Clinical Trials Register

Summary
EudraCT Number:	2016-002971-91
Sponsor's Protocol Code Number:	1386.12
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:	2018-02-06
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

2016-002971-91

A.3

Full title of the trial

A randomized, double-masked, placebo-controlled exploratory
study to evaluate safety, tolerability, pharmacodynamics and
pharmacokinetics of orally administered BI 1467335 for 12
weeks with a 12 week follow up period in patients with nonproliferative
diabetic retinopathy without center-involved
diabetic macular edema

Studio esplorativo randomizzato, in doppio mascherato, controllato con placebo per valutare sicurezza, tollerabilità, farmacodinamica e farmacocinetica del BI1467335 per os per 12 settimane di trattamento più 12 settimane di follow-up, in pazienti con retinopatia diabetica non proliferativa senza edema maculare centrale (Studio ROBIN).

A.3.1

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

A study that tests BI 1467335 in patients with diabetic eye
disease (diabetic retinopathy). It looks at the way BI 1467335 is
taken up, the effects it has, and how well it is tolerated.

studio che esamina la BI 1467335 in pazienti con retinopatia diabetica.per valutare sicurezza e tollerabilità di BI 1467335.

A.3.2

Name or abbreviated title of the trial where available

ROBIN study

Studio ROBIN

A.4.1

Sponsor's protocol code number

1386.12

A.5.4

Other Identifiers

Name:

1386-0012 o 1386.12

Number:

1386-0012 o 1386.12

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	BOEHRINGER-INGELHEIM ITALIA S.P.A.
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	BOEHRINGER-INGELHEIM ITALIA S.P.A.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Boehringer Ingelheim Pharma GmbH & Co. KG
B.5.2	Functional name of contact point	QRPE PSC CT Information Disclosure
B.5.3	Address:
B.5.3.1	Street Address	Binger Strasse 173
B.5.3.2	Town/ city	Ingelheim am Rhein
B.5.3.3	Post code	55216
B.5.3.4	Country	Germany
B.5.4	Telephone number	0018002430127
B.5.5	Fax number	0018008217119
B.5.6	E-mail	clintriage.rdg@boehringeringelheim.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	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	BI 1467335
D.3.2	Product code	BI 1467335
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	BI 1467335
D.3.9.3	Other descriptive name	BI1467335
D.3.9.4	EV Substance Code	SUB179373
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	5
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

diabetic retinopathy

retinopatia diabetica

E.1.1.1

Medical condition in easily understood language

diabetic retinopathy

retinopatia diabetica

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	10054109
E.1.2	Term	Non-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

The main objective is to evaluate ocular and systemic safety and
tolerability of BI 1467335 as
well as whether BI 1467335 monotherapy has a potential to improve
retinal lesions in
patients with moderately severe NPDR (DRSS level 47) or severe NPDR
(DRSS level 53),
without CI-DME.

In generale, l’obiettivo dello studio è valutare sicurezza e tollerabilità oculare e sistemica del BI 1467335 e valutare se in mono-terapia abbia il potenziale di migliorare le lesioni retiniche in pazienti con retinopatia diabetica non proliferativa di grado moderato-severo (DRSS level 47) o severo (DRSS level 53), senza CI-DME.

E.2.2

Secondary objectives of the trial

N.A.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Of full age (according to local legislation, usually ≥ 18 years) and ≤ 80
years at screening
2. Male or female patients. Women of childbearing potential (WOCBP)1
must be ready and
able to use two methods of contraception with at least one of them being
a highly
effective method of birth control per ICH M3 (R2) that result in a low
failure rate of less
than 1% per year when used consistently and correctly. A list of
contraception methods
meeting these criteria is provided in the patient information.
3. Diagnosis of diabetes mellitus (type 1 or type 2):
- Documented diabetes by American Diabetes Association (ADA) and/or
World Health
Organization criteria
- Antidiabetic medication stable for ≥3 months prior to screening and
expected to be
stable throughout the trial (no change in medication or the dose, except
for insulin the prescribed total daily dose change not more than 10%)
4. Glycosylated hemoglobin (HbA1c) ≤ 10% at screening
5. Non-proliferative diabetic retinopathy (NPDR) without center-involved
diabetic macular
edema (CI-DME) in the study eye at screening with NPDR level 47 or
level 53, as
determined by the CRC by using the DR severity scale (DRSS)
6. Best corrected visual acuity ETDRS letter score ≥ 70 letters in the
study eye at screening
7. Media clarity, pupillary dilation and individual cooperation sufficient
for adequate retinal
examination including fundus photographs and OCT
8. Signed and dated written informed consent in accordance with ICHGCP
and local
legislation prior to admission to the trial

