Clinical trial NCT02623426
Conditions: Uveitis Macular Edema
Keywords: uveitic macular edema uveitis
Sponsor: JHSPH Center for Clinical Trials
Start date: 2017-03-09; Completion date: 2022-02-02
Enrollment: 194 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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; arm 2: 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. arm 3: 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.
Interventions: intervention 1: Dexamethasone intravitreal implant 0.7 mg intervention 2: Intravitreal Methotrexate 400 µg intervention 3: Intravitreal Ranibizumab 0.5 mg
Intervention descriptions: intervention 1: Standard preparation as described for intravitreal injections. intervention 2: 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 3: 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.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
Macular Edema Ranibizumab v. Intravitreal anti-inflammatory Therapy (MERIT) 
Trial 
Protocol version 1.8 
20 Aug 2020 
 
 
                   ClinicalTrials.gov identifier: NCT02623426 
 
 


 
 
 
 
 
Macular Edema Ranibizumab v. Intravitreal anti-inflammatory Therapy (MERIT) 
Trial 
Protocol version 1.8 
20 Aug 2020 
 
 
 
 
 
Phase 3 study 
IND 119247 
 
Sponsor-investigator 
Janet Holbrook, PhD, MPH 
Director, MUST Coordinating Center 
Professor of Epidemiology 
Johns Hopkins Bloomberg School of Public Health 
415 N. Washington Street, 2nd Floor 
Baltimore, MD 21231 
  
 
Medical Safety Officer 
Akrit Sodhi, M.D., Ph.D. 
Assistant Professor of Ophthalmology 
Retina Division 
Smith 4039 
Wilmer Eye Institute 
Johns Hopkins Medical Institutions 
400 North Broadway Street 
Baltimore, MD 21231 
 
ClinicalTrials.gov identifier: NCT02623426 
Clinical Trials Registry – India: CTRI/2018/09/015638. 
 
 
 
 


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Document distribution 
 
 
 
Version 
 
Version date 
 
Distribution 
 
Distribution date 
1.0 
 
 
12 Aug 2015 
23 Sep 2015 
 
 
 
22 Dec 2015 
Avanti Ghanekar, OD 
Genentech, Inc, 
META-MUST  DSMC 
JHSPH IRB  
 
JHSPH IRB 
FDA 
12 Aug 2015 
23 Sep 2015 
27 Oct 2015 
05 Nov 2015 
 
04 Jan 2016 
01 Feb 2016 (delivery 
date) 
 
1.1 
28 Mar 2016 
Vanguard clinics (JHU, 
UCSF,UT) 
JHSPH IRB 
 
 
22 Apr 2016 
 
13 May 2016 
 
 
1.2 
02 Aug 2016 
JHSPH IRB 
Genentech  
FDA 
Clinical centers 
12-15 Aug 2016 
 
 
(PPM 1) 
 
 
1.3 
29 Mar 2017 
20 Apr 2017 
10 May 2017 
JHSPH IRB 
JHSPH IRB 
JHSPH IEB 
Clinical centers  
29 Mar 2017 
21 Apr 2017 
11 May 2017 
25 May 2017 (PPM 7) 
 
 
FDA  
 
15 Jun 2017 
1.4 
18 Jul 2017 
JHSPH IRB 
Genentech (E. Winsch) 
24 Jul 2017 
14 Aug 2017 
 
 
 
 
1.5 
6 Dec 2017 
 
23 Jan 2018 
16 Feb 2018 
 
16 Mar 2018 
DSMC Chair  
DSMC 
JHSPH IRB 
JHSPH IRB 
 
JHSPH IRB 
Genentech 
Clinical centers 
08 Dec 2017 
13 Dec 2017 
02 Feb 2018 
16 Feb 2018 
 
23 Mar 2018 
20 Apr 2018 
23 Apr 2018 (PPM 21) 
 
1.6 
11 Apr 2019 
 
JHSPH IRB  
Clinical centers 
FDA 
29 Apr 2019 
31 Jul 2019 
19 Aug 2019 
 
 
 
 
1.7 
16 Dec 2019 
JHSPH IRB 
19 Dec 2019 
 
 
 
 
1.8 
20 Aug 2020 
JHSPH IRB 
26 Aug 2020 
 
 
 
 
 


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Document revision history 
 
22 Dec 2015 
Title page 
Added ClinicalTrials.gov Identifier:  NCT02623426 
 
Abstract 
Corrected typographical error and divided last sentence into 2 to define the secondary 
outcomes. 
 
1.4 Study centers and investigators 
Clinic Director at University of Pennsylvania changed from John Kempen, MD, PhD to Nirali 
Bhatt, MD 
 
1.8 Rationale for trial 
Changed “uveitic macular edema persistent after intravitreal triamcinolone injection” to “uveitic 
macular edema persisting after an intravitreal corticosteroid injection”  
 
2.2 Hypotheses 
Changed “uveitic macular edema persistent after intravitreal triamcinolone injection” to “uveitic 
macular edema persisting after an intravitreal corticosteroid injection”  
 
3.3 Trial schema 
Added intravitreal methotrexate at week 4 (M02) as needed; previously additional injection only 
was permitted at week 8 (M03) as needed (per recommendation of DSMC) 
 
3.6   Eligibility 
Inclusion criterion #3 (eye level) was revised to allow macular edema persisting after intravitreal 
corticosteroid injection (which includes intravitreal dexamethasone) rather than limiting to 
macular edema persisting after intravitreal triamcinolone as follows:  Macular edema (ME) 
defined as the presence of macular thickness greater than the normal range for the OCT 
machine being used, regardless of the presence of cysts, following an intravitreal corticosteroid 
injection (≥ 28 days following intravitreal triamcinolone injection and ≥ 90 days following 
intravitreal dexamethasone implant injection)  
 
Inclusion criterion #6 (eye level):  At request of DSMC, italicized text was added to clarify that 
eye being treated with combination therapy is equivalent to use of two IOP-lowering 
medications as follows:  Baseline intraocular pressure > 5 mm Hg and ≤ 21 mm Hg (current use 
≤2 intraocular pressure-lowering medications and/or prior glaucoma surgery are acceptable — 
note that an eye being treated with a combination therapy like Combigan is counted as being 


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treated with two IOP-lowering medications, which means, for example, that an eye treated with 
Combigan and a prostaglandin analogue is not eligible for the trial;  
 
Exclusion criterion #9 (eye level):  As recommended by the DSMC, changed “uncontrolled” to 
“severe” glaucoma as follows:  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); 
 
4.1.1 Schedule of assigned treatment and 4.1.2 Additional injections 
For intravitreal methotrexate added that additional injections are permitted as needed at weeks 4 and 
8; previously additional injection as needed at week 8 only 
4.2.3   Intravitreal methotrexate injection preparation and administration 
Removed information and reference describing the use of frozen methotrexate preparations as 
requested by CC’s IRB as reference from 1988 is out of date.   
 
4.2.4   Intravitreal ranibizumab formulation, storage, and administration 
Added:  Preparation of injection as requested by CC’s IRB 
• 
Using aseptic technique, remove contents from the vial using a 5 micron, 19 gauge filter 
needle attached to a 1-cc tuberculin syringe. Remove filter needle and replace with the 
provided 30 gauge ½ inch needle for injection.  
 
5.1 Safety reporting of adverse events – General overview 
This section was revised to reflect timeframe for DSMC Medical Safety Officer’s review of SAE reports as 
agreed upon at 8 Dec 2015 DSMC meeting.  Any SAE reports of a subject death will be sent to DSMC 
Medical Safety Officer within 24 hours of receipt at the CC.  Non-death SAE reports will be sent to the 
DSMC Medical Safety Officer within 7 days of receipt at the CC.  The DSMC Medical Safety Officer will 
review each report to determine what, if any, additional actions are needed, including whether the 
other DSMC members need to be informed of the event immediately as opposed to waiting for the next 
DSMC meeting or conference call. 
 
7.2 IRB/Protection of human subjects 
Data and safety monitoring 
• 
Corrected description of new member from “statistician” to  “experienced methodologist 
for ophthalmic studies” 
• 
Clarified that DSMC will meet at least twice a year, one of these meetings being in person 
and one by conference call and that additional meetings may be arranged at the request of 
the DSMC Chair and/or the NEI Project Officer. 
• 
Revised timeframe for and clarified that the DSMC Medical Safety Officer will review all SAE 
reports between meetings as detailed in section 5.1  
 
 
Typographical errors corrected throughout document 
 


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28 Mar 2016, version 1.1 
1.4 Investigators and study centers 
• 
Changed Principle Investigators for Washington University and University of Southern California 
• 
Deleted : Southeast Clinical Research Associates, Charlotte Eye Ear Nose &Throat Associates, 
Charlotte, NC 
• 
Added: 
− Mid Atlantic Retina, Wills Eye Hospital, Philadelphia, PA  
− Mayo Clinic, Rochester, MN 
− University of Pittsburgh Medical Center Eye Center, Pittsburgh, PA 
 
3.3 Trial schema 
• 
Revised retreatment schedule to specify required time points for retreatment if retreatment 
criteria are met and added permitted time points for retreatment 
• 
Added minimum time separation between treatments to retreatment criteria 
 
3.6 Eligibility criteria 
• 
Changed “History of infectious uveitis” from eye-level exclusion criterion to patient-level  
exclusion criterion  
• 
Added eye level exclusion: Torn or ruptured posterior lens capsule 
 
4. Study treatment: section reordered and details added for clarity 
• 
4.1 Overview section added 
• 
Preparation and administration of study treatment moved to section 5 
• 
4.2 Treatment schedule by treatment arm 
− 4.2.1 Intravitreal dexamethasone 
 
Clarified that retreatment is required at M04 if retreatment criteria met 
 
Added retreatment permitted at later time points if retreatment criteria met  
− 4.2.2 Intravitreal methotrexate 
 
Clarified that retreatment is required at M02 and M03 if retreatment criteria 
met; also at M04 
 
 Added retreatment permitted at later time points if retreatment criteria 
− 4.2.3 Intravitreal ranibizumab 
 
Clarified that retreatment is required at M04 if retreatment criteria met 
− 4.2.4 Retreatment criteria 
 
Added minimum time separation between study treatments    
 
5. Study treatment preparation and administration 
• 
Added 5.1 General Requirements to specify who is permitted to administer study treatment and 
the order of procedures for bilateral injection 
• 
5.2 added standard pre-injection procedures for all study treatments  
• 
5.4.2 added details for administration of intravitreal methotrexate 
• 
5.5.3 added details for administration of intravitreal ranibizumab 
• 
5.6 added standard post-injection procedures and monitoring for all study treatments 
 
Additionally, typographical errors were corrected throughout document. 


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2 August 2016, version 1.2 
Global changes 
• 
Maximum number of IOP lowering agents for eligibility and retreatment increased from 2 to 3 
• 
Correction of typographical errors and minor text changes for sake of brevity/clarification 
 
3.3 Trial schema 
• 
Retreatment IOP criterion modified by increasing the number of IOP-lowering meds permitted 
from ≤2 to ≤3 as in:  ≤ 25 mm Hg with ≤ 3 IOP lowering agents permitted  
• 
Minimum time before retreatment:  Added clarifications that while the minimum target time 
between injections is 12 weeks for dexamethasone and 4 weeks for methotrexate and 
ranibizumab, re-injection is permitted as early as 5 days before these targets, i.e., re-injection is 
permitted as early as 79 days since previous dexamethasone injection and 23 days since 
previous methotrexate or ranibizumab injection. 
 
3.6 Eligibility  
 
Inclusion criteria 
• 
2, 3, 5, &6  - changed “28 days” to “4 weeks” for style consistency  
• 
3- Changed time following intravitreal dexamethasone from ≥90 days to ≥12 weeks for 
consistency with exclusion criterion # 15 
• 
5 - Removed upper limit of best corrected visual acuity (BCVA) for eye-level eligibility; revised 
criterion is BCVA better than 5/200  
• 
6 - Increased the maximum number of IOP lowering medications permitted from 2 to 3 as 
follows: Baseline intraocular pressure > 5 mm Hg and ≤ 21 mm Hg (current use ≤3 intraocular 
pressure-lowering medications and/or prior glaucoma surgery are acceptable —; note  that 
combination medications, e.g., Combigan  count as  two IOP-lowering medications); 
 
Exclusion criteria 
• 
5 & 6 - changed “28 days” to “4 weeks” for style consistency 
• 
3 - Added new patient-level exclusion:  History of serous retinopathy in either eye 
• 
5 - Clarification added as italicized for exclusion: 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 (P01 visit), dose stability requirement for past 4 weeks does not apply)  
• 
15 & 16  Changed exclusion for anti-VEGF agent and intravitreal  methotrexate from 
administered in past 12 weeks to administered in past 4 weeks 
 
4.1 [Treatment] overview 
• 
Pregnancy testing required for women of childbearing potential before additional intravitreal 
injections of methotrexate or ranibizumab 
 
4.2.4 Retreatment criteria  
• 
Minimum time between treatments: reduced by 5 days as follows  
- Intravitreal dexamethasone pellet: retreatment permitted as early as 79 days 
following last treatment; “minimum target” remains 12 weeks   
- Intravitreal methotrexate:  retreatment permitted as early as 23 days; “minimum 
target” remains 4 weeks   
- Intravitreal ranibizumab:  retreatment permitted as early as 23 days; “minimum 


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target” remains 4 weeks   
5. 2 Standard pre-injection procedures for all study treatments 
• 
 Added general requirements  
- Treatment administrator and assistant wear masks during injection procedure 
- Everyone (including patient) is asked not to talk during procedure (to decrease risk of 
endophthalmitis) 
• 
In last paragraph “Examples of approaches that may be used in study participants with prior 
adverse reactions associated with povidone-iodine” removed last sentence suggesting 
investigator discuss with Protocol Chair if circumstance such that alternative approaches 
presented for use of povidone-iodine are non-viable.  
 
5.3 Administration of intravitreal dexamethasone pellet; inserted following into bulleted instructions 
• 
Mark injection site ocular surface 3.5-4.0 mm posterior to limbus 
• 
Added instruction to displace the conjunctiva with a cotton top applicator held in non-dominant 
hand prior to injection 
 
5.4.2 Administration of intravitreal methotrexate 
• 
Added clarification/specification that 19 gauge needle is a filter needle 
 
6.0 Guidelines for use of difluprednate and nepafenac ophthalmic suspension 
• 
Revised guideline for use in study eye at baseline, from “dose should not be changed” to “drug 
should be stopped”. 
 
10 May 2017, version 1.3 
 
1.4 “Investigators and study centers” changed to “Resource and clinical centers” 
• 
Replaced list of clinical centers and investigators with note that Clinical Centers and Clinic 
Directors are listed in the MERIT Manual of Procedures in keeping with the convention that 
clinical centers are not listed in the protocol for multicenter trials with more than 3 clinical 
centers.   
 
1. 5 Support 
• 
Added clarification as italicized:  Genentech will provide Lucentis and support for distribution for 
clinical centers located in the U.S. only.  
 
3.3 Trial schema 
• 
Added study definition of ME improvement:  20% decrease in central subfield thickness of the 
macula or normalization of macular thickness even if there is <20% reduction  
• 
Added footnote to emphasize that* IOP criteria for initial injection of study treatment in eligible 
eye(s) is ≤21 mm Hg with ≤3 IOP-lowering agents 
 
3.6  Eligibility criteria 
Exclusion criteria  
• 
Patient level exclusion criterion #2 changed  
 
  From 
2.  History of scleritis or keratitis of any type in either eye  
 
 


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              To 
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 #11 below.) 
3. History of keratitis (with the exception of keratitis due to dry eye)in either eye; 
• 
Eye level exclusion criterion added 
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); 
 
4.1. Treatment overview 
• 
Revised text under 3rd bullet to emphasize the different pre-injection IOP criteria for initial 
treatment vs. retreatment 
• 
Added last bullet:  Treatment according to the best medical judgment of study ophthalmologist 
is permitted as deemed necessary. Repeat injections given before the protocol specified time 
points (section 4.2.) or other deviations from the treatment protocol should be reported 
expeditiously to CC on Unanticipated Event (UA) form 
 
4.2. Study treatment schedule and re-treatment criteria and subsections 
• 
Added note for all study treatments: IOP requirements for the initial injection are the same as 
for eye eligibility for the trial. If study treatment is initiated on the same day as eligibility is 
confirmed and treatment assigned, no additional IOP measurements are needed.  If 
circumstances require patient to return to clinic for injection at a later date, IOP must be checked 
and IOP-lowering agents evaluated prior to injection. If the eligibility requirements are not met, 
the injection should not be given. If the treating ophthalmologist elects to proceed with assigned 
treatment per best medical judgment, the deviation from the protocol must be reported to CC on 
an Unanticipated Event (UA) form; the UA form should be submitted as soon as possible. 
• 
General formatting of subsections modified and information repeated for completeness and 
clarification within section, e.g., in sections 4.2.2 (intravitreal methotrexate) and 4.2.3 
(intravitreal ranibizumab) a bullet “For women of child-bearing potential, negative pregnancy 
test required before all injections” was added even though this information was already 
included in the overview section and elsewhere in protocol. 
 
5.1.2 Pre-injection IOP requirements 
Added distinction between IOP requirement before initial injection ≤21 mm Hg vs. before 
retreatment injections ≤25 mm Hg  (Although IOP for study eligibility has always been  ≤21 mm Hg 
Hg with 3 or fewer IOP-lowering agents, this revision of the protocol explicitly states that  IOP 
criteria ≤21 mm Hg with 3 or fewer IOP-lowering agents need to be met before the initial study 
treatment  (as in cases when the initial study treatment is not administered on the day of 
enrollment but on a later date.) 
  
5.4 Intravitreal methotrexate preparation and administration 
5.4.1 Preparation of [intravitreal methotrexate] injection by research pharmacy 
• 
2 - clarified Sterile Water for Injection is to be preservative free  
• 
3  
- 
Added more detail to instruction for clarity and note that pharmacist may place 
appropriate administration needle on the syringe instead of a syringe cap 


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- 
Added clarification regarding volume fill: Volume fill – syringe fill of 0.5 mL is guideline.  
If research pharmacy’s existing label/practice is to fill syringe with alternative amount, 
e.g., 0.4 mL, this practice is acceptable as it will not affect the volume (0.1 mL) or dose 
injected. 
• 
4 – Changed parenthetical from (dose=2 mg) to (0.5 mL=2 mg) 
• 
Changed “filtered needle” to “filter needle” throughout 
 
5.4.2 Administration of intravitreal methotrexate 
• 
Second bullet  
- 
Deleted first subpoint (Drawing 0.2 mL into syringe…) 
- 
Revised new first (previously second) subpoint for clarity 
- 
Next subpoint  - changed 100 μL to 0.1 mL 
- 
Added needle specifications – 30 or 32 gauge ½ inch needle 
 
5.5.3   Administration of intravitreal ranibizumab (Lucentis) 
• 
Second bullet,  
- 
Second subpoint - Changed “filtered needle” to “filter needle”; revised to allow range of 
needle gauge (30 or32), specify length of needle (1/2 inch) and deleted sentence:  A 32-
gauge needle may be used in place of the 30-gauge needle, if preferred. 
- 
Third subpoint:  following “plunger advanced to” 50 μL was deleted and parentheses 
around 0.05 mL removed  
Global:  minor edits in reference to changes above and formatting and spelling corrections 
 
18 July 2017, version 1.4 
 
Abstract 
Added recurrent as italicized below 
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 for persistent or recurrent macular edema. 
 
1.8  Rationale for trial 
Added recurrent macular edema to rationale for trial as indicated in italics below 
The goal of the MERIT Trial is to compare the relative effectiveness of a repeat corticosteroid 
injection for persistent or recurrent macular edema in eyes with controlled inflammation (the 
current standard approach), versus each of the alternative non-corticosteroid modalities 
(intravitreal ranibizumab or intravitreal methotrexate) for the treatment of uveitic macular 
edema that is persistent or recurrs after an intravitreal corticosteroid injection. 
 
