Clinical Trials Register

Summary
EudraCT Number:	2005-000487-11
Sponsor's Protocol Code Number:	CRFB002D2201
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2005-10-24
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2005-000487-11

A.3

Full title of the trial

A randomized, double-masked, multicenter, phase II study assessing the safety and efficacy of two concentrations of ranibizumab (intravitreal injections) compared with non-treatment control for the treatment of diabetic macular edema with center involvement

Studio di Fase II, multicentrico, randomizzato, in doppio mascherato, per valutare la sicurezza e l'efficacia di due concentrazioni di ranibizumab (iniezioni intravitreali) in confronto a controlli non trattati, nell'edema maculare diabetico con coinvolgimento centrale.

A.4.1

Sponsor's protocol code number

CRFB002D2201

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 FARMA
B.1.3.4	Country	Italy
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	No
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	Eye drops, powder and solvent for solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ranibizumab
D.3.9.2	Current sponsor code	RFB002
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	6
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	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: 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	No
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	Eye drops, powder and solvent for solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ranibizumab
D.3.9.2	Current sponsor code	RFB002
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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	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

Treatment of diabetic macular edema

Trattamento dell'edema maculare diabetico

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	14.1
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.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective for pilot part (Group A) is to explore whether ranibizumab (6 and/or 10 mg/ml) treatment is superior to non-treatment in reducing macular edema from baseline to Month 6 in patients diagnosed with DME with center involvement. The primary objective for the confirmatory part (Group B) is to confirm the efficacy of ranibizumab (6 and/or 10 mg/ml) on visual acuity from baseline to Month 12 in patients diagnosed with DME with center involvement.

L'obiettivo primario della parte pilota (Gruppo A) e` esplorare se il trattamento con ranibizumab (6 mg/ml e/o 10 mg/ml) in pazienti con edema maculare diabetico con coinvolgimento centrale ha un' efficacia superiore nel ridurre l'edema maculare, al mese 6 rispetto al basale, in confronto ai pazienti che non ricevono alcun trattamento. L'obiettivo primario della parte confirmatoria (Gruppo B) dello studio e` confermare l'efficacia di ranibizumab (6 e/o 10mg/ml) sull'acuita` visiva dalla visita basale al mese 12 nei pazienti con diagnosi di edema maculare diabetico con coinvolgimento centrale.

E.2.2

Secondary objectives of the trial

The secondary objectives for pilot part (Group A) are to explore the effect of ranibizumab treatment on visual acuity and retinal structure, and the need for photocoagulation. For confirmatory part (Group B) to confirm the effect of ranibizumab (6 and/or 10 mg/ml) treatment superiority to sham treatment in reducing macular edema. Additional secondary objectives are to evaluate the safety of ranibizumab administered as multiple doses to patients diagnosed with DME involving the center of the macula (Group A+B), based on rates of ocular and non-ocular adverse events.

