Macular Edema, Uveitis
Conditions
Keywords
uveitic macular edema, uveitis
Brief summary
The Macular Edema Ranibizumab v. Intravitreal anti-inflammatory Therapy (MERIT) Trial will compare the relative efficacy and safety of intravitreal methotrexate, intravitreal ranibizumab, and the intravitreal dexamethasone implant for the treatment of uveitic macular edema persisting or reoccurring after an intravitreal corticosteroid injection. MERIT is a parallel design (1:1:1), randomized comparative trial with an anniversary close-out after 6 months of follow-up. The primary outcome is percent change in central subfield thickness from the baseline OCT measurement to the 12 week visit.
Detailed description
Macular edema (ME) is the most common structural complication and cause of visual impairment and legal blindness in uveitis patients. Traditional approaches to the treatment of uveitic ME have included the use of regional corticosteroid therapy, delivered periocularly, including posterior sub-Tenon's and orbital floor injections, or via the intravitreal route. While corticosteroid injections may reduce ME and improve vision, the effect is often variable with a limited duration. Persistent macular edema is a common occurrence and often requires repeated intravitreal injections of corticosteroids, which expose eyes to a significant risk of increased intraocular pressure ocular and cataract development. The often refractory nature of uveitic ME and its impact on visual function underscores the need to identify effective alternative medical therapeutic options. Recent pilot studies have shown intravitreal methotrexate (MTX) and intravitreal ranibizumab (Lucentis®, Genentech Inc., San Francisco, CA) to be promising treatments for uveitic ME, and intravitreal dexamethasone implant (Ozurdex®, Allergan, Irvine, CA) has recently been approved by the U.S. FDA for uveitic ME in patients with non-infectious uveitis. In addition to being effective, intravitreal MTX and ranibizumab potentially may have less ocular side effects than corticosteroids, particularly less IOP elevation. However, the relative efficacy of these treatments is unknown. The Macular Edema Ranibizumab v. Intravitreal anti-inflammatory Therapy (MERIT) Trial will compare the relative efficacy and safety of intravitreal methotrexate, ranibizumab, and dexamethasone implant. MERIT is a parallel design (1:1:1), randomized comparative effectiveness trial with an anniversary close-out after 6 months of follow-up. The primary outcome is percent change in central subfield thickness from the baseline OCT measurement to the 12 week visit.
Interventions
Standard preparation as described for intravitreal injections.
DRUGIntravitreal Methotrexate 400 µg
Intravitreal Methotrexate 400 µg injection procedures should be carried out under controlled aseptic conditions which include the use of sterile gloves and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide such as betadine, applied to the periocular skin, eyelid and ocular surface are required prior to the injection.
DRUGIntravitreal Ranibizumab 0.5 mg
Intravitreal Ranibizumab 0.5 mg injection procedures should be carried out under controlled aseptic conditions which include the use of sterile gloves and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide such as betadine, applied to the periocular skin, eyelid and ocular surface are required prior to the injection.
Sponsors
National Eye Institute (NEI)
JHSPH Center for Clinical Trials
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patient level inclusion criterion 1. 18 years of age or older; Eye level inclusion criteria - at least one eye must meet all of the following conditions 2. Inactive or minimally active non-infectious anterior, intermediate, posterior or panuveitis, as defined by the Standardization of Uveitis Nomenclature (SUN) Working Group criteria as ≤ 0.5+ anterior chamber cells, ≤ 0.5+ vitreous haze grade and no active retinal/choroidal lesions for a minimum of 4 weeks; 3. Macular edema (ME) defined as the presence of macular thickness greater than the normal range for the OCT machine being used (see cut points below), regardless of the presence of cysts, following an intravitreal corticosteroid injection (≥ 4 weeks following intravitreal triamcinolone injection or ≥ 12 weeks following intravitreal dexamethasone implant injection); Greater than 300 μm for Zeiss Cirrus Greater than 320 μm for Heidelberg Spectralis Greater than 300 μm for Topcon SD OCT 4. Baseline fluorescein angiogram that, as assessed by the study ophthalmologist, is gradable for degree of leakage in the central subfield; 5. Best corrected visual acuity (BCVA) 5/200 or better; 6. Baseline intraocular pressure \> 5 mm Hg and ≤ 21 mm Hg (current use of ≤3 intraocular pressure-lowering medications and/or prior glaucoma surgery are acceptable (Note: combination medications, e.g., Combigan, are counted as two IOP-lowering medications); 7. Media clarity and pupillary dilation sufficient to allow OCT testing and assessment of the fundus.
