and/or ≤9 hemoglobin) within 4 weeks prior to enrollment\* Abnormal alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥ 2 times the upper limit of normal for the lab and/or creatinine ≥ 1.5 within 4 weeks prior to enrollment\* Evidence of active tuberculosis, HIV infection, syphilis, or hepatitis B or C (patients must have a tuberculin skin test, or interferon-gamma release assay, a chest radiograph, Rapid plasma reagin / Venereal disease research laboratory test (RPR/VDRL), fluorescent treponemal antibody absorption test (FTA-ABS), or other treponemal tests, Hepatitis B surface antigen, Hepatitis C antibody tests, and HIV test within 90 days prior to enrollment)\*\* \*Testing required within 4 weeks prior to enrollment; \*\*Testing required within 90 days prior to enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving Treatment Success at 6 Months (Phase I, 0-6 Months) | 6 Months | Controlled ocular inflammation (≤ 0.5+ anterior chamber cells, ≤ 0.5+ vitreous haze, no active retinal/choroidal lesions in both eyes) with 7.5 mg/day of oral prednisone and ≤ 2 drops/day of topical 1% prednisolone acetate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving Treatment Success at 12 Months on Same Medication (Phase I, 6-12 Months) | 12 Months | Controlled ocular inflammation (≤ 0.5+ anterior chamber cells, ≤ 0.5+ vitreous haze, no active retinal/choroidal lesions in both eyes) with 7.5 mg/day of oral prednisone and ≤ 2 drops/day of topical 1% prednisolone acetate in patients who were a treatment success at the primary outcome of 6 months. |
| Number of Participants Achieving Treatment Success After Switching to Other Medication (Phase II, 0-6 Months) | 6 Months | Controlled ocular inflammation (≤ 0.5+ anterior chamber cells, ≤ 0.5+ vitreous haze, no active retinal/choroidal lesions in both eyes) with 7.5 mg/day of oral prednisone and ≤ 2 drops/day of topical 1% prednisolone acetate for patients who crossed over to other medication following treatment failure at 6 months (or earlier). |
Countries
Australia, India, Mexico, Saudi Arabia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Methotrexate oral methotrexate
Methotrexate: For the first two weeks, an introductory dose of 15 mg/week (7.5mg BID once a week) orally. After two weeks, the dose will be increased to 25 mg/week (12.5mg BID once a week)
Prednisone: All patients enrolled in the study will be initially taking concomitant oral corticosteroids at 1 mg/kg or 60 mg daily, whichever is less. Initial corticosteroid dose will be continued for 2 to 4 weeks at which point prednisone will be gradually tapered. Prednisone will be tapered to and held at 7.5 mg/day for the first 6 months of the study. | 107 |
| Mycophenolate Mofetil oral mycophenolate mofetil
Mycophenolate mofetil: For the first two weeks, an introductory dose of 500 mg BID orally. After two weeks, the dose will be increased to 1.5 g BID.
