Clinical Trials Register

Summary
EudraCT Number:	2012-005418-20
Sponsor's Protocol Code Number:	CRFB002G2302
National Competent Authority:	Slovakia - SIDC (Slovak)
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-05-20
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Slovakia - SIDC (Slovak)

A.2

EudraCT number

2012-005418-20

A.3

Full title of the trial

A 12-month, randomized, double-masked, sham-controlled, multicenter
study to evaluate the efficacy and safety of 0.5 mg ranibizumab intravitreal
injections in patients with visual impairment due to vascular endothelial
growth factor (VEGF) driven macular edema (ME)

A.3.1

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

A 12-month study to evaluate the efficacy and safety of injections of 0.5
mg ranibizumab into the eye of patients with vision loss caused by
increased accumulation of fluid within the intraretinal layers of the macula
(macular edema) and for which ranibizumab may have a positive impact

A.4.1

Sponsor's protocol code number

CRFB002G2302

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 Services AG
B.1.3.4	Country	Switzerland
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 Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Slovakia s.r.o.
B.5.2	Functional name of contact point	DRA dept.
B.5.3	Address:
B.5.3.1	Street Address	Galvaniho 15/A
B.5.3.2	Town/ city	Bratislava
B.5.3.3	Post code	821 04
B.5.3.4	Country	Slovakia
B.5.4	Telephone number	+421250706111
B.5.5	Fax number	+421250706100
B.5.6	E-mail	DRA.Slovakia@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.3.4	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.3.9.4	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	0.5 / 0.05
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.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 vascular endothelial growth factor (VEGF)
driven macular edema (ME)

E.1.1.1

Medical condition in easily understood language

Impaired vision due to increased accumulation of fluid in the back of the
eye (macula) caused by an intrinsic substance, so-called vascular
endothelial growth factor (VEGF)

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	17.0
E.1.2	Level	PT
E.1.2	Classification code	10025415
E.1.2	Term	Macular oedema
E.1.2	System Organ Class	10015919 - Eye disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	PT
E.1.2	Classification code	10047571
E.1.2	Term	Visual impairment
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

To demonstrate that an individualized regimen of intravitreal injection of
0.5 mg ranibizumab has superior efficacy compared to sham treatment
in adult patients with visual impairment due to VEGF-driven ME.
The primary objective will be assessed by the BCVA change from
baseline to Month 2.

E.2.2

Secondary objectives of the trial

Evaluate efficacy of ranibizumab vs sham treatment by
•BCVA change from baseline (BL) by visit to Mo 2
•change in CSFT and CSFV (by OCT) from BL over time to Mo 2
•presence of intra-/sub-retinal fluid (by OCT) and of active ME leakage
(by FA) at Mo 2
•rescue treatment requirement at Mo 1
Evaluate efficacy of ranibizumab by original treatment assignment by
•average BCVA change from BL to Mo1 thru Mo6 and to Mo1 thru Mo12
•change from BL in CSFT and CSFV (by OCT) by visit
•presence of intra-/sub-retinal fluid (by OCT) and of active ME leakage
(by FA) at Mo 2,6 and 12 compared to BL
•proportion of patients with ≥1, ≥5, ≥10 and ≥15 letters gain or
reaching 84 letters, from BL at Mo 2, 6 and 12
•proportion of patients with >1, >5,>10 and >15 letters loss at Mo 2,6
and 12
Assess number of ranibizumab (re)treatments by Mo 2,6 and 12
Evaluate:
•safety of ranibizumab (ocular and non-ocular AE) vs sham at Mo 2 and
over time at Mo 6 and 12
•reasons for treatment decision

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Diagnosis of active ME secondary to any causes (for adult patients:
except DME, AMD and RVO) that is primary, chronic (i.e., ME is present
for > 3 months) or recurrent, confirmed by at least one of three
following criteria::
a) Presence of posterior pole changes compatible with active ME seen by
fundus ophthalmoscopy, biomicroscopy and fundus photography
b) Presence of leakage from ME seen by fluorescein angiography (FA)
c) Presence of intra-retinal fluid/cysts seen by optical coherence
tomography (OCT)
• BCVA must be between ≥ 24 and ≤ 83 letters tested at 4 meters
starting distance using ETDRS-like visual acuity charts (approximate
Snellen chart equivalents of 20/25 and 20/320) in the study eye
• Visual loss in the study eye should be mainly due to the presence of
any eligible types of ME (for adult patients: non-DME, non-AMD and non-
RVO) based on ocular clinical, as well as FA and OCT findings