Exclusion criteria
Patient level
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Baseline Central Subfield Thickness Observed at 12 Weeks | At 12-week visit | The primary outcome is the change in central subfield thickness from baseline to 12 weeks measured on a relative scale as the the proportion of the baseline central subfield thickness. The proportion of baseline subfield thickness is estimated by a mixed effect model that includes time points for baseline, week 4, week 8, and week 12 and the treatment group. The treatment effect is the interaction (product) of time point and treatment. Contrasts of the model parameter estimates were used to calculate the change from baseline to week 12 and the comparison between treatment groups. Values less than 1 indicate a decrease in retinal thickness with lower values indicating greater decreases (improvement).The OCT outcomes were measured by masked readers. The 12-week visit was chosen as the time to assess the primary outcome because of the ranibizumab treatment schedule and the peak effect time for dexamethasone |
Countries
Australia, Canada, India, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ozurdex (0.7 mg Dexamethasone Pellet) Delivered Via Intravitreal Injection Ozurdex (0.7 mg dexamethasone pellet) delivered via intravitreal injection at week 0 Eligible eye (s) treated at week 0 Second injection required at Week 8 if retreatment criteria met Retreatment permitted at M04 and later if retreatment criteria is met.
Retreatment criteria :
1. Central subfield thickness greater than 1.1 times upper limit of normal (330 µm for Zeiss and Topcon SD OCT and 352 µm for Heidelberg OCT) and/or cystoid space(s) within 1 mm central subfield.
2. IOP of \<25 mm Hg (treatment with ≤3 IOP-lowering agents permitted), IOP criteria for initial injection of study treatment in eligible eye(s) is ≤21 mm Hg with ≤3 IOP-lowering agents | 65 |
| Ozurdex (0.7 mg Dexamethasone Pellet) Delivered Via Intravitreal Injection Ozurdex (0.7 mg dexamethasone pellet) delivered via intravitreal injection at week 0 Eligible eye (s) treated at week 0 Second injection required at Week 8 if retreatment criteria met Retreatment permitted at M04 and later if retreatment criteria is met.
Retreatment criteria :
1. Central subfield thickness greater than 1.1 times upper limit of normal (330 µm for Zeiss and Topcon SD OCT and 352 µm for Heidelberg OCT) and/or cystoid space(s) within 1 mm central subfield.
2. IOP of \<25 mm Hg (treatment with ≤3 IOP-lowering agents permitted), IOP criteria for initial injection of study treatment in eligible eye(s) is ≤21 mm Hg with ≤3 IOP-lowering agents | 77 |
| Intravitreal Methotrexate 400 µg in 0.1 mL 0.9% Sodium Chloride Solution, Preservative-free Intravitreal methotrexate 400 µg in 0.1 mL Eligible eye(s) treated at week 0 Retreatment required at M02, M03 if retreatment criteria met Retreatment permitted at M04 and later if retreatment criteria met
Retreatment criteria:
1. Central subfield thickness greater than 1.1 times upper limit of normal (330 µm for Zeiss and Topcon SD OCT and 352 µm for Heidelberg OCT) and/or cystoid space(s) within 1 mm central subfield.
2. IOP of \<25 mm Hg (treatment with ≤3 IOP-lowering agents permitted), IOP criteria for initial injection of study treatment in eligible eye(s) is ≤21 mm Hg with ≤3 IOP-lowering agents | 65 |
| Intravitreal Methotrexate 400 µg in 0.1 mL 0.9% Sodium Chloride Solution, Preservative-free Intravitreal methotrexate 400 µg in 0.1 mL Eligible eye(s) treated at week 0 Retreatment required at M02, M03 if retreatment criteria met Retreatment permitted at M04 and later if retreatment criteria met
Retreatment criteria:
1. Central subfield thickness greater than 1.1 times upper limit of normal (330 µm for Zeiss and Topcon SD OCT and 352 µm for Heidelberg OCT) and/or cystoid space(s) within 1 mm central subfield.
