Clinical Trials Register

Summary
EudraCT Number:	2017-003899-31
Sponsor's Protocol Code Number:	DBC-AMD-001-D
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-07-27
Trial 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

2017-003899-31

A.3

Full title of the trial

International, multicenter, randomised, double-blind, sham-controlled, 2x2 cross over phase III clinical trial to assess the efficacy and security of an intravitreal injection of Etamsylate in the improvement of visual acuity of patients with dry age-related macular degeneration.

Ensaio clínico internacional, multicêntrico, randomizado, duplo-cego, controlado por tratamento fingido, 2x2 cruzado em fase III para avaliar a eficácia e segurança de uma injeção intravítrea de Etamsilato na melhoria da acuidade visual de pacientes com degeneração macular seca relacionada com a idade.

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

JERICHO_D

A.4.1

Sponsor's protocol code number

DBC-AMD-001-D

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	DOBECURE, S.L
B.1.3.4	Country	Spain
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	DR. PEDRO CUEVAS
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Leon Research S.L.
B.5.2	Functional name of contact point	Carla Nascimento
B.5.3	Address:
B.5.3.1	Street Address	C/ Julia Morros s/n, Edif. Usos Comunes, Local 1 Parque Tecnológico León
B.5.3.2	Town/ city	Leon
B.5.3.3	Post code	24009
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034987261 064
B.5.5	Fax number	0034987216 243
B.5.6	E-mail	cnascimento@leonresearch.es

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	Dicynone 250mg/2ml, injectable solution
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi Aventis France
D.2.1.2	Country which granted the Marketing Authorisation	France
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	DICYNONE
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	Etamsylate
D.3.9.1	CAS number	2624-44-4
D.3.9.3	Other descriptive name	ETAMSYLATE
D.3.9.4	EV Substance Code	SUB11943MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µl microlitre(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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

Aged related macula degeneration (AMD)

Degeneração macular associada com a idade (DMA)

E.1.1.1

Medical condition in easily understood language

Aged related macula degeneration (AMD)

Degeneração macular associada com a idade (DMA)

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10025409
E.1.2	Term	Macular degeneration
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

This is a phase III study to assess the efficacy and safety of intravitreal injection of Etamsylate for the treatment of age-related macular degeneration. Its design will allow the evaluation (at 90 and 180 days) of the effects of an intravitreal injection of etamsylate, in order to establish the suitability of this treatment for AMD.

Este é um estudo de Fase III para avaliar a eficácia e a segurança de uma injeção intravítrea de Etamsilato para o tratamento da degeneração macular relacionada com a idade. O modelo do estudo permitirá a avaliação (a 90 e 180 dias) dos efeitos de uma injeção intravítrea de Etamsilato, a fim de estabelecer a adequação deste tratamento para a DMA.

E.2.2

Secondary objectives of the trial

•To assess the efficacy after 90 days of a single intravitreal injection of etamsylate in the improvement of visual acuity in patients diagnosed with dry AMD.
•To assess the efficacy after 180 days of a single intravitreal injection of etamsylate in the improvement of visual acuity in patients diagnosed with dry AMD.

•Avaliar a eficácia após 90 dias de uma única injeção intravítrea de Etamsilato na melhoria de acuidade visual em pacientes diagnosticados com DMA seca.
•Avaliar a eficácia após 180 dias de uma única injeção intravítrea de Etamsilato na melhoria de acuidade visual em pacientes diagnosticados com DMA seca.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Adult patients, aged ≥18 years, males or females.
•Diagnosis of dry AMD
•Patients with best corrected visual acuity (BCVA) between 20/25 and 20/320, measured by ETDRS optotype (Early Treatment Diabetic Retinopathy Study)
•Women of childbearing potential (defined as a premenopausal female capable of becoming pregnant) should be willing to follow and use the following highly effective contraconceptive methods:
-Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal)
-progestogen-only hormonal contraception associated with inhibition of
-Ovulation (oral, injectable or implantable)
-intrauterine device (IUD)
-intrauterine hormone-releasing system (IUS)
-bilateral tubal occlusion
-vasectomised partner
-sexual abstinence
-postmenopausal women (defined as women that have had their last menstruation at least 12 months before study inclusion).
•Patients with the capacity and disposition to follow the study protocol and procedures and that grant their informed consent in writing (signed and dated), accepting voluntarily to participate in the trial

