Clinical Trials Register

Summary
EudraCT Number:	2013-003640-23
Sponsor's Protocol Code Number:	ECR-RET-2013-05
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-11-27
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

Portugal - INFARMED

A.2

EudraCT number

2013-003640-23

A.3

Full title of the trial

Prospective, randomized, multicentre, open label, phase II / III study to assess efficacy and safety of ranibizumab 0.5 mg intravitreal injections plus panretinal photocoagulation (PRP) versus PRP in monotherapy in the treatment of subjects with high risk proliferative diabetic retinopathy. (PROTEUS)

A.3.1

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

Prospective, randomized, multicenter, open label, phase II / III study to assess efficacy and safety of ranibizumab 0.5 mg intravitreal injections plus panretinal photocoagulation (PRP) versus PRP in monotherapy in the treatment of subjects with high risk proliferative diabetic retinopathy. (PROTEUS)

A.4.1

Sponsor's protocol code number

ECR-RET-2013-05

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	AIBILI - Association for Innovation and Biomedical Research on Light and Image
B.1.3.4	Country	Portugal
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	Novartis Pharma 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	AIBILI - Association for Innovation and Biomedical Research on Light and Image
B.5.2	Functional name of contact point	4C- CCC for Clinical Research
B.5.3	Address:
B.5.3.1	Street Address	Azinhaga de Santa Combra, Celas
B.5.3.2	Town/ city	Coimbra
B.5.3.3	Post code	3000-548
B.5.3.4	Country	Portugal
B.5.4	Telephone number	+3512394801131
B.5.5	Fax number	+351239480117
B.5.6	E-mail	4c@aibili.pt

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 - 10 mg / ml solution for injection
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 - 10 mg / ml solution for injection
D.3.2	Product code	S
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.3.9.4	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	Yes
D.3.11.13.1	Other medicinal product type	Recombinant humanized monoclonal antibody.

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

Patients with type I or type II diabetes mellitus and high risk diabetic retinopathy.

E.1.1.1

Medical condition in easily understood language

Patients with type I or type II diabetes mellitus and high risk diabetic retinopathy.

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	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10036857
E.1.2	Term	Proliferative diabetic retinopathy
E.1.2	System Organ Class	100000004853

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 compare the efficacy of ranibizumab 0.5 mg intravitreal injections plus panretinal photocoagulation versus panretinal photocoagulation alone on the regression of the neovascularization area in patients with high-risk proliferative diabetic retinopathy over a 12-month treatment period.

E.2.2

Secondary objectives of the trial

To compare the following parameters between the two treatment arms:

- Changes in Best Corrected Visual Acuity from baseline to Month-12.
- Time to complete neovascularization regression.
- Recurrence of neovascularization.
- Changes in the macular retinal thickness by Optical Coherent Tomography from the baseline to Month-12.
- Need of treatment for diabetic macular edema.
- Need of vitrectomy due to the occurrence of vitreous hemorrhage, tractional retinal detachment or other complications of diabetic retinopathy.
- Treatment safety profile.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.High-risk proliferative diabetic retinopathy (HR-PDR);
i. Neovascularization in the disc ≥ 1/4 disc area OR Neovascularization Elsewhere ≥ 1/2 disc area;
ii. Neovascularization Elsewhere < 1/2 disc area + vitreous and/or pre-retinal haemorrhage and/or rubeosis;
iii. Neovascularization in the disc <1/4 disc area + vitreous and/or pre-retinal haemorrhage and/or rubeosis;
2. Best-corrected visual acuity at baseline ≥ 24 ETDRS letters score (approximate Snellen equivalent 20/320).
3. Type I or Type II diabetic subjects of either gender;
4. Age ≥ 18 years;
5. Ability to provide written informed consent;
6. Ability to return for all clinical trial visits.