L'obiettivo secondario della parte pilota (Gruppo A) e` valutare l'efficacia del trattamento con ranibizumab sull'acuita` visiva e sulla struttura retinica e sulla necessita` di ricorrere al trattamento di fotocoagulazione.L'obiettivo secondario della parte confirmatoria (Gruppo B) e` confermare l'effetto superiore del trattamento con ranibizumab (6 e/o 10 mg/ml) rispetto al trattamento sham nel ridurre l'edema maculare.L'obiettivo secondario supplementare e` valutare,in base alla frequenza degli eventi avversi oculari e non oculari,la sicurezza di ranibizumab somministrato a dosi ripetute in pazienti che presentano edema maculare diabetico con coinvolgimento centrale (Gruppo A + B).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion Criteria 1. Male or female patients >18 years of age who have signed an informed consent 2. Patients with type 1 or type 2 diabetes mellitus diagnosed ≥24 months prior to screening and a documented history of stable HbA1c ≥6.5% and ≤9.5% at the time of screening (stable HbA1c values are defined as those that do not differ at monthly assessments by more than 0.5% HbA1c). Any one of the following will be considered to be sufficient evidence that diabetes is present • Current regular use of insulin for the treatment of diabetes • Current regular use of oral antihyperglycemia agents for the treatment of diabetes • Documented diabetes by ADA and/or WHO criteria (see Study Operations Manual) 3. Patients with diabetic macular edema with center involvement in at least one eye, including those with focal or diffuse DME, as demonstrated with stereoscopic fundus photography, fluorescein angiography and optical coherence tomography within 28 days of the baseline treatment. For this eye to achieve eligibility statue it must fulfill the following three criteria at Visit 1: • The central macular thickness must be ≥300 μm in the center subfield, as assessed by OCT and confirmed by the central reading center. • BCVA score between 69 and 39 letters, inclusively, using ETDRS-like visual acuity testing charts at a testing distance of 4 meters (approximate Snellen equivalent of 20/40 to 20/160) • Decrease in vision is due to foveal thickening from DME and not due to other causes, in the opinion of the investigator 4. Patients with DME without previous laser photocoagulation or patients who have been treated at least 6 months preceding Day 1 with mild focal laser photocoagulation consisting of no more than 30 laser burns that are at least 500 μm from the center of the fovea will be allowed to enter the study. 5. Only one eye will be selected for study treatment (study eye). If both eyes are eligible, the one with the worse visual acuity, as assessed at Visit 1, will be selected for study treatment unless, based on medical reasons, the investigator deems the other eye the more appropriate candidate for study treatment. The medical reason for selecting the study eye having the better visual acuity must be described in the eCRF 6. The BCVA score in the non-study eye (fellow eye) must be ≥24 letters (approximate Snellen equivalent of 20/320) at Visit 1 7. Patients for whom, in the opinion of the investigator, laser photocoagulation in the study eye can be withheld for at least 3 months after randomization 8. Willing to return for all scheduled visits

Criteri di inclusione: 1. Pazienti adulti, di eta` > 18 anni, di entrambi i sessi, che hanno firmato consenso informato scritto prima di iniziare ogni procedura prevista dallo studio. 2. Pazienti con diabete mellito di tipo I o di tipo II , diagnosticato ≥ 24 mesi prima dello screening con HbA1c non superiore al 12% alla Visita 1 e con una storia documentata di HbA1c stabile confrontata con la misurazione precedente eseguita entro gli ultimi 6 mesi con una differenza non superiore al 1,0%. La diagnosi di diabete ai fini dell'eligibilta` allo studio si fonda sulla presenza di uno dei seguenti requisiti: • Uso regolare di insulina per il trattamento del diabete mellito • Uso regolare di antidiabetici orali per il trattamento del diabete mellito • Diabete documentato dai criteri ADA e/o WHO (vedi Manuale operativo dello studio) 3. Edema maculare diabetico con coinvolgimento centrale in almeno un occhio, compreso edema maculare diabetico focale o diffuso, dimostrato dalla stereofoto del fundus, dalla fluorangiografia e dalla tomografia a coerenza ottica, entro 28 giorni dal trattamento basale. Dovranno essere presenti i seguenti tre criteri alla Visita 1 per soddisfare l'eligibilita`: • L'ispessimento maculare centrale deve essere ≥ 300 μm nel sottocampo centrale, determinato mediante OCT e confermato dalla lettura centralizzata dell'esame. • Punteggio BCVA compreso tra 73 e 39 lettere, utilizzando le tavole di acuita` visiva ETDRS a una distanza di 4 metri (equivalente di Snellen 20/40 - 20/160 circa). • La diminuzione della vista e` dovuta a ispessimento della fovea da edema maculare diabetico e non ad altre cause, in base all'opinione dello sperimentatore. 4. Sara` scelto un solo occhio e nel caso entrambi gli occhi siano colpiti sara` scelto l'occhio con la peggiore acuita` visiva (misurata alla Visita 1), a meno che lo sperimentatore non consideri l'altro occhio come candidato piu` appropriato alla terapia. 5. Il punteggio BCVA nell'occhio non in studio deve essere ≥ 24 lettere (equivalente di Snellen 20/230 circa) alla visita del Giorno 1. 6. Pazienti nei quali, secondo l'opinione dello sperimentatore, la fotocoagulazione laser puo` essere ritardata di almeno 3 mesi dopo la randomizzazione. 7. Pazienti collaboranti e cooperativi.

