Macular Edema Ranibizumab v. Intravitreal Anti-inflammatory Therapy Trial

NCT ID: NCT02623426

Last Updated: 2023-07-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 194 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-09
• Study Completion Date: 2022-02-02

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.

Conditions

Uveitis; Macular Edema

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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:

1. 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.

2. 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;

Group Type: ACTIVE_COMPARATOR

Dexamethasone intravitreal implant 0.7 mg

Intervention Type: DRUG

Standard preparation as described for intravitreal injections.

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.

Group Type: ACTIVE_COMPARATOR

Intravitreal Methotrexate 400 µg

Intervention Type: DRUG

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.

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.

Group Type: ACTIVE_COMPARATOR

Intravitreal Ranibizumab 0.5 mg

Intervention Type: DRUG

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.

Interventions

Dexamethasone intravitreal implant 0.7 mg

Standard preparation as described for intravitreal injections.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Ozurdex; Lucentis

Eligibility Criteria

Inclusion Criteria

Patient level inclusion criterion

1. 18 years of age or older;

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.

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.

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;

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Eye Institute (NEI)

NIH

Sponsor Role: collaborator

JHSPH Center for Clinical Trials

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Douglas A Jabs, MD, MBA

Role: STUDY_CHAIR

Center for Clinical Trials and Evidence Synthesis, JHU, Baltimore, MD

Locations

Jules Stein Eye Institute, UCLA

Los Angeles, California, United States

University of California, San Francisco

San Francisco, California, United States

Anne Bates Leach Eye Hospital, University of Miami Miller School of Medicine

Miami, Florida, United States

Emory University

Atlanta, Georgia, United States

Northwestern University

Chicago, Illinois, United States

Rush University Medical Center

Chicago, Illinois, United States

University of Iowa

Iowa City, Iowa, United States

University of Louisville

Louisville, Kentucky, United States

Johns Hopkins University

Baltimore, Maryland, United States

Massachusetts Eye and Ear Infirmary

Boston, Massachusetts, United States

Ophthalmic Consultants of Boston

Boston, Massachusetts, United States

Kellogg Eye Center, University of Michigan

Ann Arbor, Michigan, United States

Duke Eye Center, Duke University

Durham, North Carolina, United States

Scheie Eye Institute, University of Pennsylvania

Philadelphia, Pennsylvania, United States

MidAtlanitc Retina, Wills Eye Hospital

Philadelphia, Pennsylvania, United States

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Vanderbilt

Nashville, Tennessee, United States

Retinal Consultants of Houston

Houston, Texas, United States

John A. Moran Eye Center, University of Utah

Salt Lake City, Utah, United States

Royal Victorian Eye and Ear Hospital

East Melbourne, Victoria, Australia

McGill University

Montreal, Quebec, Canada

LV Prasad Eye Institute - Bhubaneswar

Bhubaneswar, Odisha, India

Medical and Vision Research Foundation

Chennai, Tamil Nadu, India

LV Prasad Eye Institute - Hyderabad

Hyderabad, Telangana, India

Advanced Eye Center, Post Graduate Institute of Medical Education and Research

Chandigarh, , India

University Hospitals Bristol NHS Foundation Trust

Bristol, England, United Kingdom

Cambridge University Hospitals NHS Foundation Trust

Cambridge, England, United Kingdom

University Hospitals of Leicester NHS Trust

Leicester, England, United Kingdom

Liverpool University Hospitals NHS Foundation Trust

Liverpool, England, United Kingdom

Moorfields Eye Hospital NHS Foundation Trust

London, England, United Kingdom

Manchester University NHS Foundation Trust

Manchester, England, United Kingdom

University Hospitals Birmingham NHS Foundation Trust

Birmingham, , United Kingdom

Moorfields Eye Hospital

London, , United Kingdom

Countries

United States; Australia; Canada; India; United Kingdom

References

Multicenter Uveitis Steroid Treatment Trial (MUST) Research Group, Writing Committee:; Acharya NR, Vitale AT, Sugar EA, Holbrook JT, Burke AE, Thorne JE, Altaweel MM, Kempen JH, Jabs DA. Intravitreal Therapy for Uveitic Macular Edema-Ranibizumab versus Methotrexate versus the Dexamethasone Implant: The MERIT Trial Results. Ophthalmology. 2023 Sep;130(9):914-923. doi: 10.1016/j.ophtha.2023.04.011. Epub 2023 Jun 13.

Reference Type: DERIVED

PMID: 37318415 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

U10EY024527

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ML29257

Identifier Type: OTHER

Identifier Source: secondary_id

119247

Identifier Type: -

Identifier Source: org_study_id