Clinical Trials Register

Summary
EudraCT Number:	2017-003243-37
Sponsor's Protocol Code Number:
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2017-09-12
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2017-003243-37

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.3.2

Name or abbreviated title of the trial where available

MERIT Trial

A.4.1

Sponsor's protocol code number

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02623426

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	MUST Coordinating Centre, John Hopkins Bloomberg School of Public Health
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Vision and Eye Research Unit - Anglia Ruskin University
B.5.2	Functional name of contact point	Manjo Doug
B.5.3	Address:
B.5.3.1	Street Address	Vision and Eye Research Unit (VERU) Anglia Ruskin University, Cambridge Campus Young Street
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	CB1 2LZ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	07740429192
B.5.6	E-mail	manjo.doug@nihr.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Lucentis
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Lucentis
D.3.2	Product code	EU/1/06/374/001
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravitreal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ranibizumab
D.3.9.1	CAS number	347396-82-1
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Ozurdex
D.2.1.1.2	Name of the Marketing Authorisation holder	Allergan Pharmaceuticals Ireland
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Ozurdex
D.3.4	Pharmaceutical form	Intravitreal implant in applicator
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravitreal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Dexamethasone
D.3.9.1	CAS number	50-02-2
D.3.9.4	EV Substance Code	AS2
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.7
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Methotrexate
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord healthcare
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Methotrexate
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravitreal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	methotrexate sodium
D.3.9.4	EV Substance Code	AS3
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	400
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Uveitic macular oedema

E.1.1.1

Medical condition in easily understood language

Swelling of part of the retina called the macula, which is responsible for fine vision, occuring due to inflammation in the eye (uveitis)

E.1.1.2

Therapeutic area

Diseases [C] - Eye Diseases [C11]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10002709
E.1.2	Term	Anterior uveitis
E.1.2	System Organ Class	10015919 - Eye disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	22.1
E.1.2	Level	LLT
E.1.2	Classification code	10022557
E.1.2	Term	Intermediate uveitis
E.1.2	System Organ Class	10015919 - Eye disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10036370
E.1.2	Term	Posterior uveitis
E.1.2	System Organ Class	100000004862

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10033687
E.1.2	Term	Panuveitis
E.1.2	System Organ Class	10015919 - Eye disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10058202
E.1.2	Term	Cystoid macular oedema
E.1.2	System Organ Class	10015919 - Eye disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Macular oedema is swelling of the retina at the back of the eye. It can cause vision loss and is a common complication in patients who have the eye condition uveitis (inflammation inside the eye). The MERIT Trial was designed to compare three treatments for uveitic macular oedema, to find out which intravitreal therapy offers the best balance of effectiveness and tolerability in eyes with controlled uveitis but persistent macular edema, 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 uveitic macular oedema.
The primary outcome will be the percent change in macular thickness from the baseline to the 12 week visit.

E.2.2

Secondary objectives of the trial

Secondary outcomes will be:
• Percent change in macular thickness from baseline to the 24 week visit
• Improvement of macular oedema by OCT at the 12- and 24-week visits
• Resolution of macular oedema on OCT at the 12- and 24-week study visit
• Improvement in best corrected visual acuity at the 12- and 24- week visits
• Adverse events (i.e, cataract and IOP elevation)
• Cost-effectiveness.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria:

1.18 years of age or older;

Eye level inclusion criteria - at least one eye must meet all of the following conditions

2.Inactive or minimally active non-infectious anterior, intermediate, posterior or panuveitis, as defined by SUN132 criteria as ≤ 0.5+ anterior chamber cells, ≤ 0.5+ vitreous haze grade and no active retinal/choroidal lesions for a minimum of 4 weeks;

3.Macular edema (ME) defined as the presence of macular thickness greater than the normal range for the OCT machine being used (see cut points below), regardless of the presence of cysts, following an intravitreal corticosteroid injection (≥ 4 weeks following intravitreal triamcinolone injection or ≥ 12 weeks following intravitreal dexamethasone implant injection);

Greater than 300 μm for Zeiss Cirrus
Greater than 320 μm for Heidelberg Spectralis
Greater than 300 μm for Topcon 3DOCT

4.Baseline fluorescein angiogram that, as assessed by the study ophthalmologist, is gradable for degree of leakage in the central subfield;

5.Best corrected visual acuity (BCVA) 5/200 or better;

6.Baseline intraocular pressure > 5 mm Hg and ≤ 21 mm Hg (current use of ≤3 intraocular pressure-lowering medications and/or prior glaucoma surgery are acceptable (Note: combination medications, e.g., Combigan, are counted as two IOP-lowering medications);

7.Media clarity and pupillary dilation sufficient to allow OCT testing and assessment of the fundus.

E.4

Principal exclusion criteria

Exclusion criteria:

1. History of infectious uveitis in either eye;

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

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

4. History of central serous retinopathy in either eye;

5. Active infectious conjunctivitis in either eye;

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

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

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

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

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

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

11. History of infectious endophthalmitis;

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

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

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

15. Torn or ruptured posterior lens capsule

16. Presence of silicone oil;

17. Ozurdex administered in past 12 weeks;

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

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

E.5 End points

E.5.1

Primary end point(s)

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, 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.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 week visit

E.5.2

Secondary end point(s)

•Rate of IOP elevation of >21 mm Hg or ≥ 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 to within +2 standard deviations of the normative mean for the OCT machine used
-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
•Inflammation as graded using the semi quantitative scales used in the MUST Trial i.e., clinician grading of the presence and extent of anterior chamber cells, anterior vitreous cells, and vitreous haze based on previously published standard ordinal scales (0, trace, 1+, 2+, 3+, 4+)128-130 using the scales endorsed by the Standardization of Uveitis Nomenclature Working Group when applicable2
•Safety outcomes including elevated IOP ( >30 mm Hg thresholds ); new onset posterior subcapsular (PSC) cataract or progression of pre-existing PSC (using the Age-Related Eye Disease Study [AREDS] scheme131; vitreous hemorrhage; retinal tear/detachment; endophthalmitis; severe vision loss (≥15 Early Treatment Diabetic Retinopathy Study [ETDRS] letters) during the 24 weeks of follow-up.
•Cost-effectiveness of treatments for uveitic macular edema during the 24 weeks of follow-up will be assessed by enumerating costs of treatments and procedures for uveitis during the 24 week follow-up; participants’ utilities will be measure with the EuroQol questionnaire.
•Visual function related quality of life as measured by the NEI Visual Function Questionnaire (25 item version).

E.5.2.1

Timepoint(s) of evaluation of this end point

Evaluated at week 4, 8, 12, 16, 20 and 24

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS across all the sites

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1