•Pacientes adultos (18 anos ou mais) de ambos os sexos.
•Pacientes con DMA seca
•Pacientes com acuidade visual melhor corrigida (BCVA) entre 20/25 e 20/320, medidos pelo optótipo ETDRS (Early Treatment Diabetic Retinopathy Study)
•As mulheres com potencial para engravidar (definidas como uma mulher na pré-menopausa com capacidade para engravidar) devem estar dispostas a seguir e utilizar os seguintes métodos contraconceptivos altamente eficazes:
-Contracepção hormonal combinada (contendo estrogênio e progestogênio) associada à inibição da ovulação (oral, intravaginal ou transdérmica)
-contracepção hormonal apenas com progestagénio associada à inibição da ovulação (oral, injetável ou implantável)
-dispositivo intra-uterino (DIU)
-dispositivo de libertação de hormona intrauterina (IUS)
-oclusão tubária bilateral
-parceiro vasectomizado
-abstinência sexual
-mulheres na pós-menopausa (definidas como mulheres que tiveram sua última menstruação pelo menos 12 meses antes da inclusão no estudo).
•Pacientes com capacidade e disposição para seguir o protocolo e os procedimentos do estudo e que concedem o seu consentimento informado por escrito (assinado e datado), aceitando voluntariamente participar no estudo

E.4

Principal exclusion criteria

•Patients with grade 5 AMD in one or both eyes.
•Patients with any concomitant ocular disease that, under investigator’s judgement, could influence the development, evaluation or assessment of the AMD, such as glaucoma, permanent structural damage in the centre of the fovea, Geographic parafoveolar atrophy, Polypoid choroidal vasculopathy etc.
•Patients with ocular or periocular infection.
•Patients with any concomitant disease that, under investigator’s judgement, could influence (the disease itself or its treatment) the development, evaluation or assessment of the AMD, such as diabetes mellitus with ocular affectation, current or active systemic infection, any ocular infection, psychiatric diseases, social situation that may affect study protocol compliance etc.
•Patients treated with any intravitreal anti-VEGF agent or other intravitreal drug such as corticosteroids within the last month prior to study randomisation entry
•Pregnant or breastfeeding women (urine pregnancy test to be performed for those patients of childbearing potential patients)
•Hyper sensibility to etamsylate or any of the excipients contained in the form used for the trial.
•Patients with any of the contraindicated diseases described in the SMPC of Dycinone, such us but not limited to: porphyria, bleeding caused by treatment with anticoagulants, fibrosis/benign tumours in the uterus and patients with a recent history of stroke.
•Patients that have participated in Dry-AMD clinical trials with intervention (observational, epidemiologic or economic studies are allowed).

•Pacientes com DMA de grau 5 em um ou ambos os olhos.
•Pacientes com qualquer doença ocular concomitante que, de acordo com o julgamento do investigador, possam influenciar o desenvolvimento, avaliação ou valoração da DMA, como sejam o glaucoma, danos estruturais permanentes no centro da fóvea, atrofia parafaveolar geográfica, vasculopatia coróide polipóide, etc.
•Pacientes com infeções oculares e perioculares
•Pacientes com qualquer doença concomitante que, sob o julgamento do investigador, possa influenciar (a própria doença ou seu tratamento) o desenvolvimento, avaliação ou valoração da DMA, como diabetes mellitus com afecção ocular, infecção sistêmica atual ou ativa, qualquer infecção ocular, doenças psiquiátricas, situação social que podem afetar a conformidade com o protocolo de estudo, etc.
•Pacientes tratados com qualquer agente intravítreo anti-VEGF ou outro medicamento intravítreo como corticosteróides no último mês antes da randomização no estudo
•Mulheres grávidas ou amamentando (teste de gravidez na urina a ser realizado para as pacientes em idade fértil)
•Hipersensibilidade ao etamsilato ou a qualquer um dos excipientes contidos na forma utilizada para o ensaio.
•Pacientes com qualquer uma das doenças contra-indicadas descritas no SMPC da Dycinone, tais como, mas não limitados a: porfiria, sangramento causado pelo tratamento com anticoagulantes, fibrose/tumores benignos no útero e pacientes com história recente de acidente vascular cerebral.
•Pacientes que participaram de ensaios clínicos com AMD seca com intervenção (estudos observacionais, epidemiológicos ou económicos são permitidos).