2. 1 Objective  
Added recurrent as italicized below 
 The MERIT Trial was designed to find out which intravitreal therapy offers the best balance of 
effectiveness and tolerability in treating persistent or recurrent uveitic macular edema in eyes 
with controlled uveitis, specifically by comparing the relative efficacy and safety of intravitreal 
ranibizumab (Lucentis®) and intravitreal methotrexate to intravitreal dexamethasone implant 
(Ozurdex®) for the treatment of persistent or recurrent uveitic macular edema. 
 
 


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2.2 Hypotheses 
Added recurring as italicized below 
(1) Intravitreal injections of methotrexate will have greater efficacy than intravitreal 
injections of the dexamethasone pellet as a treatment for uveitic macular edema 
persisting or recurring after treatment with an intravitreal corticosteroid injection. 
  
(2) Intravitreal injections of ranibizumab will have greater efficacy than intravitreal 
injections of the dexamethasone pellet as a treatment for uveitic macular edema 
persisting or recurring after treatment with an intravitreal corticosteroid injection. 
 
3.3  Trial schema 
Revised retreatment criteria 
From   
Eye does not meet ME improvement definition (20% decrease in central subfield thickness of 
the macula or normalization of macular thickness even if there is <20% reduction) OR ME 
worsens at the specified time point OR eye has achieved normal central subfield thickness but 
with cystoid spaces in the 1 mm central subfield  
To  
Central subfield thickness greater than 1.1X 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 
 
3.6 Eligibility criteria : modified inclusion criterion (eye-level) #3 replacing “an” with “most recent” as 
follows: 
(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 most recent intravitreal corticosteroid injection (≥ 4 
weeks following intravitreal triamcinolone injection or ≥ 12 weeks following intravitreal 
dexamethasone implant injection); 
 
4.2.4   Retreatment criteria  
 Revised retreatment criteria  
From  
Macular edema status is one of the following  
- ME does not meet the improvement definition (a 20% decrease in central subfield 
thickness of the macula or normalization of macular thickness even if there is <20% 
reduction)  
- ME worsens at the specified time point 
- Eye has achieved normal central subfield thickness but with cystoid spaces in the 1 mm 
central subfield  
To 
Macular edema warrants retreatment if one or both of the following criteria are present: 
- Central subfield thickness greater than 1.1X upper limit of normal (330 µm for Zeiss and 
Topcon SD OCT and 352 µm for Heidelberg OCT)  
- Cystoid spaces within 1 mm central subfield 
 
7.1 Possible side effects and complications of dexamethasone 
Added:  Patients with diabetes could experience a transient elevation in blood glucose  
 


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10.  Added section: Efficacy monitoring and stopping guidelines 
 
11.2   IRB/Protection of human subjects – Data and safety monitoring 
• 
Arrangement and wording in 3rd paragraph revised for readiblity  
• 
Information on interim effectiveness analysis added to 3rd paragraph 
 
Global edits 
• 
Typographical errors corrected throughout 
• 
Added “or recurrent”; “/recurrent” as applicable throughout  
 
 
23 January 2018 and 16 February 2018*, version 1.5 
*JHSPH IRB reviewed 23 Jan version and requested 2 small changes to MTX prep (deletion of “filter” 
needle which had been inadvertently included and of requirement for IVA seal on syringe) which were 
made and revision date changed to 16 Feb 2018. 
 
Title page 
Dr. Holbrook’s title and address were updated 
3.3 Trial schema  
Retreatment at M04 if retreatment criteria met changed from required to permitted at M04 for all 
treatment arms 
 
3.6 Eligibility criteria  
The numbering of the inclusion criteria, which had started with 6 instead of with 1, was corrected 
4.2  Study treatment schedule and retreatment criteria 
4.2.1  Added new subsection: Table of study treatment schedule by treatment assigned and study 
visit  
4.2.2 Intravitreal dexamethasone pellet, 0.7 mg (Ozurdex) 
4.2.3 Intravitreal methotrexate, 400 µg in 0.1 mL  
4.2.4 Intravitreal ranibizumab (Lucentis), 0.5 mg in 0.05 mL 
• 
These subsections were renumbered to accommodate addition of section 4.2.1 and reorganized 
to list treatment requirements/options by study visit, i.e.,  M01, M02, M03, and 
M04/subsequent visits, to improve clarity 
• 
The treatment schedule for the M04 study visit was changed from required if retreatment 
criteria met to permitted if retreatment criteria met and the following clarification added: 
If there has been evidence of a treatment benefit but a participant meets retreatment 
criteria at the M04 visit, the participant should be encouraged to continue the assigned 
treatment. However, the participant may be treated according to the best medical 
judgment of the study ophthalmologist at the M04 and subsequent visits. 
 
5.2   Standard pre-injection procedures for all study treatments 


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The requirement for use of a sterile eyelid speculum was changed to:  Retract the eyelids and 
lashes away from the injection site and needle for the duration of the procedure (use of an eyelid 
speculum is optional) 
5.3 Administration of intravitreal dexamethasone pellet (Ozurdex) 
5.4.2 Administration of intravitreal methotrexate 
5.5.3 Administration of intravitreal ranibizumab (Lucentis) 
Under the first bullet in each of these sections, the italicized text was added:  use…of a sterile eyelid 
speculum or equivalent, i.e., retraction of the eyelids and lashes from the injection site 
5.4.1   Preparation of injection by pharmacy 
Replaced compounding instructions based on University of Illinois/Chicago, Eye Infirmary 
Pharmacy, March 18, 2008 with compounding instructions based on Bascom Palmer Eye Institute 
Department of Pharmacy Extemporaneous Compounding Record for Methotrexate 400 mcg/0.1 mL 
Intravitreal Injection, 24 May 2016.  The main differences are summarized in table below. 
 
*Based on USP 797, this is a low-risk compound; use of a 0.22 micron filter is not necessary to prepare a compound from 2 
sterile solutions. 
 
6.  Guidelines for use of topical corticosteroids and NSAIDS 
• 
Changed from “Guidelines for use of difluprednate and nepafenac ophthalmic suspension” to 
the more general “Guidelines for use of topical corticosteroids and NSAIDS” 
• 
Old guidelines: Difluprednate (Durezol®) and nepafenac ophthalmic suspension (Nevanac®) 
should not be introduced as treatment during trial;  If participant is using either drug in study 
eye(s) at baseline, it should be stopped at baseline. 
• 
New guidelines for topical corticosteroids (new subsection 6.1) 
- In general should not be introduced during the trial 
- If used at baseline (M01), maintain current dose except as follows 
° 
Tapering and/or discontinuing for medical issues, e.g., elevated IOP or rapidly 
progressing cataract 
° 
Transient increase in dose to treat recurrence of anterior segment inflammation 
• 
New guidelines for topical non-steroidal anti-inflammatory drugs 
Summary of changes to MTX compounding instructions, MERIT protocol version 1.4 to 1.5 
  
Protocol versions 1.4 and earlier 
(Reference: Eye Infirmary Pharmacy 
University of Illinois/Chicago, 2008) 
Protocol version 1.5 
(Reference: Bascom Palmer Eye Institute 
University of Miami, 2016)                  
0.22 micron filter 
Required  
Not required* 
Diluent  
Preservative-free sterile water for 
injection  
Preservative-free sodium chloride 0.9% 
solution 
Storage temperature 
Not specified 
2-8 ◦C 
Beyond use date 
8 hours 
24 hours 


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- In general should not be introduced during the trial 
- If used at baseline (M01), maintain current dose except if tapering and/or 
discontinuation required for medical reason, e.g., corneal melting  
Global edits 
• 
Typographical and formatting errors were corrected. 
 
16 March 2018, version 1.5 
3.3 Trial schema 
4.2 Study treatment schedule and re-treatmenet criteria 
4.2.2 Intravitreal dexamethasone 
Retreatment schedule for the dexamethasone arm revised as follows: 
• 
Changed from earliest retreatment permitted at 12 weeks (M04) if retreatment criteria met to 
retreatment required at 8 weeks (M03) if retreatment criteria met. 
• 
Minimum target for retreatment changed from 12 weeks to 8 weeks; earliest permissible 
retreatment changed from 79 to 51 days after previous treatment 
11.2 IRB/Protection of human subjects 
• 
Under Data and Safety Monitoring Committee removed the description of a voting member with 
expertise in medical ethics. The medical ethicist resigned from the committee in 2017 citing 
increase in institutional responsibilities.  
 
Non-substantive changes 
• 
 Global replacement of  “re-treatment” with “retreatment” 
• 
Section 4.2 and subsections minimal and minor wording changes for consistency and clarity 
Corrections of typographical and formatting errors throughout 
 
11 April 2019, version 1.6 
  
Cover 
Added Clinical Trials Registry – India  
 
1.4 Resource centers 
Added relocation information for Chairman’s Offcie as of 1 Aug 2019 
 
3.5  Secondary outcomes 
Revised secondary outcomes to reflect the outcomes planned for inclusion in the manuscript reporting 
the primary results 
• 
Added rate of IOP elevation of ≥24 mm Hg and ≥ 30 mm Hg; removed rate of IOP elevation of 
>21 mm Hg 


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• 
For resolution of macular edema, changed the criteria for normalization of macular thickness 
from “to within +2 standard deviations of the normative mean for the OCT machine used” to 
“<260 um on the standard scale” 
• 
Removed the following outcomes and associated references 
- 
Inflammation graded using semi-quantititive scales  
- 
New onset posterior subcapsular (PSC) cataract or progression of pre-existing PSC (using 
the Age-Related Eye Disease Study [AREDS] scheme 
- 
Cost effectiveness 
- 
Visual function related quality of life 
 
5.4.1   Preparation of [methotrexate] injection by pharmacy 
Added italicized text: If an alternative preparation of methotrexate (i.e., alternative 
compounding procedure, storage conditions or beyond use date) is to be used, it must be 
reviewed by the MERIT Protocol Chairs and/or Executive Committee and approved by the clinic’s 
governing IRB 
 
5.5.1  Formulation of ranibizumab   
Added a note that the volume fill for the ranibizumab vials donated by Genentech for U.S. 
clinical centers was changed from 0.3 mL to 0.23 mL beginning with the drug distributed in 
August 2018 but the vial size (0.3 mL) did not change. 
10.  Efficacy monitoring and stopping guidelines  
The  time point for the single pre-planned interim efficacy was changed from once 50% to 40%  
of participants have completed the 12-week visit (the primary outcome time-point).  The type I 
error thresholds were adjusted accordingly to 0.00016  (from 0.00082) at the interim analysis 
and 0.02484 (from0.02418) at the final analysis, maintaining a global 0.025 error rate over the 
course of the trial based upon O’brien-Fleming boundaries. 
11.1  Recruitment and informed consent procedures 
Revised description of clinical centers from “the majority of which are in the US and 3 are 
international (Melbourne, Australia; London, England, UK; Montreal, Canada)”  to “located in 
the United States, United Kingdom, Australia, Canada, and India”.   
 
16 December 2019, version 1.7 
 
5.5 Intravitreal ranibizumab (Lucentis( formaulaiton, storage, and administration 
Added that ranibizumab 0.5 mg dose prefilled syringe may be used; previously the protocol 
referred to only ranibizumab vials because the ranibizumab donated by Genentech for U.S. 
clinical centers was in vials.  
 


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8.4.7 Product complaints 
Added new section addressing reporting requirement for any product complaints for study treatments.   
 
 
20 August 2020, version 1.8 
 
3.6 Eligibilty criteria, patient-level inclusion criteria 
Deleted criterion numbered 4: Baseline fluorescein angiogram that, as assessed by the study 
ophthalmologist, is gradable for degree of leakage in the central subfield 
 
3.8 Data collection table 
Deleted the following: 
• 
Fundus reflex images (for phakic eyes) at M01 and M07 
• 
Fluorescein angiogram at M01 
 
 
 


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Abstract 
 
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 or recurrent 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 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 for persistent or recurrent macular edema.  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.  Secondary outcomes are:  improvement of macular 
edema based upon the MUST-accepted definition of ME improvement; resolution of macular edema 
based on the MUST-accepted definition of ME resolution (i.e., return to normative mean +/-2 standard 
deviations of the central subfield measurement); improvement in best corrected visual acuity; adverse 
events (i.e., cataract and IOP elevation); cost-effectiveness. 
 
 


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Contents 
Document distribution ........................................................................................................... 2 
Document revision history .................................................................................................... 3 
Abstract ...............................................................................................................................16 
1. Introduction ...................................................................................................................20 
1.1. Title  ....................................................................................................................20 
1.2. IND  ....................................................................................................................20 
1.3. Financial sponsor .................................................................................................20 
1.4. Resource and clinical centers ...............................................................................20 
1.5. Support .................................................................................................................20 
1.6. Background and significance ................................................................................20 
1.7. Preliminary studies ...............................................................................................28 
1.8. Rationale for trial ..................................................................................................29 
2. Objective and study hypothesis .....................................................................................30 
2.1. Objective ..............................................................................................................30 
2.2. Hypotheses ..........................................................................................................30 
3. Design ...........................................................................................................................31 
3.1. Type of study ........................................................................................................31 
3.2. Treatment arms ....................................................................................................31 
3.3. Trial schema .........................................................................................................32 
3.4. Primary outcome ..................................................................................................33 
3.5. Secondary outcomes ............................................................................................33 
3.6. Eligibility criteria ....................................................................................................34 
3.7. Randomization .....................................................................................................35 
3.8. Data collection schedule .......................................................................................36 
4. Treatment schedule.......................................................................................................37 
4.1. Overview ..............................................................................................................37 
4.2. Study treatment schedule and retreatment criteria ...............................................38 
4.2.1. Table:  Study treatment schedule by treatment assigned and study visit ..............38 
4.2.2. Intravitreal dexamethasone pellet, 0.7 mg (Ozurdex) ............................................38 
4.2.3. Intravitreal methotrexate, 400 µg in 0.1 mL ...........................................................39 
4.2.4. Intravitreal ranibizumab (Lucentis), 0.5 mg in 0.05 mL ..........................................39 
4.2.5. Retreatment criteria and pre-injection IOP requirements ......................................40 
4.2.6. Minimum time between treatments .......................................................................40 


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4.3. Treatment failures ................................................................................................40 
5. Study treatment preparation and administration ............................................................41 
5.1. General requirements ...........................................................................................41 
5.1.1. Study treatment administrator ...............................................................................41 
5.1.2. Pre-injection IOP requirements .............................................................................41 
5.1.3. Bilateral study eye injections – order of procedures ..............................................41 
5.2. Standard pre-injection procedures for all study treatments ...................................41 
5.3. Administration of intravitreal dexamethasone pellet (Ozurdex) .............................42 
5.4. Intravitreal methotrexate injection preparation and administration ........................44 
5.4.1. Preparation of injection by  pharmacy ...................................................................44 
5.4.2. Administration of intravitreal methotrexate ............................................................44 
5.5. Intravitreal ranibizumab (Lucentis) formulation, storage, and administration .........45 
5.5.1. Formulation of ranibizumab ..................................................................................45 
5.5.2. Storage of ranibizumab ........................................................................................45 
5.5.3. Administration of intravitreal ranibizumab (Lucentis) .............................................46 
5.6. Standard post-Injection procedures/monitoring for all study treatments ................46 
6. Guidelines for use of topical corticosteroids and NSAIDs ..............................................47 
6.1. Topical corticosteroids ..........................................................................................47 
6.2. Topical non-steroidal anti-inflammatory drugs ......................................................47 
7. Possible side effects and complications of study treatments .........................................48 
7.1. Intravitreal dexamethasone ..................................................................................48 
7.2. Intravitreal methotrexate .......................................................................................48 
7.3. Intravitreal ranibizumab ........................................................................................48 
7.4. Intravitreal injection...............................................................................................49 
8. Safety reporting of adverse and other events ................................................................50 
8.1. General overview .................................................................................................50 
8.2. Assessment of Safety ...........................................................................................50 
8.2.1. Specification of Safety Variables ..........................................................................50 
8.2.2. Adverse Events ....................................................................................................50 
8.2.3. Serious Adverse Events .......................................................................................51 
8.3. Methods and timing for assessing and recording safety variables ........................51 
8.3.1. Adverse Event Reporting Period ...........................................................................51 
8.3.2. Assessment of Adverse Events ............................................................................51 
8.4. Procedures for eliciting, recording, and reporting adverse events .........................52 
8.4.1. Overview ..............................................................................................................52 


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8.4.2. Diagnosis vs. Signs and Symptoms ......................................................................52 
8.4.3. Deaths ..................................................................................................................53 
8.4.4. Preexisting Medical Conditions .............................................................................53 
8.4.5. Hospitalizations for Medical or Surgical Procedures .............................................53 
8.4.6. Pregnancy ............................................................................................................53 
8.4.7. Product complaints ...............................................................................................53 
8.4.8. Post-Study Adverse Events ..................................................................................54 
8.4.9. Reconciliation .......................................................................................................54 
8.4.10. 
AEs of Special Interest (AESIs) ...................................................................54 
8.4.11. 
SAE Reporting .............................................................................................54 
8.4.12. 
CC event reporting to Genentech ................................................................55 
8.5. MedWatch 3500A Reporting Guidelines ...............................................................55 
8.6. Additional Reporting Requirements for IND Holders .............................................56 
8.7. Study Close-Out ...................................................................................................57 
9. Sample size and statistical methods ..............................................................................59 
9.1. Sample size, power and detectable differences ....................................................59 
9.2. Statistical methods ...............................................................................................59 
10. Efficacy monitoring and stopping guidelines ..................................................................61 
11. Regulatory and ethical issues ........................................................................................62 
11.1. Recruitment and informed consent procedures ....................................................62 
11.2. IRB/Protection of human subjects .........................................................................62 
12. References ....................................................................................................................64 
 


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1. Introduction 
 
1.1. 
Title 
Macular Edema Ranibizumab v. Intravitreal anti-inflammatory Therapy (MERIT) Trial  
 
1.2. 
IND  
IND 119247 
 
Sponsor-investigator 
Janet T. Holbrook, PHD, MPH, Director Coordinating Center 
Johns Hopkins University Bloomberg School of Public Health 
Baltimore, MD 
  
1.3. 
Financial sponsor 
National Eye Institute U10EY024526 
 
1.4. 
Resource and clinical centers 
 
Resource centers 
 
 
Center 
 
Director 
 
Chairman’s Office 
 
Icahn School of Medicine at  Mount Sinai ,New York, NY* 
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD† 
  * Through 31 Jul 2019 
  † As of 1 Aug 2019 
 
Douglas A. Jabs, MD, MBA 
 
Coordinating Center  
 
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 
 
Janet Holbrook, PhD, MPH 
Reading Center 
 
University of Wisconsin at Madison, Madison, WI 
 
 
Michael Altaweel, MD 
Clinical Centers and Principal Investigators are included in the MERIT Manual of Procedures 
 
 
1.5. 
Support 
Genentech will provide Lucentis® (Ranibizumab 0.5 mg per 0.05 mL) for clinical centers in the 
U.S. only and support its distribution to those clinical centers.  
 
1.6. 
 Background and significance 
The uveitides consist of over 30 diseases characterized by intraocular inflammation.1  Each of 
these diseases has its own features, course, treatments, and prognosis.  Traditionally these 
diseases have been grouped by the primary site of inflammation as: 1) anterior uveitis (cells in 


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the anterior chamber); 2) intermediate uveitis (cells in the vitreous); 3) posterior uveitis 
(chorioretinal inflammatory lesions); and 4) panuveitis (inflammation in the anterior chamber, 
vitreous and the choroid/retina).  Visual loss typically occurs due to structural complications of 
the uveitis, such as macular edema, cataract, glaucomatous optic neuropathy, epiretinal 
membrane formation, retinal neovascularization, and choroidal neovascularization. The 
frequency of visual impairment (generally defined as worse than 20/40) and blindness (generally 
defined as 20/200 or worse2) vary depending on the class of the uveitis and the specific uveitic 
disease.  Among patients with anterior uveitis 19% will have visual impairment in at least one 
eye, whereas among patients with panuveitis as many as 59% may have visual impairment in at 
least one eye.5  Uveitis is the 5th or 6th leading cause of blindness in the United States3, 4 and 
accounts for ~10% of all blindness in the United Kingdom (Lightman, S, personal 
communication).  Because the uveitides affect all ages, including children, they have a much 
greater potential for causing years of potential vision lost than age-related diseases.  Estimates 
suggest that the cost of managing uveitis is on par with that of managing diabetic macular 
edema.6  As such, the uveitides and their management represent a substantial health problem.  
 