2. IOP of \<25 mm Hg (treatment with ≤3 IOP-lowering agents permitted), IOP criteria for initial injection of study treatment in eligible eye(s) is ≤21 mm Hg with ≤3 IOP-lowering agents | 79 |
| Intravitreal Ranibizumab (Lucentis) 0.5 mg in 0.05 mL Intravitreal ranibizumab (Lucentis) 0.5 mg in 0.05 mL Eligible eye(s) treated M01+ Retreatment required at M02, M03 if retreatment criteria met Retreatment permitted at M04 and later if retreatment criteria met
Retreatment criteria:
1\) Central subfield thickness greater than 1.1 times upper limit of normal (330 µm for Zeiss and Topcon SD OCT and 352 µm for Heidelberg OCT) and/or cystoid space(s) within 1 mm central subfield. | 64 |
| Intravitreal Ranibizumab (Lucentis) 0.5 mg in 0.05 mL Intravitreal ranibizumab (Lucentis) 0.5 mg in 0.05 mL Eligible eye(s) treated M01+ Retreatment required at M02, M03 if retreatment criteria met Retreatment permitted at M04 and later if retreatment criteria met
Retreatment criteria:
1\) Central subfield thickness greater than 1.1 times upper limit of normal (330 µm for Zeiss and Topcon SD OCT and 352 µm for Heidelberg OCT) and/or cystoid space(s) within 1 mm central subfield. | 69 |
| Total | 419 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 2 |
Baseline characteristics
| Characteristic | Intravitreal Methotrexate 400 µg in 0.1 mL 0.9% Sodium Chloride Solution, Preservative-free | Total | Intravitreal Ranibizumab (Lucentis) 0.5 mg in 0.05 mL | Ozurdex (0.7 mg Dexamethasone Pellet) Delivered Via Intravitreal Injection |
|---|---|---|---|---|
| Age, Continuous | 59 years | 58 years | 57 years | 59 years |
| Concomitant systemic medication | 27 Participants | 84 Participants | 29 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 63 Participants | 189 Participants | 62 Participants | 64 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Intraocular pressure (IOP) | 15 mm Hg | 14 mm Hg | 14 mm Hg | 15 mm Hg |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 28 Participants | 8 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 22 Participants | 51 Participants | 13 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 7 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 28 Participants | 107 Participants | 41 Participants | 38 Participants |
| Region of Enrollment Australia | 2 participants | 7 participants | 3 participants | 2 participants |
| Region of Enrollment Canada | 3 participants | 8 participants | 1 participants | 4 participants |
| Region of Enrollment India | 9 participants | 27 participants | 8 participants | 10 participants |
| Region of Enrollment United Kingdom | 8 participants | 25 participants | 8 participants | 9 participants |
| Region of Enrollment United States | 43 participants | 127 participants | 44 participants | 40 participants |
| Retinal thickness at the center subfield | 476 um | 453 um | 401 um | 457 um |
| Sex: Female, Male Female | 48 Participants | 129 Participants | 40 Participants | 41 Participants |
| Sex: Female, Male Male | 17 Participants | 65 Participants | 24 Participants | 24 Participants |
| Visual acuity | 64 Standard letters | 66 Standard letters | 67 Standard letters | 68 Standard letters |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 65 | 0 / 65 | 0 / 64 |
| other Total, other adverse events | 12 / 65 | 24 / 65 | 14 / 64 |
| serious Total, serious adverse events | 6 / 65 | 7 / 65 | 3 / 64 |
Outcome results
Primary
Proportion of Baseline Central Subfield Thickness Observed at 12 Weeks
The primary outcome is the change in central subfield thickness from baseline to 12 weeks measured on a relative scale as the the proportion of the baseline central subfield thickness. The proportion of baseline subfield thickness is estimated by a mixed effect model that includes time points for baseline, week 4, week 8, and week 12 and the treatment group. The treatment effect is the interaction (product) of time point and treatment. Contrasts of the model parameter estimates were used to calculate the change from baseline to week 12 and the comparison between treatment groups. Values less than 1 indicate a decrease in retinal thickness with lower values indicating greater decreases (improvement).The OCT outcomes were measured by masked readers. The 12-week visit was chosen as the time to assess the primary outcome because of the ranibizumab treatment schedule and the peak effect time for dexamethasone
Time frame: At 12-week visit
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ozurdex (0.7 mg Dexamethasone Pellet) Delivered Via Intravitreal Injection | Proportion of Baseline Central Subfield Thickness Observed at 12 Weeks | 0.65 Proportion of baseline retinal thickness |
| Intravitreal Methotrexate 400 µg in 0.1 mL 0.9% Sodium Chloride Solution, Preservative-free | Proportion of Baseline Central Subfield Thickness Observed at 12 Weeks | 0.88 Proportion of baseline retinal thickness |
| Intravitreal Ranibizumab (Lucentis) 0.5 mg in 0.05 mL | Proportion of Baseline Central Subfield Thickness Observed at 12 Weeks | 0.79 Proportion of baseline retinal thickness |
Comparison: A sample size of 240 was calculated to provide 91% power to detect a 25% reduction for Ozurdex, a 38% reduction for Methotrexate and Lucentis assuming a standard deviation of 0.33, 25% with bilateral disease, between-eye correlation of 0.4, 10% loss to follow-up, and a two-sided type 1 error rate of 0.025 for each pairwise comparison.p-value: <0.00195% CI: [1.19, 1.56]mixed effects model
Comparison: A sample size of 240 was calculated to provide 91% power to detect a 25% reduction for Ozurdex, a 38% reduction for methotrexate and Lucentis assuming a standard deviation of 0.33, 25% with bilateral disease, between-eye correlation of 0.4, 10% loss to follow-up, and a two-sided type 1 error rate of 0.025 for each pairwise comparison.p-value: 0.01295% CI: [1.04, 1.43]mixed effects model