E.4

Principal exclusion criteria

1. A condition that in the opinion of the investigator would preclude a patient's participation in the study, e.g., unstable medical status including glycemic control and blood pressure. Patients in poor glycemic control who, within the last 4 months, initiated intensive insulin treatment (a pump or multiple daily injections) or plan to do so in the next 4 months should not be enrolled. Patients with hypertension for whom a change in antihypertensive treatment was initiated within 2 months preceding Day 1 should not be enrolled unless blood pressure is maintained for at least 1 month prior Day 1 below 150/95 mm Hg by antihypertensive treatment 2. History of systemic (e.g., oral, IV, IM, epidural, bursal) corticosteroids within 4 months prior to randomization or topical, rectal, or inhaled corticosteroids in current use more than 2 times per week

Criteri di esclusione: 1. Presenza di condizioni che a giudizio dello sperimentatore possono precludere la partecipazione del pazienti allo studio come ad esempio, condizioni mediche instabili (controllo glicemico e pressione arteriosa). Non devono essere arruolati pazienti con scarso controllo glicemico che hanno iniziato, nei 4 mesi precedenti, trattamento insulinico intensivo (pompa o iniezioni giornaliere ripetute) o abbiano in programma tale terapia nei 4 mesi successivi. Non devono essere arruolati pazienti ipertesi, nei quali e` stata attuata una modifica del trattamento antipertensivo, nei 2 mesi precedenti il Giorno 1, a meno che la PA non sia mantenuta al di sotto di 160/100mmHg dal trattamento antipertensivo per almeno 1 mese prima del Giorno 1. 2. Uso di corticosteroidi (orali, e.v., i.m., epidurali, bursali) nei 4 mesi precedenti la randomizzazione o uso attuale di corticosteroidi topici o per via inalatoria per piu` di 2 volte alla settimana. Terapia precedenti/concomitanti 3. Fotocoagulazione laser panretinica, focale periferica entro sei mesi dall'entrata nello studio. 4. E' esclusa la fotocoagulazione laser focale a griglia/centrale ad eccezione dei pazienti con trattamento di cauterizzazione laser moderato ad almeno 1000μm dal centro della fovea eseguito piu` di 6 mesi precedenti il Giorno 1 5. Somministrazione intravitreale o subtenoniana di farmaci (iniezioni di corticosteroidi o impianto di dispositivi oculari) precedente o attuale nell'occhio in studio o nell'occhio controlaterale. 6. Precedente uso di o partecipazione a uno studio clinico (entrambi gli occhi) con farmaci antiangiogenici (pegabtanib sodio, ranibizumab, anecortave acetato, inibitori della protein-chinasi C, etc.) 7. Precedente partecipazione a uno studio clinico sperimentale (esclusi vitamine e minerali) nel mese precedente al Giorno 1.

E.5 End points

E.5.1

Primary end point(s)

The primary objective is to explore whether the activity of ranibizumab (6 and/or 10 mg/ml) treatment is superior to non-treatment in reducing macular edema from baseline to Month 6 in patients diagnosed with DME with center involvement.

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

E.8.2.3.1

Comparator description

placebo

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.8.6 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

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

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	Number of subjects for this age range:	0
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.1.3	Elderly (>=65 years)	Yes
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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2005-10-24.	Yes
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	12
F.4.2	For a multinational trial
F.4.2.1	In the EEA	118
F.4.2.2	In the whole clinical trial	150

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

2005-10-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2005-09-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2008-06-17

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