Clinical Trials Register

Summary
EudraCT Number:	2017-003897-15
Sponsor's Protocol Code Number:	THR-317-002
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-01-18
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

Spain - AEMPS

A.2

EudraCT number

2017-003897-15

A.3

Full title of the trial

A Phase 2, randomised, single-masked, active-controlled, multicentre study to evaluate the efficacy and safety of intravitreal THR-317 administered in combination with ranibizumab, for the treatment of diabetic macular oedema (DME)

Estudio de fase 2, aleatorizado, con enmascaramiento único, controlado con producto activo, multicéntrico, para evaluar la eficacia y la seguridad de la administración intravítrea de THR-317 en combinación con ranibizumab, para el tratamiento del edema macular diabético (EMD)

A.3.1

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

A study to evaluate THR-317 and Lucentis® combination treatment for diabetic macular oedema

Estudio para evaluar el tratamiento combinado de THR-317 y Lucentis® para el Edema Macular Diabético

A.4.1

Sponsor's protocol code number

THR-317-002

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	ThromboGenics NV
B.1.3.4	Country	Belgium
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	ThromboGenics NV
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ThromboGenics NV
B.5.2	Functional name of contact point	Global Clinical Development
B.5.3	Address:
B.5.3.1	Street Address	Gaston Geenslaan 1
B.5.3.2	Town/ city	Leuven
B.5.3.3	Post code	B-3001
B.5.3.4	Country	Belgium
B.5.4	Telephone number	3216751310
B.5.5	Fax number	3216751311
B.5.6	E-mail	info@thrombogenics.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	THR-317 8 mg
D.3.2	Product code	THR-317
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	Monoclonal antibody TG-403
D.3.9.2	Current sponsor code	TB-403
D.3.9.3	Other descriptive name	TB-403
D.3.9.4	EV Substance Code	SUB190564
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	160
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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 Ltd
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	Ranibizumab 0.5 mg
D.3.2	Product code	Ranibizumab
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	ranibizumab
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	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

Diabetic macular oedema (DME)

Edema Macular Diabético

E.1.1.1

Medical condition in easily understood language

Diabetic macular oedema is a swelling in the light-sensitive tissue in the back of the eye (called the retina) in people with diabetes, caused by leaking of blood vessels.

El edema macular diabetic es una inflamación en el tejido sensible a la luz en la parte posterior del ojo (llamada retina) en población con diabetes, causada por una pérdida en los vasos sanguíneos.

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	10057915
E.1.2	Term	Diabetic macular oedema
E.1.2	System Organ Class	100000004853

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	10057934
E.1.2	Term	Diabetic macular edema
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 evaluate the efficacy and safety of THR-317 administered in combination with ranibizumab, in subjects with central-involved DME (CI-DME)

Evaluar la eficacia y la seguridad de THR-317, administrado en combinación con ranibizumab, en pacientes con edema macular diabético con afectación central (EMD-AC)

E.2.2

Secondary objectives of the trial

Not applicable

No aplica

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Male or female aged 18 years or older
- Type 1 or type 2 diabetes
- CI-DME with central subfield thickness of ≥ 320µm on Spectralis® SD-OCT or ≥ 305µm on non-Spectralis SD-OCT, in the study eye
- Anti-VEGF treatment naïve study eye, or poor or no response to prior treatment with ranibizumab in the study eye
- Reduced vision primarily due to DME, with BCVA ≤ 72 and ≥ 23 ETDRS letter score (≤ 20/40 and ≥ 20/320 Snellen equivalent) in the study eye
- Non-proliferative diabetic retinopathy (NPDR) of any stage in the study eye
- Written informed consent obtained from the subject prior to screening procedures

1. Hombres o mujeres de 18 años o mayores de 18 años.
2. Diabetes de tipo 1 o 2.
3. EMD-AC con grosor de subcampo central (GSC) de ≥320 μm en la tomografía de coherencia óptica de dominio espectral (TCO-DE) Spectralis® o ≥ 305 μm en la TCO-DE distinta de Spectralis en el ojo de estudio, según evaluación del CIC.
4. Ojo de estudio no tratado previamente con anti-VEGF o que haya presentado una respuesta escasa o nula al tratamiento previo con ranibizumab.
Visión reducida principalmente a causa del EMD, con una MAVC ≤ 72 y ≥ 23 letras en la puntuación de la ETDRS (equivalente a ≤ 20/40 y ≥20/320 en la escala de Snellen) en el ojo de estudio.
6. MAVC ≥ 23 letras en la puntuación de la ETDRS (equivalente a ≥20/320 en la escala de Snellen) en el ojo contralateral.
7. Retinopatía diabética no proliferativa (RDNP) de cualquier estadio en el ojo de estudio en una fotografía del fondo de ojo estándar de siete campos en color, evaluada por el CIC.
8. Consentimiento informado por escrito otorgado por el paciente antes de los procedimientos de selección