E.5 End points

E.5.1

Primary end point(s)

The trial’s primary endpoint is, for each subject, the difference in number of letters read in the ETDRS optotype between the baseline values and after 90 and 180 days of a single intravitreal injection of Etamsylate expressed in in negative decimal logarithmic units of the Minimum Angle Resolution (logMAR).

O ponto final primário do teste é, para cada paciente, a diferença no número de letras lidas no optótipo ETDRS entre os valores obtidos na visita de início (baseline) e após 90 e 180 dias da administração de uma única injeção intravítrea de Etamsilato expressa em unidades logaritmicas decimais negativas da Resolução de Ângulo Mínimo ( logMAR).

E.5.1.1

Timepoint(s) of evaluation of this end point

After 90 and 180 days from the baseline

Ao dia 90 e ao dia 180 desde a visita de início (baseline)

E.5.2

Secondary end point(s)

•Evolution from baseline at 90 and 180 days after etamsylate intravitreal injection of corrected visual acuity assessed by ETDRS optotype and expressed in in negative decimal logarithmic units of the Minimum Angle Resolution (logMAR) equivalent to the number of letters accurately read.
•Percentage of patients showing an improvement of the best-corrected visual acuity assessed with ETDRS.
•Evolution of the thickness of the central part of the macula measured by OCT.
•Evolution of the number of targeted areas of retinal pigment epithelium disappearance measured by OCT.
•Evolution of the number, location, area and volume of drusen measured by OCT and colour retinography.
•In those patients with the most advanced form of AMD (presence of geographical atrophy), the percentage of increase or decrease of the geographical atrophy area.
•Evolution of patient’s quality of life measured by Visual Function Questionnaire of National Eye Institute (VFQ-25) and EuroQol five dimensions-five levels questionnaire (EQ-5D-5L).
•Evolution compared with non-concurrent control group of corrected visual acuity assessed by ETDRS optotype. This group will include patients treated with any treatment alternatives, standard of care and observation.

•Evolução de valores entre os valores obtidos na visita de início (baseline) e os valores aos 90 e 180 dias após a injeção intravítrea Etamsylate de acuidade visual corrigida avaliada pelo optótipo ETDRS e expressa em unidades logarítmicas decimais negativas da Resolução de Ângulo Mínimo (logMAR) equivalente ao número de letras lidas com precisão.
•Percentagem de pacientes com aumento da melhor acuidade visual corrigida medida por ETDRS.
•Evolução da espessura da parte central da mácula medida por OCT.
•Evolução do desaparecimento de áreas alvo do epitélio do pigmento da retina medido por OCT.
•Evolução do número, localização, área e volume de drusas medidos por OCT e retinografia de cor
•Nos pacientes com a forma mais avançada de DMA (presença de atrofia geográfica), a percentagem de aumento ou diminuição da área geográfica de atrofia.
•Evolução da qualidade de vida do paciente, medida pelo Questionário de Função Visual do Instituto Nacional do Olho (VFQ-25) e EuroQol cinco dimensões: questionário de cinco níveis (EQ-5D-5L).
•Evolução comparada com o grupo controle não concorrente de acuidade visual corrigida avaliada pelo optótipo ETDRS. Este grupo incluirá pacientes tratados com qualquer alternativa de tratamento, tratamento padrão e observação.

E.5.2.1

Timepoint(s) of evaluation of this end point

After 90 and 180 days from the baseline

Ao dia 90 e ao dia 180 desde a visita de início (baseline)

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

E.8.1.6

Cross over

Yes

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

Tratamento fingido

Sham Treatment

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

LVLS

Última visita do último paciente

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

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

F.3.3.1

Women of childbearing potential not using contraception

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

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

Nenhum

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

2019-06-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-11-19

P. End of Trial
P.	End of Trial Status	Ongoing

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