E.4

Principal exclusion criteria

For both eyes
• Active diabetic retinopathy, active ocular/periocular infectious disease
or active severe intra-ocular inflammation (e.g., anterior chamber cells
(ACC) >2+ and/or vitreous haze (VH) >2+). Rescreening is permitted
after intra-ocular inflammation is successfully treated with antiinflammatory
therapy that does not compromise eligibility
• Confirmed intraocular pressure (IOP) ≥ 25 mmHg for any reason
• Neovascularization of the iris or neovascular glaucoma
• Inability to obtain fundus photographs, fluorescein angiograms or OCT
images of sufficient quality to be analyzed
For study eye
• ME secondary to DME, AMD or RVO (for adult patients only). RAP
lesions are exclusionary in patients 50 years of age or older
• Ocular disorders that could confound interpretation of study results,
compromise visual acuity or require medical or surgical intervention
during the 12-month study period. These include for example:
a. Presence or history of retinal detachment, macular hole, epi-retinal
membrane (if the membrane is involving the fovea)
b. Presence of cataract, leading to marked visual impairment and/or
requiring surgery during the study
c. Presence of vitreomacular traction (VMT) as the primary reason for
the ME in the opinion of the investigator
d. Diagnosis of retinitis pigmentosa (RP)
e. Diagnosis of Central Serous Chorioretinopathy (CSC, CSR)
• Any type of advanced, severe or unstable ocular disease or its
treatment, that could interfere with the primary and/or secondary
outcome evaluations including any medical condition that could be
expected to progress, recur, or change to such an extent that it could
bias the assessment of the clinical status of the patient to a significant
degree or put the patient at special risk.
• ME with a high likelihood of spontaneous resolution (e.g., central
serous chorioretinopathy (CSC) or pseudophakic ME) unless the ME
persists for > 3 months or has not improved upon topical treatment with
steroids or NSAIDsHistory of laser photocoagulation with involvement of
the macular area at any time
XML File Identifier: JPM86/zi7o8tSS09eCfH6+RpcfY=
Page 12/23
• Verteporfin photodynamic therapy (vPDT) at any time
• History of intraocular treatment with any anti-angiogenic drugs within
6 months of the baseline visit (e.g., bevacizumab [Avastin®], aflibercept
[Eylea®], pegaptanib [Macugen®], ranibizumab [Lucentis®])
• History of intravitreal treatment with steroids, e.g. triamcinolone
within 6 months prior to baseline
• History of treatment with intravitreal implants (e.g., Illuvien®,
Ozurdex®, Retisert®) at any time
• History of vitreoretinal surgery at any time (cataract surgery is not an
exclusion criterion unless a large removal of vitreous or removal of
posterior vitreous has occurred)

E.5 End points

E.5.1

Primary end point(s)

Best corrected visual acuity (BCVA) change from baseline to Month 2

E.5.1.1

Timepoint(s) of evaluation of this end point

month 2

E.5.2

Secondary end point(s)

Compared to sham treatment
• BCVA change from baseline by visit up to Month 2 in study eye
• Change in central subfield thickness (CSFT) and central subfield
volume (CSFV) in study eye from baseline over time to Month 2
• Presence of intra-/subretinal fluid in study eye at Month 2
• Presence of active chorioretinal leakage assessed by FA at Month 2
• Requirement for rescue treatment at Month 1
By original treatment assigment
• Average BCVA change in study eye from baseline to Month 1 through
Month 12
• Change from baseline in CSFT and CSFV in study eye by visit
• Presence of intra-/subretinal fluid in study eye at Month 2, Month 6
and Month 12 compared to Baseline
• Presence of active chorioretinal leakage in study eye at Month 2,Month
6 and Month 12 compared to Baseline
• Proportion of patients with ≥ 1, ≥ 5, ≥ 10 and ≥ 15 letters gain or
reaching 84 letters in study eye, from baseline at Month 2, Month 6 and
Month 12
• Proportion of patients with > 1, > 5, > 10 and > 15 letters loss at
Month 2, Month 6 and Month 12
• Number of ranibizumab treatments and retreatments to study eye by
Month 2, Month 6 and Month 12
• Type, frequency and severity of ocular and non-ocular adverse events
in the study eye up to Month 2, up to Month 6 and up to Month 12
• Reasons for treatment decision by investigator clinical judgement and
investigator-assessed evidence of disease activity from OCT and FA
images

E.5.2.1

Timepoint(s) of evaluation of this end point

see above

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

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

Yes

E.8.1.7.1

Other trial design description

open label group for adolescents

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

sham injection (adults only)

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

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

Belgium

Canada

Czech Republic

France

Germany

Hungary

Israel

Italy

Korea, Republic of

Latvia

Netherlands

Russian Federation

Singapore

Slovakia

South Africa

Spain

Switzerland

Turkey

United Kingdom

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

LVLS

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

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

157

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

120

F.4.2.2

In the whole clinical trial

187

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

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

2013-07-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-06-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-09-09

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