Macular Edema Ranibizumab v. Intravitreal Anti-inflammatory Therapy Trial

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 at the 6 month
clinic visit. The primary outcome is percent change in central subfield thickness from the
baseline OCT measurement to the 12 week visit.

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 SUN132 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 3DOCT

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 exclusion criteria

1. History of infectious uveitis in either eye;

2. History of infectious scleritis of any type in either eye (Note: History of
noninfectious scleritis that has been active in past 12 months is an eye-level
exclusion -see #13 below);

3. History of keratitis (with the exception of keratitis due to dry eye) in either eye;

4. History of central serous retinopathy in either eye;

5. Active infectious conjunctivitis in either eye;

6. Oral prednisone dose > 10 mg per day (or of an alternative corticosteroid at a dose
higher than that equipotent to prednisone 10 mg per day) OR oral prednisone dose ≤ 10
mg per day at baseline that has not been stable for at least 4 weeks (note: if patient
is off of oral prednisone at baseline (M01 study visit) dose stability requirement for
past 4 weeks does not apply);

7. Systemic immunosuppressive drug therapy that has not been stable for at least 4 weeks
(note: use of systemic methotrexate is acceptable as long as regimen has been stable
for at least 4 weeks);

8. Use of oral acetazolamide or other systemic carbonic anhydrase inhibitor at baseline;

9. Known allergy or hypersensitivity to any component of the study drugs;

10. For women of childbearing potential: pregnancy, breastfeeding, or a positive pregnancy
test; unwilling to practice an adequate birth control method (abstinence, combination
barrier and spermicide, or hormonal) for duration of trial;

Eye level exclusion criteria - at least one eye that meets all inclusion criteria
cannot have any of the following conditions

11. History of infectious endophthalmitis;

12. History of severe glaucoma as defined by optic nerve damage (cup/disc ratio of ≥ 0.9
or any notching of optic nerve to the rim);

13. History of active noninfectious scleritis in past 12 months (Note: History of
noninfectious scleritis is acceptable if the last episode of active scleritis resolved
at least 12 months prior to enrollment);

14. Presence of an epiretinal membrane noted clinically or by OCT that per the judgment of
study ophthalmologist may be significant enough to limit improvement of ME (i.e.,
causing substantial wrinkling of the retinal surface);

15. Torn or ruptured posterior lens capsule

16. Presence of silicone oil;

17. Ozurdex administered in past 12 weeks;

18. Anti-VEGF agent, intravitreal methotrexate, or intravitreal/periocular corticosteroid
administered in past 4 weeks;

19. Fluocinolone acetonide implant (Retisert) placed in past 3 years.