Prednisone: All patients enrolled in the study will be initially taking concomitant oral corticosteroids at 1 mg/kg or 60 mg daily, whichever is less. Initial corticosteroid dose will be continued for 2 to 4 weeks at which point prednisone will be gradually tapered. Prednisone will be tapered to and held at 7.5 mg/day for the first 6 months of the study. | 109 |
| Total | 216 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| 6-12 Months | Adverse Event | 0 | 0 | 3 | 2 |
| 6-12 Months | Did not want to switch antimetabolites | 0 | 0 | 9 | 11 |
| 6-12 Months | Lost to Follow-up | 2 | 0 | 0 | 0 |
| 6-12 Months | Withdrawal by Subject | 2 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Methotrexate | Total | Mycophenolate Mofetil |
|---|---|---|---|
| Age, Continuous | 36 years | 38 years | 41 years |
| Anatomic Location of Uveitis Anterior + Intermediate | 15 Participants | 29 Participants | 14 Participants |
| Anatomic Location of Uveitis Intermediate | 8 Participants | 17 Participants | 9 Participants |
| Anatomic Location of Uveitis Panuveitis | 60 Participants | 121 Participants | 61 Participants |
| Anatomic Location of Uveitis Posterior | 24 Participants | 49 Participants | 25 Participants |
| Race/Ethnicity, Customized Asian | 5 participants | 11 participants | 6 participants |
| Race/Ethnicity, Customized Black | 3 participants | 9 participants | 6 participants |
| Race/Ethnicity, Customized Indian Subcontinent | 70 participants | 139 participants | 69 participants |
| Race/Ethnicity, Customized Middle Eastern | 5 participants | 10 participants | 5 participants |
| Race/Ethnicity, Customized Native American | 2 participants | 3 participants | 1 participants |
| Race/Ethnicity, Customized Pacific Islander | 1 participants | 4 participants | 3 participants |
| Race/Ethnicity, Customized White | 25 participants | 47 participants | 22 participants |
| Region of Enrollment Australia | 11 participants | 21 participants | 10 participants |
| Region of Enrollment India | 69 participants | 136 participants | 67 participants |
| Region of Enrollment Mexico | 1 participants | 3 participants | 2 participants |
| Region of Enrollment Saudi Arabia | 4 participants | 9 participants | 5 participants |
| Region of Enrollment United States | 22 participants | 47 participants | 25 participants |
| Sex: Female, Male Female | 75 Participants | 135 Participants | 60 Participants |
| Sex: Female, Male Male | 32 Participants | 81 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 107 | 0 / 109 |
| other Total, other adverse events | 99 / 107 | 100 / 109 |
| serious Total, serious adverse events | 7 / 107 | 7 / 109 |
Outcome results
Primary
Number of Participants Achieving Treatment Success at 6 Months (Phase I, 0-6 Months)
Controlled ocular inflammation (≤ 0.5+ anterior chamber cells, ≤ 0.5+ vitreous haze, no active retinal/choroidal lesions in both eyes) with 7.5 mg/day of oral prednisone and ≤ 2 drops/day of topical 1% prednisolone acetate.
Time frame: 6 Months
Population: All randomized patient with a 6-month visit, or who were declared early treatment failures, are included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Methotrexate | Number of Participants Achieving Treatment Success at 6 Months (Phase I, 0-6 Months) | 64 Participants |
| Mycophenolate Mofetil | Number of Participants Achieving Treatment Success at 6 Months (Phase I, 0-6 Months) | 56 Participants |
Secondary
Number of Participants Achieving Treatment Success After Switching to Other Medication (Phase II, 0-6 Months)
Controlled ocular inflammation (≤ 0.5+ anterior chamber cells, ≤ 0.5+ vitreous haze, no active retinal/choroidal lesions in both eyes) with 7.5 mg/day of oral prednisone and ≤ 2 drops/day of topical 1% prednisolone acetate for patients who crossed over to other medication following treatment failure at 6 months (or earlier).
Time frame: 6 Months
Population: Patients who switched to the other medication following treatment failure at 6 months (or earlier). Patients were analyzed by the medication that they received in this second phase (Phase II, 0-6 Months).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Methotrexate | Number of Participants Achieving Treatment Success After Switching to Other Medication (Phase II, 0-6 Months) | 20 Participants |
| Mycophenolate Mofetil | Number of Participants Achieving Treatment Success After Switching to Other Medication (Phase II, 0-6 Months) | 7 Participants |
Secondary
Number of Participants Achieving Treatment Success at 12 Months on Same Medication (Phase I, 6-12 Months)
Controlled ocular inflammation (≤ 0.5+ anterior chamber cells, ≤ 0.5+ vitreous haze, no active retinal/choroidal lesions in both eyes) with 7.5 mg/day of oral prednisone and ≤ 2 drops/day of topical 1% prednisolone acetate in patients who were a treatment success at the primary outcome of 6 months.
Time frame: 12 Months
Population: Patients who were a treatment success at 6 months and continued in follow-up.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Methotrexate | Number of Participants Achieving Treatment Success at 12 Months on Same Medication (Phase I, 6-12 Months) | 48 Participants |
| Mycophenolate Mofetil | Number of Participants Achieving Treatment Success at 12 Months on Same Medication (Phase I, 6-12 Months) | 40 Participants |