E.4

Principal exclusion criteria

- Macular oedema due to causes other than DME
- Concurrent disease in the study eye, other than CI-DME, that could compromise BCVA, require medical or surgical intervention during the study period or could confound interpretation of the results
- Change of the retinal architecture in the centre of the macula of the study eye that is likely to preclude improvement in BCVA following the resolution of DME
- Previous treatments / procedures as listed below, or their planned / expected use during the study period for up to 30 days after the last study treatment:
* Ranibizumab treatment in the study eye (any time for anti-VEGF naïve subjects; 1 month for subjects with a poor or no response to ranibizumab treatment)
* Bevacizumab treatment in the study eye (any time for anti-VEGF naïve subjects; 3 months for subjects with a poor or no response to ranibizumab treatment)
* Aflibercept treatment in the study eye (any time)
* Intraocular surgery in the study eye (3 months)
* Focal / grid laser photocoagulation in the study eye (3 months)
* Panretinal laser photocoagulation in the study eye (6 months)
* Intraocular or peri-ocular corticosteroids in the study eye (4 months)
* Ozurdex® (dexamethasone intravitreal implant) in the study eye (6 months)
* Other steroid implant in the study eye (any time)
* Systemic anti-VEGF treatment (3 months)
* Systemic corticosteroids (3 months)
- Aphakic study eye
- Uncontrolled glaucoma in the study eye
- More than 8D high myopia in the study eye
- Any active ocular / intraocular infection or inflammation in either eye
- Untreated diabetes
- Glycated haemoglobin A (HbA1c) > 12%
- Uncontrolled hypertension in the opinion of the Investigator
- Pregnant or lactating female
- Female of child-bearing potential not utilising an adequate form of contraception, or planning to become pregnant or to discontinue contraceptive precautions at any time during the entire study period
- Male of reproductive potential not utilising contraception

Edema macular por causas distintas del EMD (p. ej.: extracción de catarata, tracción vítreo macular, membrana epirretiniana).
2. Enfermedad concomitante (distinta de EMD-AC) en el ojo de estudio que pudiera comprometer la MAVC, requiera una intervención quirúrgica o médica durante el periodo de estudio o pudiera alterar la interpretación de los resultados (p. ej.: cataratas, oclusión vascular retiniana, desprendimiento de retina, agujero macular, degeneración retiniana o neovascularización coroidea por cualquier causa).
3. Cambio de la estructura de la retina en el centro de la mácula del ojo de estudio que probablemente impida la mejoría de la MAVC tras la resolución del EMD-AC (p. ej.: atrofia del epitelio pigmentario de la retina, fibrosis o cicatriz subretiniana, isquemia macular, no perfusión o exudados duros, membrana epirretiniana).
4. Tratamientos/procedimientos previos enumerados a continuación, o su uso previsto o esperado durante el periodo de estudio y hasta 30 días después de la administración de la última dosis del tratamiento del estudio (salvo ranibizumab, incluido en los tratamientos del estudio):
Ranibizumab en cualquier momento para pacientes sin tratamiento previo con anti-VEGF; 1 mes para pacientes con respuesta escasa o nula al tratamiento con ranibizumab.
Bevacizumab: en cualquier momento para pacientes sin tratamiento previo con anti-VEGF; 3 meses para pacientes con respuesta escasa o nula al tratamiento con ranibizumab.
Aflibercept: en cualquier momento.
Cirugía intraocular: 3 meses.
Fotocoagulación láser en rejilla/focala: 3 meses.
Fotocoagulación láser panretiniana: 6 meses.
Ozurdex® (implante intravítreo de dexametasona): 6 meses.
Otro implante corticoesteroideo: en cualquier momento.
Tratamiento anti-VEGF: 3 meses.
Corticoesteroides: 3 meses.
Ojo de estudio afáquico.
Glaucoma no corregido en el ojo de studio.
Miopía de más de 8 dpt en el ojo de studio.
Cualquier infección o inflamación activa ocular/intraocular en cualquiera de los dos ojos.
Diabetes no tratada.
Hemoglobina glucosilada.
Hipertensión no corregida en opinión del investigador.
Mujeres embarazadas o en periodo de lactancia.
Mujeres en edad fértil que no utilicen un método anticonceptivo adecuado o quieran quedarse embarazadas o interrumpir el uso de anticonceptivos en cualquier momento durante el periodo de estudio íntegro.
Varones con capacidad reproductora que no usen anticonceptivos

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in BCVA

Cambio en la MAVC respecto del valor basal

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 84 (Month 3)

Día 84 (mes 3)

E.5.2

Secondary end point(s)

- Incidence of systemic and ocular (serious) adverse events ([S]AEs), from first administration of study treatment up to the end of the study
- Change from baseline in BCVA, by study visit
- Change from baseline in CST, based on SD-OCT, as assessed by the CRC, by study visit
- Withdrawal from repeat study treatment and reason for withdrawal

Incidencia de acontecimientos adversos y acontecimientos adversos graves (AA/AAG) sistémicos y oculares desde la administración de la primera dosis del tratamiento del estudio hasta el final de este.
• Cambio en la MAVC respecto del valor basal en cada visita del estudio
• Cambio en el GSC respecto del valor basal, en función de la TCO-DE evaluada por el CIC, en cada visita del estudio.
• Interrupción de la administración reiterada del tratamiento del estudio y motivo de la interrupción

E.5.2.1

Timepoint(s) of evaluation of this end point

From first administration of study treatment up to end of study

Desde la primera administración del tratamiento del studio hasta el fin del studio.

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

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Ranibizumab 0.5 mg in combination with sham

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

Last Subject Last Visit

Última visita del 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

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)

Standard of care

Tratamiento estándar

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

2018-04-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-02-22

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-07-18

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