Clinical Trials Register

Summary
EudraCT Number:	2011-001019-30
Sponsor's Protocol Code Number:	CRFB002EDE17
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-11-14
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2011-001019-30

A.3

Full title of the trial

A 6-month multicenter, randomized, double-masked phase IIIb-study comparing the efficacy and safety of Lucentis (Ranibizumab) intravitreal injections versus Ozurdex (Dexamethasone) intravitreal implant in patients with visual impairment due to macular edema following branch retinal vein occlusion (BRVO)

A.3.1

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

Comparison of Lucentic (Ranibizumab) and Ozurdex (Dexamethasone) for the treatment of patients with visual impairment due to macular edema following branch retinal vein occlusion

A.3.2

Name or abbreviated title of the trial where available

COMRADE-B

A.4.1

Sponsor's protocol code number

CRFB002EDE17

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	Novartis Pharma GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Hungária Kft., Pharma
B.5.2	Functional name of contact point	Public Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Bartók Béla út 43-47.
B.5.3.2	Town/ city	Budapest
B.5.3.3	Post code	1114
B.5.3.4	Country	Hungary
B.5.4	Telephone number	+361457-6500
B.5.5	Fax number	+361457-6600
B.5.6	E-mail	infoph.hungary@novartis.com

D. IMP Identification
D.IMP: 1
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	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	European Union
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	RFB002
D.3.4	Pharmaceutical form	Solution for 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.3.9.2	Current sponsor code	RFB002
D.3.9.3	Other descriptive name	not applicable
D.3.9.4	EV Substance Code	SUB22314
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	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	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	European Union
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.3.2	Product code	not applicable
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.3.9.3	Other descriptive name	DEXAMETHASONE
D.3.9.4	EV Substance Code	SUB07017MIG
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	700
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

visual impairment due to macular edema following branch retinal vein occlusion (BRVO)

E.1.1.1

Medical condition in easily understood language

visual impairment due to macular edema following branch retinal vein occlusion

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	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10054467
E.1.2	Term	Macular edema
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

The primary objective is to show that ranibizumab (administered in an individualized treatment regimen) has superior efficacy and safety compared to Dexamethasone implant (Ozurdex®) over a 6 months period.

E.2.2

Secondary objectives of the trial

•To compare the mean BCVA change at Month 6 from Baseline in patients treated with Ozurdex® versus patients treated with ranibizumab
•To compare the percentage of patients gaining / losing >= 15, >= 10 and >= 5 letters after the 6-month treatment of ranibizumab versus Ozurdex® compared to baseline.
•To compare the time to achieve a significant improvement >= 15 letters under treatment of ranibizumab versus Ozurdex®
•To evaluate whether ranibizumab has a higher change over time in BCVA compared with Ozurdex® from Baseline to Month 6
•To compare the change over time of the central retinal thickness after the 6-month treatment
•To compare changes in the quality of life according to NEI-VFQ 25, SF36 and EQ-5D questionnaires under treatment of ranibizumab versus Ozurdex® from Baseline to Month 6
•To compare the increase rate of the internal ocular pressure under the treatment of ranibizumab versus Ozurdex®

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male and female patients aged >= 18 years
2. Patients diagnosed with visual impairment due to macular edema following BRVO; diagnosis of BRVO at maximum 6 months prior to Screening
The following definition of BRVO will be used for the purposes of this study:
Venous dilatation and tortuosity with scattered intraretinal hemorrhages equal to or more than 1 disc area in one quadrant and presence of retinal edema on ophthalmoscopy. Presence of vascular leakage and/or areas of capillary nonperfusion on fluorescein angiography.
3. BCVA using ETDRS charts of 20/40 to 20/400 in the study eye
4. Signed Informed Consent

