Macular Edema Ranibizumab v. Intravitreal Anti-inflammatory Therapy Trial (MERIT)

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.

Study Overview

• Status: Completed
• Conditions: Uveitis; Macular Edema
• Intervention / Treatment: Drug: Dexamethasone intravitreal implant 0.7 mg; Drug: Intravitreal Methotrexate 400 µg; Drug: Intravitreal Ranibizumab 0.5 mg

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.

• Study Type: Interventional
• Enrollment (Actual): 194
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • East Melbourne, Victoria, Australia
      • Royal Victorian Eye and Ear Hospital
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H4A 3S5
      • McGIll University
• India
  • Chandigarh, India
    • Advanced Eye Center, Post Graduate Institute of Medical Education and Research
  • Odisha
    • Bhubaneswar, Odisha, India
      • LV Prasad Eye Institute - Bhubaneswar
  • Tamil Nadu
    • Chennai, Tamil Nadu, India
      • Medical and Vision Research Foundation
  • Telangana
    • Hyderabad, Telangana, India, 500034
      • LV Prasad Eye Institute - Hyderabad
• United Kingdom
  • Birmingham, United Kingdom, B152WB
    • University Hospitals Birmingham NHS Foundation Trust
  • London, United Kingdom, EC1V 9EL
    • Moorfields Eye Hospital
  • England
    • Bristol, England, United Kingdom, BS1 2LX
      • University Hospitals Bristol NHS Foundation Trust
    • Cambridge, England, United Kingdom, CB2 0QQ
      • Cambridge University Hospitals NHS Foundation Trust
    • Leicester, England, United Kingdom, LE1 5WW
      • University Hospitals of Leicester NHS Trust
    • Liverpool, England, United Kingdom, L7 8XP
      • Liverpool University Hospitals NHS Foundation Trust
    • London, England, United Kingdom, EC1V 2PD
      • Moorfields Eye Hospital NHS Foundation Trust
    • Manchester, England, United Kingdom, M13 (WL
      • Manchester University NHS Foundation Trust
• United States
  • California
    • Los Angeles, California, United States, 90095
      • Jules Stein Eye Institute, UCLA
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Florida
    • Miami, Florida, United States, 33136
      • Anne Bates Leach Eye Hospital, University of Miami Miller School of Medicine
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts Eye and Ear Infirmary
    • Boston, Massachusetts, United States, 02114
      • Ophthalmic Consultants of Boston
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • Kellogg Eye Center, University of Michigan
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Eye Center, Duke University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Scheie Eye Institute, University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • MidAtlanitc Retina, Wills Eye Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt
  • Texas
    • Houston, Texas, United States, 77030
      • Retinal Consultants of Houston
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • John A. Moran Eye Center, University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 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-vascular endothelial growth factor (VEGF) agent, intravitreal methotrexate, or intravitreal/periocular corticosteroid administered in past 4 weeks;
19. Fluocinolone acetonide implant (Retisert) placed in past 3 years.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dexamethasone intravitreal implant 0.7mg; Participants were randomized to a treatment group. A participant may have 1 or 2 eyes with macular edema (eligible eyes) receiving the same treatment. Eligible eye(s) treated at study visit M01 (week 0). Retreatment required at study visit M03 (8 weeks) if re-treatment criteria met. Retreatment permitted at later time points if retreatment criteria met. Re-treatment criteria: Central subfield thickness greater than 1.1X upper limit of normal (330 μm for Zeiss and Topcon Spectral Domain (SD) Optical Coherence Tomography (OCT) and 352 μm for Heidelberg OCT) and/or cystoid space(s) within 1 mm central subfield.; IOP of <25 mm Hg (treatment with ≤3 IOP-lowering agents permitted) Minimum time between treatments: minimum target is 8 weeks after last injection but re-injection permitted as early as 51 days after last injection;	Drug: Dexamethasone intravitreal implant 0.7 mg; Standard preparation as described for intravitreal injections.; Other Names: Ozurdex