E.4

Principal exclusion criteria

1. Any intraocular surgery within 6 months before trial enrolment,
including:
a. Prior scatter (panretinal) or focal/grid photocoagulation;
b. Eyes who have received YAG laser, or peripheral retinal cryoablation,
or laser retinopexy (for retinal tears only);
2. Fibrovascular proliferation with retinal traction;
3. Other cause of retinal Neovascularization (retinal vein occlusion,
radiation retinopathy or others);
4. Atrophy/scarring/fibrosis/ hard exudates involving the centre of the
macula;
5. Significant media opacities or inadequate pupillary dilation, which
might interfere with visual acuity, assessment of toxicity or fundus
photography;
6. Any likelihood that the subject will require cataract surgery within the
following 1 year;
7. Diabetic macular edema with central involvement, i.e., central macular
thickness (Central Point Thickness) > 300 ìm (Stratus OCT) equivalent
values measured by SD-OCT, adjusted according to the SD-OCT machine
used;
8. Previous vitrectomy;
9. Intraocular pressure > 21 mmHg;
10. Previous anti-VEGF therapy within the last 3 months;
11. Previous treatment with periocular and/or intravitreal
corticosteroids within the last 3 months;
12. Known serious allergies or history of hypersensitivity to fluorescein
used in angiography, or to components of Lucentis® formulation;
13. Acute ocular or periocular infection;
14. Active severe ocular or periocular inflammation;
15. Previous filtering surgery (e.g., trabeculectomy) or placement of a
glaucoma drainage device (e.g., tube-shunt surgery).
16. Systolic BP > 170 mmHg or diastolic BP > 100 mmHg;
17. HbA1C level ≥ 11% or recent signs of uncontrolled diabetes;
18. Any of the following underlying systemic diseases:
a. History or evidence of severe cardiac disease, e.g. NYHA Functional
Class III or IV, clinical or medical history of unstable angina, acute
coronary syndrome, myocardial infarction, or revascularization
procedure within 6 months prior to baseline, or ventricular
tachyarrhythmia requiring treatment;
b. History or evidence of clinically significant peripheral vascular disease
such as intermittent claudication or prior amputation;
c. Renal failure requiring dialysis or renal transplant or renal
insufficiency with creatinine levels > 2.0 mg/dl at screening;
d. Stroke (within 12 months of trial entry);
e. Any major surgical procedure within one month before trial
enrolment;
19. Subject with a condition (such as advanced, severe or unstable
disease or its treatment) or is in a situation which may put him/her at
significant risk, which may confound the study results or may interfere
significantly with the subject's participation in the study;
20. Previous radiation to the head in the region of the study eye;
21. Use of any other investigational drugs within the last 3 months (for
Diabetic Retinopathy or other condition);
22. History of malignancy of any organ system (other than localized
basal cell carcinoma of the skin), treated or untreated, within the past 5
years, regardless of whether there is evidence of local recurrence or
metastases;
23. Pregnant or nursing (lactating) women, where pregnancy is defined
as the state of a female after conception and until the termination of
gestation.
24. Women of child-bearing potential, defined as all women
physiologically capable of becoming pregnant UNLESS they are: using a
highly effective method of birth control (i.e. one that results in a less
than 1% per year failure rate when used consistently and correctly, such
as implants, injectables, combined oral contraceptives, and some
intrauterine devices - IUDs). Periodic abstinence (e.g. calendar,
ovulation, symptothermal, post-ovulation methods) are not acceptable.
Reliable contraception should be maintained throughout the study and
for 30 days after study drug discontinuation.

E.5 End points

E.5.1

Primary end point(s)

Regression of neovascularization, defined as any decrease in the area of neovascularization, from the baseline to Month-12

E.5.1.1

Timepoint(s) of evaluation of this end point

Screening Visit, Month 3, Month 7 and Month 12

E.5.2

Secondary end point(s)

- Best-corrected visual acuity - changes from baseline to Month 12
- Time to complete neovascularization regression
- Recurrence of neovascularization
- Macular retinal thickness - changes from baseline to Month 12, assessed by OCT
- Need of treatment for Diabetic Macular Edema
- Need of vitrectomy due to the occurrence of vitreous hemorrhage, tractional retinal detachment or other complications of diabetic retinopathy
- Adverse events related to the treatments.

E.5.2.1

Timepoint(s) of evaluation of this end point

Screening Visit, Month 3, Month 7 and Month 12

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Panretinal Photocoagulation

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

The end of the trial is the date of the last visit of the last subject undergoing the trial.

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.1.1.1

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)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

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

F.4.2.2

In the whole clinical trial

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)

Subjects completing the study will be treated at hospital or private clinic according to accepted medical practice.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	EVICR.net
G.4.3.4	Network Country	Portugal

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-11-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-06

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-05-27

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