E.4

Principal exclusion criteria

1. Media clarity, pupillary dilation and patient cooperation not sufficient for adequate fundus photographs
2. Central retinal thickness (CRT) < 250 µm in the study eye
3. Prior episode of RVO in the study eye
4. History of radial optic neurotomy or sheathotomy in the study eye
5. History or presence of AMD (dry or wet form) in the study eye
6. Active neovascularization in the study eye
7. Aphakia in the study eye
8. Anti-VEGF-treatment in the study or the fellow eye 3 months prior to Baseline
9. Panretinal scatter photocoagulation or sector laser photocoagulation within 3 months prior to Baseline or anticipated within the next 4 months following randomization
10. Intraocular corticosteroid use within 6 months prior to Baseline
11. History of pars plana vitrectomy
12. Intraocular surgery within 2 months prior to Baseline or anticipated within the next 6 months following randomization
13. Yttrium-aluminium-garnet (YAG) capsulotomy performed within 2 months prior to Baseline
14. Combined arterio-venous occlusion
15. Previous filtration surgery in the study eye
16. History of herpetic ocular infection
17. History of ocular toxoplasmosis
18. History of macular detachment
19. History of idiopathic central serous chorioretinopathy
20. Evidence upon examination of vitreoretinal interface disease (e.g. vitreomacular traction, epiretinal membrane), either on clinical examination or OCT, thought to be contributing to macular edema
21. An eye that, in the investigator’s opinion, would not benefit from resolution of macular edema, such as eyes with foveal atrophy, dense pigmentary changes, or dense subfoveal hard exudates
22. Any active infection in either eye (internal or external)
23. IOP  30mmHg or uncontrolled glaucoma; patients may be re-screened after 1 month if they have undergone glaucoma treatment
24. Known steroid responders
25. Any ocular condition that, in the opinion of the investigator, would alter the study outcome (e.g. uveitis or other ocular inflammatory disease, neovascular glaucoma, Irvine-Gass syndrome, or prior macula-off rhegmatogenous retinal detachment)
26. Visually significant hemorrhage obscuring the fovea and felt to be a major contributor to visual acuity. The patient should be followed and when the hemorrhage in the fovea clears to the point that it is not longer considered to be a major contributor to reduced visual acuity, the patient may be screened for the study.
27. Presence of a substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by 3 lines or more (i.e. a 20/40 cataract)
28. Evidence upon examination of pseudoexfoliationglaucom
29. Evidence upon examination of any diabetic retinopathy, defined as eyes of diabetic patients with more than one microaneurysm outside the area of the vein occlusion (includes the study eye as well as the partner eye)
30. Relevant ocular disease that may be associated with increased intraocular VEGF levels (namely uveitis, neovascular glaucoma, neovascular AMD, diabetic retinopathy, diabetic maculopathy, or ocular ischemic syndrome)
31. History of cerebral vascular accident or myocardial infarction within 12 months prior to Baseline
32. Improvement of > 10 letters on BCVA between Screening and Baseline.
33. Relevant systemic disease that may be associated with increased systemic VEGF levels (namely all active malignancies; history of successfully treated malignancies is not an exclusion criterion)
34. Uncontrolled blood pressure (defined as a systolic value of > 180 mmHg and a diastolic value of > 110 mmHg).
If a patient’s initial reading exceeds these values, a second reading may be taken 30 minutes (or more) later. If a patient’s blood pressure needs to be controlled by antihypertensive medication, the patient can become eligible if medication is taken continuously for at least 30 days prior to Baseline.
35. Women who are pregnant or breast feeding or menstruating and capable of becoming pregnant and not practicing a medically approved method of contraception during and up to at least 4 weeks after the end of treatment.
36. Current or anticipated use of systemic steroids or anticoagulants (e.g. coumadin, warfarin or heparin; the use of aspirin or clopidogrel is not excluded)
37. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer
38. History of hypersensitivity to any of the study drugs or to drugs with similar chemical structures
39. History of allergy to fluorescein
40. Any condition that, in the opinion of the investigator, would preclude participation in the study (e.g. chronic alcoholism or drug abuse, personality disorder or use of major tranquilizers, indicated difficulty in long-term follow-up)
41. Patients, who have already been randomized into this trial earlier must not be included a second time.

E.5 End points

E.5.1

Primary end point(s)

The primary objective of this study is to demonstrate the superiority of ranibizumab regarding the change in BCVA from baseline to month 6 compared to dexamethasone implant.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

E.5.2

Secondary end point(s)

For the binary secondary endpoints (VA gain/loss ≥ 15/10letters), the absolute and relative frequencies will be tabulated. For treatment comparisons, the difference in proportions and the Odds Ratio will be calculated with the respective confidence intervals and p-values. The time courses of BCVA changes will be displayed graphically (LS-means and treatment contrasts with confidence limits at each measurement time). Time to VA gain ≥ 15 will be analyzed by the Kaplan-Maier-Method.

E.5.2.1

Timepoint(s) of evaluation of this end point

6 months

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

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

LPLV

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	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.2.1	Number of subjects for this age range:	100
F.1.3	Elderly (>=65 years)	Yes
F.1.3.1	Number of subjects for this age range:	140
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	15
F.4.2	For a multinational trial
F.4.2.1	In the EEA	255
F.4.2.2	In the whole clinical trial	255

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-01-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-01-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-06-19

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