Management of Uveitis 
The initial treatment approach to a given non-infectious uveitis depends on the anatomic class:  
anterior uveitis is treated with topical corticosteroids; intermediate uveitis often is treated initially 
with regional corticosteroid injections; and posterior and panuveitides often are treated with 
systemic corticosteroids and depending on the specific disease immunosuppressive agents.1, 7  
Even when systemic agents are used, regional corticosteroid injections often are used as 
supplemental therapy for persistent or recurrent macular edema, after the evident inflammation 
is controlled.  The fluocinolone acetonide implant (Retisert®, Bausch & Lomb, Tampa, FL) is an 
alternative to systemic therapy that is similar to systemic therapy in terms of visual acuity 
outcomes, controls the inflammation better than systemic therapy, but has higher rates of ocular 
corticosteroid side effects, such as cataract and ocular hypertension.  The implant may have a 
particular role for patients poorly tolerant of systemic medications and those in whom systemic 
therapy does not adequately control the intraocular inflammation.3   Appropriate management of 
uveitis and its complications improve outcomes. Several studies have shown that control of 
inflammation results in better visual outcomes8-11 and that better control of structural 
complications, such as macular edema, is also associated with better visual outcomes.12, 13  As 
such, the proper management of uveitis and its complications is critical to maintaining/improving 
visual acuity among patients with uveitis.   
Macular edema is the most common structural complication of uveitis and the leading cause of 
visual loss in patients with uveitis.5, 14, 15 In the MUST Trial, macular edema was present in 
approximately 40% of eyes with uveitis on enrollment with a similar frequency for patients with 
intermediate uveitis, posterior uveitis, and panuveitis.16-18 A retrospective study from two uveitis 
referral centers in the Netherlands reported a similar proportion with uveitic macular edema 
(40%) and that macular edema accounted for 41% of visual impairment.5  Although some 
patients with intermediate uveitis (~25%) do not develop structural complications and do not 
need treatment, the presence of macular edema is the most common indication for treatment 
among these patients.19, 20  Among patients with intermediate uveitis (e.g. pars planitis), a 
stepped approach is used in which regional corticosteroid injections (either periocular or 
intravitreal) are the first approach typically chosen.20, 21  Control of macular edema and 
preservation of visual acuity can be accomplished with regional corticosteroid injections only in 
30 to 50% of patients who need treatment.  For patients treated with systemic agents, including 
those with posterior uveitis and panuveitis, approximately 50% of eyes with uveitic macular 
edema will have incomplete resolution of the edema (i.e. have “persistent macular edema”) 
despite apparent control of inflammation (defined as no inflammatory cells present in the 


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anterior chamber or vitreous and control of the chorioretinal inflammatory lesions), and these 
patients will require supplemental therapy for the macular edema.  Regional (periocular or 
intravitreal) corticosteroid injections typically are used as supplemental therapy in these 
cases.14, 15, 22-25  The proper management of uveitic macular edema is critical for the 
preservation of good visual acuity in patients with uveitis. 
Uveitic Macular Edema      
The pathophysiology of macular edema associated with uveitis is thought to be a consequence 
of increased vascular permeability from mediators released by inflammatory cells resulting in 
damage to the function of the vascular endothelium, retina, and retinal pigment epithelial cells 
and the subsequent accumulation of fluid into the macula, characteristically distributed in the 
outer plexiform layer of the retina.26  Exactly which mediators are critical in the pathogenesis of 
inflammatory macular edema is incompletely understood.  Corticosteroids have been the first 
line of treatment for noninfectious uveitis in general and of inflammatory macular edema in 
particular.  Corticosteroids inhibit the phospholipase A2 pathway, interfere with the release of 
inflammatory mediators, and decrease vascular endothelial growth factor (VEGF) secretion.27, 28  
Models of experimental autoimmune uveoretinitis in rats and studies in humans with uveitis and 
macular edema show an increased concentration of VEGF in the aqueous humor.29-32  VEGF is 
suspected to play a role in the loss of vascular integrity in the eye and is known to be induced 
by inflammatory cytokines, such as interleukin (IL)-1 and IL-6, which have been found to be 
elevated intraocularly among patients with uveitis.32, 33  Furthermore, aqueous VEGF 
concentrations are significantly higher in those patients with uveitic macular edema than those 
without uveitic macular edema.30  The recent use of intravitreally administered nonsteroidal 
medications with anti-inflammatory activity for the treatment of inflammatory macular edema, 
such as methotrexate, and those which inhibit VEGF activity, such as ranibizumab, offers 
potentially effective alternative treatment approaches to macular edema in this population and 
might obviate the well-known ocular side effects of corticosteroid-based therapies. 
Therapeutic options for uveitic macular edema  
The management of uveitic macular edema initially is directed toward treatment of the 
underlying inflammation with appropriate medical therapy.  Control of the inflammation often 
results in resolution of the macular edema.  Regional corticosteroid injections control the 
intraocular inflammation, as well as treating the macular edema, which is why they are the initial 
therapy for 30-50% of patients with intermediate uveitis who need treatment.  For posterior and 
panuveitis, initial therapy typically is oral corticosteroids with immunosuppression as indicated.  
Because smoking appears to increase the risk of macular edema among those with uveitis, 
smoking cessation typically is advocated.26, 34, 35  For those patients with persistent or recurrent 
macular edema, despite control of the evident inflammation, supplemental proposed medical 
treatments include regional corticosteroid injections, topical and oral nonsteroidal anti-
inflammatory drugs (NSAIDs), oral acetazolamide36, 37, intravenous infliximab infusions38, 
subcutaneous interferon-α39-41, and intravitreal injections of VEGF inhibitors, such as 
ranibizumab42.  Intravitreal methotrexate (MTX), an antimetabolite with apparent efficacy when 
systemically administered,8, 11 also has been used in pilot studies for refractory uveitis and 
persistent macular edema.26, 43-46  Regional injections of corticosteroids are the most frequently 
used treatments specifically for uveitic macular edema.  Corticosteroid injections reduce 
macular edema and improve vision, but the effect has a variable duration.47, 48  Pars plana 
vitrectomy or vitrectomy in combination with intravitreal corticosteroids have been investigated 
as treatment options for inflammatory macular edema unresponsive to medical therapy; 
however, the impact of this intervention is not clear, and a systematic review concluded that the 
efficacy of this treatment remains unproven.49, 50  The frequently persistent/recurrent nature of 
uveitic macular edema, its impact on visual function, and the plethora of potential treatments 


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with limited data supporting their use underscore the need to identify effective therapeutic 
options and have high quality evidence to support management choices.   
Regional injections can be given periocularly or intravitreally.  For periocular injections both 
triamcinolone acetonide and the “depo” preparation of methylprednisolone (Depo-Medrol®, 
Pharmacia and Upjohn Company, Division of Pfizer, New York, NY) have been used, and the 
injections may be given as a posterior, superior sub-Tenon’s injection (PST) or as an orbital 
floor injection (also known as a retrobulbar injection).24, 25, 51-63  With respect to periocular 
injections, available nonrandomized, but comparative, data suggest similar success rate with 
both approaches.64-66  With respect to the choice of drug, triamcinolone acetonide is used more 
often, as it is better tolerated if there is inadvertent intraocular injection.  For intravitreal 
injections, initial studies were performed with the Kenalog® (Bristol-Myers Squibb, Princeton, 
NJ) preparation of triamcinolone acetonide, but more recently a preservative-free preparation of 
triamcinolone has been developed for intraocular use (Triesence) and is US Food and Drug 
Administration (FDA) approved for this approach.  The estimated pharmacologic effect of a 
regional corticosteroid injection of triamcinolone, whether given by the periocular or intravitreal 
route, is approximately 3 months, although the duration of benefit in some patients with uveitis 
may be longer. The dexamethasone intravitreal pellet appears to have a pharmacologic effect 
for 5 months and is US FDA approved for the treatment of uveitis.  Although periocular and 
intravitreal injections of triamcinolone are commonly used for uveitic macular edema, there is 
regional and specialty (retina specialists vs. uveitis specialists) variation in their use without any 
comparative studies to guide the choice.  Similarly, there have been no comparative studies of 
intravitreal triamcinolone to the intravitreal dexamethasone pellet.  
Periocular corticosteroid injections:  A retrospective study from the Johns Hopkins Medical 
Institution of 126 patients (156 eyes) with uveitic macular edema who received a single 
periocular injection of corticosteroid reported clinical resolution of macular edema in 53% and 
57% of eyes at one month and three months after the injection, respectively.67  Of the 83 eyes 
that had resolution of macular edema at one month, 40% had recurrence of the macular edema 
at three months.  Of the eyes with persistent macular edema at one month, 40 eyes were 
treated with additional periocular injections, with an additional ~60% of those eyes having a 
clinical response one month later, for an overall success rate of approximately 80%.  Overall, a 
3-line improvement in visual acuity was observed in 52% at one month and in 57% at three 
months.  Side effects attributed to periocular corticosteroid injections included a rise in 
intraocular pressure (IOP) to >30 mm Hg in 19% (rate = 0.14/eye-year [EY]), newly diagnosed 
cataract in 10% (rate = 0.13/EY), and ptosis in 14% (rate = 0.09/EY).  Another similarly-sized 
retrospective study (159 eyes) evaluating PST injections of triamcinolone for uveitic macular 
edema reported that a single injection posed a similarly low risk of IOP elevation and cataract 
progression over a mean follow-up period of 12 months; however these side effects increased 
with repeated injections.68  As such, a single periocular injection of triamcinolone appears to be 
effective in ~50% of patients, and a second injection to have additional benefits.  Nearly all the 
benefit was detected by one month after the injection with limited additional benefit over the 
ensuing two months.  These data suggest that one month after a regional injection is a 
reasonable time frame for assessing the response to therapy. 
Intravitreal corticosteroids:  A retrospective case series from Moorfields Eye Hospital in London 
of 54 patients (65 eyes) evaluated intravitreal triamcinolone in patients with uveitic macular 
edema.55  Uveitic macular edema and visual acuity improved in 83% of eyes with a mean 12-
letter gain (2.4 lines) in best corrected visual acuity after a mean follow-up of 8 months. The 
most important side effect was raised IOP; 43% of eyes experienced an IOP rise >10 mm Hg.  
Although not strictly comparable, these data suggest that intravitreal triamcinolone may be 
superior to periocular triamcinolone for the treatment of uveitic macular edema, but that the 


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frequency of elevated IOP may be greater.  Similarly, a non-randomized, historically controlled 
study comparing the ocular side effects of periocular triamcinolone to intravitreal triamcinolone 
for macular edema from various causes demonstrated a significantly increased frequency of 
IOP> 30 mm Hg and the more frequent need for anti-glaucoma medication among the 
intravitreal-treated eyes.69  Studies of intravitreal triamcinolone for persistent macular edema 
after systemic therapy controls the evident inflammation, including those from Moorfields Eye 
Hospital, suggest clinical resolution of the macular edema in 85% of eyes.  Collectively, these 
data suggest that the intravitreal route may be more effective than the periocular route for the 
management of uveitic macular edema, but that the intravitreal route may be associated with a 
greater rate of ocular corticosteroid side effects.26,55,62,63  The major limitation of intravitreal 
triamcinolone are its corticosteroid-related adverse ocular effects.  The frequency of cataract 
development has been reported to range from 15-30% after a single injection70-73 and increase 
with repeated injections.74, 75  Corticosteroid-induced IOP elevations have been reported to 
occur in 25% to 45% of patients55, 70-72, 76 are dose dependent77, 78 and may be more frequent 
among children.47  In most instances, elevated IOP is transient and may be controlled with anti-
glaucoma medications.58, 79  Although the long-term prognosis of uveitic macular edema treated 
with repetitive intravitreal triamcinolone is uncertain, a recent report demonstrated improved 
best corrected visual acuity with no evidence of tachyphylaxis to repeated intravitreal injections 
of triamcinolone and no evidence of increased rates of IOP elevation after the first injection.  
However, cataract progression requiring surgery was seen in all phakic patients by the fifth 
injection.80   
In an effort to address the limited duration of action of intravitreal triamcinolone, sustained 
release implants have been developed and approved by the FDA, including the dexamethasone 
implant, Ozurdex.  This implant is a copolymer containing dexamethasone, lactic acid and 
glycolic acid, which releases dexamethasone over a six month period as it degrades slowly into 
carbon dioxide and water.  It is administered as an office based injection into the vitreous 
cavity.81-87  The safety and efficacy of a single intravitreal injection of two dexamethasone pellet 
doses (0.7mg and 0.35mg) was reported from the HURON study, a 26-week, phase III, 
prospective, multicenter, masked, sham injection-controlled, randomized clinical trial among 229 
patients with noninfectious intermediate or posterior uveitis.88  Patients were randomized 1:1:1 
to receive the higher-dose (0.7mg) pellet, the lower-dose (0.35mg) pellet, or a sham injection.  
The primary outcome was control of vitreous inflammation.  Although both implant doses were 
shown to be effective in controlling vitreous inflammation and in improving visual acuity, the 
higher dose implant proved to have a longer duration of action without a significant increase in 
untoward ocular side effects and is the dose currently in clinical use. At 8 weeks after injections, 
43% of treated eyes versus 7% in the sham group had at least a 15-letter improvement from 
baseline best corrected visual acuity, and the proportion of eyes achieving this level of 
improvement was 2- to 6-fold greater in the dexamethasone pellet groups as compared to the 
sham group at each visit throughout the study period.  Evaluation of macular edema was 
performed with time-domain OCT, and there was a significant decrease in the mean macular 
thickness for both treatment groups (-99 µm for the higher-dose group and -91 µm for the lower-
dose group) when compared to the sham-treated group -12 µm, P<0.004) at the eight-week 
visit.  The proportion of eyes with improvement and/or resolution of the macular edema were not 
reported.  The percentage of eyes with IOP ≥25 mm Hg peaked at 7.1% for the higher-dose 
implant group, 8.7% for the lower- dose implant group, and 4.2% for the sham-treated group.  At 
26 weeks, there was no statistically significant difference in the occurrence of cataract among 
groups (15% higher-dose, 12% lower-dose, and 7% sham-treated) with no patient requiring 
cataract surgery.  However, patients with a history of an elevated IOP related to topical or 
regional injection corticosteroids were excluded from this study, so the comparative rate of IOP 
elevation vs. intravitreal triamcinolone is uncertain.  Subsequent small, retrospective case series 


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also reported that the dexamethasone pellet was effective in treating noninfectious posterior 
uveitis with outcomes including decreased inflammatory activity, improved visual acuity, and an 
improvement in macular edema as evidenced by a reduction in mean central retinal thickness 
on optical coherence tomography (OCT).  However, these studies suggest that the duration of 
effect may be shorter (3-4 months) in clinical practice than that reported in the HURON trial.89-91 
Although the side effect profile of the dexamethasone pellet appears to be superior to that of 
intravitreal triamcinolone, the study design of the HURON trial limits the ability to compare 
results. 
Differing methodologies and different enrollment criteria substantially hamper comparing the 
data from these different studies.  One of the most substantial differences is the methodology 
used to evaluate macular edema.  Clinical estimates of macular edema improvement are 
heavily influenced by visual acuity improvement and may overestimate the resolution rate and 
the apparent efficacy of interventions on macular edema.  Fluorescein angiography and OCT 
measure somewhat different aspects of macular edema, vascular leakage and retinal thickness, 
respectively.  Although the two methods correlate, the correlation is moderate, as compensated 
leakage may not result in thickening, and thickening may occur without evident leakage.4  Of the 
three methods (OCT, fluorescein angiography, clinical examination), clinical examination is least 
likely to detect macular edema.4  Visual acuity loss correlates better with retinal thickness than 
with the two-dimensional area of leakage.92  Even though vision is influenced by multiple 
factors, such as media opacity, change in macular thickness on OCT correlate with visual acuity 
improvement93, suggesting that as a single measure of macular edema response for 
comparative studies, retinal thickness on OCT is a good one.       
Taken together these data suggest that intravitreal triamcinolone may be a more effective initial 
treatment than periocular triamcinolone, as the intravitreal route may be superior for the delivery 
of corticosteroids.  However, the side effects of intravitreal triamcinolone may be greater than 
those of periocular triamcinolone.  Finally, the intravitreal dexamethasone pellet may have lower 
rates of side effects than those of intravitreal triamcinolone.  However, the limited comparability 
of the different studies, the lack of comparative trials, and the widespread variation in use of 
these different agents all suggest that a clinical trial is needed to guide management.  
Furthermore, a relatively short-term trial with macular thickness on OCT as a comparative 
measure may be adequate to evaluate relative efficacy.  Somewhat longer-term follow-up (e.g. 
6 months) is needed to evaluate the duration of response and the need for additional injections. 
The MUST Research Group is conducting the PeriOcular and INTravitreal corticosteroids for 
uveitic macular edema (POINT) Trial which was designed to evaluate the comparative 
effectiveness of periocular triamcinolone injections, intravitreal triamcinolone injections, and 
intravitreal injections of the dexamethasone pellet for the initial regional treatment of uveitic 
macular edema.  POINT is funded by the same grant and is the companion study for the MERIT 
Trial.  
Management of Persistent Macular Edema      
Despite appropriate management, up to 50% of eyes with macular edema will not fully resolve 
and will have persistent macular edema.16  Although these eyes often are treated with additional 
regional corticosteroid injections, not all patients will improve, and alternative agents have been 
explored.  In addition, the occurrence of substantial rises in IOP (e.g. to 35-40 mm Hg), while 
uncommon, and to a lesser extent the occurrence of cataract, has prompted the search for 
alternative, non-steroid regional treatments.  Two agents that have been investigated have been 
intravitreal methotrexate injections and intravitreal anti-VEGF injections, such as ranibizumab. 
Methotrexate 
Methotrexate is an antimetabolite, administered weekly either orally or parenterally, used 
extensively in the treatment of rheumatoid arthritis and used for uveitis requiring 


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immunosuppression, particularly juvenile idiopathic arthritis-associated chronic anterior uveitis.  
Intravitreal methotrexate has been used successfully in the treatment of primary intraocular 
lymphoma without the occurrence of substantial adverse ocular effects.94, 95  A dose of 
400µg/0.1 mL is well tolerated by the retinal tissue and remains in a therapeutic concentration 
for 48-72 hours.96 Several case series have suggested efficacy for intravitreal injections of 
methotrexate (400µg/0.1 mL) for the treatment of chronic intermediate uveitis and posterior 
uveitis and for inflammatory macular edema.97-100  A six-month pilot study of patients with active 
intermediate, posterior, or panuveitis from Moorfields Eye Hospital examined the effect of a 
single intravitreal injection of methotrexate on visual acuity and macular edema.98  Overall, 87% 
(13/15) of patients responded with significantly improved visual acuity, significantly reduced 
macular thickness on OCT, and significantly reduced ocular inflammatory scores.  The onset of 
action appeared to be within one week of administration with a mean duration of effect of four 
months.  Visual improvements were similar to those seen with previous injections of intravitreal 
triamcinolone.  Patients who underwent a second injection had a similar response.  No patients 
had an increase in IOP.  The only evident treatment related side effect was corneal 
epitheliopathy in one patient, occurring two months following the initial injection.  These data 
suggest that intravitreal methotrexate may be effective for the treatment of uveitis and of uveitic 
macular edema and that it may have lower rates of the ocular side effects of elevated IOP and 
cataract.  However, the relative merits of this approach vs. repeat injections of intravitreal 
triamcinolone are unknown. 
Ranibizumab 
 Ranibizumab is a recombinant, humanized monoclonal antibody antigen-binding fragment 
(Fab) to VEGF, that neutralizes VEGF, and currently approved by the FDA for the treatment of 
choroidal neovascularization in age-related macular degeneration (AMD), diabetic macular 
edema, and macular edema associated with retinal vein occlusions.  Bevacizumab (Avastin®, 
Genentech, Inc., San Francisco, CA), an anti-VEGF monoclonal antibody and the parent 
molecule of the Fab fragment ranibizumab, was initially approved for the treatment of colorectal 
cancer, and is being used off-label for indications similar to those for ranibizumab.  Studies 
leading to ranibizumab’s approval for macular degeneration demonstrated a very low incidence 
of cataracts, elevated IOP and other adverse events, thus making it an attractive option with 
regard to safety.101, 102  The two-year results of the Comparison of Age-related Macular 
Degeneration Treatments Trial (CATT) supports the use of either drug as primary therapy for 
choroidal neovascularization associated with AMD, and also suggests that modification of 
monthly–dosing regimens may be feasible.103, 104  One potential advantage of using ranibizumab 
instead of bevacizumab is that it has been shown to be 5- to 20-fold more potent than full-length 
bevacizumab in bioassays measuring inhibition of human VEGF-induced endothelial cell 
mitogenesis.105  Clinically, in CATT, monthly injections of ranibizumab were the most effective in 
terms of proportion of eyes without fluid on OCT.  
The safety and efficacy of ranibizumab for the treatment of patients with diabetic macular 
edema and macular edema due to retinal vein occlusion have been demonstrated in clinical 
trials which led to US FDA approval for these indications.106, 107  Two multicenter randomized 
double-masked sham injection-controlled clinical trials in adult patients with diabetic macular 
edema showed a significant improvement in best corrected visual acuity at 24 months in the 
ranibizumab-treated group compared to the group receiving sham injections.  Mean change in 
central foveal thickness also was significantly better in ranibizumab-treated patients, with a 
mean decrease of 255 µm in central foveal thickness at 24 months in the ranibizumab group, 
compared with a 130 µm decrease in the sham injection group (P < 0.0001). Less than 5% of 
patients experienced an ocular adverse event, such as endophthalmitis, retinal detachment or 
vitreous hemorrhage, by 24 months.  Ranibizumab also is approved for the treatment of macular 
edema following branch retinal vein occlusion.108, 109  A phase III multicenter, randomized, 