1. Età compresa tra i 18 e gli 80 anni inclusi allo screening
2. Pazienti donne o uomini. Donne in età fertile (WOCBP) devono essere disposte e in grado di usare 2 metodi contraccettivi di cui almeno uno sia altamente efficace secondo ICH M3 (R2) ovvero che risulti in un tasso di gravidanze inferiore all’1% all’anno se usato correttamente e con continuità. Un elenco dei metodi contraccettivi con tali criteri si trova nell’informativa al paziente.
3. Diagnosi di diabete mellito (tipo 1 o 2):
- Diabete documentato secondo i criteri dell’American Diabetes Association (ADA) e/o della World Health Organization.
- Stabile trattamento anti-diabetico per ≥3 mesi, prima dello screening e che sia atteso stabile durante la durata dello studio (nessuna modifica nel trattamento o dosaggio , eccetto per l’insulina, che sia maggiore del 10%)
4. Emoglobina glicata (HbA1c) ≤ 10% allo screening
5. Retinopatia diabetica non proliferativa (NPDR) senza edema maculare con coinvolgimento centrale (CI-DME) nell’occhio scelto per lo studio allo screening, con livello di NPDR 47 o 53, come determinato dal reading centrale (o CRC) tramite la scala DRSS
6. Acuità visita (Best corrected) ETDRS letter score ≥ 70 lettere nell’occhio scelto per lo studio, allo screening
7. Media clarity, dilatazione pupillare e cooperazione individuale adeguati per effettuare l’esame retinico inclusi fotografie del fundus e OCT
8. Firma e data su consenso informato in accordo alle ICH-GCP e normative locali, prima dell’ammissione allo studio clinico.

E.4

Principal exclusion criteria

1. Additional eye disease in the study eye that, in the opinion of the
investigator, could
compromise or alter visual acuity during the course of the study (e.g.
vein occlusion,
uncontrolled intraocular pressure (IOP) >24 mmHg on optimal medical
treatment,
glaucoma with visual field loss, uveitis or other ocular inflammatory
disease,
vitreomacular traction, monocular vision, history of ischemic optic
neuropathy, or genetic
disorders such as retinitis pigmentosa)
2. Active center-involved DME (CI-DME) on clinical examination and OCT
central
subfield thickness above 300 μm in the study eye, as measured by
Optovue OCT
3. Anterior segment and vitreous abnormalities in the study eye that
would compromise the
adequate assessment of the best corrected visual acuity or an adequate
examination of the
posterior pole
4. Evidence of neovascularization on clinical examination including active
neovascularization of the iris (small iris tufts are not an exclusion) or
angle
neovascularization in the study eye, ruled out by gonioscopy
(documented in the last 4
weeks before screening or performed at screening)
5. Prior pan-retinal photocoagulation (defined as ≥ 100 burns placed
previously outside of
the posterior pole) in the study eye
6. History of DME or DR treatment with macular laser within 3 months
prior to screening,
or intraocular injections of medication within 6 months prior to
screening, and no more
than 4 prior intraocular injections in the study eye at any time in the
past
7. Patients treated with Monoamine Oxidase B (MAO-B) inhibitors (see
Section 4.2.2.1) at
the time or up to 3 months prior to randomization or planned initiation
during the trial
8. Current or planned, during the trial, use of medications known to be
toxic to the retina,
lens or optic nerve, or cause vision loss