Active Comparator: Intravitreal methotrexate 400µg in 0.1mL; Participants were randomized to a treatment group. A participant may have 1 or 2 eyes with macular edema (eligible eyes) receiving the same treatment. Eligible eye(s) treated at study visit M01 (week 0). Retreatment required at M02 (4 weeks) and M03 (8 weeks) if retreatment criteria met. Retreatment permitted at later time points if retreatment criteria met. Minimum time between treatments: minimum target is 4 weeks after last injection but re-injection permitted as early as 23 days after last injection.	Drug: Intravitreal 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.
Active Comparator: Intravitreal ranibizumab 0.5mg in 0.05mL; Participants were randomized to a treatment group. A participant may have 1 or 2 eyes with macular edema (eligible eyes) receiving the same treatment. Eligible eye(s) treated at study visits M01 (week 0), M02 (4 weeks), and M03 (8 weeks). Retreatment permitted at M04 (12 weeks) and at later time points if retreatment criteria met. Minimum time between treatments: minimum target is 4 weeks after last injection but re-injection permitted as early as 23 days after last injection. Re-treatment permitted at later time points if re-treatment criteria met.	Drug: Intravitreal 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.; Other Names: Lucentis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	At 12-week visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
IOP Elevation of >=24 mm Hg	Rate of IOP elevation of >=24 mm Hg during follow-u	During 24 weeks of follow-up
IOP Elevation of >=30 mm Hg	Rate of IOP elevation of >=30 mm Hg during follow-up	During 24 weeks of follow-up
IOP Elevation of >=10 mm Hg From Baseline	Rate of IOP elevation of >=10 mm Hg from baseline	During 24 weeks of follow-up
Change in Macular Thickness as Measured by OCT	Percent change in macular thickness as measured by OCT	Over 24 weeks of follow-up
>= 20% Reduction in Macular Thickness (or Normalization Even if <20% Reduction	Proportion of eyes with >=20% reduction in macular thickness (or normalization of macular thickness even if there is <20% reduction)	Over 24 weeks of follow-up
Resolution of macular edema	Proportion of eyes with resolution of macular edema defined as normalization of the macular thickness, i.e., <260 um on the standard scale	Over 24 weeks of follow-up
Change in Best-corrected Visual Acuity	Mean change in best-corrected visual acuity	Over 24 weeks of follow-up
Vitreous Hemorrhage	Count of vitreous hemorrhage as an immediate complication of injection	During 24 weeks of follow-up
Retinal Tear/Detachment	Count of retinal tears/detachments	During 24 weeks of follow-up
Endophthalmitis	Occurrence of endophthalmitis	During 24 weeks of follow-up
Severe vision loss	Severe vision loss (>= 15 standard letters)	During 24 weeks of follow-up

Collaborators and Investigators

• Sponsor: JHSPH Center for Clinical Trials
• Collaborators: National Eye Institute (NEI)
• Investigators: Study Chair: Douglas A Jabs, MD, MBA, Center for Clinical Trials and Evidence Synthesis, JHU, Baltimore, MD

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2017
• Primary Completion (Actual): October 27, 2021
• Study Completion (Actual): February 2, 2022

Study Registration Dates

• First Submitted: December 3, 2015
• First Submitted That Met QC Criteria: December 4, 2015
• First Posted (Estimated): December 7, 2015

Study Record Updates

• Last Update Posted (Actual): July 10, 2023
• Last Update Submitted That Met QC Criteria: June 20, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: uveitis; uveitic macular edema
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Uveal Diseases; Macular Degeneration; Macular Edema; Edema; Uveitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Dexamethasone; Ranibizumab; Methotrexate
• Other Study ID Numbers: 119247; U10EY024527 (U.S. NIH Grant/Contract); ML29257 (Other Identifier: Genentech (donating ranibizumab for US clinics)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No