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double-masked, controlled study followed by a 6-month observation period showed a significant 
improvement in best corrected visual acuity (18.3 letters from baseline) compared with the sham 
injection group (7.3 letters, P < 0.0001).  A significant improvement in central foveal thickness 
also occurred in the ranibizumab group (decrease of 345 µm at 6 months), compared with the 
sham injection group (158 µm decrease, P < 0.001).  The safety profile of ranibizumab was 
consistent with prior phase III clinical trials of ranibizumab in neovascular age-related macular 
degeneration, with a very low rate of endophthalmitis, retinal tear/detachment and arterial 
thromboembolic events.  A second phase III trial on vein occlusion enrolled patients with 
macular edema following central retinal vein occlusion and showed similar efficacy and safety 
as the trial evaluating branch retinal vein occlusion.110, 111  
The use of intravitreal anti-VEGF drugs has been explored for the treatment of uveitic macular 
edema, but has yet to be studied systematically for this indication.  There have been two 
prospective uncontrolled studies evaluating the effect of intravitreal ranibizumab injections on 
macular edema in patients with controlled uveitis who failed regional corticosteroid injections.  
The first, performed at the University of California, San Francisco,42 was a prospective, 
uncontrolled case series, in which patients with inactive uveitis and persistent macular edema 
who had failed periocular corticosteroid treatment were given intravitreal ranibizumab injections 
(0.5 mg) monthly for 3 months, followed by re-injection as needed for the presence of macular 
edema.  The primary outcome was the mean change best corrected visual acuity from baseline 
to three months, and the secondary outcome was the mean change in central retinal thickness 
on OCT.  At three months, the mean increase in acuity was 13 letters (2.5 lines), and the mean 
decrease in central retinal thickness was 357 μm.  Both best corrected visual acuity and central 
retinal thickness improved significantly between baseline and three months (P=0.03 for each). 
Although most patients required re-injection, the treatment success was maintained at 6 
months. There were no significant ocular or systemic adverse effects.  Hence, intravitreal 
ranibizumab led to an increase in visual acuity and improvement in uveitis-associated macular 
edema in patients refractory to or intolerant of standard, regional corticosteroid therapy.   
The second prospective study, conducted at the Bascom Palmer Eye Institute, was a study of 
patients with controlled noninfectious uveitis and persistent macular edema that tested the effect 
of monthly ranibizumab (intravitreal injections, with repeated injections determined based on 
increase or persistence of retinal thickening or of cystoid spaces).  Mean best corrected visual 
acuity improvement over 12 months was 12 letters on a logarithmic visual acuity chart (P=0.02 
for comparison with baseline) and mean reduction in central retinal thickness was 45% 
(P=0.006 vs. baseline).112  These data are highly suggestive that intravitreal ranibizumab 
injections will be useful for the treatment of uveitic macular edema, but there are caveats.  The 
sample size for both studies was small, so the side effect profile has to be inferred from the use 
of ranibizumab for other forms of macular edema and for neovascular AMD.  However, the data 
set for the relative safely of ranibizumab is substantial and the side effects consistent across 
diseases.  The second is that ranibizumab does not treat the inflammation113 and appears to be 
most useful for persistent macular edema in patients with controlled inflammation, which is the 
type of patients treated in the pilot studies.  This role is consistent with ranibizumab’s known 
effect on vascular permeability and apparent lack of effect on inflammatory pathways.   
Bevacizumab has also been investigated as an off-label treatment for uveitic macular edema.114-
117  In two retrospective case series, one of which was conducted at the Massachusetts Eye 
Research and Surgery Institute, intravitreal injections of bevacizumab were associated with a 
short-term significant improvement in uveitic macular edema as measured by OCT.115, 116  
However, neither study found a statistically significant improvement in visual acuity, and the 
magnitude of the improvement in macular thickness appeared to be less than that reported in 


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the previously cited studies with ranibizumab.  As these studies were not prospective and did 
not follow an identical protocol for all patients, it is difficult to directly compare outcomes. 
 In sum, these data suggest that persistent macular edema despite therapy for the inflammation 
remains a problem.  The typical treatment of reinjection with a regional corticosteroid has some 
benefit, but that alternate treatments may prove to be better either in terms of efficacy or of the 
side effect profile.  The absence of any comparative trials in this situation is problematic for 
developing evidence-based guidelines for the management of uveitic macular edema.  A 
randomized clinical trial evaluating the comparative effectiveness of another corticosteroid 
injection with the alternate treatments of intravitreal methotrexate and of anti-VEGF agents is 
needed.  
 
1.7. 
Preliminary studies  
The MUST Research Group is a multicenter, clinical trials research group focused on trials on 
the management of uveitis and its structural complications.  The original MUST Trial was a 
comparative effectiveness of  the fluocinolone acetonide implant to the conventional approach 
of oral corticosteroids and immunosuppression as needed for non-infectious intermediate, 
posterior, and panuveitis.  The 2-year results have been published16, and a long-term follow-up 
study is ongoing.  Results of the MUST Trial most directly relevant to this protocol are the 
estimates of macular edema in eyes with intermediate, posterior, or panuveitis (~ 40%) on 
presentation, fraction of patients with bilateral disease (~ 25%), and the persistence of macular 
edema among eyes with uveitic macular edema (~50% overall)16, 18.   
Also relevant are the MUST data on the comparability of clinical observation, fluorescein 
angiography, and OCT for identification of uveitic macular edema17.  These data show that 
visual acuity is more closely related to retinal thickness among patients with uveitic macular 
edema92, and indicate that OCT outcomes are appropriate measures for clinical trials of uveitic 
macular edema.  Two levels of response are possible:  1) resolution, a return to normal, typically 
normal thickness; and 2) improvement, a clinically meaningful change that may or may not 
return to normal, but is indicative of a response to therapy.  Because of the proliferation of OCT 
machines with slightly different normal ranges, change in retinal thickness is best expressed as 
a percent change so that it is machine independent.  Percent change in retinal thickness is 
analogous to approach used for visual acuity, where changes in the visual angle are used as 
clinical trials outcomes.  Change in best corrected visual acuity on a logarithmic acuity chart 
(e.g. ETDRS charts) typically is used, and a change of >5 letters is greater than measurement 
variability and changes of >10 letters and > 15 letters often are used as outcomes in trials.118   
Although previous data suggested that the inter-measurement variability of OCT, regardless of 
machine, was <10%, and that a 20% change in macular thickness was highly reproducible,119-124 
prior to the MUST Trial it was unclear what level of clinical change in macular thickness was 
clinically meaningful.93  In order to determine the optimal threshold for considering macular 
thickness improved (and thereby macular edema), data from the MUST Trial were analyzed to 
determine the threshold for a change in retinal thickness on OCT that best correlated with a 
change in best corrected visual acuity.93  There was a strong association between a 20% 
reduction in retinal thickness and 5-letter, 10-letter, and 15-letter improvements in best 
corrected visual acuity (P<0.0001 for the 5-letter change); the agreement for a 20% reduction in 
thickness and a 5-letter improvement in visual acuity was 83% (95% CI 70-93%).  The 20% 
change appeared optimal on receiver operator characteristic curve analyses.  The sensitivity, 
specificity, positive predictive value, and negative predictive value of a 20% decrease in retinal 
thickness for a 5-letter improvement in visual acuity were 72%, 93%, 79%, and 90%, 
respectively.  After adjusting for baseline acuity, the mean difference in the improvement in best 


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corrected visual acuity for eyes with a > 20% decrease in retinal thickness vs. those with a 
<20% decrease was 10.4 letters (P<0.01).  These data suggest that retinal thickness on OCT 
can be used as a clinically meaningful outcome in trials of treatments for uveitic macular edema. 
Furthermore, the percent change threshold allows future trials to use newer OCT machines 
once the normal range has been determined, as the outcome (percent change) is machine 
independent.  These data are supportive of the rationale for the outcomes chosen for the POINT 
and MERIT trials.   
Much of the preliminary data for the MERIT Trial (and for the companion trial POINT) have been 
generated by MUST Research Group investigators.  The data on periocular triamcinolone 
injections for uveitic macular edema were generated by the Johns Hopkins clinical center.67  
Several studies evaluating intravitreal triamcinolone injections for the treatment of uveitic 
macular edema were performed at Moorfields Eye Hospital by the investigators at the MUST 
clinical center in London, UK.55    Preliminary data on intravitreal methotrexate also were 
generated by the MUST investigators at the MUST center in London98, 99  Two of the studies 
evaluating intravitreal ranibizumab injections for persistent macular edema have been 
performed at MUST clinical centers42, 114  Collectively the MUST investigators are leaders in the 
field of uveitis and have provided much of the information used to design the  MERIT and 
POINT clinical trials.   
 
1.8. 
Rationale for trial 
Although regional corticosteroid injections reduce macular edema and improve vision in many 
patients, the effect is variable, and up to 50% of eyes with uveitic macular edema have 
persistent edema, despite control of the inflammation.16 Furthermore, the ocular side effects, of 
increased IOP and cataract formation, have been reported in a substantial proportion of patients 
treated with regional corticosteroid injections, and an increase in the risk of such side effects 
(e.g. cataract formation) may increase with multiple injections.73, 78, 125  Hence there is a need for 
alternative agents with a different side effect profile (or lower rates of side effects).  
Ranibizumab is a recombinant, humanized monoclonal antibody that is FDA-approved for the 
treatment of choroidal neovascularization in AMD, diabetic macular edema, and macular edema 
after retinal vein occlusion.101-105, 126   Phase III studies leading to ranibizumab’s approval for 
AMD and post-marketing surveillance data demonstrate a low incidence of cataracts, and 
elevated IOP, suggesting favorable safety vis-à-vis corticosteroids. Pilot studies of ranibizumab 
for uveitic macular edema showed statistically and clinically significant improvements in both 
macular edema and best corrected visual acuity.42  There is also evidence that intravitreal 
methotrexate, which also has a low rate of ocular complications, is a promising treatment for  
uveitic macular edema.97-100  The goal of the MERIT Trial is to compare the relative 
effectiveness of a repeat corticosteroid injection for persistent or recurrent macular edema in 
eyes with controlled inflammation (the current standard approach), versus each of the 
alternative non-corticosteroid modalities (intravitreal ranibizumab or intravitreal methotrexate) for 
the treatment of uveitic macular edema that is persistent or recurrs after an intravitreal 
corticosteroid injection.  Because many of these patients now are treated with the alternative 
corticosteroid (i.e. the dexamethasone pellet) rather than the reinjection of the same drug, the 
corticosteroid used for intravitreal injection in this study will be the dexamethasone pellet. The 
preliminary data suggest that alternative treatments (i.e., ranibizumab and methotrexate) may 
have greater efficacy in the situation. The MERIT Trial will be important in determining the role 
of these alternative non-corticosteroid intravitreal therapies in the treatment of uveitic macular 
edema persisting or recurring after successful control of the uveitis.  
 


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2. Objective and study hypothesis 
 
2.1. 
Objective 
The MERIT Trial was designed to find out which intravitreal therapy offers the best balance of 
effectiveness and tolerability in treating persistent or recurrent uveitic macular edema in eyes 
with controlled uveitis, specifically by comparing the relative efficacy and safety of intravitreal 
ranibizumab (Lucentis®) and intravitreal methotrexate to intravitreal dexamethasone implant 
(Ozurdex®) for the treatment of persistent /recurrent uveitic macular edema. 
 
2.2. 
Hypotheses 
(1) Intravitreal injections of methotrexate will have greater efficacy than intravitreal 
injections of the dexamethasone pellet as a treatment for uveitic macular edema 
persisting or recurring after treatment with an intravitreal corticosteroid injection. 
  
(2) Intravitreal injections of ranibizumab will have greater efficacy than intravitreal 
injections of the dexamethasone pellet as a treatment for uveitic macular edema 
persisting or recurring after treatment with an intravitreal corticosteroid injection. 
 
 
 
 
 


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3. Design 
 
3.1. 
Type of study 
• 
Randomized, three-arm, parallel design,  randomized comparative effectiveness trial 
• 
Randomization stratified by presence or absence of concomitant systemic corticosteroid 
and/or immunosuppressive therapy for any indication  
• 
Unit of randomization is patient, not eye; if both eyes meet eligibility criteria, both receive 
same treatment 
• 
Allocation ratio (1:1:1) 
• 
Multicenter 
• 
Fixed sample size, 240 (80 per treatment group) 
• 
Anniversary close-out at the 6-month clinic visit  
• 
Reading center graders and visual acuity examiners will be masked to treatment 
• 
Treating physicians and patients will be unmasked (the intravitreal therapies are different 
in appearance and have potentially different injection schedules) 
 
3.2. 
Treatment arms 
• 
Ozurdex (0.7 mg dexamethasone pellet) delivered via intravitreal injection 
• 
Methotrexate 400 µg in 0.1 mL via intravitreal injection  
• 
Ranibizumab (Lucentis) 0.5 mg in 0.05 mL via intravitreal injection 
 
 


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3.3. 
Trial schema 
 
 
 
 
Intravitreal ranibizumab (Lucentis) 0.5 mg in 0.05 mL  
M01 
(Randomization) M02 
M03 
M04 
M05 
M06 
M07 
Intravitreal methotrexate 400 µg in 0.1 mL  
Intravitreal dexamethasone (Ozurdex) 0.7 mg 
0*†§ 
4††§ 
8║††§ 
12 Δ  
16 Δ 
20 Δ 
24 Δ 
Visit ID 
Week 
Intravitreal ranibizumab arm 
   §  Eligible eye(s) treated at M01+, M02 and M03 
            Δ  Retreatment permitted at M04 and later if retreatment criteria met 
 
Intravitreal methotrexate arm  
†  Eligible eye(s) treated M01+ 
††Retreatment required at M02, M03 if retreatment criteria met   
Δ  Retreatment permitted at M04 and later if retreatment criteria met 
Intravitreal dexamethasone arm  
*  Eligible eye(s) treated M01+ 
║ Retreatment required at M03 if retreatment criteria met 
Δ  Retreatment permitted at M04 or later if retreatment criteria met 
 
Retreatment criteria  
1)
Central subfield thickness greater than 1.1X 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 critteria for initial injection of study treatment in eligible eye(s) is ≤21 mm Hg with ≤3 IOP-lowering agents  
 
   Minimum time between injections  
• 
Intravitreal dexamethasone:  minimum target 8 weeks after last injection but re-injection permitted as 
early as 51 days after last injection; 
• 
Intravitreal methotrexate: minimum target 4 weeks after last injection but re-injection permitted as early 
as 23 days after last injection 
• 
Intravitreal ranibizumab: minimum target 4 weeks after last injection but re-injection permitted as early 
as 23 days after last injection 


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3.4. 
Primary outcome 
The primary outcome is the percent change in central subfield thickness from the baseline OCT 
measurement at the 12-week visit.  The assessment of OCT outcomes will be performed by 
masked readers.  The 12-week visit was chosen as the time to assess the primary outcome 
because the ranibizumab treatment arm specifies injections at baseline (i.e., post-
randomization), 4 weeks and 8 weeks in all participants, and because the peak benefit for the 
dexamethasone pellet appears to be at the 8 to 12 weeks. 
 
3.5. 
Secondary outcomes  
• 
Rates of IOP elevation of ≥24 mm Hg, ≥30 mm Hg, and  ≥ 10 mm Hg from baseline 
during the 24 weeks of follow-up  
• 
Percent change in macular thickness as measured by OCT over the 24 weeks of follow-
up 
• 
Proportion of eyes with macular edema events over the 24 weeks of follow-up 
- ≥20% reduction in macular thickness (or normalization of macular thickness even 
if there is <20% reduction)  
- ”Resolution”, defined as normalization of the macular thickness, i.e., <260 um on 
the standard scale Worsening defined as a 20% increase in macular thickness 
from the lowest value after an injection 
- “Recurrence” defined as >20% increase in the central subfield measurement on 
OCT to an abnormal value in an eye that previously had resolution of ME 
• 
Mean change in BCVA over the 24 weeks of follow-up.  
Best-corrected visual acuity score will be measured at every study visit under 
standardized lighting conditions by certified study examiners masked to study treatment 
using logarithmic (ETDRS) visual acuity charts, according to the method described by 
Ferris, et al.127 
• 
Safety outcomes including elevated IOP ( >30 mm Hg thresholds ); vitreous hemorrhage; 
retinal tear/detachment; endophthalmitis; severe vision loss (≥15 Early Treatment 
Diabetic Retinopathy Study [ETDRS] letters) during the 24 weeks of follow-up. 
.  
 
 


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3.6. 
Eligibility criteria 
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 SUN2 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 most recent 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. Best corrected visual acuity (BCVA)  5/200 or better; 
 
5. 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); 
 
6. 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 


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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. 
 
 
3.7. 
Randomization 
After the patient has given written informed consent, eligibility has been confirmed and baseline 
data have been keyed and passed an electronic eligibility review, the patient will be randomly 
assigned to one of the three treatment groups, via a web-based system, returning the treatment 
assignment result in real time.  Beginning at this point, the patient’s data will be included for 
primary analyses, regardless of subsequent actual treatment and/or extent of adherence to 
therapy.  Randomization will be accomplished using an auditable, documented scheme 


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generating a reproducible order of assignment.  Randomization schedules will be developed by 
the Coordinating Center (CC), using permuted blocks of varying lengths, designed to yield 
expected assignment ratio of 1:1:1.  Randomization will be stratified by presence or absence of 
concomitant systemic corticosteroid and/or immunosuppressive therapy for any indication  
 
 
3.8. 
Data collection schedule 
Visit ID 
M01 
M02 
M03 
M04 
M05 
M06 
M07 
Time 
Baseline 
4-wk 
8-wk 
12-wk 
16-wk 
20-wk 
24-wk 
Medical/ophthalmic history 
X 
X 
X 
X 
X 
X 
X 
Treatment history 
X 
X 
X 
X 
X 
X 
X 
Best-corrected visual 
acuity 
X 
X 
X 
X 
X 
X 
X 
Tonometry 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic exam 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy 
X 
 
 
 
 
 
 
OCT 
X 
X 
X 
X 
X 
X 
X 
Health utility measures 
(EuroQOL, VFQ-25) 
X 
X 
X 
X 
X 
X 
X 
Adverse event monitoring 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testing 
X† 
X‡ 
X‡ 
X‡ 
X‡ 
X‡ 
X‡ 
 
† Required for all women of childbearing potential at M01 
‡ Required for women of childbearing potential before any additional intravitreal injections of methotrexate or     
ranibizumab 
 


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4. Treatment schedule  
4.1. 
Overview 
• 
Study participants are randomized to receive one of three treatments in eye(s) meeting 
eye-level eligibility criteria at baseline (M01) 
 
Note:  If only one eye is eligible at baseline then that eye will be the only study eye 
throughout the trial.  If the second eye “meets eligibility criteria” later at a later time 
point, the second eye does not become a study eye.  Rather the second eye is treated 
per best medical judgment of the study/ treating ophthalmologist. 
 