1. Altre patologie oculari dell’occhio in studio che, a giudizio dello sperimentatore, potrebbero compromettere o alterare l’acuità visiva durante il corso dello studio (ad es. occlusione di una vena, pressione intraoculare incontrollata (IOP) >24 mmHg anche a trattamento ottimizzato, glaucoma con perdita di campo visivo, uveite o altre patologie oculari infiammatorie, trazione video-maculare, visione monoculare, storia di neuropatia ischemica ottica, o patologie genetiche quali retinite pigmentosa)
2. Attiva DME con coinvolgimento centrale (CI-DME) come da esame clinico e spessore centrale sotto-campo oltre i 300 µm da OCT, nell’occhio dello studio, misurata con l’OCT Optouve
3. Anomalie del segmento interiore del vitreo nell’occhio in studio che comprometterebbe l’adeguata valutazione della acuità visiva (best corrected) o l’esaminazione corretta del polo posteriore.
4. Evidenza di neo-vascolarizzazione da esame clinico, incluse neo-vascolarizzazioni attive dell’iride (piccole lesioni o “ciuffi” non sono un’esclusione) o neo-vascolarizzazione ad angolo nell’occhio in studio, esclusa tramite la gonioscopia (documentata nelle 4 settimane prima dello screening o effettuata allo screening stesso)
5. Fotocoagulazione pan-retinica pregressa (definite come ≥ 100 bruciature effettuate in precedenza fuori dal polo posteriore) nell’occhio in studio
6. Storia di trattamento per DME o DR con laser maculare entro 3 mesi prima dello, o iniezioni intraoculari di farmaco entro 6 mesi prima dello screening, e non più di 4 pregresse iniezioni nell’occhio in studio in totale.
7. Pazienti trattati con inibitori della Mono-amino Ossidasi B (MAO-B) (vedere la Section 4.2.2.1) al momento della/fino a 3 mesi prima della randomizzazione o se ne è pianificato l’inizio durante il corso dello studio
8. Uso corrente o pianificato durante lo studio di trattamenti con nota tossicità alla retina, al cristallino o al nervo ottico, o che causi perdita della vista (vedere la Section 4.2.2.1)
9. Pazienti che debbano o scelgano di continuare ad assumere altri farmaci non consentiti (vedere Section 4.2.2.1) o farmaci che interferiscano con la condotta sicura dello studio
10. Estimated Glomerular filtration rate (eGFR) <60mL/min/1.73m2 calcolata tramite l’equazione della Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) allo screening, o se lo sperimentatore si aspetta che la filtrazione diminuisca al di sotto dei 60mL/min/1.73m2 durante lo studio
11. ALT o AST maggiori di 2 volte il limite superiore di normalità o bilirubina totale >1.5 volte il x limite superiore di normalità.
12. Ipertensione arteriosa incontrollata definita come singola misurazione della pressione sistolica >180mmHg, o 2 misurazioni consecutive della pressione sistolica>160mmHg e/o pressione diastolica >100mmHg durante terapia già ottimizzata allo screening. Qualora la pressione sia portata a ≤160/100mmHg da trattamento anti-ipertensivo entro la randomizzazione, il paziente può diventare eleggibile.
13. Sindrome di Wolff-Parkinson-White, QTc > 450 ms al basale, familiarità di QT prolungati o che assume farmaci che prolungano il QT allo screening o se ne è pianificata l’assunzione durante lo studio.
14. Diagnosi di patologia sistemica o oculare seria o incontrollata e alter condizioni che, a giudizio clinic dello sperimentatore, possano interferire con le analisi di sicurezza ed efficacia in questo studio. Si escludono anche pazienti con aspettativa di vita inferiore ai 2 anni.
15. Infezioni croniche o acute rilevanti quali HIV (Human Immunodeficiency Virus)\epatite virale o tubercolosi. Allo screening si effettueranno i test QuantiFERON® TB test e HBs Ag. I pazienti con esito positivo solo se ulteriori azioni diagnostiche/indagini (in accordo alle legislazioni locali vigenti) concluderanno che non vi è evidenza di infezioni attive.
16. Qualunque patologia maligna attiva documentata o sospetta o anamnesi di malignità entro i 5 anni dallo screening, eccetto carcinoma cutaneo delle cellule basali se appropriatamente trattato o in situ carcinoma della cervice uterina.
17. Abuso di alcol o sostanze stupefacenti o qualunque condizione che, a giudizio dello sperimentatore, renda il soggetto inaffidabile per la corretta e complete partecipazione allo studio.
18. Nota ipersensibilizzazione a qualunque componente del farmaco in studio e/o allergia alla tintura per la fluorescenza.
19. Intervento chirurgico considerato dallo sperimentatore di importanza rilevante, se effettuato entro le 12 settimane prima della randomizzazione o pianificato durante lo studio (ad es. chirurgia all’anca).
Per gli altri criteri, rifarsi alla sinossi del protocollo in italiano

E.5 End points

E.5.1

Primary end point(s)

1) proportion of patients with any ocular adverse events (according to
Common Terminology Criteria for Adverse Events (CTCAE)

1) L’endpoint primario è la proporzione di pazienti con eventi avversi oculari in accordo alla Common Terminology Criteria for Adverse Events (CTCAE)

E.5.1.1

Timepoint(s) of evaluation of this end point

1) 24 weeks

1) 24 settimane

E.5.2

Secondary end point(s)

1) Proportion of patients with at least 2 steps improvement in the study
eye on the DRSS at week 12 compared to baseline.
2) The proportion of patients with adverse events other than ocular
adverse events over the on treatment period (over 24 weeks) (according
to CTCAE).

1) Proporzione di pazienti con un miglioramento di almeno 2 steps nell’occhio in studio nella DRSS alla settimana 12 confronto al basale;
2) Proporzione di pazienti con eventi avversi non-oculari nel periodo del trattamento (24 settimane) (in accordo alla CTCAE).

E.5.2.1

Timepoint(s) of evaluation of this end point

1) 12 weeks
2) 24 weeks

1) 12 settimane
2) 24 settimane

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)

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

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)

E.8.2.2

Placebo

Yes

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

France

Germany

Greece

Italy

Norway

Spain

United Kingdom

United States

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

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

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

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

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

Yes

F.3.3.2

Women of child-bearing potential using contraception

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

100

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

nassuno

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

2018-01-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-12-14

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
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