• 
The timing of initial injections of assigned treatment, required 2nd and 3rd injections in 
ranibizumab group, and retreatment for all groups are specified in section 4.2 below 
 
• 
All injections of study treatments must be administered per protocol instructions and 
follow relevant IOP pre-injection criteria 
- Initial injection of study treatment:  IOP ≤ 21 mm Hg and ≤ 3 IOP-lowering  
agents 
- Retreatment:  IOP  <25 mm Hg and  ≤ 3 IOP-lowering  
agents  
 
• 
Pregnancy testing required for women of childbearing potential before additional 
intravitreal injections of methotrexate or ranibizumab 
 
• 
Treatment according to the best medical judgment of study ophthalmologist is 
permitted as deemed necessary. Repeat injections given before the protocol specified 
time points (section 4.2.6) or other deviations from the treatment protocol should be 
reported expeditiously to CC on Unanticipated Event (UA) form. 
 
 
 
 


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4.2. 
Study treatment schedule and retreatment criteria 
4.2.1. 
Table:  Study treatment schedule by treatment assigned and study visit 
 
Study treatment schedule by treatment assigned and study visit  
 
Treatment  
Assignment 
Study visits 
M01 
M02 
M03 
M04†† 
M05†† 
M06†† 
M07†† 
week 0 
week 4 
week 8 
week 12 
week 16 
week 20 
week 24 
Ozurdex 
Required 
None 
Required if 
criteria 
met* 
Permitted if 
criteria 
met*† 
Permitted if 
criteria 
met*† 
Permitted if 
criteria 
met*† 
Permitted if 
criteria 
met*† 
Methotrexate Required 
Required if 
criteria 
met* 
Required if 
criteria 
met* 
Permitted if 
criteria 
met* 
Permitted if 
criteria 
met* 
Permitted if 
criteria 
met* 
Permitted if 
criteria 
met* 
Ranibizumab 
Required 
Required  
Required  
Permitted if 
criteria 
met* 
Permitted if 
criteria 
met* 
Permitted if 
criteria 
met* 
Permitted if 
criteria 
met* 
* ME retreatment criteria: Central subfield thickness greater than 1.1X upper limit of normal (330 um for 
Zeiss and Topcon SD OCT and 352 um for Heidelberg OCT) and/or cystoid space(s) within 1 mm central 
subfield; IOP criteria <25 mm Hg (treatment with ≤3 IOP-lowering agents permitted) 
† A minimum of 51 days is required between Ozurdex treatments so retreatment will be an option only 
if the last treatment was administered  ≥51 days previously 
†† Alternatively, participant may be treated according to the best medical judgment of the study 
ophthalmologist at the M04 and subsequent visits 
 
4.2.2. 
Intravitreal dexamethasone pellet, 0.7 mg (Ozurdex)  
• 
M01:  Treatment required 
- Preferably administered on the day of randomization but may be administered 
up to 10 days after randomization  
- Pre-injection IOP requirements: ≤21 mm Hg and ≤3 IOP lowering agents* 
 
• 
M02:  No treatment 
 
• 
M03:  Retreatment required if criteria in section 4.2.5 are met 
 
• 
M04 or a subsequent visit:  Retreatment permitted if criteria in section 4.2.5 are 
met and if there has been at least 51 days since the last treatment. 
 
If there has been evidence of a treatment benefit but a participant meets 
retreatment criteria (see section 4.2.5) at the M04 visit, the participant should be 
encouraged to continue the assigned treatment. However, the participant may be 
treated according to the best medical judgment of the study ophthalmologist at 
the M04 and subsequent visits. 
 
 


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4.2.3. 
Intravitreal methotrexate, 400 µg in 0.1 mL  
• 
M01:  Treatment required 
- Preferably administered on the day of randomization but may be administered 
up to 10 days after randomization  
- Pre-injection IOP requirements: ≤21 mm Hg and ≤3 IOP lowering agents* 
 
• 
M02:  Retreatment required if criteria in section 4.2.5 are met  
  
• 
M03:  Retreatment required if criteria in section 4.2.5 are met 
 
• 
M04 and subsequent visits:  Retreatment permitted if the retreatment criteria in 
section 4.2.5 are met as discussed below and if there has been at least 23 days 
since the last treatment. 
 
If there has been evidence of a treatment benefit but a participant meets 
retreatment criteria at the M04 visit, the participant should be encouraged to 
continue the assigned treatment. However, the participant may be treated 
according to the best medical judgment of the study ophthalmologist at the M04 
and subsequent visits. 
 
 
• 
For women of child-bearing potential, negative pregnancy test required before all 
injections 
 
4.2.4. 
Intravitreal ranibizumab (Lucentis), 0.5 mg in 0.05 mL  
• 
M01:  Treatment required 
- Preferably administered on the day of randomization but may be administered 
up to 10 days after randomization  
- Pre-injection IOP requirements: ≤21 mm Hg and ≤3 IOP lowering agents* 
 
• 
M02:  Treatment required  
- Pre-injection IOP requirement: <25 mm Hg and ≤3 IOP lowering agents 
   
• 
M03:  Treatment required  
- Pre-injection IOP requirement: <25 mm Hg and ≤3 IOP lowering agents 
 
• 
M04 and subsequent visits:  Retreatment permitted if criteria in section 4.2.5  
and there has been at least 23 days since the last treatment. . 
 
If there has been evidence of a treatment benefit but a participant meets 
retreatment criteria at the M04 visit, the participant should be encouraged to 
continue the assigned treatment. However, the participant may be treated 
according to the best medical judgment of the study ophthalmologist at the M04 
and subsequent visits. 
 
• 
For women of child-bearing potential, negative pregnancy test required before all 
injections 
 
* Note that the IOP requirements for the initial injection are the same as for eye 
eligibility for the trial. If study treatment is initiated on the same day as eligibility is 
confirmed and treatment assigned, no additional IOP measurements are needed.If 


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circumstances require patient to return to clinic for injection at a later date, IOP must 
be checked and IOP-lowering agents evaluated prior to injection. If the eligibility 
requirements are not met, the injection should not be given. If the treating 
ophthalmologist elects to proceed with assigned treatment per best medical judgment, 
the deviation from the protocol must be reported to CC on an Unanticipated Event 
(UA) form; the UA form should be submitted as soon as possible. 
 
4.2.5. 
Retreatment criteria and pre-injection IOP requirements 
• 
Macular edema warrants retreatment if one or both of the following criteria are 
present: 
- Central subfield thickness greater than 1.1X upper limit of normal (330 µm for 
Zeiss and Topcon   SD OCT and 352 µm for Heidelberg OCT)  
- Cystoid spaces within  1 mm central subfield  
 
• 
 IOP requirements pre-injection: <25 mm Hg and ≤ 3 IOP-lowering agents 
 
• 
Negative pregnancy test required for women of childbearing potential before  
every injection of methotrexate or ranibizumab  
 
4.2.6. 
Minimum time between treatments 
• 
Intravitreal dexamethasone pellet 
- Minimum target for retreatment is 8 weeks  
- Retreatment is permitted as early as 51 days after last treatment 
 
• 
Intravitreal methotrexate 
- Minimum target for retreatment is 4 weeks 
- Retreatment is permitted as early as 23 days after last treatment 
 
• 
Intravitreal ranibizumab 
- Minimum target for retreatment is 4 weeks 
- Retreatment is permitted as early as 23 days after last treatment 
 
 
4.3. 
Treatment failures 
Eyes that demonstrate no improvement or worsening of ME as measured by the central 
subfield thickness on OCT at the 20-week visit (M06) are considered treatment failures and are 
to be treated according to best medical judgment of study/treating ophthalmologist. 
 
 


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5. Study treatment preparation and administration 
 
5.1. 
General requirements 
5.1.1. 
Study treatment administrator 
Study treatments are to be administered by an ophthalmologist who is certified as either a 
MERIT study ophthalmologist or MERIT treatment administrator. 
 
5.1.2. 
Pre-injection IOP requirements 
• 
Pre-injection IOP 
- Before initial injection of study treatment in an eye: ≤21 mm Hg  
- Before retreatment injections: <25 mm Hg 
• 
Use of 3 or fewer IOP-lowering agents  (note: a combination medication like Combigan 
is counted as two IOP-lowering medications) 
 
5.1.3. 
Bilateral study eye injections – order of procedures 
If both eyes are study eyes and injections will be given in both eyes at the same visit 
• 
All required injection procedures must be completed in the right eye prior to initiation of 
any pre-injection preparation of the left eye.   
• 
The drug to be used in the left eye should not be present in the room prior to completion 
of all right eye injection procedures.  
 
 
5.2. 
Standard pre-injection procedures for all study treatments 
• 
General requirements  
- Treatment administrator and assistant wear masks during injection procedure 
- Everyone (including patient) is asked not to talk during procedure  
• 
Treatment administrator and a second person confirm and mark study eye(s) to receive 
treatment 
- Confirm which is the study eye or eyes that is/are to receive the study treatment 
while directly viewing the Randomization (RZ) form that indicates the study eye 
or eyes 
- Mark that eye (or eyes) with a sticker or marking pen above the eye brow. 
• 
Treatment administrator and a second person confirm that the drug obtained from the 
pharmacy matches the treatment assignment printout from the MERIT randomization 
system 
• 
When the study participant is ready for the injection, apply at least one drop of topical 
anesthetic (solution or gel) to the eye 
• 
Prepare eye for injection using the following sequence of steps: 
- Consider placing 2-3 drops of 5% povidone iodine in the lower fornix and/or using 
sterile cotton-tipped applicators soaked in 5% or 10% povidone iodine to swab 
the upper and lower eyelid margins and the upper and lower eyelashes (Optional) 
-  Retract the eyelids and lashes away from the injection site and needle for the 
duration of the procedure (use of an eyelid speculum is optional) 
- Consider additional anesthesia with the application of one or two cotton-tipped 
applicators soaked in topical anesthetic over the intended injection site for at 
least 30 seconds. The use of lidocaine gel or other types of viscous anesthetic 
(e.g. TetraVisc™) is also permitted.   


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 A subconjunctival anesthetic can be used in specific circumstances in 
which the study ophthalmologist believes that topical anesthetic is not 
sufficient to minimize discomfort 
- Encourage the study participant to look superonasally during the application of 
povidone iodine.  Apply one of the following to the conjunctiva directly over and 
surrounding the intended injection site:  
 A cotton-tipped applicator soaked in 5% or 10% povidone iodine   
 A 10% povidone iodine Swabstick 
 At least 1-3 drops of 5% povidone iodine (at least enough to cover the 
intended injection site) 
- Allow 30-60 seconds for the povidone iodine to be in contact with the injection 
site before injection.   
• 
Use a sterile 4×4 pad in a single wipe to absorb excess liquid and to dry the periocular 
skin.  
 
NOTE: As indicated above, injection preparation must include the use of povidone-iodine 
either applied directly to the injection site using topical drops, a cotton-tipped applicator, or 
swabstick.  If a study participant experiences an adverse reaction to povidone-iodine, other 
approaches to limit the exposure of povidone-iodine may be permitted.  However, a study 
participant may not receive an intravitreal injection without use of povidone-iodine 
directly to the injection site just prior to the injection.   
 
Examples of approaches that may be used in study participants with prior adverse reactions 
associated with povidone-iodine include using a limited amount of povidone-iodine by 
placing a swab directly on the injection site after the lid speculum has been placed or the 
eyelids and lashes have been retracted by other means, subsequently ensuring that nothing 
further touches that site before the injection. Alternatively, study ophthalmologist could 
consider using povidone-iodine and then gently irrigating the eye with sterile saline after the 
injection to try to rinse away any remaining povidone-iodine or gently applying a sterile 
cotton tipped applicator adjacent to the intended injection site to immediately absorb excess 
povidone-iodine that has been placed 
 
 
5.3. 
Administration of intravitreal dexamethasone pellet (Ozurdex)  
• 
Injection procedures should be carried out under controlled aseptic conditions which 
include the use of sterile gloves and a sterile eyelid speculum or equivalent, i.e. 
retraction of the eyelids and lashes from the injection site and needle 
 
After completing standard pre-injection procedures (section 5.2 above) 
• 
Mark injection site ocular surface 3.5-4.0 mm posterior to the limbus 
• 
Open the foil pouch over a sterile field and gently drop the applicator on a sterile tray 
• 
Carefully remove the cap from the applicator.  
• 
Hold the applicator in one hand and pull the safety tab straight off the applicator. Do not 
twist or flex the tab.  
• 
The long axis of the applicator should be held parallel to the limbus 
• 
Displace the conjunctiva with a cotton tip applicator held in the non-dominant hand  
• 
The sclera should be engaged at an oblique angle with the bevel of the needle up (away 
from the sclera) to create a shelved scleral path.  
• 
The tip of the needle is advanced within the sclera for about 1 mm (parallel to the 
limbus), then re-directed toward the center of the eye and advanced until penetration of 


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the sclera is completed and the vitreous cavity is entered. The needle should not be 
advanced past the point where the sleeve touches the conjunctiva.  
• 
Slowly depress the actuator button until an audible click is noted.  
• 
Before withdrawing the applicator from the eye, make sure that the actuator button is 
fully depressed and has locked flush with the applicator surface.  
• 
Remove the needle in the same direction as used to enter the vitreous. 
• 
Follow standard post-injection procedures and monitoring (section 5.6 below) 
 
 
 


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5.4. 
Intravitreal methotrexate injection preparation and administration 
5.4.1. 
Preparation of injection by  pharmacy 
 
 
 
Methotrexate injections are to be prepared by a research/compounding pharmacy as detailed 
below. 
 
 
Ingredients 
Strength 
Amount 
Methotrexate preservative-free liquid vial 
25 mg/mL 
0.64 mL 
Sodium chloride solution, preservative-free 
0.9% 
3.36 mL 
 
Compounding procedure 
1. From the methotrexate 1 g (25 mg/mL) liquid vial, withdraw 0.64 mL (16 mg) and 
transfer to a sterile empty vial.  This is methotrexate vial B. 
 
2. To methotrexate vial B, add 3.36 mL of Preservative-Free Sodium Chloride 0.9% 
solution and mix well. 
 
3. From methotrexate vial B, withdraw 0.3 mL (0.1 mL desired dose plus 0.2 mL overfill)* of 
the solution into the syringe.  Replace the needle with a syringe cap. 
 
4. Label:  Methotrexate 400 mcg/0.1 mL intravitreal injection (***Contains Overfill ***)  
* Volume fill – syringe fill of 0.3 mL is guideline.  If research pharmacy’s existing label/practice is 
to fill syringe with alternative amount, this is acceptable as it will not affect the volume (0.1 mL) 
or dose injected 
 
Storage: Refrigerate (2-8°C);  
 
Expiration: Beyond use date is 24 hours 
 
Reference:  Bascom Palmer Eye Institute Department of Pharmacy Extemporaneous 
Compounding Record for Methotrexate 400 mcg/0.1 mL Intravitreal Injection, 24 May 2016. 
      
 
Additional information 
• 
Prepared syringe is for single use (one eye only) 
• 
Syringe with the excess methotrexate should be discarded in a biohazard 
container/chemotherapy bin per institutional guidelines 
• 
If an alternative preparation of methotrexate is to be used (i.e., alternative compounding 
procedure, storage conditions or beyond use date), it must be reviewed by the MERIT 
Protocol Chairs and/or Executive Committee and approved by the clinic’s governing IRB 
 
5.4.2. 
Administration of intravitreal methotrexate 
• 
Injection procedures should be carried out under controlled aseptic conditions which 
 Methotrexate is a cytotoxic agent. Use standard chemotherapy handling precautions in a biologic 
safety cabinet that provides a sterile environment when preparing this product. 


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include the use of sterile gloves and a sterile eyelid speculum or equivalent, i.e. 
retraction of the eyelids and lashes from the injection site 
 
After completing the standard pre-injection procedures (section 5.2 above) 
• 
The position of the injection site is 3.5mm-4.0mm posterior to the limbus; distance 
should be marked on ocular surface 
• 
The study ophthalmologist/treatment administrator prepares the proper volume of drug 
to be injected as follows 
- Replace the sterile syringe cap with a sterile 30-gauge or 32-guage ½ inch 
needle 
- With the needle cap removed, expel fluid at an approximately 45-degree angle 
until the plunger is advanced to 0.1 mL 
- The syringe is now ready for injection 
• 
Instruct participant to direct gaze away from syringe  
• 
Inject the drug into the vitreous cavity pointing toward the optic nerve via the pars plana.  
• 
Place a cotton swab on the site as the needle is injected to help prevent extrusion of 
medication 
• 
Follow standard post-injection procedures and monitoring (section 5.6 below) 
 
 
5.5. 
Intravitreal ranibizumab (Lucentis) formulation, storage, and administration 
5.5.1. 
Formulation of ranibizumab 
Ranibizumab is formulated as a sterile solution aseptically filled in a sterile 0.3 mL stoppered 
glass vial or in a prefilled syringe.  Each single-use vial or prefilled syringe is designed to deliver 
0.05 mL of 10 mg/mL ranibizumab aqueous solution with 10 mM histidine HCI, 10%, a-trehalose 
dihydrate, and 0.01% polysorbate 20, pH 5.5.  This results in the delivery of a 0.5 mg dose of 
ranibizumab.  Each vial and prefilled syringe contains no preservative and is suitable for single 
use only.  Either vials or prefilled syringes may be used. 
 
Notes:   
• 
The volume fill for the ranibizumab vials donated by Genentech for U.S. clinical centers 
was changed from 0.3 mL to 0.23 mL beginning with the drug distributed in August 2018 
but the vial size (0.3 mL) did not change] 
• 
After Mar 2020, Genentech will provide ranibizumab for U.S. clinical centers as  0.5 mg 
dose prefilled syringes.  
 
5.5.2. 
Storage of ranibizumab 
• 
Upon receipt, ranibizumab should be refrigerated at 2°C - 8°C (36°F - 46°F).  DO 
NOT FREEZE 
• 
Do not use beyond the expiration date   
• 
Ranibizumab should remain refrigerated.   
• 
Protect from direct light 
• 
Store in original carton until time of use 
 
Ranibizumab vials and prefilled syringes are for single use only.  Vials or prefilled syringes used 
for one subject may not be used for any other individualt.   
 
 


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5.5.3. 
Administration of intravitreal ranibizumab (Lucentis) 
• 
Injection procedures should be carried out under controlled aseptic conditions which 
include the use of sterile gloves and a sterile eyelid speculum or equivalent , i.e. 
retraction of the eyelids and lashes from the injection site 
 
After completing standard pre-injection procedures (section 5.2 above) 
• 
The position of the injection site is 3.5mm-4.0mm posterior to the limbus; distance 
should be marked on ocular surface 
• 
Preparation of proper volume of drug to be injected 
− If using ranibizumab vial, he study ophthalmologist/treatment administrator 
prepares the proper volume of drug to be injected by  
 
Drawing 0.2mL into the syringe using a sterile 19-gauge filter needle.   
 
The 19-gauge filter needle should then be removed and a sterile 30-
gauge or 32-guage ½ inch  needle should be placed onto the syringe.   
 
With the needle cap removed, fluid is expelled at an approximately 45-
degree angle until the plunger is advanced to 0.05 mL     
 
The syringe is now ready for injection 
− If using ranibizumab prefilled syringe, the study ophthalmologist/treatment 
administrator prepares the proper volume of drug to be injected as follows 
 
Remove syringe cap (snap off) 
 
Attach a 30G x ½ inch needle and remove needle cap 
 
Inspect for and dislodge any air bubbles by gently tapping on syringe 
 
Expel air and adjust durg dose by pushinjg plunger until edge below 
rubber stopper is alrighed with the 0.05 mL dose mark  
 
The syringe is now ready for injection 
 
• 
Instruct participant to direct gaze away from syringe prior to intravitreal injection 
• 
Inject the drug into the vitreous cavity pointing toward the optic nerve via the pars plana  
• 
Place a cotton swab on the site as the needle is injected to help prevent extrusion of 
medication  
• 
Follow standard post-injection procedures and monitoring (section 5.6 below) 
 
 
5.6. 
Standard post-Injection procedures/monitoring for all study treatments 
• 
Remove the lid speculum/unretract eyelid and lashes and avoid any excess pressure on 
the eye 
• 
Post-injection topical povidone-iodine may be used over the injection site at the 
administrator’s discretion 
• 
Monitor for IOP elevation and assess for any other complications either via indirect 
ophthalmoscopy immediately after injection to confirm that the central retinal artery is 
perfused (even if it is pulsating) or a vision check to confirm that there is some 
perception of vision in the study eye (for example, able to count fingers or perceive hand 
motion or light perception) and/or tonometry within 15 minutes following injection. 
 


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6. Guidelines for use of topical corticosteroids and NSAIDs 
Topical corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) have potential 
treatment effects on macular edema.  Use of these drugs in study eyes per the following 
guidelines is encouraged to minimize confounding. 
 
6.1. 
Topical corticosteroids  
• 
In general topical corticosteroids (e.g., difluprednate (Durezol®), prednisolone) should 
not be introduced during the trial  
• 
Participants using a topical corticosteroid at baseline (M01) should be maintained at their 
current dose except as follows 
- Tapering and/or discontinuing is permitted for medical issues that may arise 
during the study, such as elevated IOP or rapidly progressive cataract 
- A transient increase in dose is permitted to treat a recurrence of anterior segment 
inflammation, with the goal of tapering down to the baseline dose 
 
6.2. 
Topical non-steroidal anti-inflammatory drugs 
• 
In general topical non-steroidal anti-inflammatory drugs (NSAIDs) should not be 
introduced during trial  
• 
Participants using a topical NSAID at baseline (M01) should be maintained on their 
current dose except as follows 
- Tapering and/or discontinuing are permitted for a medical reason such as corneal 
melting  
 


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7. Possible side effects and complications of study treatments 
7.1. 
Intravitreal dexamethasone 
• 
Commonly reported events related to the drug  
- Elevated intraocular pressure (IOP) which may require medication to lower 
 
• 
Less frequently reported events related to the drug 
- Short-term visual disturbances 
- Headache 
- Cataract development 
- Elevated intraocular pressure (IOP) which may require surgery to control  
- In eyes with non-intact posterior capsule, implant migration to anterior chamber 
- Patients with diabetes could experience a transient elevation in blood glucose  
 
• 
Rare and serious events related to the drug 
- Perforation of the globe where there is thinning of the cornea or sclera 
 
• 
Possible side effects and complications related to intravitreal injections are listed in 
section 7.4 
 
 
7.2. 
Intravitreal methotrexate 
• 
Commonly reported events related to the drug 
- Reversible corneal epitheliopathy 
 
• 
Rare and serious events related to the drug 
- Sterile endophthalmitis 
 
• 
Possible side effects and complications related to intravitreal injections are listed in 
section 7.4 
 
 
7.3. 
Intravitreal ranibizumab 
• 
Commonly reported events related to the drug 
- Mild visual disturbances 
- Transient IOP increase 
 
• 
Rare and serious events related to the drug 
Potential risk of arterial thromboembolic events (ATEs. i.e., nonfatal stroke, nonfatal 
myocardial infarction, or vascular death).  However, the rates in the Lucentis clinical 
trials were low.  In two studies for treatment of macular edema following retinal vein 
occlusion, the ATE rate at 6 months was 0.8% for both the subjects treated with 
intravitreal ranibizumab (0.3 mg or 0.5 mg) and the control group. In studies for 
treatment of diabetic macular edema the ATE rates at 2 years were:  7.2% for 
subjects treated with 0.5 mg; 5.6% for 0.3 mg and 5.2 for control. Stroke rates were 
3.2.%, 1.2% and 1.6%, respectively 128. In a population based nested case-control 


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study intravitreal bevacizumab and ranibizumab were not associated with 
significant risk of ischemic stroke, acute myocardial infarction, congestive heart 
failure or venous thromboembolisms. 129 
 
• 
Possible side effects and complications related to intravitreal injections are listed in 
section 7.4 
 
 
7.4. 
 Intravitreal injection 
Risks of an intravitreal injection stem from risks associated with the injection procedure itself.  
These risks apply to all injections of study treatment above. 
• 
Commonly reported events related to injection procedure 
- Mild ocular discomfort or pain 
- Increased tearing 
- Subconjunctival hemorrhage 
- Conjunctival hyperemia   
- IOP elevation — typically transient not requiring therapy 
 
• 
Less frequently reported events related to injection procedure 
- Mild short-term ocular discomfort 
- Vitreous detachment 
 
• 
Rare and serious adverse reactions related to the injection procedure 
- Endophthalmitis 
- Retinal tear and/or rhegmatogenous retinal detachment 
- Eye inflammation  
- Vitreous hemorrhage 
- Vitreous detachment 
- Iatrogenic traumatic cataracts. 128, 130, 131 
 
 
 


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8. Safety reporting of adverse and other events  
 
8.1. 
General overview 
Adverse events (AEs) will be recorded on study data forms and submitted to the CC. Serious 
adverse events (SAEs), which include death, all hospitalizations, life-threatening illness, 
overdose, or congenital abnormalities in the offspring of subjects, will be reported to the CC as 
SAE reports within 72 hours after clinical center personnel become aware of the event. An 
assessment will be made by the clinical investigator at the managing clinical center as to 
whether the event is related to treatment.  Dr. Akrit Sodhi, the CC Safety Officer, and Dr. Alan 
Palestine, the DSMC Safety Officer, have been commissioned to review all adverse events and 
to make recommendations to the DSMC as to any actions that may be needed.  All SAEs will 
be reported expeditiously regardless of the relationship of treatment. These reports will be sent 
to the CC Medical Safety Officer for immediate review and determination as to whether the 
event meets the criteria for a safety report. Any SAE reports of a subject death will be sent to 
DSMC Medical Safety Officer within 24 hours of receipt at the CC.  Non-death SAE reports will 
be sent to the DSMC Medical Safety Officer within 7 days of receipt at the CC.  The DSMC 
Medical Safety Officer will review each report to determine what, if any, additional actions are 
needed, including whether the other DSMC members need to be informed of the event 
immediately as opposed to waiting for the next DSMC meeting or conference call.  All serious 
and unexpected events possibly related to study  treatment will be reported as safety reports to 
the NEI project officer, the FDA, the pharmaceutical supplier (where appropriate), and all 
clinical centers in accordance with FDA regulations. The CC and clinical centers will submit all 
safety reports as expedited reports to their IRBs. Reports of AEs not deemed to be unexpected 
will be submitted to the CC IRB, to the IRB of the clinical center in which the event was 
reported, as well as to any other study center IRBs which require such reports. 
 
Specific adverse event reporting requirements and instructions are detailed in the MERIT 
Manual of Procedures.  
 
 
8.2. 
Assessment of Safety 
8.2.1. 
Specification of Safety Variables  
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) that are considered related to any of the study treatments (intravitreal 
dexamethasone pellet (Ozurdex); intravitreal methotrexate; intravitreal ranibizumab (Lucentis), 
all events of death, and any study specific issue of concern. 
 
8.2.2. 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, 
regardless of attribution. 
 
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with uveitic macular edema 
that were not present prior to the AE reporting period. 
• 
Complications that occur as a result of protocol-mandated interventions. 
 


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If applicable, AEs that occur prior to assignment of study treatment associated with medication 
washout, no treatment run-in, or other protocol-mandated intervention. 
 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
 
8.2.3. 
Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
• 
It results in death (i.e., the AE actually causes or leads to death). 
• 
It is life threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death.) 
• 
It requires or prolongs inpatient hospitalization. 
• 
It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP. 
• 
It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical intervention 
to prevent one of the outcomes listed above). 
 
8.3. 
Methods and timing for assessing and recording safety variables 
The clinical center investigator is responsible for ensuring that all AEs and SAEs that are 
observed or reported during the study, are collected and reported to the Coordinating Center 
and their governing IRB.  The Coordinating Center is responsible for reported events to the 
FDA, appropriate IRB(s), and Genentech, Inc. in accordance with CFR 312.32 (IND Safety 
Reports).  
 
8.3.1. 
Adverse Event Reporting Period 
• 
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of study treatment [or “initiation of any study 
procedures”] and ends 30 days following the last administration of study treatment or 
study discontinuation/termination, whichever is earlier.  
 
• 
After this period, investigators should only report SAEs that are attributed to prior study 
treatment. 
 
8.3.2. 
Assessment of Adverse Events 
• 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately.  
 
• 
Each reported AE or SAE will be described by its duration (i.e., start and end dates), 
regulatory seriousness criteria if applicable, suspected relationship to the study 
treatment (see following guidance), and actions taken. 
 
• 
To ensure consistency of AE and SAE causality assessments, investigators should 
apply the following general guideline: 


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- Yes 
 
There is a plausible temporal relationship between the onset of the AE 
and administration of the study treatment, and the AE cannot be readily 
explained by the subject’s clinical state, intercurrent illness, or 
concomitant therapies 
And/or 
 
The AE follows a known pattern of response to the study treatment; 
and/or the AE abates or resolves upon discontinuation of the study 
treatment or dose reduction and, if applicable, reappears upon re-
challenge. 
- No 
 
Evidence exists that the AE has an etiology other than the study 
treatment (e.g., preexisting medical condition, underlying disease, 
intercurrent illness, or concomitant medication): 
And/or  
 
The AE has no plausible temporal relationship to study treatment 
administration (e.g., cancer diagnosed 2 days after first dose of study 
treatment). 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert or current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current 
Investigator Brochure (I.B.) or not identified. This includes adverse events for which the 
specificity or severity is not consistent with the description in the P.I. or I.B. For example, under 
this definition, hepatic necrosis would be unexpected if the P.I. or I.B. only referred to elevated 
hepatic enzymes or hepatitis. 
 
 
8.4. 
Procedures for eliciting, recording, and reporting adverse events 
8.4.1. 
Overview 
• 
Eliciting adverse events 
A consistent methodology for eliciting AEs at all subject evaluation time points should be 
adopted. Examples of non-directive questions include:  
- “How have you felt since your last clinical visit?” 
- “Have you had any new or changed health problems since you were last here?”  
 
• 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations. 
 
8.4.2. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the 
time of reporting, it is ok to report the information that is currently available. If a diagnosis 
is subsequently established, it should be reported as follow-up information. 
 


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8.4.3. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period, regardless of 
attribution, will be reported to the appropriate parties. When recording a death, the event 
or condition that caused or contributed to the fatal outcome should be reported as the 
single medical concept. If the cause of death is unknown and cannot be ascertained at 
the time of reporting, report “Unexplained Death”. 
 
8.4.4. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting medical 
condition should be re-assessed throughout the trial and reported as an AE or SAE only 
if the frequency, severity, or character of the condition worsens during the study. When 
reporting such events, it is important to convey the concept that the preexisting condition 
has changed by including applicable descriptors (e.g., “more frequent headaches”). 
 
8.4.5. 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE. If a subject is hospitalized to undergo a medical or surgical 
procedure as a result of an AE, the event responsible for the procedure, not the 
procedure itself, should be reported as the SAE. For example, if a subject is hospitalized 
to undergo coronary bypass surgery, record the heart condition that necessitated the 
bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
- Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
- Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
- Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
 
8.4.6. 
Pregnancy 
If a female subject becomes pregnant while receiving investigational therapy or within 30 days 
after the last dose of a study treatment, a report should be completed and expeditiously 
submitted to the Coordinating Center who will submit report to Genentech, Inc. if study 
treatment is Lucentis. Follow-up to obtain the outcome of the pregnancy should also occur. 
Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as 
serious, and expeditiously reported as an SAE. Similarly, any congenital anomaly/birth defect in 
a child born to a female subject exposed to a study treatment should be reported as an SAE. 
 
8.4.7. 
Product complaints 
A product complaint is any written or oral information received from a complainant that alleges 
deficiencies related to identity, quality, safety, strength, purity, reliability, durability, effectiveness 
or performance of a product after it has been released and distributed to the commercial market 
or clinical trial.  Clinical centers are required to report product complaints for study treatments to 
the CC on an Unanticpated Event (UA) form within 7 days of learning of the event.  
 A recent FDA update to the Post Marketing Safety Reporting (PMSR) regulation requires the 
Marketing Authorization Holder (MAH) to report product complaints to the FDA.  Genentech, the 


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MAH for ranibizumab (Lucentis), is donating the ranibizumab for U.S. clinical centers for the 
MERIT Trial.   As part of the CC’s agreement with Genentech, the CC will report any product 
complaints for ranibizumab reported for the MERIT Trial.  The CC will report complaints to 
Genentech within 15 days  
8.4.8. 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has completed or 
discontinued study participation if attributed to prior exposure to study treatment. If the 
investigator should become aware of the development of cancer or a congenital anomaly in a 
subsequently conceived offspring of a female subject who participated in the study, this should 
be reported as an SAE. 
  
8.4.9. 
Reconciliation 
The Coordinating Center (the sponsor) agrees to conduct reconciliation for the product donated 
by Genentech (i.e., Lucentis).  The Coordinating Center will agree to the reconciliation 
periodicity and format, but agree at minimum to exchange quarterly line listings of cases 
received by the other party. If discrepancies are identified, the Coordinating Center and 
Genentech will cooperate in resolving the discrepancies. The responsible individuals for each 
party shall handle the matter on a case-by-case basis until satisfactory resolution. 
 
8.4.10. 
AEs of Special Interest (AESIs)  
AEs of Special Interest are defined as a potential safety problem, identified as a result of safety 
monitoring of the Product.  
  
The Lucentis Events of Special Interest are:  
• 
Retinal pigment epithelial tear 
• 
Increased intraocular pressure to > 30mm Hg not responsive to maximal topical IOP-
lowering drugs measured on 2 separate days  
• 
Traumatic cataract 
• 
Endophthalmitis 
• 
Intraocular inflammation of greater than 2+ cells (including vitritis and uveitis) 
• 
Retinal detachment 
• 
ATEs, including stroke 
 
8.4.11. 
SAE Reporting 
Investigators must report all SAEs to the Coordinating Center who will report events as 
applicable to Genentech within the timelines described below. The completed Medwatch/case 
report should be faxed immediately upon completion to Genentech Drug Safety at: 
 
 
 
• 
Relevant follow-up information should be submitted to the Coordinating Center who will 
submit to Genentech Drug Safety as soon as it becomes available. 
• 
Serious AE reports that are related to the Lucentis and AEs of Special Interest 
(regardless of causality) will be transmitted to the Coordinating Center within three (3) 
calendar days of the Awareness Date,  The Coordinating Center will transmit Genentech 
within fifteen (15) calendar days of the Awareness Date. 
• 
Serious AE reports that are unrelated to the Lucentis will be transmitted to the 
Coordinating Center within three (3) days of the Awareness Date.  The Coordinating 


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Center will submit these reports to Genentech within thirty (30) calendar days of the 
Awareness Date. 
• 
Additional Reporting Requirements to Genentech include the following: 
• 
Any reports of pregnancy following the start of administration with the Lucentis will be 
transmitted to the Coordinating Center within seven (7) days of the Awareness date.  
The Coordinating Center will submit the report to Genentech within thirty (30) calendar 
days of the Awareness Date.  
• 
The Coordinating Center will forward all Non-serious Adverse Events originating from 
the Study in a quarterly report or a final listing with the final safety report (FSR) to 
Genentech. 
 
Note: Investigators should also report events to their IRB as required. 
 
8.4.12. 
CC event reporting to Genentech 
 
The CC will report all protocol-defined AEs, SAEs, AE of special interest, Special Situation Reports 
(including pregnancy reports) and Product Complaints with an AE for participants randomizied to or who 
received ranibizumab during the trial to Genentech by fax: 650-238-6067’ or email: usds_aereporting-
d@gene.com. 
 
The CC will report ranibizumabl Product Complaints without an AE to Genentech by email: 
kaiseraugst.global_impcomplaint_management@roche.com 
 
8.5. 
MedWatch 3500A Reporting Guidelines 
The Coordinating Center is responsible for the following. 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of the 
MedWatch 3500A form: 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
 
Follow-up Information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
• 
Summarizing new information and faxing it with a cover letter including patient identifiers 
(i.e. D.O.B. initial, patient number), protocol description and number, if assigned, brief 
adverse event description, and notation that additional or follow-up information is being 
submitted (The patient identifiers are important so that the new information is added to 
the correct initial report) 
 
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the patient for whom and adverse event was reported. For questions regarding 


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SAE reporting, you may contact the Genentech Drug Safety representative noted above or the 
MSL assigned to the study. Relevant follow-up information should be submitted to Genentech 
Drug Safety as soon as it becomes available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/medwatch/getforms.html  
 
8.6. 
Additional Reporting Requirements for IND Holders 
The Coordinating Center holds the IND for MERIT and is responsible for the following. 
For Investigator-Sponsored IND Studies, some additional reporting requirements for the FDA 
apply in accordance with the guidance set forth in 21 CFR § 600.80.  
 
Events meeting the following criteria need to be submitted to the Food and Drug Administration 
(FDA) as expedited IND Safety Reports according to the following guidance and timelines: 
 
 


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7 Calendar Day Telephone or Fax Report: 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that 
is unexpected and assessed by the investigator to be possibly related to the use of a study 
treatment. An unexpected adverse event is one that is not already described in the study 
treatment Investigator Brochure. Such reports are to be telephoned or faxed to the FDA and 
Genentech within 7 calendar days of first learning of the event. 
 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a written 
IND Safety Report, of any serious, unexpected AE that is considered reasonably or possibly 
related to the use of a study treatment. An unexpected adverse event is one that is not already 
described in the study treatment investigator brochure. 
 
Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32. All safety reports previously filed by the investigator with the IND 
concerning similar events should be analyzed and the significance of the new report in light of 
the previous, similar reports commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech, and all participating investigators within 15 calendar days of first learning of the 
event. The FDA prefers these reports on a Medwatch 3500 form, but alternative formats are 
acceptable (e.g., summary letter). 
 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
 
All written IND Safety Reports submitted to the FDA by the Investigator must also be faxed to 
Genentech Drug Safety: 
Fax: (650) 225-4682 or (650) 225-5288 
 
And to the Site IRB 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-5288 
 
IND Annual Reports 
Copies to Genentech: 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. Copies of such reports should be faxed to Genentech Drug Safety: 
 
Fax: (650) 225-4682 or (650) 225-5288 
 
8.7. 
Study Close-Out 
The Coordinating Center is responsible for the following. 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final study 
report). Additionally, any literature articles that are a result of the study should be sent to 


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Genentech. Copies of such reports should be mailed to the assigned Clinical Operations contact 
for the study: 
E-mail: lucentisgsr_coa-d@gene.com 
Fax: 866-728-4622 
 
 


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9. Sample size and statistical methods 
9.1. 
Sample size, power and detectable differences 
The study is powered to test whether intravitreal methotrexate and ranibizumab are each 
superior to intravitreal dexamethasone in terms of change in central subfield thickness.  A 
Bonferroni correction is used to adjust for the co-primary hypotheses, i.e. a two-sided type I 
error rate of 0.05/2 = 0.025 will be used to determine statistical significance.  The primary 
outcome, retinal thickness, is measured on the log-scale, which translates to an assessment of 
relative change compared to baseline. The expected percent reduction in retinal thickness from 
baseline for dexamethasone is 25% (log [0.75] = -0.2877); macular edema that persists after 
corticosteroid treatment is expected to be less likely to benefit from additional corticosteroid 
therapy.  We expect the novel treatment arms to produce a reduction of 38% (log [0.62] = -
0.4780).  A sample size of 79 independent eyes per treatment group, i.e. 79 individuals with one 
eye for each individual, will provide 91% power to demonstrate an improvement in the percent 
reduction in retinal thickness from 25% to 38% with a two-sided type I error rate of 0.025. 
Assuming a between-eye correlation of 0.4, 25% bilateral disease, and a 10% loss to follow-up, 
we need to enroll 80 individuals in each treatment arm (240 total), 8 fewer participants per arm 
than would be required if only one eye was included for individuals with bilateral disease after 
adjusting for loss to follow-up. 
We also will compare the percent change in retinal thickness for intravitreal injections of 
methotrexate and ranibizumab; however, the percent change is expected to be similar for these 
therapies and the study is not powered to detect equivalence.  The calculation presented here is 
meant to demonstrate the type of difference that would be detectable with the sample required 
for the primary hypotheses.  As noted above, we assume that the reference group will have a 
percent reduction of 38% (log [0.62]) with a standard deviation for the change in log-retinal 
thickness of 0.33.  A sample size of 79 independent eyes per treatment group (the equivalent of 
80 individuals per arm assuming 10% loss to follow-up, 25% bilateral disease and between-eye 
correlation of 0.4) provides 80% power to detect a difference between the reference percent 
change of 38% and a percent change of 46.6% (log [0.534]) with a two-sided type I error rate of 
0.05. 
 
9.2. 
Statistical methods 
The primary outcome variable is change in log retinal thickness at 12 weeks.  A linear 
regression model fitted with generalized estimating equations132 will be used to compare the 
change in log retinal thickness between each of intravitreal methotrexate and ranibizumab with 
dexamethosone.  The mean structure will include treatment effects, a time indicator for weeks 4, 
8, 12, 16, 20, and 24, and time-by-treatment interaction terms. The interaction term for 12 
weeks represents the difference in change in log retinal thickness from baseline.  An 
unstructured or Toeplitz covariance matrix will be used to model the longitudinal, within-eye 
repeated measures and the bootstrap will be used to adjust the standard errors to account for 
the between-eye correlation.   Other continuous and binary outcomes will be modeled in a 
similar manner using linear and logistic models, respectively. In addition, the models will be 
adjusted for the stratification variable used during randomization (presence or absence of 
concomitant systemic corticosteroid and/or immunosuppressive therapy). 
 
Kaplan Meier curves will be plotted to graphically portray the cumulative percent with 
improvement of ME based on OCT central subfield assessment over time for the three 
treatments.  Cox proportional hazards models taking into account the correlation between eyes 


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through a random effect (also known as a frailty model) will be used to compare the time to 
improvement of ME for the three treatment arms.  Additional time-to-event outcomes (e.g. time 
to resolution, failure, and relapse) will be analyzed in a similar manner. 
 
The rates of adverse events will be compared using a Negative Binomial model with a random 
effect for individual.  The overall burden and timing of serious adverse events will be displayed 
graphically by plotting a single line for each individual highlighting the start and stop dates of 
SAE sorted by the time of first event133. Robust standard errors will be computed for all analyses 
using statistical program-based approaches or the bootstrap, where the unit of analysis is the 
individual. In addition, the models will be adjusted for the stratification variable used during 
randomization (presence or absence of concomitant systemic corticosteroid and/or 
immunosuppressive therapy). All primary analyses will be according to treatment assignment 
(i.e. following the principles of Intention to Treat).  A sensitivity analysis of based upon treatment 
received will be performed for comparison.  Additional sensitivity analyses will be performed to 
assess the impact of missing data.  These include ‘best’ and ‘worst’ case single imputations as 
well as multiple imputation and pattern mixture approaches134, 135. 
 
 


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10. Efficacy monitoring and stopping guidelines 
 
The guidelines for the interim efficacy analyses were developed by the Data and Safety 
Monitoring Committee (DSMC) and MUST Executive Committee.  Additional unplanned efficacy 
analyses will be done if recommended by the DSMC or MUST Executive Committee. 
A single pre-planned interim efficacy analysis will be performed once 40% of participants have 
completed the 12-week visit (the primary outcome time-point).   The type I error for each of the 
co-primary comparisons is 0.025, i.e. half was allocated to each comparison to control the study 
wide type I error rate.   For each comparison, the type I error thresholds would be 0.00016 at the 
interim analysis and 0.02484 at the final analysis to maintain a global 0.025 error rate over the 
course of the trial based upon O’brien-Fleming boundaries.  
 
 


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11. Regulatory and ethical issues 
 
11.1. Recruitment and informed consent procedures 
Eligible patients will be recruited from the patient populations seen at and referred to the MUST 
Research Group clinical centers located in the United States, United Kingdom, Australia, 
Canada, and India.. Typically, patients will be identified in the course of usual clinical practice by 
the study physicians. When a potentially eligible patient is identified, the study physician and 
study coordinator will describe the study to and discuss the study with the patient. Patients 
considering enrollment will be given the consent statement and, if applicable, IRB-approved 
informational materials and be allowed time to decide about joining the study. After patients 
have time to review materials and discuss enrollment with family members when appropriate, 
the clinic coordinator or study physician will obtain written informed consent, using a written, 
local IRB-approved consent document  based on a prototype prepared by the CC and approved 
by the CC’s IRB, the JHSPH IRB Office.  The trial will be registered on www.ClinicalTrials.gov. 
Recruitment efforts and eligibility criteria for MERIT are subject to review and approval by IRBs 
and the DSMC. 
 
11.2. IRB/Protection of human subjects 
Potential risks and procedures to minimize risks to participants 
The injection procedures, dosage of medication and treatment algorithm within the study will be 
consistent with standard clinical treatment, e.g., sterile technique, prophylactic pressure 
lowering medicine instilled prior to procedure. To minimize risks associated with increased 
ocular pressure post-injection, patients with uncontrolled ocular hypertension or glaucomatous 
changes will be excluded from the trial.  Patients in the trial will not be exposed to risk beyond 
what they would be exposed to with standard clinical care for their condition. Adverse events 
encountered will be managed by the best medical judgment of the treating physician. 
 
Confidentiality 
Confidentiality of patient data will be maintained in accordance with legal regulations. Protected 
health information will be kept in a secure place. Name, social security number, address, and 
other such personal data will be kept solely at the clinical center where the patient receives 
her/his clinical care. Such information will not be transmitted to the Coordinating Center or to 
other study sites. A dataset limited so as to contain a minimal amount of protected health 
information–that required to make the data useful for accomplishing the purposes of the MUST 
Trial–may be disclosed, as needed, to collaborating study sites, the NEI, and the FDA, as will be 
stated on a study privacy acknowledgment form signed by the participant at the time of 
enrollment. Also included in the privacy acknowledgment is the statement that representatives 
of NEI, FDA, the Institutional Review Boards, and Coordinating Center may see identifying 
information while reviewing study records. This privacy acknowledgment will be designed to 
conform to specifications of HIPAA regulations, and any other relevant regulations, as approved 
by the local governing authorities invested with oversight of HIPAA regulations at each 
participating site. Clinically relevant information from the study may be placed in the patient's 
medical record. Release of protected health information to any other persons or organizations 
will require additional written consent of the patient affected, except as required by law. 
 
 


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Inclusion of children  
Patients under 18 years of age will not be included as neither ranibizumab nor the 
dexamethasone pellet is approved for pediatric use. 
 
Data and safety monitoring 
Trial monitoring will be conducted by a study Data and Safety Monitoring Committee (DSMC).  
The DSMC consists mostly of members of the standing DSMC which monitored the Multicenter 
Uveitis Steroid Treatment (MUST) Trial and now is monitoring the MUST Follow-up Study. The 
Chair of the MUST DSMC, who is a biostatistician, is unable to serve because of potential 
conflicts of interest.  Hence a new member who is an experienced methodologist for ophthalmic 
studies was appointed and the Chair of the DSMC for this protocol is one of the clinical experts. 
The committee consists of voting members with expertise in biostatistics, clinical trial design, 
and ophthalmology who were appointed by NEI and non-voting members (i.e., Study Officers).   
 
For each DSMC meeting, data will be summarized by personnel from the CC and presented to 
the DSMC. The DSMC will meet at least twice a year (one in-person meeting and one meeting 
by conference call).  Additional meetings/conference calls may be requested by DSMC Chair 
and/or NEI Project Officer.  Meeting reports will include information summaries related to 
monitoring the safety and effectiveness of the study treatments as well as study performance 
including data quality and clinic performance.  Pertinent information from outside sources such 
as a reprint of a recent publication reporting on results of other, related studies will also be 
included as available. All reports will include tables and graphs that summarize and formally 
compare baseline and adverse event data by treatment assignment, and if indicated, within 
specific subgroups.  A single interim efficacy analysis formally comparing the treatment groups 
will be performed once 50% of participants have completed the 12-week visit (See Section 10).  
Graphical and/or numeric summaries (without formal statistical comparisons) will be provided in 
the meeting books that are not associated with the interim efficacy analysis.  Additional efficacy 
analyses may be performed at the request of the DSMC if necessary.  
 
The DSMC Medical Safety Officer, appointed from among the physician voting members of the 
DSMC, will review all SAE reports received by the CC as described in section 5.1.   
 
 


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Han IC, Jaffe GJ. Comparison of spectral- and time-domain optical coherence tomography for 
retinal thickness measurements in healthy and diseased eyes. American journal of 
ophthalmology. 2009;147(5):847-58. 
123. 
Kakinoki M, Sawada O, Sawada T, Kawamura H, Ohji M. Comparison of macular thickness 
between Cirrus HD-OCT and Stratus OCT. Ophthalmic Surg Lasers Imaging. 2009;40(2):135-40. 
124. 
Kiernan DF, Hariprasad SM, Chin EK, Kiernan CL, Rago J, Mieler WF. Prospective comparison of 
cirrus and stratus optical coherence tomography for quantifying retinal thickness. American 
journal of ophthalmology. 2009;147(2):267-75. 
125. 
Galor A, Margolis R, Brasil OMF, Perez VL, Kaiser PK, Sears JE, et al. Adverse events after 
intravitreal triamcinolone in patients with and without uveitis. Ophthalmology. 
2007;114(10):1912-8. 
126. 
Regillo CD, Brown DM, Abraham P, Yue H, Ianchulev T, Schneider S, et al. Randomized, double-
masked, sham-controlled trial of ranibizumab for neovascular age-related macular 
degeneration: PIER Study year 1. American journal of ophthalmology. 2008;145(2):239-48. 
127. 
Ferris FL, 3rd, Kassoff A, Bresnick GH, Bailey I. New visual acuity charts for clinical research. 
American journal of ophthalmology. 1982;94(1):91-6. Epub 1982/07/01. PubMed PMID: 
7091289. 
128. 
LUCENTIS (ranibizumab injection) (Package Insert). Genentech Inc. South San Francisco, CA 
94080: February 2013. 
129. 
Campbell RJ, Gill SS, Bronskill SE, Paterson JM, Whitehead M, Bell CM. Adverse events with 
intravitreal injection of vascular endothelial growth factor inhibitors: nested case-control study. 
BMJ (Clinical research ed). 2012;345:e4203. Epub 2012/07/06. doi: 10.1136/bmj.e4203. 
PubMed PMID: 22763393; PubMed Central PMCID: PMCPMC3389519. 
130. 
Day S, Acquah K, Mruthyunjaya P, Grossman DS, Lee PP, Sloan FA. Ocular complications after 
anti-vascular endothelial growth factor therapy in Medicare patients with age-related macular 
degeneration. American journal of ophthalmology. 2011;152(2):266-72. Epub 2011/06/15. doi: 
10.1016/j.ajo.2011.01.053. PubMed PMID: 21664593; PubMed Central PMCID: 
PMCPMC3143287. 
131. 
Ozurdex (package insert). Allergan, Inc. Irvine, CA 92612: 2013. 
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Diggle P HP, Liang K-Y, Zeger S. Analysis of Longitudinal Data. New York: Oxford University Press 
Inc.; 2002. 
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Keene ON, Jones MRK, Lane PW, Anderson J. Analysis of exacerbation rates in asthma and 
chronic obstructive pulmonary disease: example from the TRISTAN study. Pharm Stat. 
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Daniels MJ HJ. Missing Data in Longitudinal Studies: Strategies for Bayesian Modeling and 
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Little RJA RD. Statistical Analysis with Missing Data. 2nd ed. New York: John Wiley & Sons; 2002. 
 

ICF_001.pdf: 
 
 
 
 
Macular Edema Ranibizumab v. Intravitreal anti-inflammatory Therapy (MERIT) 
Trial 
Prototype Consent 
20 Aug 2020 
 
 
                   ClinicalTrials.gov identifier: NCT02623426 
 
 


 
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JOHNS HOPKINS BLOOMBERG SCHOOL OF PUBLIC HEALTH 
 
INFORMED CONSENT DOCUMENT 
 
 
 
Study Title:  Macular Edema Ranibizumab v. Intravitreal anti-inflammatory 
Therapy (MERIT) Trial  
Principal Investigator:  Janet T. Holbrook, PhD, MPH 
Sponsor: The National Eye Institute of the National Institutes of Health 
 
PI Version Date: 20 August 2020 
 
What you should know about this study 
• You are being asked to join a research study. 
• This consent form explains the research study and your part in the study.   
• Please read it carefully and take as much time as you need.  
• You are a volunteer.  You can choose not to take part.  If you join, you may quit 
at any time. There will be no penalty if you decide to quit the study.   
• During the study, we will tell you if we learn any new information that might affect 
whether you wish to continue to be in the study. 
 
Purpose of research project 
This research is being done to test treatments for persistent or recurrent macular edema 
in patients with the eye condition uveitis.  Uveitis is inflammation inside of the eye. 
Macular edema is swelling of the retina at the back of the eye.  Macular edema can 
cause vision loss.   
 
The standard treatment for macular edema is injections of corticosteroid drugs into or 
near the eye.  Sometimes the injections work only for a short time or the macular edema 
does not completely resolve.  When this happens, the macular edema is said to be 
persistent and injections are needed more often.  In other cases, the injections work 
well and the macular edema completely resolves but it reoccurs and needs to be treated 
with more injections.  Repeated corticosteroid injections can cause side effects such as 
increase in eye pressure.  This study will test whether other drugs that are not steroids 
are more effective that intravitreal corticosteroids in treating macular edema. 
 
There are two types of corticosteroid drugs that are used as standard treatment for 
macular edema.  One type is triamcinolone.  Another type of corticosteroid drug that is 
used to treat uveitic macular edema is dexamethasone (also known as Ozurdex).  
Dexamethasone is in a pellet that releases medicine over time.  Because the medicine 
is released over time, the treatment effect lasts longer.  An applicator is used to inject a 


 
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dexamethasone pellet into the eye.  It is a standard treatment for uveitic macular edema 
approved by the FDA.     
Recent research has shown that other drugs injected into the eye can reduce macular 
edema in patients with uveitis.  These drugs may have fewer side effects than the usual 
treatments.  Two drugs that have been shown to reduce macular edema in small 
studies are methotrexate and ranibizumab (also known as Lucentis).  Methotrexate is 
not approved by the FDA for treatment of any eye conditions. However, it has been 
used both systemically and by injection directly into the eye to treat some eye 
conditions.  Ranibizumab is approved by the FDA for treating some kinds of macular 
edema but not macular edema related to uveitis.  
 
This study will compare dexamethasone, methotrexate, and ranibizumab to find out 
which is the safest and most effective in treating persistent or recurrent macular edema. 
If you join the study, one of these drugs will be injected into the vitreous of your eye 
(intravitreal injection).  The vitreous is the jelly like substance inside your eye.  
Intravitreal injection is used to place medicines inside the eye, near the retina.  Placing 
the medicines inside the eye is done to avoid effects on the rest of the body.  
 
 
Why you are being asked to participate 
You are being asked to take part in this study because you have uveitis and macular 
edema that is persistent or recurrent.  By persistent we mean that it does not respond 
completely or comes back sooner than expected after the standard treatment.  By 
recurrent we mean that the macular edema responds completely but reoccurs.  For 
people with persistent or recurrent macular edema, further treatment is often 
recommended and may be beneficial.  However, which medications will provide the 
most effective and safest choices for further treatment remain unclear. 
 
About 240 participants will be enrolled in this study at clinics in the United States, 
Australia, Canada, the United Kingdom, and India.  Up to 48 participants will be enrolled 
at this clinic. 
 
 
Sources of funding 
This study is being conducted with funding from the National Eye Institute (NEI), a part 
of the National Institutes of Health (NIH).  The NIH is a branch of the United States 
government.  Genentech, a drug company, is donating one of the study drugs, 
ranibizumab (Lucentis) for participants in the U.S.. 
 
 
Procedures 
Screening phase: 
If you agree to take part in this study and sign this consent form, the study doctor will 
need to find out if you are eligible.  
• You will be asked questions about your medical history, eye problems, and 
treatments you have received.   


 
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• Your vision will be tested.  
• Your eye pressure will be measured.   
• The front and back parts of your eye will be examined.  
• You will have a test called optical coherence tomography (OCT) to measure the 
thickness of the central part of the retina to look for swelling.   
• Women who are able to have children will have a pregnancy test.  Women who 
are pregnant or breastfeeding may not join the study.    
 
You also may be asked to sign a medical release of information form that will allow the 
study doctor to get copies of all of your medical records from other doctors or 
institutions.  
 
Study phase 
Study treatment 
If you are eligible and agree to join this study, you will be randomly (by chance, like 
drawing a number out of a hat) assigned to one of the three study treatments: 
• Dexamethasone pellet (Ozurdex) (0.7 mg)  
• Methotrexate (400 micrograms in 0.1 mL)  
• Ranibizumab (Lucentis) (0.5 mg in 0.05mL) 
 
You will have an equal chance of receiving each treatment.  Your study doctor will not 
get to choose which study treatment you receive.  
 
You will have a procedure to inject the study treatment into one or both of your eyes, 
depending on which eye(s) needs treatment.  Your study doctor or a doctor who works 
with your study doctor will perform the injection procedure.  Usually the first injection(s) 
will be given right away (on the same day).  The schedule for each study treatment is 
described below.  
  
• Dexamethasone pellet (Ozurdex)  
- You will get an injection of dexamethasone at or soon following your first 
study visit. 
- If needed, you will get another injection of dexamethasone at your 8-week 
study visit 
- At your 12-week study visit or later 
 If needed, you may get another injection of dexamethasone. 
 If your macular edema does not improve, you may be treated 
according to your study doctor’s best judgment. 
 
• Methotrexate 
− You will get an injection of methotrexate at or soon following your first 
study visit. 
− If needed, you will get another injection of methotrexate at your 4-week 
study visit and/or your 8-week study visit. 
− At your 12-week study visit or later 


 
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 If needed, you may get one or more additional injections of 
methotrexate spaced about 4 weeks apart. 
 If your macular edema does not improve, you may be treated 
according to your study doctor’s best judgment. 
 
• Ranibizumab (Lucentis) 
− You will get an injection of ranibizumab at or soon following your first study 
visit and at your 4-week and 8-week study visits. 
− At your 12-week study visit or later 
 If needed, you may get one or more additional injections of 
ranibizumab spaced about 4 weeks apart. 
 If your macular edema does not improve, you may be treated 
according to your study doctor’s best judgment. 
 
Before each injection, your intraocular (eye) pressure will be measured.  You will 
receive numbing medicine around your eye to prevent you from feeling pain.  Your eyes 
will be dilated using eye drops.  The doctor will ask you to lie in a comfortable position 
and place numbing drops in your eye.  Then your eye will be prepped and draped in the 
usual sterile fashion.  Your eye and eyelids will be cleaned with an antiseptic solution. 
Your eye will be then held open.  The drug will be drawn up in a sterile fashion in a 
syringe for injection.  The tip of the needle will be inserted into your eye and advanced 
towards the center of the eye to inject the drug.  You may feel slight pressure on the eye 
when this is done but you should not experience pain.  Once your eyes are dilated, the 
procedure takes around 15 minutes.  After the injection the doctor will check your eye. 
You will be monitored for any increase in eye pressure and allergic reactions. 
 
If your study treatment does not seem to be working for you, your doctor may discuss 
changing your treatment.  Your doctor may recommend other treatments according to 
his/her best medical judgment.  This may mean switching to another treatment or 
adjusting the time between treatments.  Even if your treatment changes, we want you to 
complete your study visits.   
 


 
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Study visit schedule 
This is a 24-week (6-month) study.  You will be asked to come in to the clinic for 7 study 
visits about a month apart.  Your first study visit will last about 4 to 5 hours.  The follow-
up visits will last from 2 to 4 hours.  You may need to visit the clinic more often for 
clinical care but that will not be part of the study.  
 
Visit Number 
Visit Type 
Time after previous 
visit 
 1 
Eligibility screening  
Study treatment assignment and 
administration 
-------- 
 2 
(4-week study visit) 
Follow-up 
4 weeks after visit 1 
3 
(8-week study visit) 
Follow-up 
4 weeks after visit 2 
4 
(12-week study visit) 
Follow-up 
4 weeks after visit 3 
 5 
(16-week study visit) 
Follow-up 
4 weeks after visit 4 
 6 
(20-week study visit) 
Follow-up 
4 weeks after visit 5 
7 
(24-week study visit) 
Follow-up 
4 weeks after visit 6 
 
 
Study procedures 
The following procedures are part of regular care for your eye condition and will be done 
at every study visit. 
  
• Medical/ophthalmic history:  You will be asked questions about your health, eyes, 
and vision.  This is to make sure that your study doctor knows about any side 
effects or other problems you may have. 
 
• Visual acuity:  You will be asked to read letters on a chart so your study doctor 
knows if your vision is getting better, worse, or staying the same.  
 
• External eye exam:  Your study doctor will look at the outside of your eye to 
check for any changes or abnormalities.  
 
• Slit-lamp exam:  Your study doctor will use a bright light to look at the inside of 
your eye to check for any changes or abnormalities. 
 


 
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• Measurement of intraocular pressure:   A tool called a “tonometer” will be used to 
check the pressure inside of your eye.  The tonometer applies a small amount of 
pressure on your cornea (clear part of the eye over the pupil).   
 
• Ophthalmoscopy:  Your study doctor will use a tool called an “ophthalmoscope” 
to look at the inside of your eyes to check for any changes or abnormalities.  
Your eyes will be dilated before this exam.  Eye drops will be placed in your eyes 
to make the pupils larger.  This will make it easier for the study doctor to see 
inside your eyes.   
 
• Optical coherence tomography (OCT):  The test is like an ultrasound of your eye, 
except it uses light instead of sound waves.  OCT measures the thickness of the 
back of the eye (central part of the retina) to look for swelling.  
 
The following procedures also will be done during the study.  
 
• Questionnaires:  You will be asked to fill out questionnaires at every study visit.  
This is done for the study, not as part of regular care for your eye condition.  The 
questions are about your health and vision and how they affect your life.  
 
• Gonioscopy:  This will be done at your first study visit only.  It is part of regular 
care for your eye condition.  Your study doctor will examine hidden structures in 
front of the iris (colored part of the eye) to check for any changes or 
abnormalities.  A special lens called a “gonioscope” will be used. 
 
• Pregnancy test:  This is done for the study, not as part of regular care for your 
eye condition.  If you are a woman who is able to become pregnant, you will have 
a pregnancy test at your first study visit.  If you are assigned to methotrexate or 
ranibizumab as your study treatment, you will have pregnancy tests before each 
additional injection of study treatment.  The test will be done on a urine sample.  
Some of the medicines and procedures in this study may not be safe for 
pregnant women.   
 
We will monitor you throughout the study.  During the study you should report all 
changes in your physical health or illnesses to the study staff.  You will be also asked 
about medications taken at the same time as the study treatment. 
 
 
Risks/discomforts 
As with all research studies, some procedures may be uncomfortable or carry small 
risks.  The treatments assigned during the study may also be uncomfortable and also 
have risks associated with them.  
 
Study Treatments – possible side effects 
  Dexamethasone pellet (Ozurdex):  


 
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• Commonly reported events related to the drug 
- Elevated pressure inside your eye (IOP) which may require medicine to 
lower occurs at a rate of about 20% per eye year.  IOP elevation, if it 
occurs, could last for several months.  Your study doctor will monitor your 
IOP during the study.  If it increases, your doctor will decide if you need 
medicine to lower it. 
 
• Less frequently reported events related to the drug 
- Short-term visual disturbances (blurry vision or floaters) 
- Headache 
- Cataract development (clouding of the lens of the eye) 
- Elevated intraocular pressure (IOP) which may require surgery to control  
- In eyes that have had a procedure to open the posterior lens capsule, the 
medication pellet sometimes moves from the middle chamber to the front 
chamber of the eye  
- In patients with diabetes blood sugar may increase for a day or so after 
the injection 
 
• Rare and serious events related to the drug 
- Perforation (hole) of the globe where there is thinning of the outer covering 
of the eye 
 
• Possible side effects related to the intravitreal injection are provided later in this 
consent 
 
 Methotrexate:  
• Commonly reported events related to the drug 
- Reversible corneal epitheliopathy (irritation on the surface of the cornea, the 
clear covering of the front of the eye).  This condition usually resolves without 
treatment.  If treatment is needed, usually lubricating eye drops are given. 
 
• Rare and serious events related to the drug 
- Non-infectious endophthalmitis (severe inflammation of the tissues inside 
of the eye not related to an infection)  
 
• Possible side effects related to the intravitreal injection are provided later in this 
consent 
 
 Ranibizumab (Lucentis): 
• Commonly reported events related to the drug 
- Mild visual disturbances (blurry vision or floaters) 
- Temporary increase in eye pressure 
- Eye pain 
 
• Rare and serious events related to the drug: 


 
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- Hypersensitivity reactions that may result in severe intraocular 
inflammation (swelling inside of the eye) 
- There is about a 1 to 2 % risk of arterial thromboembolic events (for 
example, fatal or non-fatal stroke or heart attack).  Intravitreal ranibizumab 
should be used with caution in patients with a history of stroke, heart 
attack, or transient ischemic attack (TIA). 
 
 Intravitreal injection:  
All three study treatments will be given by injection directly into the vitreous of the eye 
(intravitreal injection).  These are the risks related to intravitreal injections: 
• Likely:  
- Gritty feeling in eye after injection  
- Sensation of a foreign object in the eye 
- Bleeding under the conjunctiva (subconjunctival hemorrhage)  
- Bleeding over the white of the eye which can be quite marked but will 
resolve in time 
- Seeing floaters; these will become smaller and disappear over a couple of 
weeks 
- Injecting any medication into the eye may result in increased pressure 
within the eye and inflammation 
 
• Rare: Serious adverse reactions related to the injection procedure have occurred 
in less than 1 in 500 injections, including 
- Infection within the eye (endophthalmitis) 
 Symptoms are eye becomes red, sensitive to light, painful, or 
develops a change in vision or swelling around the eye    
 If any of these symptoms develop, call your study doctor right 
away. 
 An infection may lead to vision loss or in rare cases, loss of the 
eye.  
 Infections can be treated with a good result as long as you seek 
treatment quickly (preferably the same day). 
- Damage to the retina (retinal detachment or tear) 
- Eye inflammation  
- Bleeding within the eye (vitreous hemorrhage) 
- Iatrogenic traumatic cataracts 
 
Study Procedures - risks associated with study procedures: 
• Visual Acuity:  You may feel frustrated if you are having difficulty reading some of 
the letters on the chart.  You may experience some eye strain if you look at the 
chart for too long.  
 
• External eye exam:  You may find the bright light used during the exam to be 
uncomfortable, but it should not be painful. 
 


 
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• Slit-lamp exam:  After the doctor dilates your eyes, your vision may be blurry and 
you may have trouble focusing on objects.  You may be sensitive to bright light 
and you may need to wear dark glasses (or sunglasses).  These side effects last 
only a short time.  
 
• Measurement of intraocular pressure (IOP):  You may experience a sensation of 
pressure when the measurement tool presses against your eye.  You may find 
this sensation to be uncomfortable but not painful.  Minor scratching of the 
corneal surface may rarely occur when the pressure in the eye is measured. 
 
• Ophthalmoscopy and OCT:  You may find the bright light used during these 
procedures to be uncomfortable, but it should not be painful.  
 
• Gonioscopy:  You may experience a slight burning from the eye drops your 
doctor uses during this exam.  You may also experience blurred vision for 
several hours after the exam. 
 
• Pregnancy test:  You may have an emotional response to finding out you are 
pregnant if you were not previously aware.  
 
• Questionnaires:  You may get tired or bored when you are completing the 
questionnaires.  You do not have to answer any questions that you do not want 
to answer.  
 
 
For women   
You may not join this study if you are pregnant or breastfeeding.  If you are able to 
become pregnant, you must agree to practice birth control (abstinence, combination 
barrier and spermicide or hormonal) while you are in the study.  This precaution is taken 
because the effects of study treatments on fetal development are not fully known.  The 
effect of intravitreal ranibizumab and dexamethasone on fetal development are not 
known.  Methotrexate is known to cause fetal death and/or birth defects when it is given 
systemically.  Given systemically means when the drug is given by mouth or injection in 
a way that affects the whole body.  The risk of harm to a fetus when methotrexate is 
injected into the eye at the dose used in this study is not known.  The dose of 
methotrexate used in this study is lower than doses usually given systemically. 
If you become pregnant while you are in the study, you must agree to let the study 
doctor know.  You also will need to report any problems you have.  We will ask you to 
let us know the outcome of your pregnancy even if you have finished the study. 
 
 
General Risks 
As with all research studies, it is possible that study procedures may involve unknown 
risks. 
 


 
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Your macular edema may not get better while you are in the study.  It is possible that 
your macular edema might not respond to study treatment and could get worse.  If this 
happens you will be treated according to your study doctor’s best medical judgment.  
You will be told of any findings that might change your decision of whether to remain in 
this study.   
 
If you have any questions or concerns regarding any of these risks, please consult with 
your study doctor.  If you experience any illness or discomfort during the study, you 
should notify your study doctor.  
 
 
Benefits 
The benefits of taking part in this study for you are unknown because it is not clear 
which treatment will work best for which patients.  You will receive a general 
assessment of your uveitis and your macular edema.  Information from this study may 
be helpful in the future to other people with uveitis and macular edema.  The information 
also may help you because you may need treatment for macular edema in the future. 
 
 
Payment 
You will receive $75 for each study visit. If you complete all 7 visits you will get a total of 
$525.  If you leave the study before finishing all visits, you will be paid for the visits you 
have completed. 
 
 
Protecting data confidentiality 
All research projects carry some risk that information about you may become known to 
people outside of the study.  In order to minimize this risk, your name and other 
identifying information will be kept private.  Data collected from your study visits will be 
sent to the Coordinating Center.  The Coordinating Center is located at The Johns 
Hopkins University in Baltimore, Maryland.  Your information will be labeled with a 
unique number and special code to keep it private.  The unique number and code 
cannot be linked to your name except at the clinical center where you complete visits. 
Some of the OCTs taken of your eyes will be sent to the Photograph Reading Center 
located at the University of Wisconsin in Madison, Wisconsin. These images will also 
only be identified by the unique number and special code   
 
People at Johns Hopkins University, the National Eye Institute, the Food and Drug 
Administration, and the Institutional Review Board at this clinic may see the data 
collected from you during the study and review your records.  Also people from 
Genentech, the company that donated one of the study drugs, may review your records 
related to this study.  These people work on the study and/or need to make sure the 
study is being done correctly.  They may see your identifying information as part of their 
review.  However, they also must keep this information private.  
 


 
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Results from this study may be published in the medical journals but you will not be 
identified by name.   
 
When you join this study, you give permission for the study doctor or staff to contact you 
in the future about participating in other research studies.  You do not have to join any 
other studies unless you want to. 
 
Certificate of Confidentiality 
Your study information is protected by a Certificate of Confidentiality.  This Certificate 
allows us, in some cases, to refuse to give out your information even if requested using 
legal means.  
It does not protect information that we have to report by law, such as child abuse or 
some infectious diseases.  The Certificate does not prevent us from disclosing your 
information if we learn of possible harm to yourself or others, or if you need medical 
help.  
 
 Disclosures that you consent to in this document are not protected.  This includes 
putting research data in the medical record or sharing research data for this study or 
future research. Disclosures that you make yourself are also not protected. 
 
 
Alternatives to procedures or treatments 
You may choose not to take part in this study.  If you do not participate, you can receive 
the standard treatments for macular edema outside of this study.  You may receive 
treatments similar to the treatments in this study at the discretion of your doctor.  You 
can discuss with your doctor which treatments will benefit you the most. 
 
 
Cost of participation in the study 
You and/or your insurance will be charged for the regular medical care you need, in the 
same manner as if you were not part of this study.  Such care includes the cost of 
medications used to treat uveitis and macular edema other than your assigned study 
treatment.  The study will provide your assigned study treatment as follows: 
• If you are assigned to receive Ozurdex (dexamethasone pellet), the study will 
provide for up to 3 pellets as needed for each eligible eye; 
• If you are assigned to receive methotrexate, the study will provide up to 7 
injections as needed for each eligible eye.  
• If you are assigned to receive ranibizumab (Lucentis), the study will provide up to 
7 injections as needed for each eligible eye.  
 
Genentech, the company that makes ranibizumab (Lucentis), is donating this drug for 
the U.S. study centers. The study will pay for the other two study treatments, and for the 
cost of ranibizumab (Lucentis) for participants at centers outside of the U.S.. 
 


 
Submit Consent Documents in Microsoft Word ONLY 
 
 
Leave blank for IRB Office Use. 
IRB Office Use Only:                                         
Approval Date: 
Approved Consent IRB Version No.: 
PI Name: 
IRB No. 
 
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If you receive a treatment that you were not randomly assigned to receive, the study will 
not provide that treatment.  For example, if you are randomly assigned to receive 
methotrexate injections and the study doctor decides the injections are not helping, 
he/she may recommend you receive an Ozurdex pellet.  The cost of that Ozurdex pellet 
will be billed to your insurance and you will be responsible for any co-pays.  
 
You will also be responsible for costs not covered by insurance (for example, co-
payments) for regular medical procedures and non-study medications just as you would 
be if you were not in the study.   
What happens if you leave the study early?   
You can agree to be in the study now and change your mind later.  If you wish to stop 
participating in the study, please tell us right away.  Leaving this study early will not stop 
you from getting regular medical care at [Johns Hopkins University].  
 
If you leave the study early, [Johns Hopkins University] may use or give out your health 
information that it has already has if the information is needed for this study or any 
follow-up activities. 
 
Your study doctor may take you out of this study if staying in the study would be harmful 
to you or if you fail to follow instructions.  The sponsor or regulatory agencies may stop 
this study at any time without your consent.  If this happens, you will be notified and 
your study doctor will discuss other options with you. 
 
 
Conflict of Interest 
A conflict of interest occurs when a researcher or the University has a financial or other 
interest that might affect the researcher’s judgment when conducting a research study.  
In some situations, the results of a study might lead to a financial gain for the 
investigator(s) and/or [Johns Hopkins].  All such conflicts must be disclosed to the 
Conflict of Interest Committee.  At this time, [Johns Hopkins University] is unaware of 
any potential conflicts of interest with regard to this research study. 
 
 
Payment of treatment costs for injury or illness from study participation 
If you are hurt or become ill as a result of being in this study, contact your study doctor 
immediately.  Your study doctor will arrange for short-term emergency care or referral if 
it is needed.  However, neither [Johns Hopkins University] nor the NIH have plans that 
will pay you if you are hurt or have other bad results.  Costs of such treatment may be 
billed to you or your insurance.  Your health insurance may not pay for treatment of 
injuries as a result of your participation in this study.  You do not waive any of your legal 
rights or release anyone from liability for negligence by signing this document. 
 
 
Clinical Trial Registration 
A description of this clinical trial is available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, 


 
Submit Consent Documents in Microsoft Word ONLY 
 
 
Leave blank for IRB Office Use. 
IRB Office Use Only:                                         
Approval Date: 
Approved Consent IRB Version No.: 
PI Name: 
IRB No. 
 
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the Web site will include a summary of the results.  You can search this Web site at any 
time. 
 
 
Authorization for Disclosure of Protected Health Information for Research 
We are asking you to authorize the disclosure and use of your private health information 
for this research study.  By signing this authorization, you agree that we may release 
your private health information to us for use in this research study: 
 
Your private health information that will be used for this research includes things 
learned by the procedures described in this consent form.  The research team at your 
clinic also will collect your name, address, phone number, social security number, and 
other information that can identify you and link you to the health information collected in 
the study.  Your date of birth will be included in the information sent to the Coordinating 
Center but other identifiers such as your name will not.  After this study ends, the 
Coordinating Center will continue to store the data collected from you and other 
participants during the study.  The Reading Center will continue to store the images of 
your OCT tests. The data and images may be used for future research in uveitis and 
other health topics. 
 
The people who may receive or use your private health information include the 
researchers and their staff. The researchers and their staff are required by the Federal 
Privacy Rule to protect your private health information.  By signing this Authorization, 
you permit them to release your information to the researchers for use in this research 
study.  The researchers will try to make sure that everyone who needs to see your 
private information for this research keeps it confidential, but we cannot guarantee this. 
Although the researchers may not be covered by the Federal Privacy Rule, they will 
make an effort to protect your information using the same standards.      
 
Some other people may see your private health information outside of the research 
team.  They may include the Coordinating Center, sponsor of the study, study safety 
monitors, government regulators, and legal compliance staff.   All these people must 
also keep your information confidential. 
 
You do not have to sign this Authorization, but otherwise you may not join the study.  It 
is your choice. 
 
Your Authorization does not have an expiration date; it will continue as long as the 
research continues.  You may change your mind and take back this Authorization at any 
time.  If you take it back, the researchers may still use the private health information 
they have collected about you to that point.  To take back the Authorization, you must 
contact the researcher. 
 
 
Who do I call if I have questions or problems? 


 
Submit Consent Documents in Microsoft Word ONLY 
 
 
Leave blank for IRB Office Use. 
IRB Office Use Only:                                         
Approval Date: 
Approved Consent IRB Version No.: 
PI Name: 
IRB No. 
 
https://livejohnshopkins.sharepoint.com/sites/MUSTCoordinatingCenter/Shared Documents/MUST P Drive/Doc/MERIT/IRB 
and Consent/consent/20 08 20/20 08 20 MERIT consent.doc  
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• Call the principal investigator, [Janet Holbrook at 410-955-0930] if you have 
questions, complaints, or get sick or injured as a result of being in this study.   
 
• Call or contact the [Johns Hopkins Bloomberg School of Public Health IRB 
Office] if you have questions about your rights as a study participant. Contact the 
IRB if you feel you have not been treated fairly or if you have other concerns.  
The IRB contact information is:   
 
 
Address: 
[Johns Hopkins Bloomberg School of Public Health 
 
 
 
615 N. Wolfe Street, Suite E1100 
 
 
 
Baltimore, MD   21205] 
 
Telephone: [410-955-3193] 
 
  Toll Free: 
[1-888-262-3242] 
 
           Fax: [410-502-0584] 
 
       E-mail: [irboffice@jhsph.edu] 


 
Submit Consent Documents in Microsoft Word ONLY 
 
 
Leave blank for IRB Office Use. 
IRB Office Use Only:                                         
Approval Date: 
Approved Consent IRB Version No.: 
PI Name: 
IRB No. 
 
https://livejohnshopkins.sharepoint.com/sites/MUSTCoordinatingCenter/Shared Documents/MUST P Drive/Doc/MERIT/IRB 
and Consent/consent/20 08 20/20 08 20 MERIT consent.doc  
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What does your signature on this consent form mean? 
Your signature (or thumbprint/mark) on this form means: 
 
• You have been informed about this study’s purpose, procedures, possible benefits 
and risks. 
• You have been given the chance to ask questions before you sign. 
• You have voluntarily agreed to be in this study.  
 
________________________   _____________________________   __________ 
Print name of Adult Participant              Signature of Adult Participant                          
Date                                                           
                            
________________________   _____________________________   __________ 
Print name of Legally Authorized          Signature of LAR                                              
Date                                                           
Representative (LAR) 
___________________________________________________________________ 
Relationship of LAR to Participant  
 
Ask the participant to mark a “left thumb impression” in this box if     
the participant (or participant’s parent) is unable to provide a signature 
above.  
 
 
________________________   _____________________________   __________ 
Print name of Person Obtaining              Signature of Person Obtaining Consent          
Date                                                           
Consent 
 
 
Give one copy to the participant and keep one copy in study records